HK1074165A

HK1074165A - Alpha 2 delta ligands to treat tinnitus

Info

Publication number: HK1074165A
Application number: HK05106593.3A
Authority: HK
Inventors: 戴维．J．多利; 戴维．J．伍斯特罗
Original assignee: 沃纳-兰伯特公司
Priority date: 2002-01-31
Filing date: 2003-01-20
Publication date: 2005-11-04

Description

Alpha 2 delta ligands for the treatment of tinnitus

no marking

The present invention relates to methods of preventing or treating tinnitus (tinitus) by administering compounds having α 2 δ (alpha2delta) ligand activity. These compounds have affinity for the α 2 δ subunit of calcium channels. Such compounds are also mentioned in the literature as gamma-aminobutyric acid (GABA) analogs.

Background

Tinnitus is a medical condition affecting 10-13% of the population. Therefore, nearly 36,000,000 americans and 40,000,000 europe are suffering from the suffering of this disease. Tinnitus may be defined as the auditory sensation felt by the brain or ear in the absence of an apparent external stimulus. It is subjective in nature and a malfunction that occurs during the processing of auditory signals including perceptual and psychological factors.

Tinnitus may be induced anywhere along the auditory pathway. The appearance of persistent, annoying tinnitus is generally considered a cause of concern. Tinnitus may be accompanied by any form of sensorineural hearing impairment, particularly hearing difficulties, dullness to noise and exposure to noise. Middle ear surgery, myringoplasty, chronic supportive otitis media (chronic suppurative otitis media), and otosclerosis may all cause conductive hearing impairment as well as tinnitus.

Several α 2 δ ligands are known. The cyclic α 2 δ ligand gabapentin (gabapentin) is now commercially available (Neurontin *, Warner-Lambert Company) and is widely used clinically in the treatment of epilepsy and neuropathic pain. Such cyclic α 2 δ ligands are described in U.S. Pat. No. 4,024,175 and its division U.S. Pat. No. 4,087,544. Other series of α 2 δ ligands are described in U.S. Pat. No. 5,563,175 and U.S. Pat. No. 6,316,638. The entire contents of these patents are incorporated herein by reference.

Summary of The Invention

The present invention provides a method of preventing or treating tinnitus disorders in a mammal suffering therefrom comprising administering a therapeutically effective amount of an α 2 δ ligand, or a pharmaceutically acceptable salt thereof.

A preferred embodiment of the process of the invention uses an alpha 2 delta ligand which is a cyclic amino acid compound of the general formula I,

wherein R is₁Is hydrogen or lower alkyl and n is an integer from 4 to 6, and pharmaceutically acceptable salts thereof. A particularly preferred embodiment uses compounds in which R is₁A compound of the general formula I, i.e. 1- (aminomethyl) -cyclohexane, which is hydrogen and n is 5Alkaneacetic acids, also known as gabapentin (gabapentin), and in addition tiagabine (tiagabine). Other preferred alpha 2 delta ligands or pharmaceutically acceptable salts thereof are compounds of formula I wherein the cyclic ring is substituted, for example by alkyl, e.g. methyl or ethyl. Typical compounds of this type include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-methylcyclopentyl) acetic acid, and (1-aminomethyl-3, 4-dimethylcyclopentyl) acetic acid.

In another preferred embodiment, the process of the invention uses an α 2 δ ligand of the general formula II

Or a pharmaceutically acceptable salt thereof, wherein:

R₁is a straight or branched unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted phenyl group, or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms;

R₂Is hydrogen or methyl; and

R₃is hydrogen, methyl, or carboxyl.

Diastereomers and enantiomers of the compounds of formula II may be used in the process of the invention.

A particularly preferred embodiment of the process of the invention uses compounds of the formula II which are (R), (S), or (R, S) isomers, where R is₂And R₃Are both hydrogen, R₁Is- (CH)₂)_0-2-iso-C₄H₉。

A more preferred embodiment of the process of the invention uses a compound of the general formula II named 3-aminomethyl-5-methyl-hexanoic acid, or in particular (S) -3- (aminomethyl) -5-methyl-hexanoic acid, which is now commonly known as pregabalin (pregabalin). Pregabalin is also known as "CI-1008" and "S- (+) -3-IBG".

Another preferred embodiment of the process of the invention uses compounds of the general formula II named 3- (1-aminoethyl) -5-methylheptanoic acid or 3- (1-aminoethyl) -5-methylhexanoic acid.

Another preferred embodiment of the process of the invention uses α 2 δ ligands which are compounds of the formula III, IIIC, IIIF, IIIG or IIIH

OrOr

Or a pharmaceutically acceptable salt thereof, wherein:

n is an integer of 0 to 2;

m is an integer of 0 to 3;

r is sulfonamide (sulfonamide),

the acid amide,

the amount of phosphonic acid present,

a heterocyclic ring,

(ii) a sulfonic acid,

or a hydroxamic acid;

R₁-R₁₄Each independently selected from hydrogen or a linear or branched alkyl group containing 1 to 6 carbon atoms, an unsubstituted or substituted benzyl or phenyl group, wherein the substituents are selected from halogen, alkyl, alkoxy, hydroxy, carboxy, alkoxycarbonyl (carboakoxy), trifluoromethyl, and nitro;

a' is a bridged ring selected from:

and

wherein

Is a connecting point;

Z₁-Z₄each is independently selected from hydrogen or methyl;

o is an integer of 1 to 4; and

p is an integer of 0 to 2.

In the above formula 1, when m is 2 and n is 1, R is not sulfonic acid (Suman-Chaulan N., et al,European Journal of Pharmacology，1993；244：293-301)。

another preferred embodiment of the process of the invention uses a compound of formula III, IIIC, IIIF, IIIG or IIIH selected from:

(1-aminomethyl-cyclohexylmethyl) -phosphonic acid;

(1R-trans) (1-aminomethyl-3-methyl-cyclohexylmethyl) -phosphonic acid;

(trans) (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -phosphonic acid;

(1R-trans) (1-aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1S-cis) (1-aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1R-trans) (1-aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1R-cis) (1-aminomethyl-3-methyl-cyclopentylmethyl) -phosphonic acid;

(1 α, 3 α, 4 α) (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -phosphonic acid;

(R) (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -phosphonic acid;

(S) (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -phosphonic acid;

(1-aminomethyl-3, 3-dimethyl-cyclobutylmethyl) -phosphonic acid;

2- (1-aminomethyl-cyclohexyl) -N-hydroxy-acetamide;

(1S-trans) 2- (1-aminomethyl-3-methyl-cyclohexyl) -N-hydroxy-acetamide (acetamide);

(trans) 2- (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(1S-cis) 2- (1-aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1R-trans) 2- (1-aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1R-cis) 2- (1-aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1S-trans) 2- (1-aminomethyl-3-methyl-cyclopentyl) -N-hydroxy-acetamide;

(1 α, 3 α, 4 α)2- (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(S)2- (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

(R)2- (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -N-hydroxy-acetamide;

2- (1-aminomethyl-3, 3-dimethyl-cyclobutyl) -N-hydroxy-acetamide;

n- [2- (1-aminomethyl-cyclohexyl) -ethyl ] -methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclohexyl) -ethyl ] -methanesulfonamide (methanesulfonamide);

(trans) N- [2- (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -ethyl ] -methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl ] -methanesulfonamide;

(1R-trans) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl ] -methanesulfonamide;

(1R-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl ] -methanesulfonamide;

(1 α, 3 α, 4 α) N- [2- (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -ethyl ] -methanesulfonamide;

(S) N- [2- (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -ethyl ] -methanesulfonamide;

(R) N- [2- (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -ethyl ] -methanesulfonamide;

n- [2- (1-aminomethyl-3, 3-dimethyl-cyclobutyl) -ethyl ] -methanesulfonamide;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(trans) 3- (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(1R-trans) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(1R-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(1S-trans) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(1 α, 3 α, 4 α)3- (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(S)3- (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(R)3- (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (1-aminomethyl-3, 3-dimethyl-cyclobutylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione (thione);

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(trans) 3- (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(1R-trans) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(1R-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(1S-trans) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(1 α, 3 α, 4 α)3- (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(S)3- (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(R)3- (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

3- (1-aminomethyl-3, 3-dimethyl-cyclobutylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

c- [1- (1H-tetrazol-5-ylmethyl) -cyclohexyl ] -methylamine;

(1S-cis) C- [ 3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclohexyl ] -methylamine;

(trans) C- [3, 4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(1S-cis) C- [ 3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(1R-trans) C- [ 3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(1R-cis) C- [ 3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(1S-trans) C- [ 3-methyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(1 α, 3 α, 4 α) C- [3, 4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(S) C- [3, 3-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

(R) C- [3, 3-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

c- [3, 3-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclobutyl ] -methylamine;

n- [2- (1-aminomethyl-cyclohexyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclohexyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(trans) N- [2- (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(1R-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(1S-trans) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(1S-cis) N- [2- (1-aminomethyl-3-methyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(1 α, 3 α, 4 α) N- [2- (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(S) N- [2- (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

(R) N- [2- (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

n- [2- (1-aminomethyl-3, 3-dimethyl-cyclobutyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclohexylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(trans) 3- (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(1R-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(1S-trans) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(1S-cis) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(1R-trans) 3- (1-aminomethyl-3-methyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(1 α, 3 α, 4 α)3- (1-aminomethyl-3, 4-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(S)3- (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

(R)3- (1-aminomethyl-3, 3-dimethyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

3- (1-aminomethyl-3, 3-dimethyl-cyclobutylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

c- [1- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazoles (oxathiadiazol) -4-ylmethyl) -cyclohexyl]-methyl amine;

(1S-cis) C- [ 3-methyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclohexyl]-methyl amine;

(trans) C- [3, 4-dimethyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(1S-cis) C- [ 3-methyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(1R-trans) C- [ 3-methyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(1R-cis) C- [ 3-methyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(1S-trans) C- [ 3-methyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(1 alpha, 3 alpha, 4 alpha) C- [3, 4-dimethyl-1- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(S) C- [3, 3-dimethyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(R) C- [3, 3-dimethyl-1- (2-oxo-2, 3-dihydro-2. lambda⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

c- [3, 3-dimethyl-1- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclobutyl]-methyl amine;

(1-aminomethyl-cyclohexyl) -methanesulfonamide;

(1R-trans) (1-aminomethyl-3-methyl-cyclohexyl) -methanesulfonamide;

(trans) (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -methanesulfonamide;

(1S-trans) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1R-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1R-trans) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1S-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonamide;

(1 α, 3 α, 4 α) (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -methanesulfonamide;

(R) (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -methanesulfonamide;

(S) (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -methanesulfonamide;

(1-aminomethyl-3, 3-dimethyl-cyclobutyl) -methanesulfonamide;

(1-aminomethyl-cyclohexyl) -methanesulfonic acid (methanesulfonic acid);

(1R-trans) (1-aminomethyl-3-methyl-cyclohexyl) -methanesulfonic acid;

(trans) (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -methanesulfonic acid;

(1S-trans) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1S-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1R-trans) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1R-cis) (1-aminomethyl-3-methyl-cyclopentyl) -methanesulfonic acid;

(1 α, 3 α, 4 α) (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -methanesulfonic acid;

(R) (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -methanesulfonic acid;

(S) (1-aminomethyl-3, 3-dimethyl-cyclopentyl) -methanesulfonic acid;

(1-aminomethyl-3, 3-dimethyl-cyclobutyl) -methanesulfonic acid;

(1-aminomethyl-cyclopentylmethyl) -phosphonic acid;

2- (1-aminomethyl-cyclopentyl) -N-hydroxy-acetamide;

n- [2- (1-aminomethyl-cyclopentyl) -ethyl ] -methanesulfonamide;

3- (1-aminomethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (1-aminomethyl-cyclopentylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione

C- [1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine;

n- [2- (1-aminomethyl-cyclopentyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

3- (1-aminomethyl-cyclopentylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

c- [1- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cyclopentyl]-methyl amine;

(1-aminomethyl-cyclopentyl) -methanesulfonamide;

(1-aminomethyl-cyclopentyl) -methanesulfonic acid;

(9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -phosphonic acid;

2- (9-aminomethyl-bicyclo [3.3.1] non-9-yl) -N-hydroxy-acetamide;

n- [2- (9-aminomethyl-bicyclo [3.3.1] non-9-yl) -ethyl ] -methanesulfonamide;

3- (9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione

C- [9- (1H-tetrazol-5-ylmethyl) -bicyclo [3.3.1] non-9-yl ] -methylamine;

n- [2- (9-aminomethyl-bicyclo [3.3.1] non-9-yl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

3- (9-aminomethyl-bicyclo [3.3.1] non-9-ylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

c- [9- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -bicyclo [3.3.1]Non-9-yl]-methyl amine;

(9-aminomethyl-bicyclo [3.3.1] non-9-yl) -methanesulfonamide;

(9-aminomethyl-bicyclo [3.3.1] non-9-yl) -methanesulfonic acid;

(2-aminomethyl-adamantan-2-ylmethyl) -phosphonic acid;

2- (2-aminomethyl-adamantan-2-yl) -N-hydroxy-acetamide;

n- [2- (2-aminomethyl-adamantan-2-yl) -ethyl ] -methanesulfonamide;

3- (2-aminomethyl-adamantan-2-ylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (2-aminomethyl-adamantan-2-ylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione;

c- [2- (1H-tetrazol-5-ylmethyl) -adamantan-2-yl ] -methylamine;

n- [2- (2-aminomethyl-adamantan-2-yl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

3- (2-aminomethyl-adamantan-2-ylmethyl) -4H- [1, 2, 4] thiadiazol-5-one;

c- [2- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -adamantan-2-yl]-methyl amine;

(2-aminomethyl-adamantan-2-yl) -methanesulfonamide;

(2-aminomethyl-adamantan-2-yl) -methanesulfonic acid;

(1-aminomethyl-cycloheptylmethyl) -phosphonic acid;

2- (1-aminomethyl-cycloheptyl) -N-hydroxy-acetamide;

n- [2- (1-aminomethyl-cycloheptyl) -ethyl ] -methanesulfonamide;

3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione

N- [2- (1-aminomethyl-cycloheptyl) -ethyl ] -C, C-trifluoro-methanesulfonamide;

c- [1- (2-oxo-2, 3-dihydro-2 lambda)⁴-[1，2，3，5]Oxathiadiazol-4-ylmethyl) -cycloheptyl]-methyl amine;

(1-aminomethyl-cycloheptyl) -methanesulfonamide; and

(1-aminomethyl-cycloheptyl) -methylsulphonic acid.

Another preferred embodiment of the process of the present invention uses compounds of formula III, IIIC, IIIF, IIIG, or IIIH, wherein preferred compounds are those wherein R is selected from the group consisting of-NHSO ₂R¹⁵or-SO₂NHR¹⁵Wherein R is¹⁵A compound which is a straight or branched chain alkyl or trifluoromethyl.

Another preferred embodiment of the process of the invention uses compounds of the formula III, IIIC, IIIF, IIIG or IIIH, N- [2- (1-aminomethyl-cyclohexyl) -ethyl ] -methanesulfonamide being particularly preferred.

Another preferred embodiment of the process of the invention uses the formulae III, IIIC, IIIF, IIIG, or IIIH compounds, wherein other preferred compounds are those wherein R is phosphonic acid, -PO₃H₂The compound of (1).

Another preferred embodiment of the process of the invention uses compounds of the general formula III, IIIC, IIIF, IIIG or IIIH, of which (1-aminomethyl-cyclohexylmethyl) -phosphonic acid and (2-aminomethyl-4-methyl-pentyl) -phosphonic acid are particularly preferred.

Another preferred embodiment of the process of the invention uses compounds of formula III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a heterocycle selected from the group consisting of:

and

another preferred embodiment of the process of the invention uses compounds of the formula III, IIIC, IIIF, IIIG or IIIH, where C- [1- (1H-tetrazol-5-ylmethyl) -cyclohexyl ] -methylamine and 4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine are particularly preferred.

A particularly preferred embodiment of the process of the invention uses compounds of the general formula III, in which:

m is an integer of 0 to 2;

p is an integer of 2; and

r isOr

More preferred is a method embodiment of the present invention using a compound of formula III, IIIC, IIIF, IIIG, or IIIH, or a pharmaceutically acceptable salt thereof, named 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one.

More preferred is an embodiment of the process of the present invention using a compound of formula III, IIIC, IIIF, IIIG, or IIIH, named 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride.

Also preferred is an embodiment of the method of the present invention using a compound of formula III, IIIC, IIIF, IIIG, or IIIH, or a pharmaceutically acceptable salt thereof, designated 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one.

Also more preferred is an embodiment of the process of the present invention using the compound of formula III, IIIC, IIIF, IIIG, or IIIH named 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride.

Also preferred is an embodiment of the method of the present invention using a compound of formula III, IIIC, IIIF, IIIG, or IIIH, or a pharmaceutically acceptable salt thereof, designated C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine.

Also more preferred is an embodiment using a compound of formula III, IIIC, IIIF, IIIG, or IIIH named C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine.

Another preferred embodiment of the process of the invention uses α 2 δ ligands which are compounds of the formula IV

Or a pharmaceutically acceptable salt thereof, wherein:

R¹is hydrogen, straight or branched chain alkyl containing 1 to 6 carbon atoms or phenyl;

R²is a straight or branched chain alkyl group having 1 to 8 carbon atoms,

straight-chain or branched alkenyl groups having 2 to 8 carbon atoms,

a cycloalkyl group having 3 to 7 carbon atoms,

an alkoxy group having 1 to 6 carbon atoms,

-an alkyl cycloalkyl group,

-an alkyl-alkoxy group,

-an alkyl group OH,

-an alkyl-phenyl group,

-an alkyl-phenoxy group,

-phenyl or substituted phenyl; and is

When R is²When it is methyl, R¹Is a straight or branched alkyl group having 1 to 6 carbon atoms or a phenyl group.

Preference is given to using compounds in which R is¹Is hydrogen, R²An embodiment of the process according to the invention of the compounds of the general formula IV which are alkyl.

Another preferred embodiment of the process of the invention uses where R is¹Is methyl, R²A compound of formula IV which is alkyl.

A further preferred embodiment of the process of the invention uses compounds in which R is¹Is methyl, R²A compound of formula IV which is methyl or ethyl.

Particularly preferred are embodiments of the process of the present invention using a compound selected from the following formula IV:

3-aminomethyl-5-methylheptanoic acid;

3-aminomethyl-5-methyloctanoic acid;

3-aminomethyl-5-methylnonanoic acid;

3-aminomethyl-5-methyldecanoic acid;

3-aminomethyl-5-methylundecanoic acid;

3-aminomethyl-5-methyldodecanoic acid;

3-aminomethyl-5-methyltridecanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-5-cyclobutyl-hexanoic acid;

3-aminomethyl-5-cyclopentyl-hexanoic acid;

3-aminomethyl-5-cyclohexyl-hexanoic acid;

3-aminomethyl-5-trifluoromethyl-hexanoic acid;

3-aminomethyl-5-phenyl-hexanoic acid;

3-aminomethyl-5- (2-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (3-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (4-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (4-methoxyphenyl) -hexanoic acid; and

3-aminomethyl-5- (phenylmethyl) -hexanoic acid.

Another particularly preferred embodiment of the process of the invention uses a compound of the formula IV selected from:

(3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid;

3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP;

(3S, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP;

3-aminomethyl-4-isopropyl-hexanoic acid;

3-aminomethyl-4-isopropyl-heptanoic acid;

3-aminomethyl-4-isopropyl-octanoic acid;

3-aminomethyl-4-isopropyl-nonanoic acid;

3-aminomethyl-4-isopropyl-decanoic acid; and

3-aminomethyl-4-phenyl-5-methyl-hexanoic acid.

Another preferred embodiment of the process of the present invention uses a compound of formula IV selected from:

(3S, 5S) -3-aminomethyl-5-methoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-ethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-isopropoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-tert-butoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-fluoromethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-6-hydroxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3, 3, 3-trifluoro-propoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-oct-7-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-non-8-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-dec-7-enoic acid;

(E) - (3S, 5R) -3-aminomethyl-5-methyl-undec-7-enoic acid;

(3S, 5S) -3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclopropyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclobutyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclopentyl-hexanoic acid; and

(3S, 5S) -3-aminomethyl-5-cyclohexyl-hexanoic acid.

Yet another more preferred embodiment of the process of the present invention uses a compound of formula IV selected from:

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid;

(3S, 5R) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5, 7-dimethyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5, 8-dimethyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-9-fluoro-5-methyl-nonanoic acid;

(3S, 5S) -3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-8-phenyl-octanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenyl-hexanoic acid; and

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid.

Another preferred embodiment of the process of the invention uses α 2 δ ligands which are compounds of the general formula (1A) or (1B)

Or

Or a pharmaceutically acceptable salt thereof, wherein:

n is an integer of 0 to 2;

r is a sulfonamide,

the acid amide,

the amount of phosphonic acid present,

a heterocyclic ring,

sulfonic acid, or

Hydroxamic acid (hydroxamic acid);

a is hydrogen or methyl; and

b is

A straight-chain or branched alkyl group having 1 to 11 carbon atoms, or

-(CH₂)_1-4-Y-(CH₂)_0-4-phenyl, wherein Y is-O-, -S-, -NR'₃Wherein:

R’₃is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group or a phenyl group, wherein the benzyl group or the phenyl group may be unsubstituted or substituted with 1 to 3 substituents, each substituent being independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, carboxy, alkoxycarbonyl (carboakyloxy), trifluoromethyl, and nitro.

A preferred embodiment uses an alpha 2 delta ligand which is a compound of formula (1A) or (1B) wherein R is selected from-NHSO₂R¹⁵and-SO₂NHR¹⁵Sulfonamide (sulfonamide) of (1), wherein R is¹⁵Is straight-chain or branched alkyl or trifluoromethyl.

A particularly preferred embodiment uses a compound of formula (1A) or (1B) selected from:

4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine;

3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4] oxadiazole-5-thione, HCl;

(2-aminomethyl-4-methyl-pentyl) -phosphonic acid;

3- (3-amino-2-cyclopentyl-propyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (3-amino-2-cyclopentyl-propyl) -4H- [1, 2, 4] thiadiazol-5-one;

2-cyclopentyl-3- (2-oxo-2, 3-dihydro-2 γ)⁴-[1，2，3，5]Oxathiadiazol-4-yl) -propylamine;

3- (3-amino-2-cyclobutyl-propyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (3-amino-2-cyclobutyl-propyl) -4H- [1, 2, 4] thiadiazol-5-one; and

2-cyclobutyl-3- (2-oxo-2, 3-dihydro-2. gamma⁴-[1，2，3，5]Oxathiadiazol-4-yl) -propylamine.

Another preferred embodiment uses compounds of the general formula (1A) or (1B) in which R is phosphonic acid, -PO₃H₂。

Another preferred embodiment uses compounds of the general formula (1A) or (1B), where R is

Or

More preferred is an embodiment using a compound of formula (1A) or (1B) wherein R is

Or

Also more preferred is the embodiment using a compound of formula (1A) or (1B) named 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 3, 4] oxadiazol-5-one, or a pharmaceutically acceptable salt thereof.

More preferred is the embodiment using the compound of formula (1A) or (1B) named 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride.

Another embodiment of the invention uses an α 2 δ ligand which is a compound of formula V, VI, VII, or VIII

Or

Or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 4, and each stereogenic center, if any, can independently be R or S.

A preferred embodiment uses compounds of formula V, VI, VII, or VIII, wherein n is an integer from 2 to 4.

Another preferred embodiment uses compounds of the formula V.

A more preferred embodiment uses a compound of formula V, VI, VII, or VIII selected from:

(1 α, 6 α, 8 β) (2-aminomethyl-octahydro-indene (inden) -2-yl) -acetic acid;

(2-aminomethyl-octahydro-inden-2-yl) -acetic acid;

(2-aminomethyl-octahydro-pentalene (pentalen) -2-yl) -acetic acid;

(2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid; and

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid.

(2-aminomethyl-octahydro-inden-2-yl) -acetic acid.

Yet another more preferred embodiment uses a compound of formula V, VI, VII, or VIII selected from:

(1 alpha, 5 beta) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1. alpha., 5. beta.) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 alpha, 5 beta) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid,

(1 α, 6 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 β) (2-aminomethyl-octahydro-azulen-2-yl) -acetic acid,

(1 alpha, 5 beta) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1. alpha., 5. beta.) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 alpha, 5 beta) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid,

(1 α, 6 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1 alpha, 3 alpha, 5 alpha) (3-aminomethyl-bicyclo [3.2.0] hex-3-yl) -acetic acid,

(1 alpha, 3 alpha, 5 alpha) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid,

(1 α, 6 α, 8 α) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 α, 9 α) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1 alpha, 3 beta, 5 alpha) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1 α, 3 β, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 alpha, 3 beta, 5 alpha) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid,

(1 α, 6 α, 8 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 α, 9 β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

((1R, 3R, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3S, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3S, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3R, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3R, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1R, 3S, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3S, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3R, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((3. alpha. R, 5R, 7. alpha. S) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((2R, 4. alpha. S, 8. alpha. R) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4. alpha. S, 9. alpha. R) -2-aminomethyl-decahydro-benzocycloheptene (benzocyclohepten) -2-yl) -acetic acid,

((2R, 4. alpha. S, 9. alpha. R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((1R, 3R, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3S, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3S, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3R, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3R, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1R, 3S, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3S, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3R, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((3. alpha. R, 5R, 7. alpha. R) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((2R, 4. alpha. R, 8. alpha. R) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4. alpha. R, 9. alpha. R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2R, 4. alpha. R, 9. alpha. R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid, and

((2R, 4. alpha. R, 9. alpha. R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid.

A more preferred embodiment uses a compound of formula V, VI, VII, or VIII, named (1 α, 3 α, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, or a pharmaceutically acceptable salt thereof.

Still more preferred embodiments use a compound of formula V, VI, VII, or VIII named (1 α, 3 α, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride.

Other preferred embodiments of the present invention relate to the above method for treating tinnitus, wherein the α 2 δ ligand used is selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(S, S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid;

(R, S) -3-aminomethyl-5-methyl-octanoic acid;

(S, R) -3-aminomethyl-5-methyl-octanoic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, wherein the cyclobutyl ring is in the trans (trans) position of the methylamino group; and

c- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine.

These compounds can be prepared as described below or as described in world patent application WO99/21824, published on 6.5.1999, world patent application WO 00/76958, published on 21.12.2000, or world patent application WO 01/28978, published on 26.4.2001. The entire contents of these applications are incorporated herein by reference.

A more preferred embodiment uses the hydrochloride salt of 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one.

Detailed Description

Preferred α 2 δ ligands for use in the method of the invention are selected from cyclic amino acids of formula I. These cyclic amino acids are described in U.S. Pat. No. 4,024,175 and its division U.S. Pat. No. 4,087,544, both of which are incorporated herein by reference.

Another preferred method uses α 2 δ ligands of formula II, which are described in U.S. patent No. 5,563,175, incorporated herein by reference.

Another preferred method uses α 2 δ ligands of formula III, IIIC, IIIF, IIIG, or IIIH, which are described in PCT International publication WO 99/31075, incorporated herein by reference.

Another preferred method uses α 2 δ ligands of formula IV, which are described in PCT International publication No. WO 00/76958, incorporated herein by reference.

Other preferred alpha 2 delta ligands for use in the process of the invention are compounds of the general formulae (1A) and (1B), which are described in PCT International publication WO 99/31074, which is incorporated herein by reference.

PCT International publication WO 01/28978, which is incorporated herein by reference, describes other preferred α 2 δ ligands for use in the methods of the present invention, which are compounds of formulae V, VI, VII, and VIII.

Other preferred alpha 2 delta ligands for use in the methods of the invention are described in PCT International application WO99/31057, which is incorporated herein by reference. The alpha 2 delta ligand is a compound of general formulas (1D) and (1E)

And

or a pharmaceutically acceptable salt thereof, wherein:

n is an integer of 0 to 2;

r is a sulfonamide,

the acid amide,

the amount of phosphonic acid present,

a heterocyclic ring,

(ii) a sulfonic acid,

hydroxamic acid; and

x is-O-, -S (O)₂-, or NR'₁Wherein R'₁Is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, benzyl, -C (O) R'₂Wherein R'₂Is a straight or branched alkyl group having 1 to 6 carbon atoms, a benzyl or phenyl group or-CO₂R’₃Wherein R'₃Is a linear or branched alkyl radical having 1 to 6 carbon atoms, or a benzyl radical, wherein the benzyl or phenyl radical may be unsubstituted or substituted by 1 to 3 substituentsSubstituents selected from halogen, trifluoromethyl, and nitro.

Other preferred alpha 2 delta ligands which may be used in the process of the invention are described in PCT International application WO98/17627, which is incorporated herein by reference. This embodiment uses an alpha 2 delta ligand which is a compound of the formula

Or a pharmaceutically acceptable salt thereof, wherein:

r is hydrogen or lower alkyl;

R₁is hydrogen or lower alkyl;

R₂is composed of

A straight-chain or branched alkyl group having 7 to 11 carbon atoms, or

-(CH₂)_(1-4)-X-(CH₂)_(0-4)-phenyl, wherein

X is-O-, -S-, -NR₃-, wherein

R₃Is alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms, benzyl or phenyl;

wherein phenyl and benzyl may be unsubstituted or substituted with 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, alkoxycarbonyl, trifluoromethyl, amino, and nitro.

Other preferred alpha 2 delta ligands which may be used in the process of the invention are described in PCT International application WO99/61424, which is incorporated herein by reference. Embodiments of the methods of the present invention employ α 2 δ ligands that are compounds of formula (1), (2), (3), (4), (5), (6), (7), or (8)

Or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁-R₁₀each independently selected from hydrogen or a linear or branched alkyl group containing 1 to 6 carbon atoms, benzyl, or phenyl;

m is an integer of 0 to 3;

n is an integer of 1 to 2;

o is an integer of 0 to 3;

p is an integer of 1 to 2;

q is an integer of 0 to 2;

r is an integer of 1-2;

s is an integer of 1 to 3;

t is an integer of 0 to 2; and

u is an integer of 0 to 1.

All of the U.S. patents and WO publications cited above are hereby incorporated by reference.

Terms are defined as follows, or as they appear in the specification at each time.

It should be understood that the terms "used," "utilizing," and "with," along with their derivatives, may be used interchangeably in describing embodiments of the present invention.

The phrase "lower alkyl" refers to a straight or branched alkyl group or radical (radial) containing 1 to 6 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

Unless otherwise defined, the term "alkyl" is a straight or branched chain group containing 1 to 8 carbon atoms, including, but not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, t-butyl, and octyl. The alkyl group may be unsubstituted or substituted with hydroxyl or 1 to 3 fluorine atoms. Preferred groups are methyl and ethyl.

The term "alkenyl" is a straight or branched chain group having 2 to 8 carbon atoms containing 1 or 2 or 3 double bonds, including but not limited to vinyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-hexen-3-yl, and hept-1, 3-dien-7-yl. The alkenyl group may be unsubstituted or substituted with 1 to 3 fluorine atoms.

The term "cycloalkyl" refers to cyclic groups containing 3 to 7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, and cycloheptyl.

The benzyl and phenyl groups may be unsubstituted or substituted by 1 to 3 groups each independently selected from halogen, especially fluorine, alkoxy, alkyl, and NH₂Is substituted with the substituent(s).

Halogen includes fluorine, chlorine, bromine, and iodine.

The term "alkoxy" refers to the group-O-alkyl, wherein alkyl is as defined above.

The terms used to define the compounds of the general formulae (1A), (1B), III, IIIC, IIIF, IIIG, and IIIH of the present invention are as follows.

Sulfonamides being of those general formula-NHSO₂R¹⁵or-SO₂NHR¹⁵Wherein R is¹⁵Is a straight or branched chain alkyl group having 1 to 6 carbon atoms or a trifluoromethyl group.

The amide is of the formula-NHCOR¹²A compound of formula (I) wherein R¹²Straight or branched chain alkyl groups containing 1-6 carbons, benzyl, and phenyl.

Phosphonic acid as-PO₃H₂。

Sulfonic acid being-SO₃H。

Hydroxamic acids are

Heterocyclic is a group containing 1-2 rings with 1-6 heteroatoms selected from oxygen, nitrogen, and sulfur.

Preferred heterocycles are

And

unless otherwise defined, the term alkyl is a straight or branched chain group containing 1 to 11 carbon atoms, including, but not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, t-butyl, pentyl, hexyl, and n-hexyl, heptyl, octyl, nonyl, decyl, and undecyl.

Unless otherwise defined, cycloalkyl groups contain 3 to 8 carbon atoms and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The benzyl and phenyl groups may be unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, carboxy, alkoxycarbonyl, halogen, CF₃Nitro, alkyl, and alkoxy. Preferably by halogen.

Alkoxy is as previously defined for alkyl.

Halogen is fluorine, chlorine, and bromine, preferably fluorine and chlorine.

Alkoxycarbonyl is-COO alkyl, wherein alkyl is as defined above. Preferred are methoxycarbonyl and ethoxycarbonyl.

Such as n.s.gee et al, j.biol.chem., 1996, 271: 5879 the extent of binding to the α 2 δ subunit can be determined using a radioligand binding analyzer using [3H ] gabapentin and the α 2 δ subunit from porcine brain tissue as described in 5776.

Bauer, in "insulating and professional insulating uses a physiological Animal Model", Journal of the Association for Research in Otolarynggology, 2/1: the efficacy of compounds for treating tinnitus can be assessed by the method described in 054-064 (2001).

The requirement for the practice of the method of the invention is that the α 2 δ ligand, or a pharmaceutically acceptable salt thereof, is administered in an amount therapeutically effective for the treatment of tinnitus. Such tinnitus treatments will generally be in an amount of from about 1 to about 300mg/kg of the patient's body weight. For adult patients of normal weight, the usual dosage is about 10 to 5000 mg/day. In clinical treatment, a specific therapeutically effective amount may be required by regulatory agencies such as the food and drug administration ("FDA") in the united states.

In view of the experience of the practitioner or veterinarian, the results of published clinical studies, the age, sex, weight and general condition of the patient (e.g., mammal), and the type and extent of the disease, the disease or condition being treated (condition), the use of other therapeutic agents, and any other factors considered by the patient, in determining which elements constitute an effective or therapeutically effective amount of the α 2 δ ligand or pharmaceutically acceptable salt thereof for treating tinnitus according to the methods of the present invention, typically many factors will be considered by the practitioner or veterinarian. Likewise, the dosage administered may fall within the ranges or concentrations enumerated above, or may vary outside of such ranges or concentrations, i.e., either low or high, with such ranges varying depending upon the requirements of the individual patient, the severity of the condition being treated, and the particular therapeutic regimen being employed. Determining the appropriate dosage for a particular situation is within the skill of a physician or veterinarian. In general, treatment may begin with the use of a smaller dose of α 2 δ ligand than the optimal dose for the particular patient. Thereafter the dosage may be increased in small increments until the optimum effective amount in such a case is reached. For convenience, the total daily dose may be divided into several portions and administered in one portion of the day, if desired.

Pharmaceutical compositions of the α 2 δ ligand or a pharmaceutically acceptable salt thereof may be prepared by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and anhydrous oral solutions and suspensions, and parenteral solutions in packaging containing one or more number of dosage units and suitable for sub-division into individual doses.

Some examples of suitable pharmaceutical carriers include: the medicinal diluent is gelatin capsule; sugars such as lactose and sucrose; starches, such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, and cellulose acetate phthalate (cellulose acetate phthalate); gelling; talc powder; stearic acid; magnesium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter (oii theobroma); propylene glycol, glycerol; sorbitol; polyethylene glycol; water; agar; (brown) alginic acid; isotonic saline, and phosphate buffer; and other compatible materials commonly used in pharmaceutical compositions.

The compositions used in the present invention may also contain other components, such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are generally used in relatively small amounts. If desired, the composition may also contain other therapeutic agents commonly used to treat tinnitus. In addition, if desired, the composition may also contain other therapeutic agents commonly used to treat secondary symptoms, such as depression or anxiety which may or may not be accompanied by tinnitus. For example, the composition may contain aspirin, naprosyn (naprosyn), or similar anti-inflammatory analgesic agents.

The percentage of active ingredient in the aforementioned composition may vary within wide limits, but for practical purposes it is preferred that the concentration is at least 10% in the solid composition and at least 2% in the original liquid composition. The most satisfactory compositions are those in which a relatively high percentage of active ingredient is present, for example up to about 95%.

The preferred mode of administering the α 2 δ ligand or a pharmaceutically acceptable salt thereof is oral or parenteral. For example, an effective intravenous dose is between 5 and 50mg, and an effective oral dose is between 20 and 800 mg. The dosage is within the range of dosages used to treat conditions that cause tinnitus, such as osteoarthritis, or it may be determined by the physician as needed by the patient, as previously described.

The α 2 δ ligand or a pharmaceutically acceptable salt thereof may be administered in any form. Preferably, administration is in unit dose form. The unit dosage forms of the α 2 δ ligands or pharmaceutically acceptable salts thereof for use in the present invention may also include other compounds useful in the treatment of disorders that cause tinnitus.

Compounds of formula I, II, III, IIIC, IIIF, IIIG, IIIH, IV, (1A), (1B), V, VI, VII, or VIII or pharmaceutically acceptable salts thereof are used in the present invention, including gabapentin, pregabalin (pregabalin), 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, advantages of 2, 4] oxadiazol-5-one hydrochloride, the hydrochloride of (1 α, 3 α, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, or (3S, 5R) -3-aminomethyl-5-methyloctanoic acid include: these compounds are relatively non-toxic, easy to prepare, well tolerated, IV readily available and the drugs can be administered orally. In addition, these drugs in particular are not normally metabolized in the body.

The methods of the invention are useful in human and veterinary medicine for treating or preventing tinnitus in mammals. Mammals include humans, cats, dogs, horses, cattle, pigs, and sheep.

Some compounds useful in the methods of the present invention are capable of further forming pharmaceutically acceptable salts, including but not limited to acid adducts and/or basic salts. Acid addition salts are formed with basic compounds and base addition salts are formed with acidic compounds. All of these forms fall within the scope of the compounds used in the methods of the present invention.

Pharmaceutically acceptable acid addition salts of basic compounds useful in the methods of the present invention include non-toxic salts derived from inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as non-toxic salts derived from organic acids, such as aliphatic mono-or dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate (fumarate), maleate, mandelate (mandelate), benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are amino acid Salts such as arginine Salts, as well as gluconate and galacturonate Salts (see, e.g., Berge S.M.et al, "Pharmaceutical Salts", J.of Pharma.Sci., 1977; 66: 1).

The acid addition salts of the basic compounds used in the process of the present invention are prepared in accordance with conventional procedures by contacting the free base form of the compound with a sufficient amount of the appropriate acid to form the non-toxic salt. The free base form of the compound may be regenerated by contacting the acid addition salt thus formed with a base and isolating the free base form of the compound in accordance with conventional procedures. The free base forms of the compounds prepared according to the process of the present invention differ slightly from their corresponding acid addition salt forms in certain physical properties such as solubility, crystal structure, hygroscopicity, etc., but for the purposes of the present invention the free base forms of the compounds are equivalent to their corresponding acid addition salt forms.

The pharmaceutically acceptable base addition salts of acidic compounds of the process of the present invention are prepared in accordance with conventional procedures by contacting the free acid form of the compound with a non-toxic metal cation, for example an alkali or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include sodium ion (Na)⁺) Potassium ion (K)⁺) Magnesium ion (Mg)²⁺) Calcium ion (Ca)²⁺) And the like. Examples of suitable amines are N, N' -dibenzyl 1, 2-ethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, 1, 2-ethylenediamine, N-methylglucamine, and procaine (see, e.g., Berge, supra, 1977).

The base addition salts of acidic compounds useful in the process of the present invention may be prepared by contacting the free acid form of the compound with a sufficient amount of a suitable base to form a salt according to conventional methods. The free acid form of the compound can be regenerated by contacting the salt form thus formed with an acid and then isolating the free acid of the compound according to conventional methods. The free acid form of the compounds used in the process of the invention differs somewhat from their corresponding salt forms in certain physical properties such as solubility, crystal structure, hygroscopicity, etc., but for the purposes of the present invention the salts are equivalent to their corresponding free acids.

Certain compounds useful in the methods of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are expressly contemplated to be within the scope of the present invention.

Certain compounds useful in the methods of the invention have one or more chiral centers, each of which may be present in the R or S configuration. The methods of the invention may employ any diastereomeric, enantiomeric, or stereoisomeric form of the α 2 δ ligand, or a pharmaceutically acceptable salt thereof, and mixtures thereof.

In addition, certain compounds useful in the methods of the invention may exist as geometric isomers, such as the homo (entgegen, E) and trans (zusammen, Z) isomers of alkenyl groups. The methods of the invention may employ any of the cis (cis), trans (trans), cis (syn), trans (anti), homotropic (entgegen), or reverse (zusammen) isomers of an α 2 δ ligand or a pharmaceutically acceptable salt thereof, and mixtures thereof.

Certain compounds useful in the methods of the invention may exist in two or more tautomeric forms. The tautomeric forms of the compounds may vary from one another, e.g. via enolization/dealenolization etc. The methods of the invention may employ any tautomeric form of the α 2 δ ligand, or a pharmaceutically acceptable salt thereof, and mixtures thereof.

Intermediates for the synthesis of α 2 δ ligands or pharmaceutically acceptable salts thereof useful in the methods of the present invention, as well as pharmaceutically acceptable salts thereof, can be prepared by one of ordinary skill in the art of organic chemistry by varying a variety of synthetic procedures well known in the art of organic chemistry. These synthetic steps can be found in some of the documents listed, for example, in Reagents for Organic Synthesis, Fieser and Fieser, John Wiley &Sons, Inc, New York, 2000; comprehensive organic transformations, Richard c.larock, VCH Publishers, Inc, New York, 1898; the company of Organic Synthesis Methods, 1989, Wiley-Interscience; advanced Organic Chemistry, 4^thedition, Jerry March, Wiley-Interscience, New York, 1992; or Handbook of Heterocyclic Chemistry, Alan R.Katritzky, Pergamon Press Ltd, London, 1985. Alternatively, the skilled artisan can make extensive searches of available databases, such as those available from Chemical Abstracts Service, Columbus Ohio or MDL Information Systems GmbH (formerly Beilsteininformation Systems G)mbH), Frankfurt, Germany, found methods in the chemical literature for preparing these intermediates.

The compounds useful in the process of the present invention may be prepared using starting materials, reagents, solvents, and catalysts that are commercially available from commercial sources, or they may be conveniently prepared by adapting the procedures described in the references or sources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts for preparing compounds of The invention include, for example, The Aldrich chemical Company, and other Sigma-Aldrich Corporation, st.

Synthesis of some of the compounds useful in the methods of the present invention may use starting materials, intermediates, or reaction products containing reactive functional groups. During chemical reactions, the reactive functional groups may be protected by the use of protecting groups, such that the reactive functional groups are substantially inert to the reaction conditions employed. Where a protecting group is desired, the protecting group is introduced onto the starting material prior to completion of the reaction step. Once the protecting group is no longer needed, the protecting group can be removed. It is obvious to be within the scope of the ordinary skill in the art to introduce protecting groups during the synthesis of α 2 δ ligands or pharmaceutically acceptable salts thereof and then remove them. The steps of introducing and removing protecting Groups are known and can be referred to, for example, as Protective Groups in Organic Synthesis, 2^nded., Greene T.W. and Wuts P.G., John Wiley&Son, New York: new York, 1991, hereby incorporated by reference. In this case, for example, the amino group, the hydroxyl group, and other groups can be protected with the following protecting groups: carboxylic acyl groups such as formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, tert-Butoxycarbonyl (BOC), β, β, β -Trichloroethoxycarbonyl (TCEC), and β -iodoethoxycarbonyl; aralkyloxycarbonyl groups, e.g. benzyloxycarbonyl (CBZ), p-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl Alkylcarbonyl (FMOC); trialkylsilyl groups such as Trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and other groups such as triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, o-nitrobenzenesulfonyl, diphenylphosphinyl, p-toluenesulfonyl (Ts), methanesulfonyl, trifluoromethylsulfonyl, and benzyl. Examples of the step of removing the protecting group include: hydrogenating the CBZ group, for example, under a hydrogen pressure of 50psi in the presence of a hydrogenation catalyst such as 10% palladium-carbon; acidolysis of the BOC group, e.g., reaction of the silyl group with fluoride ions in hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, etc., followed by reductive cleavage of the TCEC group using metallic zinc.

The process for the preparation of the α 2 δ ligands or pharmaceutically acceptable salts thereof for use in the methods of the present invention is incorporated by reference to the above patents or patent application publications or is described in the schemes below.

The compounds of formulae III, IIIC, IIIF, IIIG, and IIIH can be prepared according to the methods described below.

Sulfonamides can be synthesized by the general route outlined in scheme 1.

Scheme 1

Reagent:

(i) diethyl cyanomethylphosphonate, sodium hydride, tetrahydrofuran;

(ii) nitromethane, tetrabutylammonium fluoride, tetrahydrofuran;

(iii) borane methyl sulfide, toluene;

(iv) triethylamine, R¹⁵SO₂Cl, tetrahydrofuran;

(v) 10% Pd-C, hydrogen, methanol.

Tetrazoles can be synthesized by the general route outlined in scheme 2.

Scheme 2

Reagent:

(i) trimethylsilylazide, trimethylaluminum (2M hexane solution), toluene;

(ii) raney nickel, methanol.

Amides can be synthesized by the general route outlined in scheme 3.

Scheme 3

Reagent:

(i) diethyl cyanomethylphosphonate, sodium hydride, tetrahydrofuran;

(ii) nitromethane, tetrabutylammonium fluoride, tetrahydrofuran;

(iii) borane methyl sulfide, toluene;

(iv) triethylamine, R¹⁵COCl, tetrahydrofuran;

(v) 10% Pd-C, hydrogen, methanol.

Synthesis of, for example, the general route outlined in scheme 4

The heterocyclic ring of (1).

Scheme 4

(i)NH₂OH·HCl，Et₃N；

(ii) iBuOCOCl, pyridine, followed by reflux in xylene;

(iii)Fe/HCl。

compound 2 can be obtained by treating compound 1[ (1-nitromethyl-cyclohexyl) acetonitrile ] with hydroxylamine hydrochloride in the presence of a base such as triethylamine.

Heterocyclic compound 3 can be prepared from compound 2 by treatment with isobutyl chloroformate in the presence of a base such as pyridine, followed by reflux in a solvent such as xylene. The nitro compound (compound 3) can be converted to the desired amine by reduction, for example with iron and hydrochloric acid.

The general route outlined by scheme 5a can be synthesized, for example

The heterocyclic ring of (1).

Scheme 5a

The general route outlined by scheme 5b can be synthesized, for example

The heterocyclic ring of (1).

Scheme 5b

The general route outlined by scheme 6 below can be synthesized, for example

The heterocyclic ring of (1).

Scheme 6

(i)NH₂OH·HCl，Et₃N；

(ii)1, 1' -thiocarbonyldiimidazole followed by DBU or DBN;

(iii)Fe/HCl。

Heterocyclic compound 3 can be prepared from compound 2 by treatment with 1, 1' -thiocarbonyldiimidazole followed by treatment with a base such as 1, 8-diazabicyclo- [4, 5, 0] -undec-7-ene (DBU) or 1, 5-diazabicyclo- [2.2.2] octane (DBN).

The nitro compound (compound 3) can be converted to the desired amine by reduction, for example with iron and hydrochloric acid.

Synthesis according to the general route shown in scheme 7, for example

The heterocyclic ring of (1).

Scheme 7

(i)NH₂OH·HCl，Et₃N；

(ii)1, 1' -thiocarbonyldiimidazole followed by silica gel or BF₃·OEt₂；

(iii)Fe/HCl。

Heterocyclic compound 3 can be prepared from compound 2 by treatment with 1, 1' -thiocarbonyldiimidazole followed by treatment with silica gel or boron trifluoride etherate.

Synthesis of, for example, the general route outlined in scheme 8

The heterocyclic ring of (1).

Scheme 8

(i)NH₂OH·HCl，Et₃N；

(ii) Pyridine, SOCl₂；

(iii)Fe/HCl。

Heterocyclic compound 3 can be prepared from compound 2 by treatment with thionyl chloride in the presence of a base such as pyridine.

The following examples are illustrative of the synthesis of compounds of formula III, IIIC, IIIF, IIIG, or IIIH and are not meant to limit the scope of the invention.

Example 1

Reagent:

(i) diethyl cyanomethylphosphonate, sodium hydride, tetrahydrofuran;

(ii) nitromethane, tetrabutylammonium fluoride, tetrahydrofuran;

(iii) borane methyl sulfide, toluene;

(iv) triethylamine, methylsulfonyl chloride, tetrahydrofuran;

(v) 10% Pd — C, hydrogen, methanol then HCl.

Cyclohexylethylenenitrile (2)

Sodium hydride (60% in oil, 0.80g, 20mmol) was suspended in 50mL tetrahydrofuran and frozen in ice under nitrogen. A solution of diethyl cyanomethylphosphonate (3.85g, 22mmol) in 10mL of tetrahydrofuran was added dropwise and stirring was continued for 15 minutes to give a clear solution. A solution of cyclohexanone (1.90g, 19mol) in 5mL tetrahydrofuran was added and the reaction mixture was then warmed to room temperature. The solution was clarified and the residue was washed three times with diethyl ether. The solution and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica eluting with 4: 1 heptane/ethyl acetate to give the desired product as a colourless oil (1.5g, 67%).

¹H NMR 400MHz(CDCl₃)：δ1.50(m，6H)，2.25(t，J＝5.6Hz，2H)，2.49(t，J＝6.8Hz，2H)，5.04(s，1H)。

IR vmax 2933，2859，2217，1633，1449

(1-Nitromethyl-cyclohexyl) -acetonitrile (3)

The nitrile (compound 2, 0.78g, 6.44mmol), nitromethane (0.80g, 13.11mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 10mL, 10mmol) were heated to 70 ℃ in 20mL tetrahydrofuran overnight. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica chromatography eluting with 3: 1 heptane/ethyl acetate to give the desired product as a yellow oil (0.83g, 71%).

¹H NMR 400MHz(CDCl₃)：δ1.57(s，10H)，2.63(s，2H)，4.52(s，2H)。

To C₉H₁₃N₂O₂Analytical calculation of (a):

C，59.32；H，7.74；N，15.37。

measured value: c, 59.40; h, 7.65; and N, 15.18.

2- (1-Nitromethyl-cyclohexyl) -ethylamine (4)

Borane methylsulfide (2.0M in toluene, 1.3mL, 2.6mmol) was added to a solution of compound 3(0.4g, 2.2mmol) in toluene (10mL) under nitrogen. After heating to 60 ℃ for 3 hours, the mixture was cooled and then 15mL of methanol and 15mL of 4M HCl in dioxane were added in sequence. After 1 hour of reflux, the mixture was evaporated to dryness. Crystallization from ethyl acetate afforded the desired product as colorless crystals (0.23g, 47%); mp 170-.

¹H NMR 400MHz(d₆-DMSO)：δ1.30-1.50(m，10H)，1.64-1.69(m，2H)，2.82-2.86(m，2H)，4.57(s，2H)，7.89(s，3H)。

To C₉H₁₈N₂O₂·HCl·0.2H₂Analytical calculation of O:

C，47.77；H，8.64；N，12.38。

measured value: c, 47.80; h, 8.66; and N, 12.64.

N- [2- (1-Nitromethyl-cyclohexyl) -ethyl ] -methanesulfonamide (5)

Triethylamine (0.64g, 6.3mmol) was added dropwise to a solution of the amine hydrochloride (compound 4, 0.70g, 3.1mmol) and methanesulfonyl chloride (0.36g, 6.3mmol) in tetrahydrofuran (35 mL). After stirring at room temperature for 2 hours, the mixture was filtered, diluted with ethyl acetate, washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/heptane to give colorless crystals (0.39g, 47%); mp 86-88 ℃.

¹H NMR 400MHz(d₆-DMSO)：δ1.35-1.50(m，10H)，1.55-1.60(m，2H)，2.89(s，3H)，2.99-3.06(m，2H)，4.55(s，2H)，6.93(t，J＝6Hz，1H)。

To C₁₀H₂₀N₂O₄Analytical calculation of S:

C，45.44；H，7.63；N，10.60；S，12.13。

measured value: c, 45.77; h, 7.64; n, 10.58; and S, 12.17.

N- [2- (1-aminomethyl-cyclohexyl) -ethyl ] -methanesulfonamide hydrochloride (6)

10% Palladium-carbon was added to a solution of Compound 5(0.35g, 1.3mmol) in methanol (50mL) under nitrogen. The mixture was shaken under 40psi of hydrogen for 6 hours and then filtered through a keiselguhr. The filtrate was evaporated to dryness. 4N HCl in dioxane and diethyl ether were added sequentially to give the product as a colourless crystalline solid (0.33g, 92%); mp 196 and 199 ℃.

¹H NMR 400MHz(d₆-DMSO)：δ1.25-1.45(m，10H)，1.55-1.60(m，5H)，2.70-2.75(m，2H)，2.90-2.95(m，5H)，6.86(t，J＝6.0Hz，1H)，7.86(bs，3H)。

To C₁₀H₂₂N₂O₂S·HCl·0.25H₂Analytical calculation of O:

C，43.63；H，8.60；N，10.17。

measured value: c, 43.43; h, 8.64; and N, 9.95.

Example 2

Reagent:

(i) trimethylsilylazide, trimethylaluminum (2M hexane solution), toluene;

(ii) raney nickel, hydrogen, methanol and then HCl.

1- (1H-tetrazol-5-ylmethyl) -cyclohexanecarbonitrile (2)

Under nitrogen, the mixture was quenched with a mixture of dinitriles (Griffiths g., Mettler h., Mills l.s., and Previdoli f.,Helv.Chim.Acta,74: 309(1991)) (1.48g, 10mmol) in toluene (20mL) was added sequentially trimethylsilyl azide (1.15g, 10mmol) and trimethylaluminum (5mL, 2.0M in hexane, 10 mmol). After heating to 90 ℃ overnight, the mixture was cooled and ethyl acetate, ice and 6N hydrochloric acid were carefully added. The aqueous phase is extracted with ethyl acetate, the extracts are washed with water, dried over magnesium sulfate and then evaporated to dryness. Crystallization gave the desired product (158mg, 8%).

C- [1- (1H-tetrazol-5-ylmethyl) -cyclohexyl ] -methylamine hydrochloride (3)

A solution of tetrazole (compound 8, 158mg, 0.83mmol) in methanol was added to a methanol suspension of washed Raney nickel. The mixture was shaken under 40psi of hydrogen for 3.5 hours, then filtered to remove the catalyst and evaporated to dryness. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous phase was separated and evaporated to dryness. Recrystallization from methanol/diethyl ether gave the desired product (44mg, 23%); mp 176-.

¹H NMR 400MHz(d₆-DMSO)：δ1.20-1.60(m，10H)，2.84(s，2H)，3.07(s，2H)，8.06(bs，3H)。

Example 3

Reagent:

(i) diethyl cyanomethylphosphonate, sodium hydride, tetrahydrofuran;

(ii) nitromethane, tetrabutylammonium fluoride, tetrahydrofuran;

(iii) borane methyl sulfide, toluene;

(iv) triethylamine, acetyl chloride, tetrahydrofuran;

(v) 10% Pd — C, hydrogen, methanol then HCl.

Cyclohexylethylenenitrile (2)

Sodium hydride (60% in oil, 0.80g, 20mmol) was suspended in 50mL tetrahydrofuran and frozen in ice under nitrogen. A solution of diethyl cyanomethylphosphonate (3.85g, 22mmol) in 10mL tetrahydrofuran was added dropwise and stirring continued for 15 minutes to give a clear solution. A solution of cyclohexanone (1.90g, 19mmol) in 5mL tetrahydrofuran was added and the reaction mixture was then warmed to room temperature. The solution was clarified and the residue was washed three times with ether. The solution and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica eluting with 4: 1 heptane/ethyl acetate to give the desired product as a colourless oil (1.5g, 67%).

IR vmax 2933，2859，2217，1633，1449。

(1-Nitromethyl-cyclohexyl) -acetonitrile (3)

The nitrile (compound 2, 0.78g, 6.44mmol), nitromethane (0.80g, 13.11mmol) and tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 10mL, 10mmol) were heated to 70 ℃ in 20mL tetrahydrofuran overnight. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica eluting with 3: 1 heptane/ethyl acetate to give the desired product as a yellow oil (0.83g, 71%).

¹H NMR 400MHz(CDCl₃)：δ1.57(s，10H)，2.63(s，2H)，4.52(s，2H)。

To C₉H₁₃N₂O₂Analytical calculation of (a):

C，59.32；H，7.74；N，15.37。

measured value: c, 59.40; h, 7.65; and N, 15.18.

2- (1-Nitromethyl-cyclohexyl) -ethylamine (4)

To C₉H₁₈N₂O₂·HCl·0.2H₂Analytical calculation of O:

C，47.77；H，8.64；N，12.38。

measured value: c, 47.80; h, 8.66; and N, 12.64.

N- [2- (1-Nitromethyl-cyclohexyl) -ethyl ] -acetamide (5)

The amine hydrochloride (compound 4, 0.50g, 2.25mmol) was reacted with acetyl chloride (0.20g, 2.55mmol) and triethylamine (0.45g, 4.45mmol) in tetrahydrofuran as described in step 4 of example 1. Purification by silica chromatography eluting with ethyl acetate afforded the desired product as a crystalline solid (0.35g, 69%); mp 68-70 ℃.

¹H NMR 400MHz(CDCl₃)：δ1.40-1.60(m，10H)，1.60-1.65(m，2H)，1.98(s，3H)，3.30-3.40(m，2H)，4.40(s，2H)，5.59(bs，1H)。

N- [2- (1-aminomethyl-cyclohexyl) -ethyl ] -acetamide hydrochloride (6)

Compound 5(0.30g, 1.3mmol) was hydrogenated in the presence of 10% palladium on carbon according to the procedure described in example 1, step 5 to give the product as the hydrochloride salt (0.35g, 100%).

¹H NMR 400MHz(d₆-DMSO)：δ1.20-1.40(m，10H)，1.40-1.50(m，2H)，1.81(s，3H)，2.75(q，J＝6.0Hz，2H)，2.95-3.05(m，2H)，7.99(bs，3H)，8.06(t，J＝4.8Hz，1H)。

IR vmax 3625，2929，1628，1553，1446，1373，1298。

Example 4

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one; hydrochloride salt

[1- (tert-Butoxycarbonylamino-methyl) -cyclohexyl ] -acetic acid (2)

A solution of gabapentin (1) (9.37g, 0.0547mol) in 125mL of 1N NaOH and 50mL of THF was cooled to 0 deg.C, and then a solution of di-tert-butyl dicarbonate (13.1g, 0.06mol) in 200mL of THF was slowly added. The reaction mixture was stirred at room temperature for 2 hours and concentrated on a rotary evaporator to remove THF. KH for concentrated solution₂PO₄Saturated and extracted 3 times with EtOAc. The EtOAc extracts were washed 2 times with brine and MgSO₄And (5) drying. Evaporation gave 14.8g (100%) of a white solid, mp109-111 ℃.

¹H NMR(CDCl₃) δ 1.2-1.4(m, 19H), 2.27(s, 2H), 3.11(d, 2H, J ═ 6.84Hz), 4.95 (broad peak, 1H).

MS(APCI)m/z 272(M+1)。

To C₁₄H₂₅NO₄Analytical calculation of (a):

C，61.97；H，9.29；N，5.16。

measured value: c, 62.36; h, 9.27; n, 5.19.

(1-carbamoylmethyl-cyclohexylmethyl) -carbamic acid tert-butyl ester (3)

Reacting [1- (tert-butoxycarbonylamino-methyl) -cyclohexyl]-acetic acid (2) (152g, 0.56mol) was dissolved in 1L THF and triethylamine (66.2g, 0.65mol) and cooled to-10 ℃. After 1 hour, isobutyraldehyde (84.7g, 0.62mol) was added and the heterogeneous mixture was stirred at 0 ℃ for 15 minutes. Ammonia gas was bubbled through the cold reaction mixture for 30 minutes and the mixture was cooled to room temperature. After stirring for 16 h, the reaction mixture was evaporated to dryness on a rotary evaporator, the residue was dissolved in water, extracted 3 times with EtOAc, washed 2 times with brine and MgSO ₄And (5) drying. Evaporation gave an oil which was crystallized from pentane to give 116.5g (77%) of white crystals; mp 123-.

¹H NMR(CDCl₃)δ1.2-1.6(m，19H)，2.12(s，2H)，3.13(d，2H，J＝7.08Hz)，4.97(s，IH)，5.43(s，1H)，7.34(s，1H)。

MS(APCI)271 m/z.(M+1)。

To C₁₄H₂₆N₂O₃Analytical calculation of (a):

C，62.19；H，9.69；N，10.36。

measured value: c, 62.00; h, 9.72; and N, 9.96.

(1-cyanomethyl-cyclohexylmethyl) -carbamic acid tert-butyl ester (4)

Cyanuric chloride (39.5g, 0.214mol) was added to a solution of (1-carbamoylmethyl-cyclohexylmethyl) -carbamic acid tert-butyl ester (3) (116g, 0.429mol) in 400mL of DMF. An ice-water bath was used to moderate the exotherm, and the reaction mixture was then stirred at room temperature for 1.5 hours. The mixture was poured into a flask containing 120g (1.43mol) NaHCO₃Ice-water, extracted 4 times with EtOAc. The extract was washed with water 1 time, brine 2 times, and then Na₂SO₄And (5) drying. Evaporation gave an oil which was dissolved in 3: 1 hexane/EtOAc and filtered through silica gel. Evaporation gave white crystals (86.5g, 80%); mp 54-58 ℃.

¹H NMR(CDCl₃) δ 1.3-1.5(m, 19H), 2.30(s, 2H), 3.15(d, 2H, J ═ 7.00Hz), 4.60 (broad peak, 1H).

MS(APCI)m/z 253(M+1)。

To C₁₄H₂₄N₂O₂Analytical calculation of (a):

C，66.63；H，9.59；N，11.10。

measured value: c, 66.64; h, 9.52; n, 10.80.

[1- (N-Hydroxyureido (carbamimidoyl) methyl) -cyclohexylmethyl ] -carbamic acid tert-butyl ester (5)

Preparation of hydroxylamine hydrochloride (69.5g, 1.00mol)The DMSO (300mL) suspension was cooled in ice-water and triethylamine (106.7g, 1.05mol) was added. The heat evolved brought the temperature to 20 ℃. The mixture was stirred at this temperature for 15 minutes, then triethylamine hydrochloride was filtered and washed with THF. The filtrate was concentrated to remove THF, then (1-cyanomethyl-cyclohexylmethyl) -carbamic acid tert-butyl ester (4) (50.4g, 0.2mol) was added and the mixture was heated at 75 ℃ for 15 minutes. After cooling, the reaction mixture was diluted with water (1L) and extracted 3 times with EtOAc. The EtOAc extracts were washed with saturated KH₂PO₄Washed 1 time with saturated NaHCO₃Washed 1 time, brine 2 times, then Na₂SO₄And (5) drying. Evaporation gives a gummy solid which is taken up in Et₂Trituration in O gave white crystals, 25.2g (44%); mp 125-.

¹H NMR(CDCl₃)δ1.3-1.5(m 19H)，1.99(s，2H)，3.12(d，2H J＝6.84Hz)，4.93(t，1H，J＝6.84Hz)，5.40(s，1H)。

MS(APCI)m/z 286(M+1)。

To C₁₄H₂₇N₃O₃Analytical calculation of (a):

C，58.92；H，9.54；N，14.72。

measured value: c, 58.96; h, 9.80; n, 14.65.

BOC-gabapentin amidoxime carbamate (6)

Reacting [1- (N-hydroxyureidomethyl) -cyclohexylmethyl]A solution of tert-butyl carbamate (5) (25.1g, 0.088mol) and pyridine (7.82g, 0.099mol) in DMF (200mL) was placed in ice-water and cooled while isobutyraldehyde (12.32g, 0.09mol) was added dropwise. After 15 min, the water bath was removed and the mixture was stirred at room temperature for 2 h, diluted with water and extracted 3 times with EtOAc. The extract was washed with water 1 time, brine 2 times, and then Na ₂SO₄And (5) drying. Evaporation gave 34g (100%) of an oil which was used without further purification.

MS(APCI)m/z 386(M+1)。

[1- (5-oxo-4, 5-dihydro- [1, 2, 4] oxadiazol-3-ylmethyl) -cyclohexylmethyl ] -carbamic acid tert-butyl ester (7)

BOC-gabapentin amidoxime carbamate (33.88g, 0.088mol) was dissolved in xylene (250mL) and heated at reflux for 2.5 hours. Xylene was removed by evaporation and the residue was dissolved in Et₂In O, 3 extractions were performed with 75mL of 1N NaOH. The alkaline extract is saturated KH₂PO₄Acidified and then treated with Et₂And extracting for 3 times by using O. Et (Et)₂Saturated KH for O extract₂PO₄Washed 1 time, brine 2 times, then Na₂SO₄And (5) drying. Evaporation gave 17.9g (65%) of a milky colored solid, mp 140-.

¹H NMR(CDCl₃)δ1.0-1.6(m，19H)，2.42(s，2H)，3.00(d，2H，J＝7.32Hz)，4.86(t，1H，J＝7.08Hz)，11.30(s，1H)。

MS(APCI)m/z 312(M+1)。

To C₁₅H₂₅N₃O₄Analytical calculation of (a):

C，57.86；H，8.09；N，13.49。

measured value: c, 58.21; h, 8.31; and N, 13.30.

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one; hydrochloride (8)

A solution of BOC-gabapentin oxadiazolone (17.7g, 0.0568mol) in 4M HCl in dioxane (200mL) was allowed to stand for 1.5 hours. Concentrate to 1/2 volumes, then add Et₂O gave a precipitate which was removed by filtration and recrystallized from MeOH to give white crystals (12.98g, 92.7%) mp209-212 ℃.

¹H NMR(DMSO-d₆)δ1.2-1.5(m，10H)，2.64(s，4H)，2.79(s，2H)，7.98(s，3H)，12.35(s，1H)。

MS(APCI)m/z 212(M+1)。

To C₁₀H₁₇N₃O₂Analytical calculation of HCl:

C，48.49；H，7.32；N，16.96；Cl，14.31。

Measured value: c, 48.71; h, 7.18; n, 17.03; cl, 14.32.

Example 5

[1- (5-thio-4, 5-dihydro- [1, 2, 4] oxadiazol-3-ylmethyl) -cyclohexylmethyl ] -carbamic acid tert-butyl ester (9)

Containing [1- (N-hydroxyureidomethyl) -cyclohexylmethyl group]A solution of a mixture of tert-butyl carbamate (4.85g, 0.017mol), 90% 1, 1' -thiocarbonyldiimidazole (3.96g, 0.02mol) and DBU (10.39g, 0.068mol) in MeCN (150mL) was stirred at room temperature for 19 hours. The reaction mixture was evaporated to dryness and suspended in saturated KH₂PO₄Then extracted 3 times with EtOAc. The EtOAc extract was washed with saturated KH₂PO₄Washed 2 times, brine 2 times, then Na₂SO₄And (5) drying. Evaporation was followed by filtration through silica gel, eluting with 3: 1 EtOAc in hexanes, to give a solid after evaporation which was then treated with Et₂Recrystallization from O/hexane gave a light red solid, 2.6g (47%), mp 160-.

¹H NMR(CDCl₃)δ1.1-1.6(m，19H)，2.53(s，2H)，3.00(d，2H，J＝7.33Hz)，4.90(t，1H，J＝7.08Hz)，12.88(s，1H)。

MS(APCI)m/z 328(M+1)。

To C₁₅H₂₅N₃O₃Analytical calculation of S:

C，55.02；H，7.70；N，12.83；S，9.79。

measured value: c, 55.34; h, 7.80; n, 12.72; s, 9.43.

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazole-5-thione; hydrochloride (10)

Mixing [1- (5-thio-4, 5-dihydro- [1, 2, 4]]Oxadiazol-3-ylmethyl) -cyclohexylmethyl]Tert-butyl carbamate (9) (2.5g, 0.0076mol) was dissolved in 4M HCl and 1, 4-dioxane (75mL) and stirred at room temperature. The precipitate formed was filtered off and then washed with MeOH-Et ₂Recrystallization of O gave 1.31g (66%) of a white solid, mp 210-.

¹H NMR(DMSO-d₆)δ1.2-1.5(m，10H)，2.79-2.85(m，4H)，7.99(s，3H)。

MS(APCI)m/z 228(M+1)。

To C₁₀H₁₇N₃Analytical calculation of OS & HCl:

C，45.53；H，6.88；N，15.93；S，12.16；Cl，13.44。

measured value: c, 45.92; h, 6.71; n, 15.83; s, 11.81; cl, 13.48.

Example 6

Reagent:

(i) trimethylsilyl azide, dibutyltin oxide, toluene

(ii) Nickel catalyst, methanol

Synthesis of 9- (1H-tetrazol-5-ylmethyl) -bicyclo [3.3.1] nonane-9-carbonitrile (2)

To a solution of the dinitrile (see WO 9733859) (1.2g, 6.38mmol) in toluene (10mL) was added successively trimethylsilyl azide (1.48g, 12.87mmol) and dibutyltin oxide (0.16g, 0.64 mmol). After heating to 95 ℃ for 3 days, the mixture was diluted with ethyl acetate, washed with 1N HCl and water, dried over magnesium sulfate and then evaporated to dryness. Crystallization gave the desired product (0.3g, 20%); mp189-191 ℃.

400MHz NMR(d₆-DMSO)δ1.50-1.70(m，4H)，1.75-2.10(m，10H)，3.48(s，2H)。

Synthesis of C- [9- (1H-tetrazol-5-ylmethyl) -bicyclo [3.3.1] non-9-yl ] -methylamine hydrochloride (3)

A solution of the tetrazole from step 1 (0.60g, 2.59mmol) in methanol (100mL) was added to a methanol suspension of the washed nickel catalyst. The mixture was shaken overnight under 40psi of hydrogen, then filtered to remove the catalyst and evaporated to dryness. The residue was dissolved in methanol while adding ethereal hydrogen chloride. Ether was added and filtered to give the desired product (0.19g, 22%), mp 232-.

400MHz NMR(d₆-DMSO)δ1.40-1.70(m，8H)，1.75-1.95(m，4H)，2.05-2.15(m，2H)，3.13(s，2H)，3.29(s，2H)，8.0(bs，3H)。

Example 7

Reagent:

(i) ethyl cyanoacetate, NaH, THF;

(ii) KCN, EtOH and water are refluxed;

(iii) trimethylsilyl azide, dibutyltin oxide, toluene;

(iv) nickel catalyst, methanol

Synthesis of 2- (1H-tetrazol-5-ylmethyl) -adamantane-2-carbonitrile (4)

Prepared according to the same method as for 9- (1H-tetrazol-5-ylmethyl) -bicyclo [3.3.1] nonane-9-carbonitrile in example 4.

Synthesis of C- [2- (1H-tetrazol-5-ylmethyl) -adamantan-2-yl ] -methylamine hydrochloride (5)

The nitrile obtained in step 3 (0.47g, 1.9mmol), prepared in a similar manner, was shaken with a nickel catalyst (a full scoop, washed) overnight under 50psi of hydrogen. Filtration through kieselguhr, evaporation, and subsequent treatment with methanol and ethereal hydrogen chloride gave the desired product as a crystalline product with methanol and acetonitrile (25mg, 5%); mp 250-252 ℃.

400MHz NMR δ 1.49(s, 2H), 1.54(d, J ═ 13.7Hz, 2H), 1.59(d, J ═ 13.7Hz), 1.67(s, 2H), 1.83(s, 1H), 1.90(s, 1H), 1.97(d, J ═ 12.9Hz, 2H), 2.19(d, J ═ 12.7Hz, 2H), 3.15(s, 2H), 3.34(s, shielded by water), 7.99(bs, 3H).

Mass spectrum ES⁺248(100％，(M+H)⁺)。

Example 8

Reagent:

(i) ethyl cyanoacetate, ammonium acetate, acetic acid, toluene

(ii) Potassium cyanide, hydrous ethanol

(iii) Trimethylsilyl azide, dibutyltin oxide, toluene

(iv) Nickel catalyst, methanol

Synthesis of (trans) cyano- (3, 4-dimethyl-cyclopentylidene) -acetic acid ethyl ester (2)

Trans-3, 4-dimethylcyclopentanone (2.91g, 25.94mmol), ethyl cyanoacetate (2.93g, 25.93mmol), ammonium acetate (0.20g, 2.60mmol), and acetic acid (0.31g, 5.17mmol) were heated in a Dean-Stark trap (Dean-Stark trap) with refluxing toluene for 24 hours. After cooling, it was filtered through kieselguhr and evaporated to give the desired product as a white (off-white) solid (5.0g, 93%).

400MHz NMRδ1.08(d，J＝6.0Hz，3H)，1.09(d，J＝6.4Hz，3H)，1.34(t，J＝7.2Hz，3H)，1.55-1.70(m，2H)，2.30-2.45(m，2H)，3.08(dd，J＝20.0Hz，8.0Hz，1H)，3.43(dd，J＝20.0Hz，7.0Hz，1H)，4.26(q，J＝7.1Hz，2H)。

Mass spectrum ES⁺208.19(M+H)⁺，225.19，230.16(100％，(M+Na)⁺)。

Synthesis of (trans) 1-cyanomethyl-3, 4-dimethyl-cyclopentylnitrile (3)

The product from step 1 was refluxed with a solution of potassium cyanide (1.57g, 24.2mmol) in ethanol/10% water (50mL) overnight. Evaporation to dryness and purification by chromatography using 1: 1 ethyl acetate/heptane afforded 2.9g (74%) of the desired product as a yellow oil. A1: 1 ethyl acetate/heptane tlc rf value of 0.45 was used.

400MHz NMRδ1.05(d，J＝8.4Hz，3H)，1.07(d，J＝8.8Hz，3H)，1.49(dd，J＝13.2，11.6Hz，1H)，1.60-1.70(m，1H)，1.75-1.90(m，1H)，1.96(dd，J＝13.6，14.8Hz，1H)，2.19(dd，J＝14.0，8.4Hz，1H)，2.48(dd，J＝13.2，6.4Hz，1H)，2.73(s，2H)。

Synthesis of (trans) 3, 4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentanecarbonitrile (4)

The dinitrile from step 2 (1.62g, 10mmol) was heated to 100 ℃ overnight with a solution of trimethylsilyl azide (2.84g, 24.7mmol) and dibutyltin oxide (0.24g, 0.96mmol) in toluene (50 mL). The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water. Dried over magnesium sulfate and then evaporated to dryness. Purification by chromatography using ethyl acetate afforded the desired product as a colorless oil, 0.94g, (46%).

Mass spectrum ES⁺206.23(M+H)⁺，228.26(M+Na)⁺。

400MHz NMR CDCl₃δ1.04(d，J＝7.2Hz，3H)，1.05(d，J＝6.4Hz)，1.56(dd，J＝11.6，11.6Hz，1H)，1.55-1.65(m，1H)，1.65-1.75(m，1H)，1.83(dd，J＝13.6，9.2Hz，1H)，2.27(dd，J＝14.0，8.0Hz)，2.35(dd，J＝13.0，6.8Hz，1H)，3.36(s，2H)。

Synthesis of (trans) C- [3, 4-dimethyl-1- (1H-tetrazol-5-ylmethyl) -cyclopentyl ] -methylamine hydrochloride (5)

The tetrazole from step 3 (0.90g, 0.44mmol) and nickel catalyst (one full scoop, washed) were shaken overnight in methanol (200 mL). The mixture was filtered with kieselguhr and evaporated to dryness. The residue was treated with methanol and ethereal (ethereal) hydrogen chloride and then stirred with di-tert-butyl dicarbonate (0.80g, 3.67mmol) and sodium bicarbonate (0.80g, 9.52mmol) in aqueous dioxane (1: 1, 20mL) overnight. The mixture was diluted with ethyl acetate and the aqueous phase was separated, acidified and extracted 3 times with ethyl acetate. The extract was dried over magnesium sulfate, filtered and evaporated to give a colorless oil. The oil was stirred overnight in dioxane (5mL) with 4M hydrogen chloride and then evaporated to dryness to give 0.24g (76%) of the desired product.

400MHz d₆-DMSOδ0.88(d，J＝6.4Hz，3H)，0.89(d，J＝5.6Hz，3H)，1.15-1.25(m，3H)，1.35-1.45(m，1H)，1.70-1.80(m，2H)，2.82(d，J＝13.2Hz，1H)，2.89(d，J＝13.2Hz，1H)，3.04(d，J＝15.2Hz，1H)，3.05(d，J＝15.2Hz，1H)。

Mass spectrum ES⁺210 100％，(M+H)⁺。

To C₁₀H₁₉N₅·HCl·0.5H₂Elemental analysis calculated for O:

C，47.14；H，8.31；N，27.49。

measured value: c, 47.23; h, 7.97; n, 27.16.

Wherein R is¹And R²The compounds of formula IV as defined above may be prepared according to the following process.

General synthetic schemes

Method 1 (scheme 9)

a)LiAlH₄；

b) Pyridinium dichromate;

c) triethylphosphoacetone, NaH;

d) nitromethane DBU;

e)i.H₂Pd/C; HCl; ion exchange chromatography.

Method 2 (scheme 10)

X ═ OEt or a chiral oxazolidine adjuvant.

a) Triethylphosphorodioxyacetone (triethylphosphonoacetate), NaH;

b) NaOH, ii, trimethylacetyl chloride (pivaloyl chloride), Et₃N，XH；

c)R¹MgBr，CuBr₂ DMS；

d)NaHMDS，BrCH₂CO₂tBu；

e) R ═ tert-butyl i₂O₂；ii.BH₃，iii.TsCl，ET₃N，iv.NaN₃，DMSO；

f) Lioh, H ═ ethyl i₂O₂；ii.BH₃，iii.PTSA，THF；iv.HBr EtOH，v.NaN₃DMSO；

g)i.H₂Pd/C; hcl, iii ion exchange chromatography.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Synthesis of example 9: 3-aminomethyl-5-methylheptanoic acid

a)PDC，CH₂Cl₂；

b) NaH, triethylphosphoacetone;

c)DBU，CH₃NO₂；

d)H₂，10％Pd/C；

e)6N HCl, reflux, ion exchange resin (Dowex 50WX8, strongly acidic).

3-methyl-1-pentanal 11

To a stirred suspension of pyridinium dichromate (112.17g, 298.1mmol) in dichloromethane (500mL) was added 3-methyl-1-pentanol 10(15g, 146.79 mmol). After stirring for 2.5 hours, 400mL of (ethyl) ether was added and stirring was continued for 5 minutes. The filtrate of the mixture was concentrated to at least a volume and treated with a magnesium silicate (Florisil) column. The compound was eluted with petroleum ether and further subjected to silica gel column chromatography using 10% ether in petroleum ether as eluent to give 11(6.5g, 44%).

¹H-NMR(CDCl₃)δ9.72，(d，-CHO)，2.38(dd，1H，-CH₂CHO)，2.19(dd，1H，-CH₂CHO)，1.95(m，1H，C₂H₅(CH₃)CHCH₂)，1.4-1.0(m)，0.9-0.8(m)。

5-methyl-2-heptenoic acid ethyl ester 12

After sodium hydride (60% dispersion, 2.4g, 65mmol) was washed with hexane, it was suspended in 60mL of dimethoxyethane. While cooling in ice water, triethylphosphoacetone was slowly added for about 5 minutes. The reaction was stirred at 0 ℃ for 15 minutes, and then 20mL of a solution of 3-methyl-1-pentanal 11(6.5g, 65mmol) in methoxyethane was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic layer was separated, and the aqueous portion was discarded. The solution was washed with brine 2 times and then dried over magnesium sulfate. Evaporation of the solvent gave 12(6.75g, 61%).

¹H-NMR(CDCl₃)δ6.89(m，1H，-CH₂CH：CHCOOEt)，5.77(d，1H，-CH₂CH：CHCOOEt)，4.16(q，2H，-COOCH₂CH₃) 2.15 and 1.98(1H singlet and multiplet, -CH)₂CH：CHCOOEt)，1.48(m，1H，C₂H₅(CH₃)CHCH₂) 1.30-1.10(m), and 0.83.

5-methyl-3-nitromethylheptanoic acid ethyl ester 13

A solution of ethyl 5-methyl-2-heptanoate 12(6.75g, 39.70mmol), DBU (6.0g, 39.7mmol), nitromethane (21.97g, 359.9mmol) in 80mL acetonitrile was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was concentrated to an oil. The ethereal solution of the oil was washed with 1N HCl, brine and then dried. Evaporation gave a light oil (light oil) which was chromatographed on silica gel eluting with 5% to 10% diethyl ether in petroleum ether to give 13(3.6g, 42%).

¹H-NMR(CDCl₃)δ4.49-4.39(m)，4.12-4.07(m)，3.61(m)，2.36(m)，1.36-1.18(m)，0.86-0.79。

3-aminomethyl-5-methylheptanoic acid (example 9)

Ethyl 5-methyl-3-nitromethylheptanoate 13(3.6g) was hydrogenated in ethanol in the presence of 20% Pd/C and then evaporated to give 14. 30mL of 6 equivalents of hydrochloric acid was added to reflux overnight. The solvent was evaporated under reduced pressure and the residue azeotroped with toluene. The aqueous solution of the residue was treated with Dowex 50WX 8-100 ion exchange resin which had been washed to neutrality with HPLC purity water. The column was eluted with water until the eluent was at neutral pH, then 0.5N NH was added₄The OH solution eluted to give a fraction containing 3-aminomethyl-5-methylheptanoic acid. Combining the fractions and reusing C ₁₈And (4) performing column chromatography treatment. The compound was eluted with 40% aqueous methanol and crystallized from methanol-ether to give example 9630 mg.

¹H-NMR(CD₃OD)δ2.83(m，1H)，2.75(m，1H)，2.35(m，1H)，2.15(m，1H)，1.95(1H，bs)，1.38(1H，m)，1.3-1.15(m，2H)，1.14-0.95(m，2H)，0.80(m，2CH₃)。

MS found molecular ions at (M +1)174, and other ions at 156, 139, and 102.

To C₉H₁₉NO₂Analytical calculation of (a):

C，62.39；H 11.05；N 8.08。

measured value: c, 62.00; h, 10.83; and N, 7.98.

The following examples can be prepared in a similar manner.

3-aminomethyl-5-methyl-heptanoic acid;

3-aminomethyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-nonanoic acid;

3-aminomethyl-5-methyl-decanoic acid;

3-aminomethyl-5-methyl-undecanoic acid;

3-aminomethyl-5-methyl-dodecanoic acid;

3-aminomethyl-5-methyl-tridecanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-5-cyclobutyl-hexanoic acid;

3-aminomethyl-5-cyclopentyl-hexanoic acid;

3-aminomethyl-5-cyclohexyl-hexanoic acid;

3-aminomethyl-5-trifluoromethyl-hexanoic acid;

3-aminomethyl-5-phenyl-hexanoic acid;

3-aminomethyl-5- (2-chlorophenyl) -hexanoic acid;

3-aminomethyl-5- (3-chlorophenyl) -hexanoic acid;

3-aminomethyl-5- (4-chlorophenyl) -hexanoic acid;

3-aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (4-methoxyphenyl) -hexanoic acid; and

3-aminomethyl-5- (phenylmethyl) -hexanoic acid.

Example 10: synthesis of (3R, 4S) 3-aminomethyl-4, 5-dimethyl-hexanoic acid

Example 10

Reagents and conditions:

a) (R) - (-) -4-phenyl-2-oxazolidinone, (CH)₃)₃CCOCl，Et₃N, LiCl, THF, -20 to 23 ℃;

b)MeMgCl，CuBrSMe₂，THF，-35℃；

c)NaHMDS，BrCH₂CO₂tBu, THF, -78 ℃ to-40 ℃;

d)LiOH，H₂O₂，THF，H₂O，25℃；

e)BH₃SMe₂，THF，0-25℃；

f) pTsCl, pyridine, 25 ℃;

g)NaN₃，DMSO，60℃；

h) raney nickel, MeOH, H₂；

i)3M HCl, reflux, ion exchange resin (Dowex 50WX8, strongly acidic).

[ R- (E) ]3- (4-methyl-pent-2-enoyl)) -4-phenyl-oxazolidin-2-one 16

Trimethylacetyl chloride (7.8g, 0.065mol) was added to a solution of acid 14(6.9g, 0.06mol) and triethylamine (18g, 0.187mol) in THF (200mL) at-20 ℃. After 1 hour, lithium chloride (2.35g, 0.55mol) and (R) - (-) -4-phenyl-2-oxazolidinone (8.15g, 0.05mol) were added, and the thick suspension was then heated to room temperature. After 20 hours, the suspension was filtered and the filtrate was concentrated. The resulting solid was recrystallized from hexane/ethyl acetate (5: 1) to give oxazolidinone 16 as a white solid (8.83g, 68%).

¹H NMR(CDCl₃) δ 7.35(m, 5H), 7.18(dd, 1H, J ═ 15.4 and 1.2Hz), 7.02(dd, 1HJ ═ 15.4 and 6.8Hz), 5.45(dd, 1H, J ═ 8.8 and 3.9Hz), 4.68(t, 1H, J ═ 8.8Hz), 4.22(dd, 1H, J ═ 8.8 and 3.9Hz), 2.50(m, 1H), 1.04(d, 1H, J ═ 1.4Hz), 1.02(d, 1H, J ═ 1.4 Hz).

MS, m/z (relative intensity): 260[ M + H, 100% ].

(3R，3R^*)3- (3, 4-dimethyl-pentanoyl) -4-phenyl-oxazolidin-2-one 17

To a solution of copper (I) bromide-dimethyl sulfide complex in THF (45mL) at-20 deg.C was added methylmagnesium chloride (3M in THF). After 20 minutes, a solution of oxazolidinone 16(3.69g, 0.014mol) in THF (20mL) was added dropwise for 10 minutes. After 2.5 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride. The resulting two layers were separated and the aqueous phase was extracted with ether. The combined organic phases were washed with 1M hydrochloric acid and then with 5% aqueous ammonium hydroxide. The organic phase was dried (MgSO)₄And concentrated to give oxazolidinone 17 as a white solid (3.39g, 88%).

¹H NMR(CDCl₃) δ 7.30(m, 1H), 5.40(dd, 1H, J ═ 8.8 and 3.7Hz), 4.63(t, 1H, J ═ 8.8Hz), 4.21(dd, 1H, J ═ 8.8 and 3.7Hz), 2.85(dd, 1H, J ═ 16.1 and 5.6Hz), 2.8(dd, 1H, J ═ 16.1 and 8.5Hz), 1.90(m, 1H), 1.56(m, 2H), 0.83(d, 3H, J ═ 6.8Hz), 0.78(d, 3H, J ═ 6.8Hz), 0.75(d, 3H, J ═ 6.8 Hz).

MS, m/z (relative intensity): 276[ M + H, 100% ].

[3R-(3R^*(R^*)，4S^*) -4, 5-dimethyl-3- (2-oxo-4-phenyl-oxazolidine-3-carbonyl) -hexanoic acid tert-butyl ester 18

Bis (trimethylsilyl) aminated (amide) sodium (14.4mL, 0.014mol, 1M in THF) was added to a solution of oxazolidinone 17(3.37g, 0.012mol) in THF (35mL) at-78 ℃. After 35 minutes, tert-butyl bromoacetate (3.5g, 0.018mol) was added while the solution was immediately heated to-40 ℃. After 3 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The resulting two layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (9: 1-5: 1 gradient of hexane/ethyl acetate) afforded ester 18(3.81g, 82%) as a white solid.

¹H NMR(CDCl₃) δ 7.35(m, 5H), 5.37(dd, 1H, J ═ 8.4 and 3.1Hz), 4.67(t, 1H, J ═ 8.7Hz), 4.41(dt, 1H, J ═ 12.0 and 3.5Hz), 4.25(dd, 1H, J ═ 8.68 and 3.1Hz), 2.65(dd, 1H, J ═ 16.9 and 12.0Hz), 2.25(dd, 1H, J ═ 16.9 and 3.5Hz), 1.6(m, 1H), 1.45(m, 1H), 1.23(s, 9H), 1.02(d, 1H, J ═ 6.5Hz), 0.93(d, 1H, J ═ 6.7Hz), 0.80(d, 1H, J ═ 7.0 Hz).

MS, m/z (relative intensity): 429[ M-H + CH₃CN，100％]，388[M-H，20％]。

(3R, 4S) -2- (1, 2-dimethyl-propyl) -succinic acid 4-tert-butyl ester 19

To a solution of oxazolidinone 19(3.62g, 9.3mmol) in THF (54 mL)/water (15mL) was added lithium hydroxide (20mL of 0.8M aqueous solution, 0.016mol)/H ₂O₂(5.76mL of a 30% aqueous solution). After 7 hours, the solution was diluted with water and sodium sulfite (. about.10 g) was added. Stirring was continued for 0.5 h, the two layers were separated and the aqueous phase was extracted with ether. The aqueous phase is then treated with 1M hydrochloric acid to make it acidic (pH2) and extracted with diethyl ether. The combined organic phases were dried (MgSO)₄) And concentrated.Flash chromatography (5: 1 hexanes/ethyl acetate) afforded acid 19(2.1g, 95%) as a colorless oil.

¹H NMR(CDCl₃) δ 3.0(m, 1H), 2.55(dd, 1H, J ═ 16.6 and 11.2Hz), 2.27(dd, 1H, J ═ 16.6 and 3.4Hz), 1.70(m, 1H), 1.53(m, 1H), 1.45(m, 1H), 1.43(s, 9H), 0.95(d, 1H, J ═ 6.8Hz), 0.90(d, 1H, J ═ 6.6Hz), 0.83(d, 1H, J ═ 6.8 Hz).

MS, m/z (relative intensity): 243[ M-H, 100% ].

(3R, 4S) -3-hydroxymethyl-4, 5-dimethyl-hexanoic acid tert-butyl ester 20

Borane-dimethylsulfide complex (16mL of a 0.032mol solution in 2M THF) was added to a stirred solution of acid 19(1.96g, 8mmol) in THF (20mL) at 0 ℃. After 20 hours, methanol was added until no more bubbles were formed and the solution was concentrated. Flash chromatography (5: 1 hexanes/ethyl acetate gradient) afforded alcohol 20 as a colorless oil (1.29g, 70%).

¹H NMR(CDCl₃)δ3.62(m，1H)，2.32(m，1H)，2.14(m，1H)，1.6(m，1H)，1.45(s，9H)，1.35(m，1H)，0.93(d，1H，J＝6.8Hz)，0.86(d，1H，J＝6.8Hz)，0.77(d，1H，J＝6.9Hz)。

MS, m/z (relative intensity): 175[ M-tBu, 100% ].

(3R, 4S) -4, 5-dimethyl-3- (toluene-4-sulfonyloxymethyl) -hexanoic acid tert-butyl ester 21

P-toluenesulfonyl chloride (847mg, 4.4mmol) was added to the stirred CH solution of alcohol 6(850mg, 3.7mmol), DMAP (10mg, 0.08mmol) and triethylamine (1.23mL, 8.88mmol) at 0 deg.C₂Cl₂(20mL) of the solution, the solution was heated to room temperature. After 15 hours, the reaction mixture was washed with 1N hydrochloric acid and brine in this order. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (100-92% hexanes/ethyl acetate gradient) afforded tosylate 7(1.22g, 86%) as a thick gum.

¹H NMR(CDCl₃)δ7.80(d，2H，J＝8.2Hz)，7.25(d，2H，J＝8.2Hz)，3.92(m，1H)，2.38(s，3H)，2.20(m，2H)，1.95(m，1H)，1.40(m，1H)，1.32(s，9H)，1.27(m，1H)，0.78(d，1H，J＝6.6Hz)，0.73(d，1H，J＝6.6Hz)，0.63(d，1H，J＝7.1Hz)。

MS, m/z (relative intensity): 311[ 85% ], 198[ 100% ], 157[ 95% ].

(3R, 4S) -3-azidomethyl-4, 5-dimethyl-hexanoic acid tert-butyl ester 22

A solution of tosylate 21(1.19g, 3.1mmol) and sodium azide (402mg, 6.2mmol) in DMSO (15mL) was heated to 60 ℃ for 2.5 hours. Water (100mL) was added and the solution was extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (9: 1 hexanes/ethyl acetate) afforded azide 22(628mg, 80%) as a colorless oil.

¹H NMR(CDCl₃) δ 3.4(dd, 1H, J ═ 12.21 and 6.11Hz), 3.3(dd, 1H, J ═ 21.11 and 6.59Hz), 2.30(dd, 1H, J ═ 15.14 and 3.66Hz), 2.25(m, 1H), 2.05(dd, 1H, J ═ 15.14 and 9.04Hz), 1.55(m, 1H), 1.45(s, 9H), 1.35(m, 1H), 0.95(d, 1H, J ═ 6.59Hz), 0.90(d, 1H, J ═ 6.83Hz), 0.80(d, 1H, J ═ 7.08 Hz).

MS, m/z (relative intensity): 228[ M-N₂，35％]，172[M-N₂tBu，100％]。

(3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid tert-butyl ester 23 and [4R- [4R ]^*(S^*)]]-4- (1, 2-dimethyl-propyl) -pyrrolidin-2-one 24

A solution of azide 8(640mg, 2.5mmol) and Raney nickel (1g) in methanol (50mL) was shaken for 4 hours under a hydrogen atmosphere. The solution was filtered and the filtrate was concentrated to give a mixture of amine 23 and lactam 24, which was used without further purification.

(3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid (example 10)

A3M hydrochloric acid solution of amine 23 and lactam 24(500mg) was heated to reflux for 9 hours and then stirred at room temperature for 15 hours. The solution was concentrated and the resulting solid was subjected to a series of purifications including: ion exchange chromatography (Dowex 50WX8, strong acid) treated to form an oxalate, followed by ion exchange chromatography (Dowex 50WX8, strong acid) afforded example 10(343mg) as a white solid.

¹H NMR(D₂O) δ 2.87(m, 2H), 2.22(dd, 1H, J ═ 15.4 and 3.4Hz), 2.12(m, 1H), 1.93(dd, 1H, J ═ 15.4 and 9.5Hz), 1.38(m, 1H), 1.12(m, 1H), 0.77(d, 1H, J ═ 6.6Hz), 0.74(d, 1H, J ═ 6.6Hz), 0.70(d, 1H, J ═ 6.8 Hz).

MS, m/z (relative intensity): 174[ M + H, 100% ].

The following examples can be prepared in a similar manner:

3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP;

(3S, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP;

3-aminomethyl-4-isopropyl-hexanoic acid;

3-aminomethyl-4-isopropyl-heptanoic acid;

3-aminomethyl-4-isopropyl-octanoic acid;

3-aminomethyl-4-isopropyl-nonanoic acid;

3-aminomethyl-4-isopropyl-decanoic acid; and

3-aminomethyl-4-phenyl-5-methyl-hexanoic acid.

Method 3 (scheme 11)

Wherein

R₃OMe or H

R₄＝Me，Et

n＝0-2

The compound having structure 30 can be prepared from the compound having structure 29 by treating with an aqueous acid solution such as hydrochloric acid or the like at a temperature around room temperature and refluxing. Alternatively, the compound having structure 30 can also be prepared from the compound having structure 32 by reacting with trifluoroacetic acid at, for example, CH₂Cl₂Or EtOAc and the like. Compound 32 can be prepared by hydrolysis of Boc protected lactam, such as compound 31, in basic medium, and compound 31 itself can be prepared from a compound having structure 29 by treatment with di-tert-butyl dicarbonate in a solvent such as THF. For example, Boc-lactam 31 can be treated with aqueous sodium hydroxide to give acid 32.

Compounds having structure 29 can be prepared from compounds having structure 28(n ═ 0) by treatment with sodium or lithium metal in aqueous ammonia. The reaction is preferably carried out using metallic sodium in aqueous ammonia. Alternatively, a compound having structure 29 can also be prepared from a compound having structure 28(n ═ 1 or 2) by treatment with eerie ammonium nitrate in a mixture of acetonitrile and water. Other methods known in the literature for removing substituted alkoxybenzyl Groups from nitrogen are described in Green, Protective Groups in Organic Synthesis, Wiley, 2ed, 1991, and these methods can also be used in the present invention.

Compounds having structure 28 can be prepared from compounds having structure 27 (where LG is a suitable leaving group such as halide or alkyl sulfonate, preferably using iodide) by carbon-carbon double bond formation reactions known in the art. Several methods described in the literature for coupling organohalides or organoalkylsulfonates with organometallic reagents in the presence of various metal salts are outlined in Comprehensive Organic Synthesis, volume 3: 413, the present invention may also use these methods. For example, a compound having structure 28 can be prepared from a compound having structure 27 (where LG is iodide) by treatment with the appropriate secondary halides (chloride and iodide) in the presence of magnesium metal, iodine, and copper dimethyl sulfide bromide in a solvent such as tetrahydrofuran. As an alternative, it is also possible to use a solution according to El Marini, Synthesis, 1992: 1104, in combination with the above-described method. Thus, compounds having structure 28 can be prepared from compounds having structure 27 (where LG is iodide) by treatment with a suitable methyl-substituted secondary halide such as iodide in the presence of magnesium, iodine, and lithium tetrachlorocuprate in a solvent such as tetrahydrofuran.

The compound having structure 27 includes a suitable leaving group that is capable of nucleophilic substitution with a suitable nucleophile. Examples of such leaving groups include halides such as chloride, bromide or iodide, and sulfonates such as mesylate, tosylate, triflate (triflate), trifluorotosylate (nosylate), and the like. Compounds having structure 27 (where LG ═ iodide) can be prepared from compounds having structure 26 by treatment with iodine, triphenylphosphine, and imidazole in solvents such as toluene.

The compound having structure 26 can be prepared from the compound having structure 25 by treatment with a metal borohydride, such as sodium borohydride, in a solvent such as tetrahydrofuran or DME.

According to a method analogous to Zonetic et al, J.org.chem., 1980; 45: 810-814 or Nielsen et al alJ.Med.chem., 1990; 33: 71-77, Compound 25 can be prepared using a suitable benzylamine, such as, but not limited to, benzylamine, 4-methoxybenzylamine or 2, 4-dimethoxybenzylamine.

Alternatively, as described below, a compound having structure 26 can be treated with sodium metal and aqueous ammonia to provide 4-hydroxymethyl-pyrrolidone, which 4-hydroxymethyl-pyrrolidone can be iodinated to provide 4-iodomethyl-pyrrolidone. Following the above procedure, 4-iodomethyl-pyrrolidone can then be coupled to an organometallic reagent without protecting the nitrogen on the lactam.

Similar to the above methods, a lactam having structure 33 (see Nielsen et al, J.Med.Chem., 1990; 33: 71-77 for general methods of preparation) can be used to form a stable stereochemistry at the C3 position of the product amino acid.

Compounds that may be prepared according to this method include:

3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

3-aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid

3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-5-methyl-nonanoic acid;

(3S) -3-aminomethyl-5-methyl-decanoic acid;

(3S) -3-aminomethyl-5-methyl-undecanoic acid;

(3S) -3-aminomethyl-5, 7-dimethyl-octanoic acid;

(3S) -3-aminomethyl-5, 8-dimethyl-nonanoic acid;

(3S) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid;

(3S) -3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S) -3-aminomethyl-5-cyclopropyl-hexanoic acid;

(3S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S) -3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S) -3-aminomethyl-5-methyl-hept-6-enoic acid;

(3S) -3-aminomethyl-5-methyl-oct-7-enoic acid;

(3S) -3-aminomethyl-5-methyl-non-8-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-non-7-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-dec-7-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-dec-7-enoic acid;

3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-heptanoic acid;

3-aminomethyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-nonanoic acid;

3-aminomethyl-5-methyl-decanoic acid;

3-aminomethyl-5-methyl-undecanoic acid;

3-aminomethyl-5, 7-dimethyl-octanoic acid;

3-aminomethyl-5, 8-dimethyl-nonanoic acid;

3-aminomethyl-5, 9-dimethyl-decanoic acid;

3-aminomethyl-5, 6-dimethyl-heptanoic acid;

3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-hept-6-enoic acid;

3-aminomethyl-5-methyl-oct-7-enoic acid;

3-aminomethyl-5-methyl-non-8-enoic acid;

(E) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(E) -3-aminomethyl-5-methyl-non-6-enoic acid;

(Z) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) -3-aminomethyl-5-methyl-non-7-enoic acid;

(E) -3-aminomethyl-5-methyl-dec-7-enoic acid; and

(Z) -3-aminomethyl-5-methyl-dec-7-enoic acid.

Method 4 (scheme 12)

The compound having structure 40 can be prepared from the compound having structure 39 by treatment with diethylaminosulfur trifluoride in a solvent such as dichloromethane at a temperature between-78 ℃ and room temperature. Others are described, for example, in Wilkinson, chem.rev.1992; 92: the alcohol fluorination methods illustrated in 505-519 are known and may also be used. As described above for method 3, compounds having structure 40 can be converted to the essential γ -amino acids.

A compound having structure 39 can be prepared from a compound having structure 38 by treating osmium tetroxide and sodium periodate in a solvent such as THF and water, and then reducing the resulting intermediate with sodium borohydride in a solvent such as ethanol.

Compounds having structures 38 and 34 can be prepared from compounds having structure 33 according to the principles described in method 3.

Alternative methods of synthesizing alcohol 39(n ═ 0) include: treating the compound having structure 36 with a metal borohydride such as sodium borohydride in a solvent such as tetrahydrofuran or DME yields a compound having structure 37, which is fluorinated in a manner similar to the method for preparing the compound having structure 40. The compound having structure 36 can be prepared from the compound having structure 35 by treating with sodium chloride or lithium chloride in DMSO aqueous solution at a temperature around room temperature and refluxing. The reaction is preferably carried out using sodium chloride in refluxing aqueous DMSO. Compounds having structure 35 can be prepared from compounds having structure 34 by treatment with a suitable diester of methylmalonic acid, e.g., dimethyl methylmalonate, etc., with sodium hydride in a solvent such as DMSO or THF. The reaction is preferably accomplished by adding NaH and lactam 34 (wherein LG is preferably iodide or as defined in method 3) pre-dissolved in DMSO sequentially to a DMSO solution of dimethyl methylmalonate.

As described in the above methods, compounds 39 and 37 can be converted to free amino acids with hydroxyl groups.

The following compounds can be prepared according to this method:

(3S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S) -3-aminomethyl-9-fluoro-5-methyl-nonanoic acid;

(3S) -3-aminomethyl-7-hydroxy-5-methyl-heptanoic acid; and

(3S) -3-aminomethyl-6-hydroxy-5-methyl-hexanoic acid.

Method 5 (scheme 13)

Compounds having structure 41 can be prepared from compounds having structure 39 by treatment with a suitable alkyl iodide (or alkyl sulfonate) such as methyl iodide with a base such as n-butyl lithium hydride or sodium hydride in a solvent such as DMSO or THF. The reaction is preferably accomplished by adding NaH and alkyl iodide sequentially to a DMSO solution of the alcohol, then heating the reaction mixture at about room temperature and refluxing. The conversion of a compound having structure 41 to a γ -amino acid has been described previously.

Alternatively, compounds having structure 41 can be derived from compounds having structure 42 (wherein LG ═ iodide, bromide, or sulfonate, as exemplified in method 3) by treatment with a suitable alkoxy anion in a solvent such as DMSO or THF. The compound having structure 42 can also be used as a substrate in a carbon-carbon double bond formation step in a process as outlined in method 3.

Compounds that may be prepared according to this method include:

(3S) -3-aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S) -3-aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (3, 3, 3-trifluoro-propoxy) -heptanoic acid;

(3S) -3-aminomethyl-6-hydroxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S) -3-aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid; and

(3S) -3-aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid.

Method 6 (scheme 14)

As indicated above, compounds having structure 53 can be prepared from compounds having structure 45 according to methods such as Hoekstra et al, Organic Process Research and Development, 1997; 1: 26-38 by the method.

The compound having structure 45 can be prepared from the compound having structure 44 by treatment with a water/sulfuric acid solution of chromium trioxide. Alternative methods of removing the paraffin from 44 can be used such as Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186, ACS 1990: 77 by the methods described in detail.

A compound having structure 44 (wherein R₂Alkyl, branched alkyl, cycloalkyl, alkyl-cycloalkyl) can be prepared from (S) -citronellyl bromide by carbon-carbon double bond formation reactions known in the art and described in method 3. Substitution of the halide of (S) -citronellyl bromide with an alkoxy anion, wherein R ═ alkoxy or phenoxy ethers (such suitable substituents are of formula 1), may also be used to prepare compounds having structure 44. Alternatively, (S) -citronellol can also be used to prepare compounds having structure 44 by treating (S) -citronellol with a base such as sodium hydride and then treating the resulting alkoxide with a suitable alkyl halide to obtain ethers. In another method, (S) -citronellyl bromide (or a suitable sulfonate, such as but not limited to (S) -3, 7-dimethyl-oct-6-enyl methylsulfonate) can be reduced with a suitable metal borohydride or aluminum hydride such as LAH to give (R) -2, 6-dimethyl-oct-2-ene.

It will be appreciated by those skilled in the art that selection of the appropriate R-or S-citronellol or R-or S-citronellyl bromide will give the desired product amino acid isomeric at its C5 position.

Compounds that may be prepared according to this method include:

(3S, 5S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S, SS) -3-aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S, SS) -3-aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

(3S, SS) -3-aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S, SR) -3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, SR) -3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, SR) -3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, SR) -3-aminomethyl-5-methyl-decanoic acid;

(3S, SR) -3-aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5, 8-dimethyl-nonanoic acid;

(3S, SS) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, SR) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid; and

(3S, SR) -3-aminomethyl-5, 10-dimethyl-undecanoic acid.

Method 7 (scheme 15)

Compounds having structure 58 can be prepared from compounds having structure 57 by reacting boron trifluoride diethyl etherate (borontrifluoride diethyl etherate) and triethylsilane in the presence of, for example, CH₂Cl₂Is treated in the solvent of (1). Alternatively, other methods such as Meyers, j.org.chem., 1993; 58: 36-42 by treating a compound having structure 57 with sodium cyanoborohydride in a solvent such as THF/methanol in 3% HCl in methanol.

Compounds having structure 57 can be prepared from compounds having structure 56 by reaction of dimethylamine in a solvent such as DMF, according to Koot, Tetrahedron lett, 1992; 33: 7969 and 7972.

Compounds having structure 56 can be prepared from compounds having structure 54 by treating the appropriate primary halide 55 (iodide, bromide, or chloride) with tBuLi under standard transmetallation conditions and then treating the resulting organometallic reagent with an appropriate copper salt, such as, but not limited to, cupric chloride, cupric bromide, or cupric iodide. The resulting organocuprate is added to a solution of the lactam (see Koot et al, J. org. chem., 1992; 57: 1059-1061 for the preparation of chiral lactam 54), such as THF, etc. Koot, Tetrahedron lett, 1992; 33: 7969-7972 exemplify this method in detail.

It will be appreciated by those skilled in the art that selection of the appropriate R-or S-primary halide 55 will give the desired product amino acid isomeric at its C5 position.

Compounds that may be prepared according to this method include:

(3S, 5S) -3-aminomethyl-5-methoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-ethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-isopropoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-tert-butoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-fluoromethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid;

(3S, 5R) -3-aminomethyl-5, 7-dimethyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5, 8-dimethyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5, 10-dimethyl-undecanoic acid;

(3S, 5S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclopropyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5S) -3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, SR) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-hept-6-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-oct-7-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-non-8-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-dec-7-enoic acid; and

(E) - (3S, 5R) -3-aminomethyl-5-methyl-undec-7-enoic acid.

Method 8 (scheme 16)

Compounds having structure 60 can be prepared from compounds having structure 59 by reacting an appropriately substituted phenol (including phenol) with a suitable compound selected from the group consisting of phenol: 1 under the conditions described for the preparation.

The compound having structure 59 can be prepared from the compound having structure 39 by treatment with an aqueous ammonia solution of sodium metal, lithium, or the like. The reaction is preferably carried out using an aqueous ammonia solution of sodium metal.

Direct hydrolysis of compound 60 can yield the desired amino acid or can use a method of hydrolyzing the Boc-protected lactam.

Compounds that may be prepared according to this method include:

(3S) -3-aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S) -3-aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6- (4-nitro-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6- (3-nitro-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6- (2-nitro-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6-phenoxy-hexanoic acid; and

(3S) -3-aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid.

Method 9 Synthesis of C-4 substituted analogs (scheme 17)

The compound having structure 64 can be prepared from the compound having structure 63 by treating 63 in an organic solvent such as methanol under 50psi of hydrogen in the presence of a catalyst such as raney nickel and a base such as triethylamine. The resulting product is then treated with an aqueous acid solution, e.g., 6n hcl, at a temperature around room temperature and refluxed. The resulting mixture can be subjected to ion exchange chromatography to isolate product 64.

Compounds having structure 63 can be prepared from compounds having structure 62B by treatment with a suitable base, such as, but not limited to, sodium hydride, n-butyl lithium, and the like, and an alkylating agent, such as tert-butyl bromoacetate (bromoacetate) or benzyl bromoacetate, in a solvent such as DMSO or THF, and the like. The reaction is preferably accomplished by treating a solution of the compound having structure 62B in THF with sodium hydride, followed by alkylation of the resulting anion with t-butyl bromoacetate.

The compound having structure 62B can be prepared from the compound having structure 62A by treating with a solution of sodium chloride, e.g., aqueous DMSO, at a temperature of about 50 ℃ and refluxing.

The compound having structure 62A can be prepared from the compound having structure 61 by treatment with a suitable alkyl metal halide, such as an alkyl lithium reagent or an organomagnesium halide in a solvent such as THF or diethyl ether, in the presence of a copper salt, such as, but not limited to, copper iodide, copper bromide dimethyl sulfide. Alternatively, the reaction may be accomplished by treating a solution of the nitrile, for example diethyl ether, with a chloride of an alkyl magnesium at or below room temperature.

The compound having structure 61 can be prepared according to the methods described in the known literature for the condensation of isobutyraldehyde with methyl cyanoacetate.

The method 10 comprises the following steps: c-4 substitution (scheme 18)

3-substituted α 2 δ ligands 72 with double branching can be prepared from azides 71 in two steps: the azide 71 is hydrogenated in the presence of a noble metal catalyst such as 5% palladium on carbon and the resulting lactam is then hydrolyzed by refluxing with a strong acid such as 6N HCl. The final product 72 can be isolated by ion exchange chromatography.

Compound 71 can be prepared in two steps: the lactone, e.g. 70, is treated with HBr in a solvent, e.g. ethanol, at a temperature of e.g. 0 ℃, and the resulting bromide is then reacted with sodium azide in a solvent, e.g. dimethyl sulfoxide, at a temperature between 10 ℃ and 80 ℃.

Lactone 70 can be prepared in two steps: a compound such as 69 is oxidized with an oxidizing agent such as sodium periodate in a solvent such as acetonitrile at a temperature between 0 ℃ and 100 ℃ in the presence of a catalytic amount of ruthenium trichloride, followed by treatment of the resulting compound with a solution of potassium carbonate in methanol at a temperature between 25 ℃ and 70 ℃, followed by treatment with an acid such as p-toluenesulphonic acid in a solvent such as refluxing THF at room temperature, or with an aqueous solution of the acid such as HCl.

Compounds such as 69 can be prepared by: a compound such as 68 is reduced with a hydride reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or THF, and the resulting alcohol is then reacted with an acylating agent such as acetic anhydride in the presence of a base such as triethylamine or pyridine.

The compound having structure 68 can be prepared by reacting a compound such as 67 with hydrogen in a solvent such as methanol in the presence of a noble metal catalyst such as 5% palladium-carbon at about 50 psi. Compounds having general formula 67 may be prepared by reacting a compound having structure 66 with an ethanol solution saturated with hydrogen bromide gas. Compounds such as 66 may be prepared from compounds such as 65 by treatment with a compound having a strong base such as lithium diisopropylamine in a solvent such as THF, for example at a temperature of-78 deg.C, and then reacting the resulting anion with a compound such as benzyl bromide or benzyl iodide. Optical forms of compounds having structure 68 (R ═ H or lower alkyl) can be prepared by methods known in the literature (Davies, J.org.chem., 1999; 64 (23): 8501-; Koch J.org.chem., 1993; 58 (10): 2725-37; Afonnso, Tetrahedron, 1993; 49 (20): 4283-92; Bertus, Tetrahedron, Asymmetry 1999; 10 (7): 1369-.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 11: synthesis of 3-aminomethyl-5-methyl-octanoic acid

1-benzyl-4-hydroxymethyl-pyrrolidin-2-one 74

Sodium borohydride (8.0g, 0.211mol) was added to a solution of methyl-1-benzyl-5-oxo-3-pyrrolidinecarboxylate 73 (see Zonetic et al, J. org. chem., 1980; 45: 810-. The reaction was cooled to room temperature while adding 200mL of water. The reaction was quenched with 1M citric acid and then concentrated under reduced pressure. The residue was extracted with dichloromethane, dried over magnesium sulphate and evaporated to dryness to give 17.47g, 62% of alcohol 74 as a clear oil.

¹H NMR(CDCl₃)δ7.30(m，5H)，4.38(d，1H，J＝14.7)，4.46(d，1H，J＝14.7)，3.56(m，2H)，3.36(m，1H)，3.10(m，1H)，2.52(m，2H)，2.26(m，1H)。

MS, m/z (relative intensity): 207[ M +2H, 66% ].

IR (KBr)3345, 2946, 2866, 1651, 1445, 1025, 737, and 698cm^-1。

1-benzyl-4-iodomethyl-pyrrolidin-2-one 75

To a solution of alcohol 74(11.18g, 0.056mol) in toluene (210mL) was added sequentially triphenylphosphine (20.0g, 0.076mol), imidazole (10.8g, 0.159mol), and iodine (19.0g, 0.075 mol). After the suspension was stirred for 1.5 hours, the supernatant was poured into another flask. The viscous yellow residue was washed twice with diethyl ether and the washings combined. The solvent was removed by evaporation and the residue chromatographed on silica, eluting with 1: 1 acetone/hexane to give 7.92g, 46% iodolactam 75 as a yellow oil.

¹H NMR(CDCl₃)δ7.25(m，5H)，4.38(d，1H，J＝146), 4.46(d, 1H, J ═ 14.6), 3.38(dd, 1H, J ═ 7.8 and 2.2), 3.20(dd, 1H, J ═ 5.6 and 4.4), 3.12(dd, 1H, J ═ 7.3 and 2.4), 2.96(dd, 1H, J ═ 5.8 and 4.4), 2.60(m, 2H), 2.22(dd, 1H, J ═ 10.5 and 9.7).

MS, m/z (relative intensity): 224[ M-H-Bn, 94% ], 317[ M +2H, 64% ].

IR 3027, 2917, 1688, 1438, 1267, and 701cm^-1。

1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76

To a solution of magnesium turnings (0.50g, 0.021mol) in 15mL of anhydrous THF under nitrogen were added iodine crystals and 2-bromopentane (2.88g, 0.019 mol). After the exothermic reaction, the reaction was cooled in an ice-water bath at regular intervals and stirred at room temperature for 2 hours. 8 ml of Li were added at 0 deg.C₂CuCl₄(from 84mg LiCl and 134mg CuCl₂10mL of anhydrous THF), then a further solution of 1-benzyl-4-iodomethyl-pyrrolidin-2-one 75 in 15mL of anhydrous THF is added dropwise and the resulting suspension is stirred at 0 ℃ for 3 hours. Stirring was continued for 1 hour at room temperature and then quenched with saturated ammonium chloride solution. Water was added to dissolve the formed precipitate, then the solution was extracted with ether and dried over magnesium sulfate. The solvent was removed by evaporation under vacuum and the residue was chromatographed on silica, eluting with 1: 1 acetone/hexane to give 1.13g, 69% of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76.

¹H NMR(CDCl₃)δ7.30(m，5H)，4.44(m，2H)，3.32(m，1H)，2.86(m，1H)，2.56(m，1H)，2.40(m，1H)，2.10(m，1H)，1.30(m，6H)，1.10(m，1H)，0.90(m，6H)。

MS, m/z (relative intensity): 261[ M +2H, 100%]，301[M-H+CH₃CN，82％]，260[M+H，72％]。

4- (2-methyl-pentyl) -pyrrolidin-2-one 77

A 250mL three necked flask equipped with a dry ice condenser was frozen to-78 ℃. Aqueous ammonia (80mL) was condensed in the flask while adding a solution of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76(1.67g, 0.006mol) in 15mL THF. The uncleaved sodium pellet was added until a dark blue color continued to develop. The cooling tank was removed and the reaction was stirred at reflux (-33 ℃) for 1 hour. The reaction was quenched with ammonium chloride and the excess ammonia was removed by evaporation. The resulting residue was diluted with water, extracted with dichloromethane and then dried over magnesium sulfate. After evaporation of the solvent, subsequent chromatography on silica eluting with 1: 1 acetone/hexane afforded 0.94g, 86% 4- (2-methyl-pentyl) -pyrrolidin-2-one 77.

¹H NMR(CDCl₃)δ6.25(br，1H)，3.44(m，1H)，2.95(m，1H)，2.54(m，1H)，2.40(m，1H)，1.98(m，1H)，1.30(m，6H)，0.80(m，6H)。

MS, m/z (relative intensity): 212[ M +2H + CH₃CN，100％]，171[M+2H，72％]，170[M+1H，65％]。

3-aminomethyl-5-methyl-octanoic acid (example 11)

4- (2-methyl-pentyl) -pyrrolidin-2-one 77(0.94g, 0.007mol) was dissolved in 70mL of 6N HCl and refluxed for 20 hours. The solution was evaporated in vacuo and the aqueous solution of the residue was treated with Dowex 50WX 8-100 (strongly acidic) ion exchange resin which had been washed with HPLC pure water. The column was eluted with water until the eluent was at constant pH and then eluted with 5% ammonium hydroxide solution. The ammonium hydroxide eluent was evaporated and then azeotroped with toluene. The white solid was washed with acetone, filtered, and then dried in a vacuum electric oven for 24 hours to give 0.61g, 59% of the amino acid.

¹H NMR(CDCl₃)δ3.00(m，1H)，2.85(m，1H)，2.48(m，1H)，2.30(m，1H)，2.14(brm，1H)，1.60(brm，1H)，1.38(m，4H)，1.18(m，2H)，0.60(m，6H)。

MS, m/z (relative intensity): 188[ M + H, 100% ].

Example 12: synthesis of 3-aminomethyl-5, 7-dimethyl-octanoic acid

Example 12

1- (4-methoxy-benzyl) -5-oxo-pyrrolidine-3-carboxylic acid methyl ester 79

To a 0 ℃ solution of 4-methoxybenzylamine (42g, 0.306mol) in methanol (40mL) was added a solution of dimethyl methylenesuccinate (48g, 0.306mol) in methanol (13 mL). The solution was stirred at room temperature for 4 days. To the solution was added 1N HCl and diethyl ether in that order. The two layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO)₄). The drying agent is removed by filtration and the desired product 79 is precipitated from the solution, collected and dried under vacuum. 23.26g, 29%.

MS, m/z (relative intensity): 264[ M + H, 100% ].

To C₁₄H₁₇N₁O₄Analytical calculation of (a):

C，63.87；H，6.51；N，5.32。

measured value: c, 63.96; h, 6.55; and N, 5.29.

4-hydroxymethyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one 80

At room temperature, NaBH is added₄(15g, 0.081mol) was added portionwise to a solution of the ester 79 in ethanol (600 mL). After 4.5 hours, water (. about.200 mL) was carefully added to the solution and the solution was stirred at room temperature overnight. The resulting solid was removed by filtration and the filtrate was concentrated to give alcohol 80 as an oil. 15.33g, 81%.

MS, m/z (relative intensity): 235[ M + H, 100% ].

4-iodomethyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one 81

To a solution of alcohol 80(12.9g, 0.055mol) in PhMe was added triphenylphosphine (C20g, 0.077mol), imidazole (10.8g, 0.16mol), and iodine (19g, 0.075 mol). The suspension was stirred at room temperature for 5 hours. Saturated sodium thiosulfate solution was added and the two layers were separated. The aqueous phase was extracted with ether and the combined organic phases were washed with brine and dried (MgSO)₄) And concentrated. The residue was treated with flash chromatography (6: 1-4: 1 toluene/acetone) to give iodide 81 as an oil. 11.9g, 63%.

MS, m/z (relative intensity): 346[ M + H, 100% ].

4- (2, 4-dimethyl-pentyl) -1- (4-methoxy-benzyl) -pyrrolidin-2-one 82

Using a procedure analogous to the preparation of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76, 4- (2, 4-dimethyl-pentyl) -1- (4-methoxy-benzyl) -pyrrolidin-2-one was obtained as an oil. 1.22g, 29%.

MS, m/z (relative intensity): 304[ M + H, 100% ].

4- (2, 4-dimethyl-pentyl) -pyrrolidin-2-one 83

To a 0 deg.C solution of this lactam (1.17g, 3.86mmol) in MeCN (20mL) was added a solution of cerium ammonium nitrate (4.2g, 7.7mmol) in water (10 mL). After 50 minutes, an additional amount of cerous ammonium nitrate (2.1g, 3.86mmol) was added and after 1 hour the mixture was adsorbed on silica and flash chromatographed to give an oil.

MS, m/z (relative intensity): 183[ M + H, 100% ].

3-aminomethyl-5, 7-dimethyl-octanoic acid (example 12)

This amino acid was obtained as an oil using a method analogous to that for the preparation of 3-aminomethyl-5-methyl-octanoic acid (example 3).

MS, m/z (relative intensity): 202[ M + H, 100% ].

Example 13: synthesis of (S) -3-aminomethyl-5-methyl-octanoic acid

Example 13

(S) -4-hydroxymethyl-1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 84

To a solution of ester 33(49g, 0.198mol) in EtOH (600mL) was added sodium borohydride (22g, 0.595 mol). After 7 hours, 1M citric acid was carefully added until no more bubbles were formed and water was added to quench the reaction completely. Ethanol was removed under reduced pressure and ethyl acetate was added. The resulting two layers were separated, the aqueous phase was extracted with EtOAc and the combined organic phases were dried (MgSO₄) And concentrated to obtain heavy oil.

MS, m/z (relative intensity): [ M + H, 100% ].

(S) -4-iodomethyl-1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 85

Iodide 85 was obtained as an oil using a procedure similar to that used to iodide compound 80. 35.2g, 56%.

To C₁₃H₁₆I₁N₁O₁Analytical calculation of (a):

C，47.43；H，4.90；N，4.25。

measured value: c, 47.41; h, 4.83; and N, 4.17.

4- (2-methyl-pentyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 86

Using a procedure similar to that for 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76 gives 2.71g, 81.0% 86 as an oil.

MS, m/z (relative intensity): 274[ M +1H, 100%]，315[M+H+CH₃CN，65％]。

(S) -4- (2-methyl-pentyl) -pyrrolidin-2-one 87

Using a procedure similar to that for preparation of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 gives 1.14g, 72.8% 87 as an oil.

MS, m/z (relative intensity): 170[ M +1H, 10%]，211[M+1H+CH₃CN，90％]。

Example 13: (S) -3-aminomethyl-5-methyl-octanoic acid

This amino acid (example 5) was obtained in an analogous manner to the preparation of 3-aminomethyl-5-methyl-octanoic acid (example 11) in an amount of 0.88g, 74.3%.

¹H NMR(CD₃OD)δ2.95(m，1H)，2.80(m，1H)，2.40(m，1H)，2.25(m，1H)，2.05(brm，1H)，1.50(brm，1H)，1.30(m，4H)，1.10(m，2H)，0.90(m，6H)。

MS, m/z (relative intensity): 188[ M +1H, 100%]，186[M-1H，100％]，229[M+1H+CH₃CN，30％]。

Example 14: synthesis of (S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid

(S) -4- (2-methyl-pent-4-enyl-1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 88

The adduct 88 was obtained as an oil following a procedure analogous to the preparation of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76. 6g, 74%.

MS, m/z (relative intensity): 272[ M + H, 100% ].

(S) -4- (4-hydroxy-2-methyl-butyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 89

Mixing OsO₄(2mL of a 4 wt% t-BuOH solution) was added to olefin 88(5.8g, 0.021mol) in THF/H ₂O (3: 1, 100mL) solution. After 1 hour, sodium periodate (11.4g, 0.053mol) was added. After 2 hours, the suspension was filtered and the solid was washed with dichloromethane. The filtrate was concentrated and the residue was azeotroped with toluene. The residue was dissolved in ethanol and sodium borohydride (2) was added5 g). The suspension was stirred at room temperature overnight. 1N citric acid was added and the mixture was diluted with ether. The resulting two layers were separated, the aqueous phase was extracted with ether and the combined organic phases were dried (MgSO₄) And concentrated. The residue was purified by flash chromatography (1: 1 hexanes/EtOAc) to afford an oil. 4.2g, 73%.

MS, m/z (relative intensity): 276[ M + H, 100% ].

(S) -4- (4-methoxy-2-methyl-butyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 90

To a solution of alcohol 89(2g, 7.66mmol) in DMSO (60mL) was added NaH (368mg, 60% oil solution) at room temperature. After 30 min, iodomethane (1.08g, 7.66mmol) was added and the solution was stirred at room temperature overnight, finally the reaction was diluted with water (500 mL). The resulting solution was extracted with ether and the combined organic extracts were dried (MgSO)₄) And concentrated. Flash chromatography of the residue (90% -50% hexane/acetone) afforded product 90(1.1g, 52%) as an oil.

MS，m/z 290[M+H，100％]。

(S) -4- (4-methoxy-2-methyl-butyl) -pyrrolidin-2-one 91

Lactam 91 was obtained as an oil using a procedure analogous to that for the synthesis of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77.

MS，m/z 186[M+H，100％]。

Example 14: (S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid

The procedure was followed analogously to the synthesis of example 3. The amino acid isolated by ion exchange chromatography was recrystallized from methanol/ethyl acetate to give example 6 as a white solid.

MS，m/z 204[M+H，100％]。

To C₁₀H₂₁N₁O₃Analytical calculation of (a):

C，59.09；H，10.41；N，6.89。

measured value: c, 58.71; h, 10.21; n, 6.67.

Example 15: synthesis of (S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid

Example 15

2-methyl-2- [ (S) -5-oxo-1- ((S) -1-phenyl-ethyl) -pyrrolidin-3-ylmethyl ] -malonic acid dimethyl ester 92

To a solution of dimethyl methylmalonate (1.06g, 7.29mmol) in DMSO (7mL) at room temperature was added NaH (291mg of 60% oil dispersion). After no more bubbles had formed, a solution of lactam 85(2g, 7.29mol) in DMSO (5mL) was added. After 1 hour, water was added and the aqueous solution was extracted with ether. The combined organic extracts were dried (MgSO)₄) And concentrated. Flash chromatography (1: 1 hexane/acetone) of the residue afforded the product as an oil (1.7g, 81%).

MS，m/z 348(M+H，100％)。

2-methyl-3- [ (S) -5-oxo-1- ((S) -1-phenyl-ethyl) -pyrrolidin-3-yl ] -propionic acid methyl ester 93

Ester 92(483mg, 1.4mmol), NaCl (104mg, 1.8mmol), water (105. mu.l) and DMSO (5mL) were heated to reflux for 2 h. The solution was cooled to room temperature, water was added, and the aqueous solution was extracted with diethyl ether. The combined organic extracts were dried (MgSO)₄) And concentrated. Flash chromatography of the residue (80% -66% hexane/acetone) afforded the product as an oil (160mg, 40%).

MS，m/z 290(M+H，100％)。

(S) -4- (3-hydroxy-2-methyl-propyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 37

To a solution of ester 93(4.82g, 0.017mol) in ethanol (100mL) was added NaBH₄(3.7g, 0.10mol) and the mixture was then heated to reflux for 2.5 hours. The solution was cooled to 0 ℃, 1M citric acid was carefully added, and then water was added. The solution was concentrated to half the added volume and extracted with ether. The combined organic extracts were dried (MgSO)₄) And concentrated. Flash chromatography (1: 1 hexane/acetone) of the residue afforded the product as an oil (2.6g, 59%).

MS，m/z 262(M+H，100％)。

(S) -4- (3-fluoro-2-methyl-propyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 94

To-78 ℃ DAST (1g, 6.2mmol) in CH₂Cl₂(20mL) to which CH of alcohol 37 was added₂Cl₂(10mL) of the solution. After 1 hour the solution at-78 ℃ was warmed to room temperature. After 7 hours the solution was carefully quenched with saturated aqueous sodium bicarbonate and the two layers were separated. The organic phase was dried (MgSO) ₄) And concentrated. Flash chromatography of the residue (90% -66% hexane/acetone) afforded the product as an oil (600mg, 37%).

MS，m/z 264(M+H，100％)。

(S) -4- (3-fluoro-2-methyl-propyl) -pyrrolidin-2-one 95

This lactam was obtained as an oil (242mg, 68%) in a manner analogous to that used for preparation of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77.

MS，m/z 159(M，100％)。

Example 15: (S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid

The procedure was followed in analogy to the synthesis of example 11. The amino acid isolated by ion exchange chromatography was recrystallized from methanol/ethyl acetate to give example 15 as a white solid.

MS，m/z 177(M，100％)。

To C₈H₁₆F₁N₁O₂:0.02H₂O analyzerCalculating the value:

C，54.11；H，9.10；N，7.89。

measured value: c, 53.75; h, 9.24; and N, 7.72.

Example 16: synthesis of (S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid

Example 16

(S) -4- (3-methoxy-2-methyl-propyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 96

Using a procedure analogous to the synthesis of (S) -4- (4-methoxy-2-methyl-butyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 90 gave diethyl ether 96 as an oil (90mg, 37%).

MS，m/z 276(M+H，100％)。

(S) -4- (3-methoxy-2-methyl-propyl) -pyrrolidin-2-one 97

Using a procedure analogous to that for the synthesis of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 gives 97 as an oil (760mg, 93%).

MS，m/z 171(M+H，100％)。

Example 17: (S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid

The procedure was followed in analogy to the synthesis of example 11. The amino acid isolated by ion exchange chromatography was recrystallized from methanol/ethyl acetate to give example 16 as a white solid.

MS，m/z 190(M+H，100％)。

To C₉H₁₉N₁O₃Analytical calculation of (a):

C，57.12；H，10.12；N，7.40。

measured value: c, 57.04; h, 10.37; and N, 7.30.

The product of the second precipitation from the mother liquor (1: 5 ratio of the C5 isomer from¹H NMR measurement).

MS，m/z 190(M+H，100％)。

Example 17: (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid hydrochloride

(R) -2, 6-dimethyl-non-2-ene 98

To a 0 deg.C solution of (S) -citronellyl bromide (50g, 0.228mol) in THF (800mL) was added LiCl (4.3g) followed by CuCl₂(6.8 g). After 30 minutes, methylmagnesium chloride (152mL of 3M THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours the solution was cooled to 0 ℃ and saturated aqueous ammonium chloride was carefully added. The resulting two layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated to give an oil. 32.6 g; 93 percent. Used without further purification.

¹³C NMR(100MHz；CDCl₃)131.13，125.28，39.50，37.35，32.35，25.92，25.77，20.31，19.74，17.81，14.60。

(R) -4-methyl-heptanoic acid 99

To a solution of alkene 98(20g, 0.13mol) in acetone (433mL) was added CrO₃(39g, 0.39mol) of H₂SO₄(33mL)/H₂O (146mL) solution for 50 min. Adding a certain amount of CrO after 6 hours ₃(26g, 0.26mol) of H₂SO₄(22mL)/H₂O (100mL) solution. After 12 hours the solution was diluted with brine and extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (gradient 6: 1-2: 1 hexanes/EtOAc) afforded product 99 as an oil. 12.1 g; 65 percent.

MS, m/z (relative intensity): 143[ M-H, 100% ].

(4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100

To a solution of acid 99(19g, 0.132mol) and triethylamine (49.9g, 0.494mol) in THF (500mL) at 0 deg.C was added trimethylacetyl chloride (20g, 0.17 mol). After 1 hour LiCl (7.1g, 0.17mol) and the oxazolidinone (30g, 0.17mol) were added in succession. The mixture was warmed to room temperature, after 16 hours the filtrate was removed by filtration and the solution was concentrated under reduced pressure. Flash chromatography (7: 1 ethane/EtOAc) afforded product 100 as an oil. 31.5 g; 79 percent.

[α]_D＝5.5(c 1 CHCl₃A solution).

MS, m/z (relative intensity): 304[ M + H, 100% ].

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester 101

To a solution of oxazolidinone 100(12.1g, 0.04mol) in THF (200mL) at-50 deg.C was added NaHMDS (48mL of a 1M solution in THF). After 30 minutes t-butyl bromoacetate (15.6g, 0.08mol) was added. The solution was stirred at-50 ℃ for 4 hours and then warmed to room temperature. After 16 hours, a saturated aqueous ammonium chloride solution was added and the two layers were separated. The aqueous phase was extracted with ether and the combined organic phases were dried (MgSO) ₄) And concentrated. Flash chromatography (9: 1 hexanes/EtOAc) afforded 10112 g of the product as a white solid; 72 percent.

[α]_D＝30.2(c 1 CHCl₃A solution).

¹³C NMR(100MHz；CDCl₃)176.47，171.24，152.72，133.63，128.87，125.86，80.85，78.88，55.34，39.98，38.77，38.15，37.58，30.60，28.23，20.38，20.13，14.50，14.28。

(S) -2- ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester 102

To a 0 deg.C solution of ester 101(10.8g, 0.025mol) in water (73mL) and THF (244mL) was added a solution containing LiOH (51.2mL of a 0.8M solution) and H₂O₂(14.6mL of a 30% solution). After 4 hours, 12.8mL of LiOH (0.8M solution) and 3.65mL of H were added₂O₂(30% solution). After 30 minutes, sodium bisulfite (7g), sodium sulfite (13g), and water (60mL) were added, followed by hexane (100mL) and ether (100 mL). The two layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil, which was dissolved in heptane (300 mL). The resulting solid was removed by filtration, and the filtrate was dried (MgSO)₄) And concentrated to give an oil (6g, 93%) which was used without further purification.

MS, m/z (relative intensity): 257[ M + H, 100% ].

(3S, 5R) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103

To a solution of acid 102(3.68g, 0.014mol) in THF (100mL) at 0 deg.C was added BH₃.Me₂(36mL of 2M THF solution, Aldrich) and the solution was warmed to room temperature. After 15 hours ice (to control the exotherm) and brine were carefully added to the solution in sequence. The solution was extracted with ether and the combined organic phases were dried (MgSO) ₄) And concentrated under reduced pressure. Flash chromatography (4: 1 hexanes/EtOAc) afforded alcohol 103 as an oil (2.0g, 59%).

¹³C NMR(100MHz；CDCl₃)173.56，80.85，65.91，39.74，39.20，38.90，35.65，29.99，28.31，20.18，19.99，14.56。

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104

To the CH of alcohol 103(1.98g, 8.1mmol) at room temperature₂Cl₂To a solution (40mL) were added triethylamine (2.4g, 0.024mol), DMAP (20mg) and tosyl chloride (2.3g, 0.012 mol). After 14 hours 1N HCl was added and the layers separated. The aqueous phase was extracted with ether and the combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (95% hexane/EtOAc) afforded the oilTosyl ester 104(2.94g, 91%) as a solid.

¹³C NMR(100MHz；CDCl₃)171.60，144.92，133.07，130.02，128.12，80.80，72.15，39.73，38.09，37.89，32.67，29.71，28.22，21.83，20.10，19.54，14.49。

(3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105

A solution of tosylate 104(2.92g, 7.3mmol) and sodium azide (1.43g, 0.02mol) in DMSO (30mL) was heated to-50 ℃. After 2 hours the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic phases were dried (MgSO)₄) And concentrated to give 1.54g of oil, 79%. Further purification by flash chromatography (95% hexanes/EtOAc) afforded an oil.

[α]_D＝-8.3(c 1 CHCl₃A solution).

¹³C NMR(100MHz；CDCl₃)172.01，80.73，54.89，39.73，39.46，39.00，33.40，29.85，28.30，20.15，19.82，14.52。

(S) -4- ((R) -2-methyl-pentyl) -pyrrolidin-2-one 107 and tert-butyl (3S, 5R) -3-aminomethyl-5-methyl-octanoate 106

The azide 105 was treated with 5% Pd/C while shaking under hydrogen atmosphere for 20 hours, and then 200mg of 5% Pd/C was added. After 6 hours the filtrate was concentrated to give an oil which was filtered¹H NMR was confirmed as a mixture of primary amine 106 and lactam 107(1.75g), which was used without further purification.

Example 17: (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid hydrochloride

The mixture containing amine 106 and lactam 107(1.74g) was treated with 3N HCl (40mL), and the solution was added to 50 ℃ for 4 hours, then cooled to room temperature. After 12 hours the solution was concentrated and the residue was recrystallized from ethyl acetate to give 605mg of the amino acid as a white solid.

MS, m/z (relative intensity): 188[ M + H, 100% ].

To C₁₀H₂₁N₁O₂:H₁Cl₁Analytical calculation of (a):

C，53.68；H，9.91；N，6.26。

measured value: c, 53.83; h, 10.12; and N, 6.07.

Example 18: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid

Methanesulfonic acid (S) -3, 7-dimethyl-oct-6-enyl ester 108

To CH of S- (-) -citronellol (42.8g, 0.274mol) and triethylamine (91mL, 0.657mol) at 0 deg.C₂Cl₂(800mL) solution was added methanesulfonyl chloride (26mL, 0.329mol) in CH₂Cl₂(200mL) of the solution. After 2 hours, the solution was washed with 1N HCl and brine at 0 ℃. The organic phase was dried (MgSO) ₄) And concentrated to give an oil (60.5g, 94%) which was used without further purification.

¹H NMR(400MHz；CDCl₃)5.05(1H，m)，4.2(2H，m)，2.95(3H，s)，1.98(2H，m)，1.75(1H，m)，1.6(3H，s)，1.5(4H，m)，1.35(2H，m)，1.2(1H，m)，0.91(3H，d，J＝6.5Hz)。

(R) -2, 6-dimethyl-oct-2-ene 109

Lithium aluminum hydride (3.8g, 0.128mol) was added to a solution of olefin 108(60g, 0.256mol) in THF (1L) at 0 deg.C. After 7 hours, 3.8g of lithium aluminum hydride was added, and the solution was heated to room temperature. After 18 hours, a further 3.8g of lithium aluminium hydride are added. After 21 hours, the reaction was quenched by careful addition of 1N citric acid and the solution was then diluted with aqueous saline. The resulting phases were separated and the organic phase was dried (MgSO)₄) And concentrated to give an oil (60.5g, 94%) which was used without further purification.

MS, m/z (relative intensity): 139[ M-H, 100% ].

(R) -4-methyl-hexanoic acid 110

Using a method analogous to the synthesis of (R) -4-methyl-heptanoic acid 99, the acid was obtained as an oil (9.3g, 56%).

MS, m/z (relative intensity): 129[ M-H, 100% ].

(4R, 5S) -4-methyl-3- ((R) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 111

Using a procedure analogous to the synthesis of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100, oxazolidinone 111 was obtained as an oil (35.7g, 95%).

MS, m/z (relative intensity): 290[ M + H, 100% ].

(3S, 5R) -5-methyl-3- [1- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -formyl ] -heptanoic acid tert-butyl ester 112

Using a procedure analogous to the preparation of (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester 101, 112 was obtained as an oil (7.48 g; 31%).

(S) -2- ((R) -2-methyl-butyl) -succinic acid 4-tert-butyl ester 113

To ester 112(7.26g, 0.018mol) in H at 0 deg.C₂O (53mL) and THF (176mL) were added to a solution containing LiOH (37mL of 0.8M solution) and H₂O₂(10.57mL of a 30% solution) and heating the resulting solution to room temperature. After 2 hours, sodium sulfite (7g), sodium sulfate (13g), and water (60mL) were added, the two layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil, which was dissolved in heptane (200 mL). The resulting solid was removed by filtration, and the filtrate was dried (MgSO)₄) And concentrated to give an oil (4.4g) which was used as isAnd (5) purifying.

(3S, 5R) -3-hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 114

Using a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-hydroxymethyl-5-methyl-octanoate 103, alcohol 114 was obtained as an oil (2.68g, 69%).

MS, m/z (relative intensity): 216[ 89% ] ]，174[M-(CH₃)₃C，100％]。

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -heptanoic acid tert-butyl ester 115

To 114 alcohol (2.53g, 0.011mmol) CH at 0 deg.C₂Cl₂To a solution (140mL) was added pyridine (2.6g, 0.033mol), DMAP (100mg), and tosyl chloride (3.15g, 0.016mol), the solution was heated to room temperature for 3.5 hours, and then DMAP and TsCl (3.15g) were added. After 14 hours, 1N HCl was added and the layers were separated. The organic phase was washed with brine and then dried (MgSO)₄) And concentrated. Flash chromatography (95% -86% hexanes/EtOAc) afforded tosylate 115 as an oil (1.53g, 36%).

¹³C NMR(100MHz；CDCl₃)130.03，128.12，72.18，37.89，37.71，32.67，31.49，29.88，28.22，21.83，19.07，11.37。

(3S, 5R) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 116

Using a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105, 0.956g, 97% oil was obtained.

MS, m/z (relative intensity): 228[ M-N₂，80％]。

(S) -4- ((R) -2-methyl-butyl) -pyrrolidin-2-one 118 and (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid tert-butyl ester 117

Azide 116(689mg) was treated with 20% Pd/C (90mg) in THF (20mL) and shaken under a hydrogen atmosphere for 36 h. The catalyst was removed by filtration and the resulting oil was used without further purification.

Example 18: (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid

The mixture of amine 117 and lactam 118 was treated with 6N HCl and the resulting solution was heated to 50 ℃ for 17 hours, then cooled to room temperature and concentrated. The resulting oil was subjected to ion exchange chromatography (Dowex, strong acid resin) using 5% ammonium hydroxide to give a milky solid, which was recrystallized from methanol/ethyl acetate to give (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid, example 10.

MS, m/z (relative intensity): 174[ M + H, 100% ].

To C₁₉H₁₉N₁O₂Analytical calculation of (a):

C，62.39；H，11.05；N，8.08。

measured value: c, 62.23; h, 11.33; and N, 7.89.

Example 19: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-octanoic acid

Example 19

(S) -2, 6-dimethyl-non-2-ene 119

Adding CuCl₂(5.36g, 39.7mmol) and LiCl (3.36, 80.0mmol) were stirred in dry THF (40mL) for 15 min. To the resulting solution was added a solution of methylmagnesium chloride (3.0M) in THF (168mL) under a nitrogen atmosphere at 0 deg.C and stirred at that temperature for 15 minutes. To the reaction suspension was slowly added a solution of (R) - (-) -citronellyl bromide (55.16g, 251.8mmol) in THF (100mL), and the mixture was stirred at 0 ℃ for 2.5 hours. The mixture was warmed to room temperature and then stirred for another 1 hour. The mixture was cooled to 0 ℃ and saturated ammonium chloride solution was added to terminate the reaction. The suspension is then extracted in diethyl ether, washed with water, MgSO ₄Drying. The solution was concentrated under reduced pressure to give 36.3 g; 94% of (S) -2, 6-dimethyl-non-2-ene as an oil.

MS, m/z (relative intensity): 153[ M-1H, 100%]，194[M-1H+CH₃CN，45％]。

(S) -4-methyl-heptanoic acid 120

To a solution of (S) -2, 6-dimethyl-non-2-ene 119(39.0g, 253.2mmol) in acetone (1L) at 0 ℃, jones reagent (2.7M, 600mL) was added dropwise for 1.5 hours, followed by stirring at room temperature for 18 hours. The reaction mixture was poured into saturated Na₂SO₄In solution and extracted in ether. Washed with brine and concentrated in vacuo. The oily residue was dissolved in methanol (70mL) and 1M NaOH (700mL) and stirred for 30 min. CH for the aqueous solution₂Cl₂Washing, acidification with 10% HCl and then in CH₂Cl₂Extracting. The resulting solution was MgSO₄Drying and concentrating to dryness to give 24.22 g; 66% of (S) -4-methyl-heptanoic acid as oil.

MS, m/z (relative intensity): 143[ M-1H, 100% ].

(4R, 5S) -4-methyl-3- ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 121

Using a procedure analogous to the preparation of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100, 1216.2 g of (4R, 5S) -4-methyl-3- ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one was obtained as an oil; 80.0 percent.

MS, m/z (relative intensity): 304[ M +1H, 90%]，355[M+1H+CH₃CN，60％]。

(3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester 122

A solution of n-BuLi (1.6M) in hexane (18.0mL, 30.1mmol) was added dropwise to a solution of diisopropylamine (4.6mL, 32.6mmol) in anhydrous THF (50mL) at-5 ℃ under a nitrogen atmosphere, maintaining the temperature below 0 ℃ during the addition. Stirring the mixture at-5 deg.CThis was left for 20 minutes and then cooled to-78 ℃. A solution of 121(7.6g, 25.1mmol) in dry THF (12mL) was added to the LDA solution and stirred at-78 deg.C for 30 minutes. T-butyl bromoacetate (4.8mL, 32.6mmol) was added to the reaction while stirring at-78 deg.C for an additional 2 hours. It was warmed to room temperature before stirring for an additional 18 hours. Saturated NaH for reaction₂PO₄The solution was quenched, extracted into ethyl acetate, then MgSO₄And (5) drying. The solution was concentrated to give a solid residue, which was dissolved in hot hexane. The hexane solution was cooled to room temperature and then further cooled in an ice-water bath. The resulting precipitate was collected and air dried to give 1224.3 g as a fluffy white solid; 41 percent.

MS, m/z (relative intensity): 362[ M-C (CH)₃)₃+1H，100％]，418[M+1H，20％]。

(S) -2- ((S) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester and (3S, 5S) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123

To a mixed solution of ester 122 in THF (203.0mL) and water (61.0mL) at 0 deg.C was added a solution containing 30% H₂O₂(12.2mL) and LiOH (0.8M, 42.7 mL). The resulting solution was stirred at 0 ℃ for 4 hours. To the reaction was added sodium sulfite (7g), sodium sulfate (13g), and water (60 mL). A1: 1 mixture of diethyl ether/hexane (200mL) was then added and the organic phase was separated. The aqueous phase was extracted with ether and the combined organic extracts were MgSO₄Dried and concentrated in vacuo. The residue was dissolved in heptane and stirred for 5 minutes. The resulting precipitate was filtered and the filtrate was concentrated to dryness to give an oil.

(3S, 5S) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123

Following a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-hydroxymethyl-5-methyl-octanoate 103, 1234.0 g were obtained as an oil; 76.0 percent.

MS, m/z (relative intensity): 230[ M-C (CH)₃)₃+1H+CH₃CN，100％]，189[M-C(CH₃)₃+1H，70％]。

(3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 124

Following a procedure analogous to the preparation of (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104, 6.9g 124 were obtained.

MS, m/z (relative intensity): 343[ M-C (CH)₃)₃+1H，70％]，384[M-C(CH₃)₃+1H+CH₃CN，100％]。

(3S, 5S) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 125

Following a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105, 2.9g are obtained; 66% was 125 as an oil.

MS, m/z (relative intensity): 212[ M-C (CH)₃)₃-1H，45％]。

(3S, 5S) -3-aminomethyl-5-methyl-octanoic acid tert-butyl ester 126

A mixture containing 125(2.8g, 10.4mmol) and 10% Pd/C (1.0g) in methanol (50.0mL) was hydrogenated at 41PSI for 96 hours. The solution was filtered to give 1.7g of crude product 126, which was used without further purification in the next step.

MS, m/z (relative intensity): 244[ M +1H, 100%]，285[M+1H+CH₃CN，25％]。

Example 19(3S, 5S) -3-aminomethyl-5-methyl-octanoic acid

Following a procedure analogous to the preparation of example 18(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid, example 19, 380 mg; 29.0 percent.

¹H NMR(CD₃OD)δ2.90(dd，J＝3.9，8.8Hz，1H)，2.80(dd，J＝7.6，5.1Hz，1H)，2.40(dd，J＝3.2，12.51Hz，1H)，2.20(dd，J＝8.8，6.8Hz，1H)，2.05(m，1H)，1.55(m，1H)，1.30(m，3H)，1.10(m，2H)，0.85(m，6H)。

MS, m/z (relative intensity): 187[ M +1H, 100%]，211[M+1H+CH₃CN，30％]。

Example 20: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid

Example 20

(S) -2, 6-dimethyl-oct-2-ene 127

(R) - (-) -citronellyl bromide (49.1g, 224.2mmol) was added dropwise to a solution of LAH (1.0M) in THF (336mL, 336mmol) at 0 deg.C for 45 min. After a further 4 hours, stirring was continued at 0 ℃. The reaction was slowly quenched with saturated ammonium chloride solution followed by diethyl ether (100 mL). Filtering the resulting white slurry, filtering the filtrate over MgSO₄And (5) drying. The solution was concentrated under reduced pressure to give 26.2 g; 83% is 127 as an oil.

MS, m/z (relative intensity): 180[ M-1H + CH ]₃CN，100％]，139[M-1H，90％]。

(S) -4-methyl-hexanoic acid 128

Using a procedure similar to that used to prepare compound 120, 15.9g of 128 were obtained as an oil.

MS, m/z (relative intensity): 129[ M-1H, 100%]，170[M-1H+CH₃CN，70％]。

(4R, 5S) -4-methyl-3- ((S) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 129

Using a procedure analogous to that used to prepare (4R, 5S) -4-methyl-3- ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 121, 35.0g of crude (4R, 5S) -4-methyl-3- ((S) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 129 was obtained as an oil. It was used without further purification in the next step.

MS, m/z (relative intensity): 290[ M +1H, 100%]，331[M+1H+CH₃CN，20％]。

(3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -heptanoic acid tert-butyl ester 130

Using an analogous procedure to that used to prepare tert-butyl (3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate 122, 4.60g, 25.4% 130 was obtained as a white solid.

MS, m/z (relative intensity): 348[ M-C (CH)₃)3+1H，100％]，443[M-1H+CH₃CN，100％]，402[M-1H，55％]，404[M+1H，45％]。

(3S, 5S) -3-hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 131

Using a method similar to that used to prepare tert-butyl (3S, 5S) -3-hydroxymethyl-5-methyl-octanoate 123 gives 1.2g, 52.1% 131 as an oil.

MS, m/z (relative intensity): 175[ M-C (CH)₃)₃+1H，100％]，173[M-C(CH₃)₃-1H，100％]，216[M-C(CH₃)₃+1H+CH₃CN，95％]。

(3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -heptanoic acid tert-butyl ester 132

Following a procedure analogous to that for the preparation of (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104, 2.1g of 132 are obtained as an oil. The product was used without further purification in the next step.

MS, m/z (relative intensity): 329[ M-C (CH)₃)₃+1H，85％]，370[M-C(CH₃)₃+1H+CH₃CN，65％]。

(3S, 5S) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 133

Following a procedure analogous to that for the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105, 0.76g, 54.0% 133 were obtained as an oil.

MS，m/z (relative intensity): 198[ M-C (CH)₃)₃1H，100％]。

(3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid tert-butyl ester 134

Using a method similar to that used to prepare tert-butyl (3S, 5S) -3-aminomethyl-5-methyl-octanoate 126 gives 0.62g of 134 as an oil. The product was used without further purification in the next step.

MS, m/z (relative intensity): 230[ M +1H, 100%]，271[M+1H+CH₃CN，45％]。

Example 20(3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid

Using a method analogous to that used in example 19, (3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid (0.3g, 65.1%) was obtained as a white solid.

¹H NMR(CD₃OD)δ2.80-3.00(m，2H)，2.40(m，1H)，2.20(dd，J＝8.2，7.1Hz，1H)，2.05(m，1H)，1.30-1.50(m，3H)，1.00-1.20(m，2H)，0.9(m，6H)。

MS, m/z (relative intensity): 187[ M +1H, 100% ]，211[M+1H+CH₃CN，30％]。

MS, m/z (relative intensity): 174[ M +1H, 100%]，172[M-1H，100％]，215[M+1H+CH₃CN，20％]。

Example 21: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride

(R) -4-methyl-octanoic acid 136

Lithium chloride (0.39g, 9.12mmol) and copper (I) chloride (0.61g, 4.56mmol) were dissolved together in 45mL THF at room temperature and stirred for 15 min, then cooled to 0 deg.C while ethyl magnesium bromide (1M THF solution, 45mL, 45mmol) was added. (S) -citronellyl bromide (5.0g, 22.8 m) was added dropwisemol), then the solution was slowly heated to room temperature overnight with stirring. By careful addition of saturated NH₄Quench the reaction with Cl (aq) and simultaneously with Et₂O and saturated NH₄The Cl (solution) was stirred for 30 min. The phases were separated and the organic phase was dried (MgSO)₄) And concentrated. The crude product was used without further purification.

To a solution of olefin 135(3.8g, 22.8mmol) at 0 deg.C in 50mL of acetone was added Jones' reagent (2.7M H)₂SO₄Solution, 40mL, 108mmol), the solution was slowly warmed to room temperature overnight with stirring. The mixture is in Et₂O and H₂The phases were separated, the organic phase was washed with brine and dried (MgSO)₄) And concentrated. The residue was purified by flash chromatography (8: 1 hexanes: EtOAc) to afford 2.14g (59%) of acid 136 as a colorless oil: LRMS: m/z 156.9(M +); ¹H NMR(CDCl₃): δ 2.33(m, 2H), 1.66(m, 1H), 1.43(m, 2H), 1.23(m, 5H), 1.10(m, 1H), 0.86(m, 6H). By mixing 26.7g CrO₃And 23mL H₂SO₄The reaction was allowed to proceed and then diluted to 100mL with water to make a 2.7M solution of Jones reagent.

(4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one 137

To a solution of acid 136(2.14g, 13.5mmol) in 25mL CH at 0 deg.C₂Cl₂To the solution was added 3 drops of DMF followed by oxalyl chloride (1.42mL, 16.2mmol) to cause a significant amount of gas to form. The solution was warmed directly to room temperature, stirred for 30 minutes and concentrated. At the same time, n-butyllithium (1.6M in hexane, 9.3mL, 14.9mmol) was added dropwise to a solution of oxazolidinone (2.64g, 14.9mmol) at-78 deg.C in 40mL THF. The mixture was stirred for 10 minutes while a 10ml solution of the acid chloride in thf was added dropwise. The reaction was stirred at-78 ℃ for 30 minutes, then directly warmed to room temperature and quenched with saturated NH₄Cl (solution) quench. The mixture is in Et₂O and saturated NH₄The phases were separated by separation between the Cl (solution), the organic phase was washed with brine and dried (MgSO)₄) And concentrated to give 3.2g of oxazolidinone 137 as a colorless oil.

LRMS：m/z 318.2(M+)；¹H NMR(CDCl₃): δ 7.34(m, 5H), 5.64(d, J ═ 7.3Hz, 1H), 4.73 (quintuple, J ═ 6.8Hz, 1H), 2.96(m, 1H), 2.86(m, 1H), 1.66(m, 1H), 1.47(m, 2H), 1.26(m, 5H), 1.13(m, 1H), 0.88(m, 9H). The crude product was used without further purification.

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester 138

To a solution of-78 deg.C diisopropylamine (1.8mL, 12.6mmol) in 30mL THF was added n-butyllithium (1.6M hexane solution, 7.6mL, 12.1mmol), and the mixture was stirred for 10 minutes while a solution of oxazolidinone 137(3.2g, 10.1mmol) in 10mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8mL, 12.1mmol) was added dropwise rapidly at-50 deg.C, and the mixture was heated slowly to 10 deg.C for 3 hours. The mixture is in Et₂O and saturated NH₄The phases were separated by separation between the Cl (solution) and the organic phase was dried (MgSO)₄) And concentrated. The residue was purified by flash chromatography (16: 1-8: 1 hexanes: EtOAc) to give 2.65g (61%) of the ester 138 as a colorless crystalline solid, mp 84-86 ℃. [ alpha ] to]_D ²³+17.1(c＝1.00，CHCl₃)；¹H NMR(CDCl₃): δ 7.34(m, 5H), 5.62(d, J ═ 7.3Hz, 1H), 4.73 (quintuple, J ═ 6.8Hz, 1H), 4.29(m, 1H), 2.67(dd, J ═ 9.8, 16.4Hz, 1H), 2.40(dd, J ═ 5.1, 16.4Hz, 1H), 1.69(m, 1H), 1.38(s, 9H), 1.28(m, 7H), 1.08(m, 1H), 0.88(m, 9H);¹³C NMR(CDCl₃) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. To C ₂₅H₃₇NO₅Analytical calculation of (a): c, 69.58; h, 8.64; and N, 3.25. Measured value: c, 69.37; h, 8.68; and N, 3.05.

(S) -2- ((R) -2-methyl-hexyl) -succinic acid 4-tert-butyl ester 139

To a solution of ester 138 at 0 deg.c (2.65g,6.14mmol) in 20mL of THF was added a pre-cooled (0 ℃ C.) solution of LiOH monohydrate (1.0g, 23.8mmol) and hydrogen peroxide (30 wt.% in water, 5.0mL) in 10mL of H₂And (4) O solution. The mixture was stirred vigorously for 90 minutes, then allowed to warm to room temperature while stirring for 90 minutes. By adding 100mL of 10% NaHSO₃(solution), the reaction was quenched at 0 ℃ with Et₂And (4) extracting. The phases were separated and the organic phase was washed with brine and dried (MgSO)₄) And concentrated. The crude acid 139 was used without further purification.

(3S, 5R) -3-hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester 140

To a solution of the crude acid 139(6.14mmol) at 0 deg.C in 30mL THF was added borane-dimethyl sulfide complex (2.0M THF solution, 4.6mL, 9.2mmol) and the mixture was slowly heated to room temperature overnight. Until the acid consumption was complete (5 mL calculated), BH was added₃-a DMS. Quench the reaction by addition of MeOH, then Et₂O and saturated NaHCO₃The layers were separated. The phases were separated and the organic phase was washed with brine and dried (MgSO)₄) And concentrated to give alcohol 140. LRMS: m/z 226.1; ¹H NMR(CDCl₃): δ 3.63(dd, J ═ 11.0, 4.2Hz, 1H), 3.42(dd, J ═ 11.0, 6.8Hz, 1H), 2.30(dd, J ═ 14.9, 7.6Hz, 1H), 2.20(dd, J ═ 14.9, 5.6Hz, 1H), 2.03(m, 2H), 1.42(s, 9H), 1.24(m, 6H), 1.02(m, 2H), 0.85(m, 6H). The crude product was used without further purification.

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -nonanoic acid tert-butyl ester 141

To a solution of alcohol 140(6.14mmol) at 0 ℃ in 30mL CH₂Cl₂DMAP (0.1g) and p-toluenesulfonyl chloride (1.37g, 7.2mmol) were added to the solution, and triethylamine (1.8mL, 13mmol) was further added dropwise rapidly. Immediately after the addition, the mixture was heated to room temperature and stirred overnight without having to finish the reaction prematurely. The mixture is in Et₂The phases are separated by separation between O and 1N HCl (solution), and the organic phase is treated with saturated NaHCO₃(solution) washed and dried (MgSO)₄) And concentrated to give phenylmethanesulfonyl ester 141. The product was used without further purification.

(3S, 5R) -3-azidomethyl-5-methyl-nonanoic acid tert-butyl ester 142

In analogy to the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105, azide 142 was obtained as a colorless oil.

LRMS：m/z 200.1；¹H NMR(CDCl₃)：δ3.31(dd，J＝12.2，4.2Hz，1H)，3.19(dd，J＝12.2，5.9Hz，1H)，2.22(m，1H)，2.10(m，1H)，1.39(s，9H)，1.21(m，8H)，1.00(m，2H)，0.81(m，6H)。

Example 21(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride

In the presence of 20% Pd/C at 45psi H ₂In EtOH (R), azide 142(1.0g) was hydrogenated for 15 hours to give the crude amino ester 143, which was concentrated and used without further purification. To the amino ester 143 was added 6mL 6N HCl (solution) while the mixture was heated to reflux for 90 minutes, cooled and concentrated. Recrystallization from EtOAc: hexane afforded 0.38g (45% azide) of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride (HCl salt) as a colorless crystalline solid, along with 82mg (10% azide) of the second product. mp is 146-. LRMS: m/z 200.1(M +);¹HNMR(CDCl₃): δ 2.87(dd, J ═ 13.2, 5.4Hz, 1H), 2.79(dd, J ═ 13.2, 7.3Hz, 1H), 2.29(d, J ═ 6.8Hz, 2H), 2.08(m, 1H), 1.31(m, 1H), 1.09(m, 7H), 0.92(m, 1H), 0.68(m, 6H). To C₁₁H₂₄NO₂Analytical calculation of Cl: c, 55.57; h, 10.17; and N, 5.89. Measured value: c, 55.69; h, 10.10; and N, 5.86.

Example 22: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid

(S) -acid 145 was prepared from (R) -citronellyl bromide according to the procedure described above for the preparation of (R) -4-methyl-octanoic acid 136. Yield phaseWhen the temperature of the molten metal is higher than the set temperature,¹h NMR spectra and the (R) -acid enantiomer thereof¹The H NMR spectrum was the same. LRMS: m/z 158.9(M + 1).

Oxazolidinone 146 was prepared from acid 145 following the procedure described above for the preparation of (4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one 137. LRMS: m/z 290.1 (M-27); ¹HNMR(CDCl₃): δ 7.38(m, 3H), 7.28(m, 2H), 5.64(d, J ═ 7.1Hz, 1H), 4.74 (quintuple, J ═ 6.8Hz, 1H), 2.92(m, 2H), 1.71(m, 1H), 1.42(m, 7H), 1.18(m, 1H), 0.88(m, 9H).

Tert-butyl ester 147 was prepared from oxazolidinone 146 following the procedure described above for preparation of compound 138.

LRMS：m/z 348.1(M-83)。

Alcohol 149 was prepared from tert-butyl ester 147 as described above for tert-butyl (3S, 5R) -3-hydroxymethyl-5-methyl-nonanoate 140. LRMS: m/z 156.9 (M-100);¹H NMR(CDCl₃)：δ3.60(dd，J＝11.0，4.6Hz，1H)，3.45(dd，J＝11.0，6.8Hz，1H)，2.24(m，2H)，2.04(m，2H)，1.42(s，9H)，1.17-1.38(m，7H)，1.11(m，1H)，0.84(m，6H)。

example 22: (3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid

(3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid is obtained from 149 by the process described above for the preparation of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride. The crude HCl salt thus obtained was purified by ion exchange chromatography on a Dowex 50WX 850-100 mesh, H-type resin using 10% NH₄OH as eluent gave the free base. The wax-like solid was treated with Et₂O washing 2 times, then drying to get amorphous white solid, mp 144-. LRMS: m/z 172.0 (M-28);¹H NMR(CDCl₃)：δ2.76(d，J＝5.9Hz，2H)，2.14(m，1H)，1.96(m，2H)，1.25(m，1H)，1.12(m，6H)，0.96(m，2H)，0.66(m，6H)。

example 23: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid

(R) -2, 6-Dimethylundec-2-ene 153

Using a procedure analogous to that for (S) -2, 6-dimethyl-non-2-ene 119, 153 was obtained as a colorless oil (20.16g, 98%). ¹H NMR(400MHz，CDCl₃)δ5.10-5.06(m，1H)，2.10-1.89(m，2H)，1.66(s，3H)，1.58(s，3H)，1.34-1.23(m，4H)，1.15-1.06(m，2H)，0.88-0.81(m，11H)。

(R) -4-methylnonanoic acid 154

(R) -2, 6-Dimethylundec-2-ene 153(10.03g, 55.03mmol) was dissolved in acetone (270mL) and cooled to 0 ℃. Dropwise addition of Jones reagent (CrO)₃/H₂SO₄) (2.7M, 120mL) and the reaction was warmed to room temperature for 18 h. Pour reaction into water/Na₂SO₄(200mL), the aqueous layer was extracted with ethyl acetate (4X 100 mL). The combined organic phases were dried (MgSO)₄) Filtered and rotary evaporated to give an oil, which is dissolved in CH₂Cl₂(400mL) and cooled to-78 ℃. Ozone was bubbled through the reaction until it turned blue to remove traces of impurity (6E) (3S) -3, 7-dimethylocta-1, 6-diene. Dimethyl sulfide (5mL) was added and the reaction stirred at room temperature for 2 h. The solvent was removed and the crude product was chromatographed on silica, eluting with 20% EtOAc in hexanes to give an oil. The oil was dissolved in diethyl ether (100mL) and extracted with 10% NaOH (2X 25 mL). The aqueous layers were combined and extracted with ether (50 mL). The aqueous layer was cooled to 0 ℃ and acidified with HCl. The acidic layer was extracted with EtOAc (3X 100mL) and the combined extracts were MgSO₄Drying, filtration and rotary evaporation gave 154(6.86g, 54%) as an oil.¹H NMR(400MHz，CDCl₃)δ2.40-2.25(m，4H)，1.70-1.62(m，2H)，1.47-1.11(m，8H)，0.87-0.84(m，6H)；[α]_D＝-11.4(c 1 CHCl₃A solution).

(4R, 5S) -4-methyl-3- ((R) -4-methyl-nonanoyl) -5-phenyl-oxazolidin-2-one 155

Compound 154(6.504g, 37.76mmol) was dissolved in THF (95mL) and cooled to 0 ℃. Triethylamine (19.74mL, 141.6mmol) was added dropwise, followed by trimethylacetyl chloride (6.98mL, 56.64 mmol). The white thick suspension was stirred at 0 ℃ for 90 minutes. LiCl (1.86g, 41.54mmol), (4R) -4-methyl-5-phenyl-1, 3-oxazolidin-2-one (6.824g, 38.51mmol), (and THF (70mL) were added and the reaction was warmed to room temperature overnight. The solvent was removed by evaporation. The solid was dissolved in EtOAc, filtered, and washed thoroughly with EtOAc. The filtrate was washed with water (2X 50mL), and brine. The organic layer was MgSO₄Dried, filtered and rotary evaporated. The crude product was chromatographed on silica, eluting with 10% EtOAc in hexanes to give 155 as an oil (10.974g, 88%).

¹H NMR(400MHz，CDCl₃) δ 7.44-7.35(m, 3H), 7.31-7.26(m, 2H), 5.66(d, J ═ 7.33Hz, 1H), 4.76 (quintuple, J ═ 7.03Hz, 1H), 3.04-2.96(m, 1H), 2.93-2.86(m, 1H), 1.74-1.66(m, 1H), 1.52-1.47(m, 1H), 1.46-1.36(m, 2H), 1.27-1.16(m, 2H), 0.92-0.87(m, 8H); [ alpha ] to]_D＝+34.1(c 1 CHCl₃A solution).

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -decanoic acid tert-butyl ester 156

In analogy to the procedure for the preparation of tert-butyl (3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate 122 was obtained (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl-decanoate tert-butyl ester 156 as oil (0.668g, 90%).¹H NMR(400MHz，CDCl₃) δ 7.41-7.28(m, 5H), 5.63(d, J ═ 7.33Hz, 1H), 4.74 (quintuple, J ═ 6.84Hz, 1H), 4.33-4.26(m, 1H), 2.68(dd, J ═ 16.4, 9.77Hz, 1H), 2.41(dd, J ═ 16.6, 4.88Hz, 1H), 1.68 (quintuple, J ═ 6.6Hz, 1H), 1.50-1.32(m, 10H), 1.28-1.21(m, 1H), 1.15-1.08(m, 1H), 0.90-0.86(m, 9H);

MS(APCI)m/z 348(M⁺-97，100％)；[α]_D＝+18.8(c 1 CHCl₃a solution).

(S) -2- ((R) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 157

Compound 156(5.608b, 12.59mmol) was dissolved in THF/H₂O (60mL/14mL) and cooled to 0 ℃. Mix LiOH (1N, 18.89mL) and H₂O₂(35%, 4.45mL, 50.4mmol) which was then added dropwise to the reaction, maintaining T < 5 ℃. The reaction was stirred at 0 ℃ for 4 hours and Na was added dropwise₂SO₃(6.3g) and NaHSO₃(3.4g) 50mL of H₂The reaction was quenched with O solution. The reaction was stirred for 15 minutes and the layers were separated. The aqueous layer was extracted with EtOAc (3X 100mL) and the combined extracts were MgSO₄Drying, filtration and rotary evaporation gave an oil. The crude product was dissolved in EtOAc (10mL) and heptane (250mL) was added dropwise. The suspension was stirred for 20 minutes, the solids were removed by filtration and washed with heptane. The filtrate was washed with 60 ℃ H ₂O (100mL) Wash, MgSO₄Drying, filtration and rotary evaporation gave 157(3.52g) as an oil. This product was used directly in the next step.

(3S, 5R) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 158

Compound 157(3.52g, 12.3mmol) was dissolved in anhydrous THF (123mL) and cooled to 0 ℃. Borane-dimethyl sulfide complex (10M, 3.69mL) was added dropwise and the reaction was warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0 ℃ and quenched by dropwise addition of MeOH (20 mL). The reaction was stirred for 18 hours and then the solvent was removed by rotary evaporation. The crude product was chromatographed on silica, eluting with 20% EtOAc in hexanes to give 158 as an oil (2.28g, 68%).¹H NMR(400MHz，CDCl₃)δ3.65-3.59(m，1H)，3.43(dd，J＝11.1，6.96Hz，1H)，2.31(dd，J＝14.9，7.57Hz，1H)，2.21(dd，J＝15.1，5.62Hz，1H)，2.06-2.02(m，1H)，1.43(s，9H)，1.40-1.25(m，4H)，1.07-1.13(m，1H)，1.03-0.96(m，1H)，0.86-0.84(m，6H)；MS(APCI)m/z 216(M+-56，100％)。

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 159

Compound 158(2.27g, 8.33mmol) was dissolved in CH₂Cl₂(30mL) and cooled to 0 ℃. Tosyl chloride (1.91g, 10.0mmol) and catalyst DMAP were added, followed by triethylamine (2.55mL, 18.33mmol) dropwise. The reaction was then stirred at 0 ℃ for 18 hours. The solvent was removed by rotary evaporation (under reduced pressure) and the crude product was washed with EtOAc and filtered. The solid was washed with EtOAc, and the filtrate was washed with 0.5N HCl (20mL), brine (30mL), MgSO ₄Dried, filtered and then rotary evaporated. The oil was chromatographed on silica, eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to give 159 as an oil (3.399g, 96%).¹H NMR(400MHz，CDCl₃)δ7.75(d，J＝8.30Hz，2H)，7.31(d，J＝8.30Hz，2H)，3.99(dd，J＝9.65，3.54Hz，1H)，3.89(dd，J＝9.52，5.37Hz，1H)，2.42(s，3H)，2.28(dd，J＝14.7，6.23Hz，1H)，2.19-2.14(m，1H)，2.10(dd，J＝14.9，6.35Hz，1H)，1.38(s，9H)，1.31-1.17(m，3H)，1.08-0.81(m，2H)，0.79-0.76(m，6H)；[α]_D＝-10.1(c 1 CHCl₃A solution).

(3S, 5R) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 160

Compound 159(3.01g, 7.05mmol), sodium azide (1.26g, 19.40mmol) and DMSO (12mL) were mixed and heated to 60 ℃ for 3 hours. EtOAc (100mL) was added to the reaction and filtered. The solid was washed with EtOAc (20mL) and the crude product was chromatographed on silica by evaporation of the filtrate, eluting with 5% EtOAc in hexanes to give 160 as an oil (1.86g, 89%).

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid tert-butyl ester 161

A solution of compound 160(1.86g, 6.25mmol) in THF (50mL) was shaken under hydrogen pressure over 5% Pd/C for 8 h, during which the hydrogen was changed 3 times. The catalyst was removed by filtration and the filtrate was evaporated. The crude product is chromatographed on silica, eluting with methanol to give an oil161(1.21g, 71%) of the paste.¹H NMR(400MHz，CDCl₃)δ2.70(dd，J＝12.9，4.40Hz，1H)，2.54(dd，J＝12.7，6.59Hz，1H)，2.26(dd，J＝14.5，6.96，1H)，2.12(dd，J＝14.5，6.47Hz，1H)，1.91(m，1H)，1.91(m，1H)，1.43(s，12H)，1.39-1.25(m，4H)，1.14-1.07(m，1H)，1.03-0.97(m，1H)，0.86-0.82(m，6H)。

Example 23(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid

Compound 161(1.20g, 4.44mmol) was heated to 50 ℃ in 3N HCl (30mL) for 4 hours. The solvent was removed by evaporation, and the oil was washed with toluene and evaporated. The crude product was passed through an ion exchange column (Dowex 50WX 8-100, strong acid), sequentially with water and 0.5N NH ₄OH is eluted. (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid (0.725g, 75%) was isolated as a white solid: mp-174-175 ℃;

¹H NMR(400MHz，CDCl₃)δ 2.83(dd，J＝12.69，4.88Hz，1H)，2.70(dd，J＝13.1，7.45 Hz，1H)，2.08(d，J＝6.59Hz，2H)，1.98(m，1H)，1.28-1.20(m，1H)，1.19-1.09(m，2H)，0.99-0.91(m，2H)，0.66(m，6H)；MS(APCI)m/z 215(M+，10％)，174(M+-41，100％)；[α]_D＝-5.7(c 1.025 H₂o solution).

Example 24: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-decanoic acid

(S) -2, 6-dimethyl-undec-2-ene 162

N-propylmagnesium chloride/diethyl ether solution (2.0M, 228mL) in N₂Freezing to-20 ℃ under atmosphere. LiCl (3.87g, 91.25mmol) and CuCl were mixed₂(6.13g, 45.63mmol), and distilled THF (456mL) and stirred for 30 min. Adding the Li to the Green's reagent through a cannula₂CuCl₄Solution, stirring the obtained solution at-20 deg.C for 30 deg.CAnd (3) minutes. R- (-) -citronellyl bromide (50g, 228.1mmol) was dissolved in THF (60mL) and added dropwise to the Green's solution. The reaction was stirred at 0 ℃ for 1 hour. The reaction was cooled to-40 ℃ and NH was then added dropwise₄Cl (saturated, 200mL) was quenched. The layers were separated and the aqueous layer was extracted with ether (3X 100 mL). The combined organic layers were washed with MgSO₄Drying, filtration and rotary evaporation gave an oil. The crude product was chromatographed on silica eluting with hexanes to give 162 as a colorless oil (9.15g, 22%).¹H NMR(400MHz，CDCl₃)δ5.10-5.06(m，1H)，2.10-1.89(m，2H)，1.66(s，3H)，1.58(s，3H)，1.34-1.23(m，4H)，1.15-1.06(m，2H)，0.88-0.81(m，11H)。

(S) -4-methylnonanoic acid 163

Compound 162(7.97g, 43.7mmol) was dissolved in acetone (214mL) and cooled to 0 ℃. Dropwise addition of Jones reagent (CrO) ₃/H₂SO₄) (2.7M, 95mL), then the reaction was heated to room temperature for 18 hours. Pour reaction into water/Na₂SO₄(200mL), the aqueous layer was extracted with ethyl acetate (4X 100 mL). The combined organic layers were washed with MgSO₄Drying, filtration and rotary evaporation gave an oil. The crude oil was chromatographed on silica eluting with hexane to give 163(5.56g, 74%) as a colorless oil.¹H NMR(400MHz，CDCl₃)δ2.40-2.25(m，4H)，1.70-1.62(m，2H)，1.47-1.11(m，8H)，0.87-0.84(m，6H)；MS APCI m/z 170.9(M-1，100％)。

(4R, 5S) -4-methyl-3- ((S) -4-methyl-nonanoyl) -5-phenyl-oxazolidin-2-one 164

Using a method similar to the preparation of compound 155 except that (S) -4-methylnonanoic acid 163(5.56g, 32.27mmol) was used as a reactant, 164 was obtained as an oil (10.70g, 100%).¹HNMR(400MHz，CDCl₃) δ 7.42-7.34(m, 3H), 7.28(d, J ═ 6.59Hz, 2H), 5.64(d, J ═ 7.33Hz, 1H), 4.74 (quintuple, J ═ 6.78Hz, 1H), 2.94-2.85(m, 2H), 1.73-1.67(m, 1H), 1.47-1.43(m, 1H), 1.39-1.22(m, 7H), 0.90-0.84(m, 8H).

(3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -decanoic acid tert-butyl ester 165

Using a procedure similar to that for the preparation of compound 156 gave 165 as an oil (4.25g, 61%). MS (APCI) M/z 446 (M)⁺+1，10％)，390(M⁺-55，100％，-tBu)。

(S) -2- ((S) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 166

Using a method similar to that for the preparation of compound 157, 166 was obtained as an oil (5.81g) except that ester 165(8.42g, 18.89mmol) was used as a reactant. This product was used directly in the next step. MS (APCI) M/z 285(M-1, 100%).

(3S, 5S) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167

In analogy to the procedure for preparation of compound 158, except that (S) -2- ((S) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 166(5.78g, 20.18mmol) was used as a reactant, 167(4.18g, 76%) was obtained as an oil.¹H NMR(400MHz，CDCl₃)δ3.64-3.58(m，1H)，3.84-3.42(m，1H)，2.28-2.20(m，1H)，2.09-2.02(m，1H)，1.43(s，9H)，1.26-1.18(m，8H)，1.11-1.04(m，2H)，0.87-0.83(m，6H)；MS(APCI)m/z 217(M+-55，50％，-tBu)。

(3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 168

Obtained in analogy to the preparation of compound 159 except using (3S, 5S) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167(4.164g, 15.29mmol) as a reactant was 168(4.17g, 64%) as an oil.¹H NMR(400MHz，CDCl₃)δ7.75(d，J＝8.30Hz，2H)，7.31(d，J＝8.30Hz，2H)，3.97(dd，J＝9.52，4.15Hz，1H)，3.90(dd，J＝9.52，5.13Hz，1H)，2.42(s，3H)，2.28，2.19-2.13(m，2H)，1.37(s，9H)，1.27-1.01(m，11H)，0.85(t，J＝7.08Hz，3H)，0.76(d，J＝6.35Hz，3H)。

(3S, 5S) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 169

Obtained as an oil 169(2.77g, 96%) using a method similar to the preparation of compound 160 except that (3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 168(4.155g, 9.74mmol) was used as a reactant. MS (APCI) M/z 270 (M)⁺-27，30％，-N₂)，214(M⁺-87，100％，-tBu，-N₂)。

(3S, 5S) -3-aminomethyl-5-methyl-decanoic acid tert-butyl ester 170

170(1.648g, 72%) was obtained as an oil using a method similar to that for the preparation of compound 161 except that (3S, 5S) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 169(2.50g, 8.405mmol) was used as a reactant. MS (APCI) M/z 272 (M)⁺+1，100％)。

Example 24(3S, 5S) -3-aminomethyl-5-methyl-decanoic acid

Example 16 (72%) was obtained as a white solid using a method similar to the preparation of example 15, except that tert-butyl (3S, 5S) -3- (aminomethyl) -5-methyldecanoate 170(1.6g, 6.00mmol) was used as a reactant. MS (APCI) M/z 272 (M)⁺+1，100％)。mp＝174-175℃；¹H NMR(400MHz，CD₃OD)δ2.91(dd，J＝12.9，3.91Hz，1H)，2.83(dd，J＝12.7，7.57Hz，1H)，2.43(dd，J＝15.6，3.17Hz，1H)，2.19(dd，J＝15.6，8.80Hz，1H)，2.08-2.04(m，1H)，1.53(m，1H)，1.38-1.27(m，7H)，1.78-1.03(m，2H)，0.90-0.86(m，6H)，0.66(m，6H)；MS(APCI)m/z 216(M⁺+1，100％)，214(M-1，100％)；[α]_D= 21.4(c 1 MeOH solution).

Example 25: synthesis of (3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid

Example 25

(S) -2-benzyl-3-methyl-butan-1-ol 172

Reference JACS 1997; 119: 6510. amide 171.

Large scale production of (S) -2-benzyl-3-methylbutyl acetate 173 from 171

N-butyllithium (10M in hexane, 100mL, 1000mmol, 3.9 equiv.) was added to a solution of diisopropylamine (108.9g, 150.9mL, 1.076mol, 4.20 equiv.) in THF (600mL) at-78 ℃. The resulting solution was stirred for 10 minutes and heated to 0 ℃ maintaining this temperature for 10 minutes. A portion of borane-ammonia complex (31.65g, 1.025mmol, 4.0 equiv.) was added and the suspension was stirred at 0 ℃ for 15 minutes, held at 23 ℃ for 15 minutes and then cooled to 0 ℃. To the cold hydride was added a solution of amide 171(86g, 256.41mmol, 1 eq.) in THF through a cannula for 3 minutes. The reaction was stirred at 23 ℃ overnight and then cooled to 0 ℃. Excess hydride was quenched by slowly adding 3N HCl (700 mL). The reaction mixture was washed with more aqueous hydrochloric acid (3N, 200mL), and brine, then extracted with ether (4X 15 mL). The ether solution was concentrated to at least volume, 200mL of 2N NaOH was added, and stirred at 23 ℃ for 2.5 hours. More ether was added and the layers were separated. The aqueous layer was saturated with brine and extracted with ether (3X 200 mL). The combined organic phases were washed with brine and dried over sodium sulfate. Flash chromatography of the residue (petroleum ether-25% diethyl ether-TEA) afforded 172 g of alcohol, 50 g. NMR (CDCl) ₃)δ7.35-7.16(m，5H，C₆H₅) 3.55 (near t, 2H, -CH)₂OH)，2.71(dd，1H，ArCH₂CH-)，2.52(dd，1H，ArCH₂CH)，1.87(m，1H，CHCH(Me)，1.67(m，1H，CH(Me)₂)，0.98(d，3H，CH₃) And 0.96(d, 3H, CH)₃)。

A3.3 g sample was kept for analysis, and the remainder was immediately acetylated at room temperature (50 mL triethylamine, 32mL DMAP 4.6 acetic anhydride) overnight. Then treating with silica gel chromatography, eluting with petroleum ether (pet ether) and 10% diethyl ether solution62g 173 were obtained. NMR (CDCl)₃)δ7.30-7.14(m，5H，C₆H₅)，3.98(m，2H，-CH₂OAc)，2.71(dd，1H，ArCH₂CH-)，2.51(dd，1H，ArCH₂CH)，1.99(s，3H，CH₃C ═ O), 1.82(m, 1H, chch (me) and ch (me)₂)，0.97(d，3H，CH₃) And 0.95(d, 3H, CH)₃)。

(S) -acetoxymethyl-4-methyl-pentanoic acid 174 and (S) -4-isopropyl-dihydro-furan-2-one 175

Acetate 173(15g, 68.18mmol) was dissolved in CH₃CN (150mL), carbon tetrachloride (150mL) and HPLC pure water (300mL) were stirred simultaneously. Sodium periodate (262.50g, 1220mmol) and ruthenium chloride (650mg, 3.136mmol) were added successively. After stirring overnight, it was diluted with ether and water and filtered through a pad of celite. The organic phase was separated and the aqueous phase was further extracted with ether. The solvent was removed by evaporation after drying over magnesium sulfate. To the residue was added potassium carbonate (42g), refluxed overnight in methanol (250mL), and then cooled to room temperature. After evaporation, the solid was dissolved with water and then concentrated. Hydrochloric acid was added to adjust the pH to 2. Chloroform was added and then extracted overnight. The organic phase was separated and the aqueous phase was further extracted with chloroform. The combined organic extracts were dried and evaporated, the product was purified on a silica gel column and the compound was eluted with 20% diethyl ether in dichloromethane. The eluate was detected by tlc and the spots were checked by I ₂And detecting the KI solution. The eluates were combined to give 4.6g of lactone 175. NMR (CDCl)₃)δ4.38(dd，1H，CH_aH_bO), 3.93 (close to t, 1H, CH)_aH_bO)，2.54(dd，1H，CH_cH_dC ═ O), 2.23(m, 2H, CHCH (me) and CHCH_dC＝O)，1.60(m，1H，CH(Me)₂)，0.92(d，3H，CH₃) And 0.85(d, 3H, CH)₃)。

(3R, 4R) -3-benzyl-4-isopropyl-dihydro-furan-2-one 176

Lithium bis (trimethylsilyl) amide (1.0M THF solution, 92mL, 92mmol) was added to (S) - β - (2-propyl) - γ -butyrolactone 175(11.68g, 91.25 mmol) over 3-5 minutes under argon at-78 deg.Cmmol) in anhydrous THF (100 mL). After stirring for 1 hour, a solution of benzyl iodide (21.87g, 100.37mmol) in dry THF was added quickly. Stirring was continued for 1.5 hours and the reaction was quenched by the sequential addition of aqueous brine and ethyl acetate solution at-78 ℃. The organic phase was separated and the aqueous phase was further extracted with ether. Silica gel chromatography eluting first with 5% dichloromethane in petroleum ether and finally with 10% diethyl ether in petroleum ether afforded 11.6g, 58% of the desired compound. NMR (CDCl)₃)δ7.19(m，5H，C₆H₅) 4.02 (close to t, 1H, CH)_aH_bO)，3.87(dd，1H，CH_aH_bO)，2.98(d，2H，ArCH₂)，2.57(q，1H，BnCHC＝O)，2.05(m，1H，CHCH(Me)₂，1.55(m，1H，CH(Me)₂)，0.81(d，3H，CH₃) And 0.72(d, 3H, CH)₃)。

(2R, 3R) -2-benzyl-3-bromomethyl-4-methyl-pentanoic acid ethyl ester 177

Lactone 176(6.5g, 29.8mmol) was dissolved in absolute ethanol (80mL) and cooled in an ice-water bath. Anhydrous HBr was bubbled through the solution for 1 hour, stirring overnight at room temperature while maintaining the reaction in an anhydrous system. It was poured into a mixture of ice-cooled petroleum ether and brine. The organic phase was separated and the aqueous phase was further extracted with petroleum ether. The combined organic solutions were washed repeatedly with cold water and then dried. The solvent was removed in vacuo to give 7.0g of crude product. NMR (CDCl) ₃)δ7.27(m，5H，C6H5)，4.02(m，2H，CH₃CH₂O)，3.70(dd，1H，CH_aH_bBr)，3.55(dd，1H，CH_aH_bBr)，2.97(m，2H，ArCH₂)，2.83(q，1H，BnCHC＝O)，2.11(m，1H，CHCH(Me)₂，1.97(m，1H，CH(Me)₂)，1.10(t，3H，CH₃CH₂O)，0.96(d，3H，CH₃) And 0.93(d, 3H, CH)₃)。

(2R, 3R) -2-benzyl-3, 4-dimethyl-pentanoic acid ethyl ester 178

Bromo ester 177(7.25g, ca. 80% pure) in the presence of 20% Pd/C (1.0g) containing triethylA solution of the amine (3.2mL) in ethanol (100mL) was hydrogenated overnight. It was filtered through a celite pad and the filter cake was washed with ethanol. The solvent was removed by evaporation, the residue was dissolved in diethyl ether and the solid (Et) was isolated₃Hcl) under reduced pressure. The solids were removed by filtration. The filtrate was concentrated and the above steps were repeated to remove all the hydrochloride. The product was subjected to silica gel column chromatography and eluted with petroleum ether to give 3.35g of the desired debrominated compound. NMR (CDCl)₃)δ7.21(m，5H，C₆H₅)，3.95(m，2H，CH₃CH₂O)，2.85(m，2H，ArCH₂)，2.64(q，1H，BnCHC＝O)，1.85(m，1H，CHCH(Me)₂，1.62(m，1H，CH(Me)₂)，1.05(t，3H，CH₃CH₂O)，0.95(d，3H，CH₃)，0.84(d，3H，CH₃And 0.82(d, 3H, CH)₃). MS display 290(M + CH)₃CN), 249(M +1), and the rest at 203. Further elution with diethyl ether gave the lactone (2.25g), which was continued from the previous step.

Acetic acid (2R, 3R) -2-benzyl-3, 4-dimethyl-pentyl ester 179

Ethyl ester 178(3.20g, 12.85mmol) was dissolved in anhydrous diethyl ether and cooled in an ice-water bath under an inert atmosphere. Lithium aluminium hydride (500mg, 13.15mmol) was added and the suspension stirred at room temperature overnight. Excess LAH was consumed by careful addition of ethyl acetate while the reaction was stirred in an ice-water bath. Saturated sodium sulfate was carefully added to condense the aluminum which separated out at room temperature as a white precipitate. The reaction mixture was diluted with dichloromethane, and then anhydrous sodium sulfate was added to dry the mixture. After filtration, the solution was concentrated to give 3.0g of oil.

This product (3.0g) was dissolved in dichloromethane (30mL) and triethylamine (2.5mL), DMAP (200mg), followed by addition of anhydrous acetic acid (1.5 mL). It was stirred at room temperature for 3 hours and diluted with ether. The ether solution was washed with water, 1N HCl, saturated sodium bicarbonate, brine, and then dried. The solution was concentrated in vacuo to give 1793.16 g of an acetoxy compound. NMR (CDCl)₃)δ7.19(m，5H，C₆H₅)，4.03(m，2H，CH₃CH₂O)，2.69(m，2H，ArCH₂)，2.09(m，1H，BnCHCH₂O)，2.02(s，3H，CH₃C＝O)，1.68(m，1H，CH₃CHCH(Me)₂，1.23(m，1H，CH(Me)₂)，0.87(d，3H，CH₃)，0.84(d，3H，CH₃) And 0.81(d, 3H, CH)₃)。

(R) -4- ((R) -1, 2-dimethyl-propyl) -dihydro-furan-2-one 180

To a solution of aromatic compound 179(5.0g, 20.16mmol) in HPLC pure acetonitrile (60mL), carbon tetrachloride (60mL), and water (120mL) was added sodium periodate (86.24g, 403.32mmol, 20 equiv.), followed by RuCl₃(414mg, 10 mol%). The mixture was stirred vigorously at room temperature overnight and then diluted with dichloromethane (400 mL). The solid precipitate was removed by filtration through a pad of celite. The organic phase was separated and the aqueous phase was further extracted with dichloromethane. The combined organic extracts were concentrated and the residue was dissolved in ether and treated with magnesium silicate column. The compound was eluted with 3% methanol in ether and evaporated to give a paste which was dissolved in methanol (100 mL). Potassium carbonate (8.0g) was added to the solution, and the mixture was refluxed for 6 hours. The solvent was removed by evaporation and the solid residue was dissolved in water. While stirring under cooling in an ice-water bath, the pH was adjusted to 2 by adding concentrated hydrochloric acid. Chloroform (200mL) was added to the solution and stirred at room temperature overnight. The organic phase was separated and the aqueous phase was further extracted with chloroform. After drying, the solvent was evaporated to give 1805.0 g of lactone. NMR (CDCl) ₃) Delta 4.36 (near t, 1H, CH)_aH_bO), 3.85 (close to t, 1H, CH)_aH_bO)，2.46(m，2H，CH_cH_dC＝O)，2.13(m，2H，CHCH₂C＝O)，1.60(m，1H，CH(Me)₂)，1.35(m，1H，CH₃CHCH(Me)₂)，0.86(d，3H，CH₃) And 0.72(t, 3H, CH)₃)。

(3R, 4R) -3-bromomethyl-4, 5-dimethyl-hexanoic acid ethyl ester 181

Lactone 180(5.0g) was dissolved in absolute ethanol (25mL) while stirring with argon. Cooling in ice water bathWhile anhydrous HBr gas was bubbled through the mixture for 45 minutes, maintaining room temperature overnight. The mixture was poured into ice water-brine and hexane. The organic phase was separated and the aqueous phase was further extracted with hexane. The combined organic extracts were dried and then evaporated. Flash chromatography on silica gel eluting with 10% diethyl ether in petroleum ether afforded 1813.54 g of the bromo ester. NMR (CDCl)₃)δ4.14(q，2H，CH₃H₂O)，3.60(dd，1H，CH_aH_bBr)，3.41(dd，1H，CH_cH_bBr)，2.54(dd，1H，CH_aH_bC＝O)，2.44(dd，1H，CH_aH_bC＝O)，2.22(m，1H，O＝CCH₂CHCH₂Br)，1.67(m，1H，CHCH₃CH(Me)₂，1.37(m，1H，CH(Me)₂)，1.26(t，3H，CH₃CH₂O)，0.94(d，3H，CHCH₃CH(Me)₂)0.81(d，3H，((CH₃)₂)CHCH₃CH) and 0.79(d, 3H, ((CH)₃)₂)CHCH₃CH)。

(3R, 4R) -3-azidomethyl-4, 5-dimethyl-hexanoic acid ethyl ester 182 and example 25(3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid

A solution of bromo ester 181(3.54g, 13.34mmol), sodium azide (1.04g, 16.13mmol) in dry DMF (8.0mL) was stirred at room temperature overnight. Water (16mL) and hexane were added, the organic phase was separated, and the aqueous phase was further extracted with hexane. This was dried and evaporated to give 3.0g of azido ester. NMR (CDCl)₃)δ4.14(q，2H，CH₃H₂O)，3.48(dd，1H，CH_aH_bN₃)，3.21(dd，1H，CH_cH_bN₃)，2.34(m 2H，CH_aH_bC＝O)，2.20(m，1H，O＝CCH₂CHCH₂N₃)，1.60(m，1H，CHCH₃CH(Me)₂. The compound is hydrogenated (HPL, 66480X 100). The crude product after hydrogenation was dissolved in 6N HCl and refluxed overnight. The solvent was evaporated in vacuo and the residue azeotroped with toluene. The crude product was further purified by column chromatography on an ion exchange column (Dowex 50Wb x 8-10) 0) Purification, washing to neutrality with HPLC pure water, followed by 0.5N NH₄The compound was washed with OH solution. The product was recrystallized from methanol to yield 720 mg. NMR (CD)₃OD)δ3.04(dd，1H，CH_aH_bNH₂)，2.82(dd，1H，CH_cH_bNH₂)，2.52(dd，1H，Ch_aH_bC＝O)，2.40(dd，1H，CH_aH_bC＝O)，2.07(m，1H，O＝CCH₂CHCH₂NH₂)，1.67(m，1H，CHCH₃CH(Me)₂，1.35(m，1H，CH(Me)₂)，0.97(d，3H，CHCH₃CH(Me)₂，0.88(d，3H，((CH₃)₂)CHCH₃CH) and 0.83(d, 3H, ((CH)₃)₂)CHCH₃CH)。[α]D-5.3(c, MeOH, 1.9 mg/mL). To C₉H₁₉NO₂Analytical calculation of (a): c62.39, H11.05, N8.08. Measured value: c62.01, H11.35, N7.88. MS shows ion at 215(M + CH)₃CN)，197(M+Na⁺)，174(M+H⁺). The derivatives were analyzed by reverse phase HPLC, which Hypersil BDS C₁₈At 5 μm, the mobile phase was 50/50 CH with 0.1% TFA₃CN-Water, a purity of 99.93% at a retention time of 8.21 minutes was obtained.

Examples 26 to 28: synthesis of 3-aminomethyl-4-isopropyl-heptanoic acid

Example 26R ═ nPr

Example 27R ═ nBu

Example 28R Et ═ Et

2-cyano-4-methyl-2-pentenoic acid methyl ester 61

Isobutyraldehyde (30.0g, 416mmol), methyl cyanoacetateA solution of (20.6g, 208mmol), ammonium hydroxide (3.2g, 41.6mmol) and acetic acid (5.0g, 83.2mmol) in 500mL toluene was heated to reflux in a dean-Stark trap for 12 hours. The mixture was cooled to room temperature and then separately saturated NaHSO ₃(3X 100mL), saturated NaHCO₃(3X 100mL), and 100mL of brine. The organic layer was washed with Na2SO₄Drying and evaporating to remove the solvent. The residual oil was distilled under vacuum (0.5mmHg, b.p. ═ 115-.

2-cyano-3-isopropyl-hexanoic acid methyl ester 183

To 2.0M Et of propylmagnesium chloride₂To a solution of O (9.8mL, 19.6mmol) was added a solution of 2-cyano-4-methyl-2-pentenoic acid (3.0g, 19.6mmol) in 50mL THF cooled to-40 deg.C in an IPA/dry ice bath under argon atmosphere. The solution was stirred for 4 hours and the reaction was quenched by the addition of 50mL of saturated KH₂PO₄And (6) quenching. THF was removed by evaporation and the residual oil was purified by using 50% CH under moderate pressure₂Cl₂Hexane/silica gel chromatography. The yield of methyl 2-cyano-3-isopropyl-hexanoate oil was 1.9g (50%).

2-cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl ester 1-methyl ester 184

To a solution of methyl 2-cyano-3-isopropyl-hexanoate (1.9g, 9.6mmol) in 10mL of THF was added a solution of NaH paste (washed with hexane, 0.23g, 9.6mmol) frozen in an ice-water bath under argon atmosphere in 20mL of THF. The solution was stirred for 10 min and tert-butyl bromoacetate (2.1g, 10.6mmol) was added. The solution was warmed to room temperature. After 12 hours, the reaction was quenched by the addition of 50mL of saturated KH ₂PO₄Quench and evaporate THF. In Et₂Extract the organic product in O (3X 50mL) and then combine the organic layers with MgSO₄And (5) drying. The solvent was removed by evaporation and the residual oil was purified by using 25% hexane/CH under moderate pressure₂Cl₂The silica gel chromatography treatment of (1). The yield of 2-cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl ester 1-methyl ester oil was 1.3g (42%).

3-cyano-4-isopropyl-heptanoic acid tert-butyl ester 185

The resulting mixture contained 2-cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl 1-methyl ester (1.3g, 4.2mmol), NaCl (0.25g, 4.2mmol), and H₂O (0.15g, 8.3mmol) was heated to 130 ℃ in 25mL DMSO for 12 hours. The mixture was cooled to room temperature and diluted with 100mL of brine. Organic product in Et₂O (3X 50 mL). Combine the organic layers and consume 50mL of H₂O and 50mL brine. With Na₂SO₄Drying and removal of the solvent by evaporation gave 0.8g (75% yield) of tert-butyl 3-cyano-4-isopropyl-heptanoate as an oil.

4- (1-isopropyl-butyl) -2-pyrrolidone 186

3-cyano-4-isopropyl-heptanoic acid tert-butyl ester (0.8g, 3.2mmol) at 50psi H₂Next, reduction in MeOH with TEA and RaNi. When calculating the amount of H₂After complete absorption, the catalyst was removed by filtration and the solvent was evaporated to give 0.6g (100% yield) of 4- (1-isopropyl-butyl) -2-pyrrolidone as an oil.

Example 26: 3-aminomethyl-4-isopropyl-heptanoic acid

4- (1-isopropyl-butyl) -2-pyrrolidone (0.6g, 2.3mmol) was heated to reflux in 50mL of 6.0M HCl for 12 hours. The solution was cooled to room temperature and filtered through celite. The filtrate was evaporated and the residual solid was recrystallized from MeOH/EtOAc. 0.035g (6% yield) of the HCl salt of 3-aminomethyl-4-isopropyl-heptanoic acid are obtained, mp 160-.¹H NMR(CD₃OD)δ0.9(m，9H)，1.30(m，5H)，1.78(m，1H)，2.30(m，2H)，2.45(m，1H)，2.95(m，2H)。MS(APCI，CH₃CN，H₂O)201(M⁺，100％)。

Example 27: 3-aminomethyl-4-isopropyl-octanoic acid

Prepared according to the method of example 26. 0.13g (15%) of 3-aminomethyl-4-isopropyl-octanoic acid are obtained. mp 160-.¹H NMR(CD₃OD)δ0.9(m，9H)，1.30(m，7H)，1.78(m，1H)，2.30(m，1H)，2.45(m，2H)，2.95(m，2H).MS(APCI，CH₃CN，H₂O)198(M-17，100％)，216(M⁺，50％)。

Example 28: 3-aminomethyl-4-isopropyl-hexanoic acid

Prepared according to the method of example 26. 0.11g (42%) of 3-aminomethyl-4-isopropyl-hexanoic acid are obtained. mp is 170 and 180 ℃.¹H NMR(CD₃OD)δ0.9(m，9H)，1.18(m，1H)，1.39(m，3H)，1.78(m，1H)，2.30(m，1H)，2.45(m，1H)，2.95(m，2H)。MS(APCI，CH₃CN，H₂O)188(M⁺，100％)。

Example 29

Synthesis of unsaturated ester 188

(S) - (-) -citronellal 187(2.0mL, 11.03mmol) was stirred in anhydrous tetrahydrofuran (30mL) with methyl triphenylphosphoranylideneacetate (3.69g, 11.03mmol) at 40 ℃. After 8 hours the mixture was cooled to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was stirred with n-pentane (50 mL). After 1 hour the solid was removed by filtration while the solvent was removed in vacuo to give an oil which was purified by flash chromatography (silica. ethyl acetate: heptane 1: 9) to give 2.05g (88%) of 188 as an oil.

¹H NMR(400MHz)(CDCl₃)δ0.90(3H，d，J＝6Hz)；1.12-1.40(2H，m)；1.60(3H，s)；1.62(1H，m)；1.68(3H，s)；2.01(3H，m)；2.21(1H，m)；3.73(3H，s)；5.08(1H，m)；5.82(1H，d，J＝16Hz)；6.94(1H，m)。

MS(CI⁺)(m/z)：211(MH⁺，75％)，179(78％)，151(100％)。

IR (film) (cm)^-1)v：1271，1436，1728，2917。

Synthesis of Nitro ester 189

Ester 188(2.02g, 9.6mmol) was reacted with 1, 8-diazabicyclo [5, 4, 0 ] at room temperature]Undec-7-ene (1.44mL, 9.6mmol) was dissolved in nitromethane (25mL) with stirring. After 23 hours the mixture was diluted with diethyl ether (150mL), washed first with water (50mL) and then 2N HCl (50 mL). The organic phase was collected and dried (MgSO)₄) The solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate: heptane 3: 7) to give 2.26g (87%) 189 as an oil. It should be noted that: the compound and all products are equimolar mixtures of two diastereomers.

¹H NMR(400MHz)(CDCl₃) δ 0.90(2 × 3H, single d, J ═ 6 Hz); 1.09-1.58(10H, m); 1.602(6H, s); 1.685(6H, s); 1.94(4H, m); 2.42(4H, m); 2.66(2H, m); 3.70(6H, s); 4.42(4H, m); 5.07(2H, m).

MS(CI⁺)(m/z)：272(MH⁺，90％)，240(100％)，151(100％)。

IR (film) (cm)^-1)v：1554，1739，2918。

Synthesis of lactam 191

Nitro ester 189(2.09g, 7.7mmol) was dissolved in methanol (75mL) and shaken on Raney nickel (catalyst, pre-washed with water and then methanol) under a hydrogen atmosphere (39psi) at 35 ℃. After 17 hours, the mixture was filtered through celite. The solvent was removed in vacuo to give an oil.¹H NMR showed that the double bond had been partially reduced and therefore continued reaction was not further purified. A sample of this partially reduced product (440mg, 2.1mmol) was dissolved in methanol (40mL) and shaken up on 5% Pd-C under a hydrogen atmosphere (39 psi). After 18 hours the catalyst was removed by filtration over celite to give 442mg (99% as partially reduced product) of a clear oil which was not purified. It should be noted that: the compound and all products are equimolar mixtures of two diastereomers.

¹H NMR(400MHz)(CDCl₃)δ0.88(18H，m)；1.04-1.58(20H，m)；1.96(2H，m)；2.40(2H，m)；2.58(2H，m)；2.98(2H，m)；(3.45(2H，m)，5.82(2H，br s)。MS(CI⁺)(m/z)：212(MH⁺，100％)。

Synthesis of example 29

Lactam 191(428mg, 2.0mmol) was heated to reflux in 6N HCl (20 mL). After 5 h the mixture was cooled to room temperature and washed with dichloromethane (2X 10 mL). The aqueous phase was collected and the solvent removed in vacuo. The residue was dissolved in water (10mL) and lyophilized to give 382mg (71%) of example 29 as a white solid. It should be noted that: the compound is an equimolar mixture of two diastereomers.

¹H NMR(400MHz)(d₆-DMSO)δ0.82(18H，m)；0.95-1.55(20H，m)；2.05-2.45(6H，m)；2.75(4H，m)；7.98(6H，br s)。

MS(CI⁺)(m/z)：230([MH-HCl]⁺，90％)，212(100％)。

Microanalysis: to C₁₃H₂₈NO₂Calculated Cl:

C 58.74；H 10.62；N 5.27。

measured value: c58.46; h10.50; and (4) N5.33.

It will be apparent to those skilled in the art that the use of (R) - (+) -citronellal will yield a compound having the opposite C5-stereochemistry to example 29.

The synthesis of compounds of general formula (1A) or (1B) is illustrated in scheme 19 below and examples 30-33.

Tetrazoles of general formula (1A) can be synthesized by the route outlined in scheme 19.

The following examples are illustrative of the present invention and are not meant to limit the scope of the invention.

Example 30

4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine

The compound 3{2- [ (2-cyano-ethylcarbamoyl) -methyl ] -4-methyl-pentyl } -carbamic acid tert-butyl ester in scheme 19

Compound 2(8.0g, 0.03mol) (prepared from (BOC) according to conventional methods ₂And pregabalin) was cooled in an ice-water bath in a solution of 250mL anhydrous THF. Triethylamine (4.62mL, 0.033mol) was added followed by isobutyl chloroformate (4mL, 0.031 mol). The reaction was stirred at 0 ℃ for about 15 minutes during which time a precipitate formed. A solution of 3-aminopropionitrile fumarate (3.95g, 0.03mol) dissolved in 35mL of 1M NaOH and 300mL of THF was placed in a separate flask. The mixture was cooled to 0 ℃ and then treated with 4 portions of the previously formed mixed anhydride. To the mixture was added 35mL of 1M NaOH prior to the addition of each anhydride. The reaction was stirred for 24 hours and then concentrated to remove THF. The resulting aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulfate. The solvent was removed under low pressure to give 6.6 g of a green oil. MS (APCI) M/z312(M + 1).

The compound 4[ 4-methyl-2- (1- (2-cyano-ethyl) -tetrazol-5-ylmethyl) -pentyl ] -carbamic acid tert-butyl ester and the compound 5[ 4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentyl ] -carbamic acid tert-butyl ester in scheme 19

Cyanoamide (6.5g, 0.0209mol) and triphenylphosphine (11.06g, 0.042mol) were dissolved in 300mL anhydrous THF. DEAD (6.7mL, 0.0425mol) and TMSN were used in solution ₃(5.75mL, 0.043 mol). The reaction was stirred for 24 hours, then the mixture was cooled to 0 ℃ and 46.9g (NH) was dissolved in 900mL₄)₂Ce(IV)NO₃The aqueous solution of (1). The reaction mixture was concentrated to remove THF and three more portions of CH were added₂Cl₂And (4) extracting. The combined organic layers were washed with brine and Na₂SO₄Drying, removing under reduced pressureDesolventization gave an oil which was plugged through silica gel to give the product mixed with triphenylphosphine oxide. The crude product was dissolved in 200mL THF and 50mL 2N NaOH. The mixture was heated to reflux for 2 hours and then stirred at room temperature overnight. THF was removed under reduced pressure and the resulting residue was diluted with water. After extraction with ether, the aqueous phase was acidified to pH 7 and extracted with 21mL of 4N HCl. Reusing the aqueous phase with solid KH₂PO₄And (4) saturation. By CH₂Cl₂The aqueous mixture is extracted. The organic extracts were washed with brine, Na₂SO₄And (5) drying. The solvent was removed by evaporation under reduced pressure to give 3.4g of an isolate as a pale yellow oil.

4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine

The product from the previous step (0.9g, 3.18mmol) was dissolved in 20mL of 4M HCl in dioxane. The reaction was allowed to stand for 1 hour. A solid formed, 10mL of diethyl ether was added and the reaction filtered to give 780mg of example 30 as a white solid; MS (APCI) M/z 184(M + 1).

Example 31

Isobutyl GABA oxadiazole thione (G), also known as 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4] oxadiazole-5-thione; HCl

BOC-isobutyl GABA (B)

A solution of di-tert-butyl dicarbonate (13.1g, 0.06mol) in THF (200mL) was added to a solution of isobutyl GABA (9.95g, 0.056mol) in 1N NaOH (125mL) and THF (50mL) cooled in an ice-water bath for 10 minutes. The reaction mixture was stirred at room temperature for 3 hours, concentrated to remove THF, and saturated KH was used₂PO₄Saturated and extracted 3 times with EtOAc. The extract was washed with brine 2 times, MgSO₄Drying and evaporation gave 13.8g (95%) of a white solid, mp 84-88 ℃. MS (APCI) M/z 260(M + 1).

BOC-isobutyl GABA amide (C)

A solution of BOC-isobutyl GABA (6.78g, 0.026mol) and triethylamine (3.0g, 0.030mol) was cooled to 0 deg.C and isobutyl chloroformate (3.9g, 0.029mol) was slowly added. After stirring at 0 ℃ for 20 minutes, ammonia gas was bubbled through the reaction mixture for 30 minutes, and then the mixture was stirred at room temperature for 18 hours. The mixture was concentrated to remove THF, suspended in water, and extracted 3 times with EtOAc. Extracting with 10% Na₂CO₃Washed 1 time, 2 times with brine and then with Na₂SO₄And (5) drying. Evaporation gave 4.9g (73%) of an oil which was used without further purification. MS (APCI) M/z 259(M + 1).

BOC-isobutyl GABA nitrile (D)

Cyanuric chloride (1.66g, 0.009mol) was added rapidly to a solution of BOC-isobutyl GABAA amide (4.6g, 0.0178mol) in DMF (15mL) while stirring at room temperature for 30 minutes. The reaction mixture was poured into cold NaHCO₃(4.2g, 0.05mol) in water (150 mL). Adding solid K₂CO₃Bringing the pH to 9, using CH for the mixture₂Cl₂Extracted 2 times, washed 1 time with brine, then Na₂SO₄And (5) drying. Evaporating to give an oil, filtering it over silica gel, CH₂Cl₂EtOAc elution gave 3.8g of oil (89%), which was used without further purification. MS (APCI) M/z 240(M), 239 (M-1); IR (film) 2215cm^-1。

BOC-isobutyl GABA amidoxime (E)

A solution of hydroxylamine was obtained by adding triethylamine (7.62g, 0.075mol) to a suspension of hydroxylamine hydrochloride (5.21g, 0.075mol) in DMSO (25 mL). After 15 min the triethylamine hydrochloride was filtered off and BOC-isobutyl GABA nitrile (3.61g, 0.015mol) was added to the filtrate. The mixture was heated at 75 ℃ for 17 hours. The mixture was diluted with water and extracted 3 times with EtOAc. The extract was washed with brine 2 times and Na₂SO₄Drying, evaporating to give an oil, filtering through a short silica gel column, and adding CH₂Cl₂EtOAc elution afforded 3.2g (78%) as an oilA compound (I) is provided.¹H NMR(CDCl₃)δ0.84(d，6H，J＝6.35Hz)，1.11(m，2H)，1.40(s，9H)，1.63(m，1H)，3.05(m，1H)，3.15(m，1H)，4.85(m，1H)，5.43(m 1H)；MS(APCI)274(M+1)。

BOC-isobutyl GABA oxadiazole thione (oxadiazolenethione) (F)

A solution of Boc-isobutyl GABA amidoxime (0.5g, 0.00183mol), DBU (1.12g, 0.00736mol) and 90% 1, 1' -thiocarbonyldiimidazole (0.398g, 0.002mol) in MeCN (12mL) was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, dissolved in EtOAc and taken up in KHSO₄And (4) washing the solution. The EtOAc layer was extracted with 1N NaOH (100 mL). The alkaline extract was washed with Et₂O washing, and KH washing with saturated water₂PO₄Acidified and extracted 3 times with EtOAc. The extract was washed with water 1 time, brine 1 time, and then MgSO₄And (5) drying. Evaporation gave an oil, 0.25g (43%).

¹H NMR(CDCl₃)δ0.84(d，6H，J＝6.59Hz)，1.1(m，2H)，1.41(s，9H)，1.65(m，1H)，1.85(m，1H)，2.60(m，2H)，3.1(m，2H)，4.94(m，1H)，12.8(s，1H)。MS(APCI)316(M+1)。

BOC-isobutyl GABA oxadiazole thione (0.25g, 0.79mmol) was dissolved in 4MHCl in dioxane (10mL) for 1 hour at room temperature. After evaporation, the residue was recrystallized from MeCN to give example 31 as cream crystals, 0.108g, mp 183-185 ℃.¹H NMR(DMSO-d⁶) δ 0.84(d, 6H, J ═ 6.59Hz), 1.1(m, 2H), 1.41(s, 9H), 1.65(m, 1H), 0.80(d, 6H, J ═ 6.59Hz), 1.06(m, 1H), 1.25(m, 1H), 1.55(m, 1H), 2.1(m, 1H), 2.7(m, 4H), 7.95(s, 3H); MS (APCI)216(M + 1). To C ₉H₁₇N₃₀Analytical calculation of HCl at S deg.C: c, 42.93; h, 7.21; n, 16.69; cl, 14.08. Measured value: c, 43.38; h, 7.24; n, 16.29; cl, 14.17.

Example 32

Isobutyl GABA oxadiazolone (J), also known as 3- (2-aminomethyl-4-methylpentyl) -4H- [1, 2, 4] oxadiazol-5-one; HCl

BOC-isobutyl GABA amidoxime carbamate (H)

Isobutyl chloroformate (0.253g, 0.00185mol) was added dropwise to a solution of BOC-isobutyl GABA amidoxime (0.5g, 0.00183mol) and pyridine (0.158g, 0.002mol) in DMF (10mL) at 0 ℃. After 30 min the reaction mixture was diluted with water at this temperature and then extracted 3 more times with EtOAc. The extract was washed with water 1 time, brine 1 time, and MgSO₄And (5) drying. Evaporation gave an oil, 0.7g (100%), which was used without further purification. MS (APCI) M/z 374(M + 1).

BOC-isobutyl GABA oxadiazolone (I)

BOC-isobutyl GABA amidoxime carbamate (0.7g, 0.00183mol) was dissolved in xylene (20mL) and heated at reflux for 2 hours. Evaporation gave a dark glassy oil which was dissolved in Et₂In O, extraction was performed with 1N NaOH. The alkali phase is saturated KH₂PO₄Acidified and extracted 3 times with EtOAc. The extract was washed with brine, MgSO ₄Drying and then evaporation gave a brown oil, 0.25g (46%), which was used without further purification. MS (APCI) M/z 300(M + 1).

BOC-isobutyl GABA oxadiazolone (0.25g, 0.835mmol) was dissolved in 4M HCl in dioxane and allowed to stand for 2.5 hours. After evaporation the residue was taken up in MeCN-Et₂Recrystallization of O gave example 32 as a tan solid, 53mg (27%), mp 181-.¹H NMR(DMSO-d⁶) δ 0.80(d, 6H, J ═ 6.35Hz), 1.1(m, 2H), 1.25(s, 9H), 1.60(m, 1H), 2.10(m, 1H), 2.5-2.8(m, 4H), 7.95(s, 3H), 12.39(s, 1H). MS (APCI)216(M + 1). To C₉H₁₇N₃O₂Analytical calculation of HCl C: c, 45.86; h, 7.70; n, 17.83; cl, 15.04. Measured value: c, 45.40; h, 7.55; n, 16.79; cl, 15.81.

Example 33

Preparation of (2-aminomethyl-4-methyl-pentyl) -phosphonic acid (9)

Preparation of 2-isobutyl-succinic acid-4-tert-butyl ester-1-methyl ester (2):

methyl 4-methylpentanoate (10.0g, 76.8mmol) was added to a 150mL solution of LDA in tetrahydrofuran at-78 deg.C under argon. After 15 minutes, the anionic solution was added via cannula to a solution of tert-butyl bromoacetate (22.5g, 115.2mmol) in 50ml THF at-78 ℃ and the solution was stirred for 45 minutes. The reaction mixture was then warmed to room temperature and 100ml of saturated KH was used ₂PO₄And (6) processing. THF was removed by evaporation in Et₂The organic phase was extracted with O (3X 50 mL). Et (Et)₂Extracting with 10% Na₂S₂O₃Washing, MgSO₄And (5) drying. The solvent was removed by evaporation and the residual oil was distilled under vacuum (0.1mmHg) to give 11.1g (59% yield) of 2-isobutyl-succinic acid-4-tert-butyl ester-1-methyl ester with a boiling point of 65 ℃ to 72 ℃. NMR (H)¹，400MHz，CDCl₃)δ0.9(6H，m)；δ1.2(1H，m)；δ1.4(9H，s)；δ1.5(2H，m)；δ2.3(1H，dd)；δ2.5(1H，dd)；δ2.8(1H，m)；δ3.6(3H，s)。

Preparation of 2-isobutyl-succinic acid-4-tert-butyl ester (3):

2-isobutyl-succinic acid-4-tert-butyl ester-1-methyl ester (11.1g, 45.4mmol) and LiOH ℃ H at room temperature₂O(2.0g，47.7mmol) At 180mL of 3: 1 IPA/H₂Stir in O overnight. The reaction mixture was washed with Et₂O extraction (3X 25 mL). With saturated KH₂PO₄The aqueous phase was acidified to pH 4 and re-used with Et₂O extraction (3X 50 mL). Et (Et)₂O extract with MgSO₄Drying and then evaporation gave 8.0g (77% yield) of 4-tert-butyl 2-isobutyl-succinate as an oil. NMR (H)¹，400MHz，CDCl₃)δ0.9(6H，m)；δ1.3(1H，m)；δ1.4(9H，s)；δ1.6(2H，m)；δ2.3(1H，dd)；δ2.6(1H，dd)；δ2.8(1H，m)。

Preparation of 4-isobutyl-dihydro-furan-2-one (4):

a solution of 4-tert-butyl 2-isobutyl-succinate (8.0g, 34.7mmol) in 100mL THF was cooled to 0 deg.C under argon and borane-methyl sulfide complex (2.6g, 34.7mmol) was added. The reaction mixture was stirred at 0 ℃ for 10 minutes and then at room temperature overnight. The solution was cooled to 0 ℃ and 100mL MeOH was added. The solvent was evaporated off and the residual oil was dried under high vacuum for 2 hours. The residual oil was dissolved in 100mL THF and a catalytic amount of p-toluenesulfonic acid was added. The solution was heated to reflux overnight. After cooling to room temperature, the solvent was evaporated and the oil was dissolved in Et ₂O (100 ml). Et was obtained₂Using 2.0N Na for O solution₂CO₃Extraction (2X 50mL) followed by 100mL brine MgSO₄And (5) drying. Et removal by evaporation₂After O, the residual oil was treated with medium pressure chromatography (MPLC) using 20% EtOAc/hexanes to give 4.4g (89% yield) of 4-isopropyldihydro-furan-2-one as an oil. NMR (H)¹，400MHz，CDCl₃)0.9(6H，m)；δ1.3(2H，dd)；δ1.5(1H，m)；δ2.1(1H，m)；δ2.6(2H，m)；δ3.6(1H，m)；δ4.4(1H，m)。

Preparation of 3-bromomethyl-3-isobutyl-propionic acid ethyl ester (5):

a solution of 4-isobutyl-dihydro-furan-2-one (4.4g, 30.9mmol) in anhydrous EtOH (50mL) was cooled to 0 ℃ and saturated with HBr by passing HBr gas through it for 10 min. The solution was warmed to room temperature and stirred for 2.5 hours. The mixture was diluted with 150mL of brine,then using Et₂O extraction (3X 100 mL). MgSO (MgSO)₄After drying, the solvent was evaporated to give 4.9g (yield 63%) of ethyl 3-bromomethyl-3-isobutyl-propionate as an oil. NMR (H)¹，300MHz，CDCl₃)δ0.9(6H，d)；δ81.3(5H，m)；δ1.6(1H，m)；δ2.3(1H，m)；δ2.5(1H，dd)；δ3.2(1H，dd)；δ3.6(1H，dd)；δ4.1(2H，q)。

Preparation of ethyl 3- (diethoxy-phosphorylmethyl) -5-methyl-hexanoate (6):

3-bromomethyl-3-isobutyl-propionic acid ethyl ester (4.6g, 18.3mmol) was heated in an oil bath at 170 ℃ under argon. Triethyl phosphite (3.6g, 22mmol) was added dropwise over 2 hours. After complete addition, the oil bath temperature was raised to 190 ℃ for 4 hours. The reaction mixture was cooled to room temperature and the product was treated with MPLC using EtOAc to give 2.7g (48% yield) of ethyl 3- (diethoxy-phosphorylmethyl) -5-methyl-hexanoate. NMR (H) ¹，400MHz，CDCl₃)δ0.8(6H，d)；δ1.2(5H，m)；δ1.3(6H，m)；δ1.6(1H，m)；δ1.7(1H，d)；δ1.8(1H，d)；δ2.3(2H，m)；δ2.5(1H，dd)；δ4.1(6H，m)。

Preparation of 3- (diethoxy-phosphorylmethyl) -5-methyl-hexanoic acid (7):

3- (diethoxy-phosphorylmethyl) -5-methyl-hexanoic acid ethyl ester (1.0g, 3.2mmol) was dissolved in 10mL EtOH at 0 ℃ with NaOH (1.8mL, 2.0M). After 15 minutes, the reaction mixture was warmed to room temperature and stirred overnight. EtOH was evaporated and then 50mL of 2.0M NaOH was added. Et solution₂O extraction (2 × 50mL) followed by acidification to pH 1 with concentrated hydrochloric acid. The acidic solution was extracted with EtOAc (3X 50mL) and the combined extracts were MgSO₄Drying and then evaporation gave 0.65g (72% yield) of 3- (diethoxy-phosphorylmethyl) -5-methyl-hexanoic acid as an oil. NMR (H)¹，400MHz，CDCl₃)δ0.9(6H，d)；δ1.3(8H，m)；δ1.6(1H，m)；δ1.8(2H，m)；δ2.3(1H，m)；δ2.5(2H，m)；δ4.1(4H，m)。

Preparation of diethyl [2- (benzyloxycarbonylamino-methyl) -4-methyl-pentyl ] phosphate (8):

a solution of 3- (diethoxy-phosphorylmethyl) -5-methyl-hexanoic acid (0.65g, 2.3mmol), diphenyl-di-phosphoryl-azide (0.76g, 2.8mmol), triethylamine (0.47g, 4.6mmol) and benzyl alcohol (0.5g, 4.6mmol) in 100mL toluene was heated to reflux overnight. The toluene was evaporated and the residual oil was dissolved in 50mL EtOAc. The EtOAc solution was treated with 1.0N HCl (2X 50mL), saturated NaHCO, respectively₃(2X 50mL), and 50mL of brine. Na (Na) ₂SO₄After drying, the solvent was then removed by evaporation to give an oil, which was treated with MPLC using EtOAc. [2- (benzyloxycarbonylamino-methyl) -4-methyl-pentyl]The yield of diethyl phosphate was 0.46g (52%). NMR (H)¹，400MHz，CDCl₃)δ0.9(6H，m)；δ1.1-1.4(9H，m)；1.7(2H，m)；δ2.0(1H，m)；δ3.1(1H，m)；δ3.3(1H，m)；δ4.1(4H，q)；δ5.0(2H，s)；δ5.7(1H，bs)；δ7.3(5H，m)。

Preparation of (2-aminomethyl-4-methyl-pentyl) -phosphoric acid (9):

reacting [2- (benzyloxycarbonylamino-methyl) -4-methyl-pentyl]A20 mL aqueous solution of 47% HBr of diethyl phosphate (0.46g, 1.2mmol) was heated at reflux overnight. The solution was cooled to room temperature and water was removed by evaporation. The residual solid was dissolved in 10mL of water and passed through Celite^*545 filtering, and passing through Dowex^*50 ion exchange column (bed volume 30 mL). 200mL of water and 150mL of 3% NH were used for the column₄OH and 150mL 10% NH₄OH is eluted. The basic eluate was collected and evaporated to give 0.14g of a white solid. By using P at 60 ℃ under vacuum₂O₂Drying gave 0.11g (47%) of example 33, (2-aminomethyl-4-methyl-pentyl) -phosphoric acid. NMR (H)¹，400MHz，CD₃OD) δ 0.9(6H, m); δ 1.2(2H, t); δ 1.4(1H, m); δ 1.7(2H, m); δ 2.1(1H, m); δ 2.7(1H, dd); δ 3.0(1H, dd). MS (M/e)196(M +1, 100%). To C₇H₁₈NO₃Analytical calculation of P: c-43.07, H-9.29 and N-7.18. Measured value: c-43.08, H-8.62 and N-6.89.

The following examples are illustrative of the preparation of compounds of formulae V-VIII.

Example 34

(±) - (1 α, 6 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid hydrochloride

Step (i)

Sodium hydride (0.11mg, 2.7mmol) was stirred with THF (5mL) under argon at 0 ℃. Triethylphosphorylacetone (0.5mL) was added dropwise, and the solution was stirred for 10 minutes. A solution of methanone (0.37g, 7.7mmol) in THF (5mL) was added dropwise with stirring and warmed to room temperature. After 18 hours, the reaction mixture was partitioned between water (80mL) and diethyl ether (3X 20 mL). The solvent was removed in vacuo to give a yellow oil, which was purified by flash chromatography (silica, heptane/EtOAc 19: 1) to give 0.34g (62%) of the ester as a colorless oil:¹H NMR(CDCl₃) (400 MHz): 1.05-1.29(9H, m, ring proton + CH)₃) 1.76-1.78(2H, m, ring proton), 1.87-1.97(2H, m, ring proton), 2.0-2.16(2H, m, ring proton), 2.51-2.56(1H, dd, J ═ 5.7, 27.5Hz, ring proton), 3.12-3.18(1H, dd, J ═ 5.4, 18.8Hz, ring proton), 4.12-4.20(2H, m, CH, ring proton), 1.87-1.97(2H, m, ring proton), 2.0-2.16(2H, m, ring proton), 2.51-2.56(1H, dd, J ═ 5₂)，5.77(1H，s，CH)。

MS(ES+)m/e 209[M+H)⁺100％。

Step (ii)

The ester (0.34g, 1.63mmol) was dissolved in THF (5mL) while stirring under argon. Nitromethane (0.25mL) was added and the reaction heated to 60 ℃. TBAF (2.3mL) was added dropwise to the hot solution for 1 hour, followed by stirring for 4 hours. The reaction was partitioned between 2N HCl and diethyl ether, and the diethyl ether layer was washed with brine. The solvent was removed in vacuo to give a yellow oil which was purified by flash chromatography (silica, heptane/EtOAc 19: 1) to give 0.264g (60%) of the product as a colorless oil.

¹H NMR(CDCl₃) (400 MHz): delta 0.97-1.30(11H, m, ring proton + CH)₃) 1.73-1.95(6H, m, 2xCH +4 ring protons), 2.5(1H, d, J ═ 16.6Hz, CH)₂CO₂Et)，2.7(1H，d，J＝16.6Hz，CH₂CO₂Et，4.12-4.18(2H，m，CH₂)，4.49-4.51(1H，d，J＝11.5Hz，CH₂NO₂)，4.73-4.75(1H，d，J＝11.5Hz，CH₂NO₂)。

Step (iii)

Nitro ester (0.24g, 0.9mmol) and sponge nickel were dissolved together in methanol. The reaction was hydrogenated at 50psi, 30 ℃ for 15 hours. The reaction mixture was filtered through celite and the solvent removed in vacuo to yield 0.18g (85%) of the product as a yellow solid. The product is a mixture of lactam and amino ester.

Step (iv)

The amino ester was dissolved in 6N HCl (5mL) and dioxane (2.5mL) and heated to reflux for 4 hours. The solution was washed with dichloromethane (3X 5mL) and the aqueous portion was removed in vacuo to give 0.196g (99%) of example 34 as a colorless solid.

¹H NMR(DMSO)(400MHz)：δ0.86-1.04(2H，m)，1.08-1.17(6H，m)，1.60-1.78(6H，m)，2.35-2.39(1H，d，J＝16Hz，CH₂CO₂H)，2.46(1H，m，CH₂CO₂H)，2.83-2.87(1H，d，J＝13Hz，CH₂NH₂)，2.97-3.00(1H，d，J＝13Hz，CH₂NH₂)，7.91(2H，bs，NH₂)。

MS(ES+)m/e 212[M+H]⁺100％。

HPLC, Prodigy C18 column, 5% methanol/acetonitrile. Retention time 3.00 min, purity 99%.

Example 35

(±) - (1 α, 5 β) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid hydrochloride

Step (i)

Sodium hydride (0.6g, 14.5mmol) was stirred with THF (50mL) under argon at 0 ℃. Triethylphosphoacetone (2.9mL) was added dropwise and the solution stirred for 10 min. A solution of methanone (1.8g, 14.5mmol) in THF (10mL) was added dropwise with stirring and warmed to room temperature. After 18 hours, the reaction mixture was partitioned between water (250mL) and diethyl ether (3X 50 mL). The solvent was removed in vacuo to give a yellow oil which was purified by flash chromatography (silica, heptane/EtOAc 19: 1) to give 1.95g (69%) of the ester as a colorless oil. ¹H NMR(CDCl₃)(400MHz)：δ1.14-1.19(2H，m，CH₂)，1.25-1.29(3H，m，CH₃)，1.55-1.79(4H，m，2xCH₂)，2.03-2.10(4H，m，2xCH₂)，2.45-2.55(1H，dd，CH)，3.05-3.15(1H，dd，CH)，4.12-4.17(2H，q，J＝7.3，14.4Hz，COCH₂，5.76(1H，m，CH)。

Step (ii)

The ester (1.9g, 10mmol) was dissolved in THF (15mL) while stirring under argon. Nitromethane (1.4mL) was added and the reaction heated to 60 ℃. TBAF (14mL) was added to the hot solution for 1 hour, followed by stirring for 5 hours. The reaction was partitioned between 2N HCl and diethyl ether and the diethyl ether layer was washed with brine. Diethyl ether was removed in vacuo to give an orange oil which was purified by flash chromatography (silica, heptane/EtOAc 19: 1) to give 1.59g (64%) of the product as a colourless oil.¹H NMR(CDCl₃)(400MHz)：δ1.14-1.31(7H，m，CH₃+ ring proton), 1.64-1.72(1H, m, ring proton), 1.03-1.09(1H, m, ring proton), 2.00-2.05(2H, m, ring proton), 2.57-2.61(1H, d, J ═ 16.4Hz, CH, c, H, m, g ═ 1H, m, ring proton), c, g, m₂CO₂Et)，2.71-2.75(1H，d，J＝16.4Hz，CH₂CO₂Et)，4.12-4.18(2H，q，J＝7.1，14.2Hz，OCH₂CH₃)，4.56-4.59(1H，d，J＝11.5Hz，CH₂NO₂)，4.77-4.80(1H，d，J＝11.5Hz，CH₂NO₂). IR (impurity free) 2957, 2870, 1731, 1547, 1374, 1182, 1030cm^-1。

Step (iii)

Nitro ester (1.59g, 5.9mmol) was dissolved in methanol (40mL) along with sponge nickel. The reaction was hydrogenated at 50psi, 30 ℃ for 5 hours. The reaction mixture was filtered through celite and the solvent removed in vacuo to yield 1.08g (97%) of lactam as a pure white solid.¹H NMR(CDCl₃) (400 MHz): δ 1.08-1.11(2H, m, ring proton), 1.23-1.28(2H, m, ring proton), 1.62-1.68(4H, m), 1.82-1.89(2H, m), 2.00-2.06(2H, m), 2.30-2.40(2H, m, CH) ₂CO)，3.29-3.30(2H，M，CH₂NH)，5.45(1H，bs，NH)。MS(ES⁺)m/e 180[M+H]⁺3％，359[2M+H]⁺21％，381[2M+Na]⁺100％。

Step (iv)

The lactam was dissolved in 6N HCl (20mL) and dioxane (80mL) and heated to reflux for 4 hours. The solution was washed with dichloromethane (3X 10mL) and the water evaporated in vacuo to give example 35 as a colorless solid, 0.65g (84%).¹H NMR (DMSO) (400 MHz): δ 1.0-1.18(4H, m, ring proton), 1.52-1.72(6H, m, ring proton), 1.95-2.02(2H, m, ring proton), 2.33-2.67(2H, m, CH)₂CO₂H)，2.90-2.94(1H，d，J＝12.9Hz，CH₂NH₂)，3.00-3.03(1H，d，J＝12.7Hz，CH₂NH₂)，7.94(2H，bs，NH₂)。MS(ES⁺)m/e 198[M+H]⁺100 percent. LCMS (ELSD) Prodigy ODS 350 mm X2 mm column, 5% -50% MeCN/H₂And O. The retention time was 2.30 minutes and the molecular weight was found to be 198. The purity was 100%.

Example 36

(1 alpha, 3 alpha, 5 alpha) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid hydrochloride

Step (i)

Triethylphosphoacetonide (2.3mL, 11.6mmol) was slowly added (for 10 min) to a suspension of NaH (0.45g, 11.3mmol) in THF (25mL) at 0 deg.C under argon, followed by 5(1.29g, 10.4mmol, 2X 3mL of THF solution). The reaction was warmed to room temperature and stirred for 4 hours, after which it was diluted with water (100mL), extracted with ether (2X 200mL), washed with saturated brine (50mL), MgSO₄And (5) drying. Column chromatography (9: 1 heptane/ethyl acetate) afforded the product as a colorless oil, 1.75g, 86%.

IR (film) (cm)^-1)v＝2964，1713，1655，1371，1208，1125，1040。

¹H NMR(CDCl₃)：δ5.72(1H，m)，4.14(2H，q，J＝7.2)，3.02-2.92(1H，m)，2.72-2.54(3H，m)，2.52-2.42(1H，m)，2.28-2.20(1H，m)，1.85-1.31(6H，m)，1.27(3H，t，J＝7.2)。(m/z AP⁺195(MI +1) was 100%.

Step (ii)

TBAF (24mL, 24.0mmol) was added to a solution of compound 6(2.75g, 22.2mmol) and THF (22mL), and nitromethane (4.4mL, 8.14mmol) was added. The reaction was heated (60 ℃ oil bath) for 4.75 h, then diluted with ethyl acetate (100mL), then washed with 2M HCl (30mL) and saturated brine (40mL), MgSO₄Drying, and concentrating under reduced pressure. Column chromatography (9: 1 heptane/ethyl acetate) gave 0.73g of product as a colourless oil in 20% yield. For products¹H NMR determined as a 9: 1 mixture of diastereomers.¹H NMR(CDCl₃)：δ4.67(1H，s)，4.60(1H，s)，4.15(2H，q，J＝7.2)，4.14(2H，q，7.2)，2.58(2H，s)，2.49(2H，s)，2.12-2.0(2H+2H，m)，1.63-1.49(4H+4H，m)，1.44-1.36(2H+2H，m)，1.28(3H，t，J＝7.2)，1.27(3H，t，J＝7)，1.16-1.04(2H+2H，m)。

Step (iii)

A solution of compound 7(0.88g, 3.45mmol) in methanol (100mL) was hydrogenated over a sponge nickel catalyst at 30 ℃ and 56psi for 5 hours. The sponge nickel catalyst was washed several times with water and then methanol before use. After the hydrogenation reaction was complete, the reaction mixture was filtered through celite and the resulting solution was concentrated in vacuo to give a yellow solid, 0.62g, 80%.¹H NMR(CDCl₃)：δ5.43(1H，br s)，3.15(2H，s)，2.56-2.44(3H，m)，1.99(2H，dd，J＝12.6，8.2)，1.64-1.50(2H，m)，1.44-1.34(3H，m)，1.22-1.14(2H，m)。m/z ES⁺226(MI +1) was 100%.

Step (iv)

A solution of compound 8 in 6M HCl (30mL) and dioxane (10mL) was heated to reflux for 4 hours (100 ℃ oil bath). After cooling the reaction was diluted with water (40mL), the reaction was washed with dichloromethane (3X 40mL) and concentrated in vacuo to afford example 36 as white crystals with a 6: 1 diastereomer ratio. The product was recrystallized twice from ethyl acetate/methanol to give a 10: 1 mixture of diastereomers.

m/z ES⁺198(MI +1) was 100%.

¹H NMR(D₂O)：δ3.03(2H，s)，2.50-2.36(4H，m)，1.84(2H，dd，J＝12，8)，1.41(4H，s)，1.26(2H，s)，1.02(2H，m)。

HPLC column ═ Prodigy ODS3, room temperature ═ 0.87, and purity ═ 100%.

Example 37

(1 α, 6 α, 8 α) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid hydrochloride

Synthesis of Compound 1

1, 2 indan-2-one (1.0g, 7.6mmol), 1, 2-ethylene glycol (0.43mL, 7.6mmol) and p-toluenesulfonic acid were refluxed in benzene (40mL) with a dean-Stark trap for 6 hours. The mixture was cooled and diluted with ethyl acetate (100mL) and washed with saturated sodium bicarbonate solution (60 mL). The organic layer was discarded, and the aqueous layer was extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with brine, MgSO₄Dried and then the solvent was evaporated under reduced pressure. Chromatography of the residue (SiO)₂Pentane/ethyl acetate, 97: 3) gave acetal 1 as a colorless oil (1.14g, 85%); r_f(heptane/ethyl acetate, 8: 2) 0.36; v. of_max(film)/cm^-1 1483，1331，1291，1105；δ_H(400MHz；CDCl₃)：7.19-7.14(4H，m，Ph)，4.02(4H，s，2xCH₂CO₂，3.18(4H，s，2xCH₂O)。

Synthesis of Compound 2

A solution of the acetal compound 1(0.5g, 2.84mmol) in ethanol (50mL) was shaken over a catalytic amount of 5% rhodium-aluminum under a hydrogen atmosphere (70Psi, 50 ℃ C.) for 16 hours. The catalyst was removed by filtration and the solvent was then removed by evaporation under reduced pressure to give acetal compound 2 as a colorless oil (0.51g, 99%); v. of _max(film)/cm^-1 2923，1449，1337，1192，1115，1089；δ_H(400MHz；CDCl₃)：3.89-3.86(4H，m，2xCH₂O)，2.10-2.00(2H，m)，1.88(2H，dd，J＝13.9，7.6)，1.81(2H，dd，J＝13.7，7.0)，1.56-1.26(6H，m)。

Synthesis of Compound 3

Acetal compound 2(1.01g, 5.54mmol) was stirred in a mixture containing 2N hydrochloric acid (10mL) and acetone (10mL) for 24 hours. After completion, tlc showed that the starting acetal compound had been completely consumed. Saturated sodium carbonate solution (20mL) was added and the mixture was extracted with ether (3X 25 mL). The combined ether extracts were washed with brine and dried (MgSO)₄) Is removed by evaporation under reduced pressureA solvent. Chromatography of the residue (SiO)₂Pentane/diethyl ether, 95: 5) gave ketone 3 as a colorless oil (0.75g, 97%); r_f(heptane/ethyl acetate, 8: 2) 0.42; v. of_max(film)/cm^-1 1743(C＝O)；δ_H(400MHz；CDCCl₃)：2.37-2.28(2H，m)，2.20(2H，dd，J＝18.5，7.5)，2.12(2H，dd，J＝18.7，6.3)，1.65-1.24(1OH，m)。

Synthesis of Compound 4

Triethylphosphoacetone was added dropwise to a stirred suspension of NaH (0.22g of a 60% oil dispersion, 5.43mmol) in THF (15mL) at 0 deg.C under argon. After 20 minutes, a solution of ketone 3(0.75g, 5.43mmol) in THF (6mL) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. Water (5mL) was added, and the mixture was washed with diethyl ether (15 mL. times.3). The combined organic portions were washed with brine and dried (MgSO₄). The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Pentane/diethyl ether, 95: 5) gave ester 4 as a colorless oil (0.81g, 72%); r _f(heptane/ethyl acetate, 8: 2) 0.66; v. of_max(film)/cm^-1 1715(C＝O)，1652(C＝C)；δ_H(400MHz；CDCCl₃): 5.80(1H, quintet, J ═ 2.2, CHCO)₂Et)，4.15(2H，q，J＝7.1，CO₂CH₂Me)，2.79(1H，dd，J＝19.5，8.1)，2.69(1H，ddt，J＝19.8，7.3，2.3)，2.47(1H，dd，J＝17.3，7.2)，2.34(1H，ddt，J＝17.3，5.6，1.8)，2.14(1H，m)，2.02(1H，m)，1.60-1.22(8H，m)；m/z(ES⁺)209(M+H，57％)，455(2M+K，67)。

Synthesis of Compounds 5 and 6

Ester 4(0.45g, 2.16mmol), nitromethane (0.24mL, 4.31mmol) and tetrabutylammonium fluoride (3.10mmol in 1M THF, 3.10mmol) were heated in THF to 65 ℃ for 4 hours. The mixture was cooled, diluted with ethyl acetate (20mL) and acidified with dilute hydrochloric acid (15 mL). The organic layer was discarded and the aqueous layer was further extracted with ethyl acetate (2X 15 mL). The combined organic phases were washed with brine and dried (Mg)SO₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Pentane/diethyl ether, 98: 2) to give nitro esters 5 and 6(0.35g, 60%) as yellow oils in a ratio of 9: 1; r_f(heptane/ethyl acetate, 9: 1) 0.28; v. of_max(film)/cm^-1 1732(C＝O)，1547(NO₂)，1375(NO₂) (ii) a Major isomer 5: delta_H(400MHz；CDCCl₃)：4.61(2H，s，CH₂NO₂)，4.15(2H，q，J＝7.2，OCH₂Me)，2.70(2H，s，CH₂CO₂Et)，2.06(2H，m)，1.81(2H，dd，J＝13.9，7.1)，1.56(2H，dd，J＝13.1，6.8)，1.51-1.22(8H，m)1.28(3H，t，J＝7.2)。

Synthesis of Compounds 7 and 8

A solution of mixtures 5 and 6(0.81g, 3.01mmol) in methanol (30mL) was shaken over a catalytic amount of a sponge nickel catalyst under a hydrogen atmosphere (50Psi, 30 ℃) for 12 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give a mixture of 9: 1 amino esters 7 and 8 as a white solid (0.42g, 72%); v. of_maxx (film)/cm^-13214(NH), 1706(C ═ O); major isomer 7: delta _H(400MHz；CDCCl₃)：5.57(1H，br s，NH)，3.20(2H，s，CH₂NH)，2.36(2H，s，CH₂CO)，2.04-1.94(2H，m)，1.77(2H，dd，J＝13.2，7.0)，1.62(2H，dd，J＝13.4，6.7)，1.60-1.20(8H，m)；m/z(ES⁺)387(2M+H，97％)。

Synthesis of example 37

A mixture of 7 and 8 (0.42g, 2.17mmol) was dissolved in 1, 4-dioxane (8mL) and hydrochloric acid (20mL of 6N solution), and the mixture was refluxed for 6 hours. After cooling, the mixture was diluted with water (20mL) and washed with dichloromethane (2X 15 mL). The aqueous layer was evaporated under reduced pressure to give a mixture containing 9: 1 of acids 9 and 10 as a white solid (0.43g, 79%). Recrystallizing with ethyl acetate/methanol to obtainNeat acid, example 37(0.27 g); delta_H(400MHz；d₆-DMSO)：12.3(1H，br s，CO₂H)，7.94(2H，br s，NH₂)，2.90(2H，s，CH₂NH₂)，2.52(2H，s，CH₂CO₂H)，1.97(2H，br s)，1.65(2H，dd，J＝13.5，6.7)，1.54-1.20(10H，m)；m/z(ES⁺)212(M + H, 100%); (found: C, 56.4; H, 8.74; N, 5.43. C)₁₂H₂₁NO₂·1HCl·0.5H₂Theoretical value of O: c, 56.1; h, 9.03; n, 5.45%); LCMS (Prodigy C1850 mm X4.6 mmid column, 5% -50% acetonitrile/water); the retention time was 1.53 minutes and the purity was 98%.

Example 38

Synthesis of Compound 1

N-butyllithium (5.1mL of a 2.5M solution in hexane, 12.75mmol) was added dropwise to a stirred mixture of nitromethane (0.34mL, 6.3mmol) in THF (20mL) and HMPA (2mL) at-78 ℃ under argon. The mixture was then warmed to-60 ℃ and stirred for 1 hour. Cool to-78 deg.C and add 3(0.79g, 5.73 mmol). The mixture was then warmed to-60 ℃ and stirred for 2 hours. The mixture was quenched by the addition of saturated ammonium chloride solution (5 mL). After warming to room temperature, dilute hydrochloric acid (10mL) and diethyl ether (30mL) were added. The organic layer was separated and the aqueous layer was further extracted with ether (2X 25 mL). The combined organic extracts were washed with brine and dried (MgSO) ₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Pentane/diethyl ether, 95: 5) to give nitro-alcohol 1(0.50g, 43%) as a white solid; r_f(heptane/ethyl acetate, 9: 1) 0.14; v. of_max(CH₂Cl₂)/cm^-1 3424(OH)，1548(NO₂)，1379(NO₂)；δ_H(400MHz；CDCl₃)：4.45(2H，s，CH₂NO₂)，3.26(1H，s，OH)，2.04-1.95(2H，m)，1.85-1.80(4H，m)，1.64-1.24(8H，m)。

Synthesis of Compound 2

A mixture containing Compound 1(0.50g, 2.49mmol) and concentrated sulfuric acid (1 drop) was heated to 50 ℃ in acetic anhydride (1mL) for 5 minutes. After the mixture was cooled, it was partitioned between ether (100mL) and water (50 mL). The ether layer was washed with brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure to give nitro-acetate 2 as a colourless oil (0.49g, 82%; r_f(heptane/ethyl acetate, 9: 1) 0.44; v. of_max(film)/cm^-1 1739(C＝O)，1551(NO₂)，1375(NO₂)；δ_H(400MHz；CDCL₃)：4.88(2H，s，CH₂NO₂)，2.38-2.00(8H，m)，2.07(3H，s，MeCO)，1.62-1.32(6H，m)。

Synthesis of Compound 3

A solution of potassium methoxide (0.15g, 2.04mmol) in methanol (3mL) was added dropwise to a stirring solution of 2(0.49g, 2.04mmol) in methanol (5mL) at 0 deg.C. After 10 min, the mixture was partitioned between ether (100mL) and water (50 mL). The ether layer was washed with brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Pentane/diethyl ether, 98: 2) to give nitro-olefin 3(0.21g, 57%) as a pale yellow oil; r_f(heptane/ethyl acetate, 8: 2) 0.54; v. of _max(film)/cm^-1 1643(C＝C)，1509(NO₂)，1342(NO₂)；δ_H(400MHz；CDCL₃): 7.12(1H, quintuple, J2.0, CHNO)₂)，3.01(1H，ddt，J＝20.5，8.0，2.1)，2.90(1H，ddt，J＝20.5，7.3，2.1)，2.54(1H，ddt，J＝17.8，7.1，2.0)，2.43(1H，ddt，J 17.7，5.6，1.9)，2.21(1H，m)，2.12(1H，m)，1.60-1.24(8H，m)。

Synthesis of Compound 4

Under argon at-78 deg.CA solution of ethyl acetate (0.12mL, 1.22mmol) in THF (2mL) was added dropwise to a stirring solution of lithium bis (trimethylsilyl) amide (1.22mL of 1M solution in THF, 1.22 mmol). After 20 min, a solution of 3(0.21g, 1.16mmol) in THF (1mL) was added and the mixture was stirred for 2 h. The mixture was quenched by the addition of saturated ammonium chloride solution (3mL) and then warmed to room temperature. The mixture was diluted with ether (20mL) and diluted hydrochloric acid (15mL) was added. The organic layer was separated and the aqueous layer was further extracted with ether (2X 10 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Heptane/ethyl acetate, 99: 1) to give nitro-ester 4(0.13g, 41%) as a colourless liquid; r_f(heptane/ethyl acetate, 9: 1) 0.32; v. of_max(film)/cm^-1 1731(C＝O)，1547(NO₂)，1375(NO₂)；δ_H(400MHz；CDCl₃)：4.73(2H，s，CH₂NO₂)，4.14(2H，q，J＝7.1，CO₂CH₂Me)，2.58(2H，s，CH₂CO₂Et)，2.07(2H，m)，1.71-1.66(4H，m)，1.60-1.24(8H，m)，1.26(3H，t，J＝7.2，CO₂CH₂Me)；7MHz(ES⁺)270(M+H，100％)。

Synthesis of Compound 5

A solution of 4(0.122g, 0.45mmol) in methanol (40mL) was shaken over a catalytic amount of a sponge nickel catalyst under a hydrogen atmosphere (60Psi, 30 ℃) for 6 hours. The mixture was filtered and the solvent was removed by evaporation under reduced pressure to give amino-ester 5(0.084g, 96%) as a white solid; v. of _max(film)/cm^-1 3228(NH)，1665(C＝O)；δ_H(400MHz；CDCl₃)：5.49(1H，br s，NH)，3.34(2H，s，CH₂NH)，2.25(2H，s，CH₂CO)，2.10-1.98(2H，m)，1.77(2H，dd，J＝13.2，7.1)，1.65(2H，dd，J＝13.2，6.8)，1.62-1.20(8H，m)。

Synthesis of example 38

(2-aminomethyl-octahydro-inden-2-yl) -acetic acid 5(0.083g, 0.43mmol) was dissolved in 1, 4Dioxane (2mL) and hydrochloric acid (8mL of a 6N solution), and the mixture was refluxed for 5 hours. After cooling, the mixture was diluted with water (20mL) and washed with dichloromethane (2X 15 mL). The aqueous layer was removed by evaporation under reduced pressure to give acid 6 as a white solid (0.097g, 91%). It was recrystallized from ethyl acetate/methanol to give example 38(0.057 g); delta_H(400MHz；d₆-DMSO)：7.90(2H，br s，NH₂)，3.02(2H，s，CH₂NH₂)，2.43(2H，s，CH₂CO₂H)，2.00(2H，br s)，1.53-1.24(12H，m)；m/z(ES⁺)212(M + H, 100%); LCMS (Prodigy C1850 mm × 4.6mmid column, 5% -50% acetonitrile/water) retention time 1.12 min, 100% purity.

Example 39

(1 alpha, 3 alpha, 5 alpha) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride

Synthesis of Compound 1

Lithium aluminum hydride (69.4mL of a 1M solution in diethyl ether, 69.4mmol) was added dropwise to a stirring solution of cis-cyclobutane-1, 2-dicarboxylic acid (5g, 34.7mmol) in THF (60mL) at 0 deg.C under argon. The mixture was warmed to room temperature and stirred for 16 hours. After cooling to 0 deg.C, the mixture was quenched by careful addition of water (2.7mL), sodium hydroxide solution (2.7mL of a 15% w/v solution), and water (8.1 mL). The mixture was stirred for 15 minutes and the precipitate was removed by filtration. Removal of the solvent by evaporation under reduced pressure gave alcohol 1 as a colourless oil (4.0g, 98%); delta _H(400MHz；CDCl₃)：3.85(2H，m)，3.6(2H，m)，3.2(2H，s)，2.7(2H，m)，2(2H，m)；1.55(2H，m)；δ_C(400MHz；CDCl₃)：63.15，37.83，20.40。

Synthesis of Compound 2

Methanesulfonyl chloride (6.2mL, 79.1mmol) was added dropwise to the stirring 1(4.0g, 34.4 mmol) under argon at-40 deg.C) In dichloromethane (150 mL). Triethylamine (12.0mL, 86.0mmol) was then added dropwise and the mixture was slowly warmed to room temperature. After stirring for 16 h, the mixture was quenched by addition of dilute hydrochloric acid (50 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2X 50 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Pentane/ether, 6: 4) gave mesylate 2 as a white solid (6.1g, 73%); r_f(heptane/ethyl acetate, 1: 1) 0.18. Delta_H(400MHz；CDCl₃)：4.3(4H，m)，3.05(6H，s)，2.9(2H，m)，2.2(2H，m)，1.8(2H，m)；δ_C(400MHz；CDCl₃)：69.51，37.45，35.28，21.09。

Synthesis of Compound 3

Anhydrous lithium bromide (10.6g, 121.8mmol) was added dropwise to a stirring mixture of a solution of 2(5.95g, 24.4mmol) in acetone (50mL) under argon and the mixture refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure and the residue was dissolved in diethyl ether (50mL), washed successively with water (50mL), brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Pentane/diethyl ether, 95: 5) to give bromide 3 as an orange liquid (5.36g, 86%); r _f(heptane/ethyl acetate, 8: 2), 0.82. Delta_H(400MHz；CDCl₃)：3.6(2H，m)，3.45(2H，m)，2.85(2H，m)，2.1(2H，m)，1.7(2H，m；δ_C(400MHz；CDCl₃)：39.70，33.79，23.95。

Synthesis of Compound 4

To a cooled suspension of (0 ℃) potassium hydride (1.58g, 39.5mmol) (previously washed 3 times with pentane) in tetrahydrofuran (22mL) under argon was added a solution of methylmethylthiomethylsulfoxide (1.36mL, 13.04mmol, previously dried for 3 hours over molecular sieves) in tetrahydrofuran (3mL) for 1 hour. After stirring for a further 30 minutes, a solution of 3(3.17g, 13.1mmol) in THF (2mL) was added over 1 hour at 0 ℃. The reaction mixture was then warmed to room temperature and stirredAnd (4) at night. The mixture was quenched by addition of aqueous ammonium chloride (6mL, 25%). After 10 minutes, the solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in diethyl ether (20mL) and 9N sulfuric acid (0.05mL) was added. After stirring for 30 hours, saturated sodium bicarbonate was added. The ether phase was separated off and concentrated to 5 mL. Saturated sodium bisulfite solution (1.5g) was added and the mixture was stirred for 30 minutes. The two phases were separated. The ether phase was stirred with a saturated solution of sodium bisulfite (0.5g) for a further 30 minutes. The phases were separated and the collected aqueous phase was treated with aqueous sodium hydroxide (5mL, 20%) and extracted with ether. The ether phase was dried (MgSO)₄) Concentration under reduced pressure gave compound 4(0.16g, 11%) as a yellow liquid. Delta _H(400MHz；CDCl₃)：3.0(2H，m)，2.15-2.45(6H，m)，1.65(2H，m)。

Synthesis of Compound 5

Triethylphosphoacetonide (0.32mL, 1.61mmol) was added dropwise to a stirring suspension of sodium hydride (0.059g of a 60% oil dispersion, 1.47mmol) in tetrahydrofuran (2mL) at 0 ℃ under argon. After 20 minutes, a solution of ketone 4(0.16g, 1.45mmol) in THF (1mL) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. Water (5mL) was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO)₄). The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Heptane/ethyl acetate, 95: 5) to give ester 5 as a colorless oil (0.166g, 0.92mmol, 64%); delta_H(400MHz；CDCl₃)：5.9(1H，s)，4.2(2H，q)，3.15(1H，d)，2.9(1H，m)，2.8(1H，m)；2.65(2H，m)，2.3(1H，d)，2.15(2H，m)，1.5(2H，m)，1.3(3H，t)；δ_C(400MHz；CDCl₃)：169.51，166.98，113.37，59.62，43.23，38.79，38.45，36.20，25.62，24.95，14.44。

Synthesis of Compound 6

Ester 5(0.152g, 0.84mmol), nitromethane (0.092mL, 1.7mmol) and tetrabutylammonium fluoride (1.03mL of a 1M solution in THF, 1.03mmol) were heated to 65 ℃ in THF (1mL) for 4 hours. MixingAfter cooling, the mixture was diluted with ether (30mL) and acidified with 2N hydrochloric acid (5 mL). The organic layer was washed with brine and dried (MgSO)₄) The solvent was then removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Heptane/ether, 95: 5) to give nitro-ester 6(0.085g, 0.35mmol, 41%) as a colorless liquid; delta _H(400MHz；CDCl₃)：4.4(2H，s)，4.15(2H，q)，2.75(2H，bs)，2.7(2H，s)，2.3(2H，m)；2.1(2H，m)，1.65(4H，m)，1.15(3H，t)；δ_C(400MHz；CDCl₃)：171.48，79.68，60.52，50.10，44.15，41.06，37.36，25.76，14.28。

Synthesis of Compounds 7A and 7B

A solution of the nitro ester 6(0.076g, 0.31mmol) in methanol (10mL) was shaken over a catalytic amount of sponge nickel catalyst under a hydrogen atmosphere (50Psi, 30 ℃ C.) for 12 hours. After the mixture was filtered, the solvent was evaporated under reduced pressure to give a mixture (0.05g) containing lactam 7A and amino ester 7B as a white solid. It was used without further purification and treatment.

Synthesis of example 39

7A and 7B (0.05g) were dissolved in hydrochloric acid (2mL of a 6N solution), and the mixture was refluxed for 4 hours. After cooling, the solvent was evaporated under reduced pressure to give the acid as a white solid. It was recrystallized from ethyl acetate/methanol to afford pure example 39(0.045g, 0.2mmol, 64%); delta_H(400MHz；D₂O)：3(2H，s)，2.85(4H，m+s)，2.35(2H，m)，2.1(2H，m)，1.75(4H，m)。δ_C(400MHz；D₂O)：167.5，46.64，43.89，42.03，40.89，36.08，23.91。m/z(ES⁺)184(M+H，100％)。

Example 40

(±) - (1 α, 5 β) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride

Synthesis of Compound 1

Lithium aluminum hydride (134.8mL of a 1M solution in diethyl ether, 134.8mmol) was added dropwise to a stirring solution of cis-cyclobutane-1, 2-dicarboxylic acid (9.71g, 67.39mmol) in THF (120mL) at 0 deg.C under argon. The mixture was warmed to room temperature and then stirred for 16 hours. The mixture was cooled to 0 ℃ and quenched by careful addition of water (5.2mL), sodium hydroxide solution (5.2mL of a 15% w/v solution), and water (15.7 mL). The mixture was stirred for 15 minutes and filtered to remove the precipitate. Removal of the solvent by evaporation under reduced pressure gave alcohol 1 as a pale yellow oil (6.73g, 57.64mmol, 85%); delta _H(400MHz；CDCl₃)：3.85(2H，m)，3.6(2H，m)，2.9(2H，s)，2.7(2H，m)，2(2H，m)；1.55(2H，m)。

Synthesis of Compound 2

Methanesulfonyl chloride (29.3mL, 373.8mmol) was added dropwise to a stirring solution of 1(8.85g, 75.8mmol) in dichloromethane (500mL) at-40 ℃ under argon. Triethylamine (63.4mL, 454.4mmol) was added dropwise and the mixture was slowly warmed to room temperature. After stirring for 16 h, the mixture was quenched by addition of dilute hydrochloric acid (100 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2X 100 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Heptane/ethyl acetate, 6: 4) to give mesylate 2 as a white solid (15.89g, 58.3mmol, 77%); delta_H(400MHz；CDCl₃)：3.0(6H，m)，2.6(2H，m)，2.05(2H，m)，1.8(2H，m)。

Synthesis of Compound 3

Anhydrous lithium bromide (25g, 287.3mmol) was added to a stirring mixture of 2(15.84g, 57.4mmol) and acetone (150mL) under argon and the mixture refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure and the residue was dissolved in diethyl ether (100mL), washed successively with water (100mL) and brine and dried (MgSO)₄) The solvent was evaporated under reduced pressure to give bromide 3 as an orange liquid (13.5g, 55.8mmol, 97%))；δ_H(400MHz；CDCl₃)：3.5(4H，m)，2.45(2H，m)，2.05(2H，m)，1.6(2H，m)。

Synthesis of Compound 4

To a cooled (0 ℃ C.) suspension of potassium hydride (1.08g, 27mmol), which had been washed 3 times with pentane beforehand, in THF (15mL) under argon was added a solution of methylmethylthiomethylsulfoxide (0.93mL, 8.92mmol, which had been dried over molecular sieves for 3 hours) in THF (2mL) for 1 hour. After stirring for a further 30 minutes, a solution of 3(2.16g, 8.93mmol) in THF (1mL) was added at 0 ℃ over 1 hour. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched by addition of aqueous ammonium chloride (6mL, 25%). After 10 min, the solid was removed by filtration and the filtrate was concentrated. The residue was dissolved in diethyl ether (20mL) and 9N sulfuric acid (0.03mL) was added. After stirring for 30 hours, saturated sodium bicarbonate was added. The ether phase was separated off and concentrated to 5 mL. A saturated solution of sodium bisulfite (1.5g) was added, and the mixture was stirred for 30 minutes. The two phases were separated. The ether phase was stirred with a saturated solution of sodium bisulfite (0.5g) for a further 30 minutes. The phases were separated and the collected aqueous phase was treated with sodium hydroxide solution (5mL, 20%) and extracted with ether. Drying (MgSO) ₄) The ether phase was evaporated under reduced pressure to remove the solvent to give 4(0.141g, 15%) as a yellow liquid; delta_H(400MHz；CDCl₃)：2.25(4H，m)，2.0(4H，m)，1.7(2H，m)。

Synthesis of Compound 5

Triethylphosphoacetonide (0.28mL, 1.41mmol) was added dropwise to a stirring suspension of sodium hydride (0.052g of a 60% oil dispersion, 1.47mmol) in tetrahydrofuran (2mL) at 0 ℃ under argon. After 20 minutes, a solution of ketone 4(0.141g, 1.28mmol) in THF (1mL) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. Water (5mL) was added, and the mixture was extracted. The combined organic extracts were washed with brine and dried (MgSO)₄) The solvent was removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Heptane/ethyl acetate, 95: 5) to give ester 5(0.092g, 0.51mmol, 40%) as a colorless oil; delta_H(400MHz；CDCl₃)：5.85(1H，s)，4.1(2H，q)，3.1(1H，d.d)，2.45(1H，d.d)，2.2(2H，m)，1.75(2H，m)，1.4(2H，m)，1.25(3H，t)；δ_C(400MHz；CDCl₃)：170.53，166.57，115.13，59.62，47.06，45.69，39.89，37.24，28.52，28.17，14.44。

Synthesis of Compound 6

Ester 5(0.09g, 0.5mmol), nitromethane (0.055mL, 1.02mmol) and tetrabutylammonium fluoride (0.61mL of a 1M solution in THF, 0.61mmol) were heated together in THF (1mL) to 65 ℃ for 4 hours. After the mixture was cooled, it was diluted with ether (30mL) and acidified with 2N hydrochloric acid (5 mL). The organic layer was washed with brine and dried (MgSO)₄) The solvent was then removed by evaporation under reduced pressure. Chromatography of the residue (SiO)₂Heptane/diethyl ether, 95: 5) to give nitro-ester 6(0.063g, 0.26mmol, 52%) as a colorless liquid; delta _H(400MHz；CDCl₃)：4.65(2H，[AB]q)，4.15(2H，q)，2.65(2H，[AB]q), 1.2-1.95(3H, t and m, 13H); delta_C(400MHz；CDCl₃)：171.28，82.42，60.56，49.97，45.80，45.32，42.88，40.19，40.09，27.64，14.26。

Synthesis of Compounds 7A and 7B

A solution of nitro-ester 6(0.063g, 0.26mmol) in methanol (10mL) was shaken over a catalytic amount of sponge nickel catalyst under a hydrogen atmosphere (50Psi, 30 ℃ C.) for 12 hours. After the mixture was filtered, the solvent was evaporated under reduced pressure to give a mixture (0.051g) containing lactam 7A and amino-ester 7B as a white solid. It was used without further purification and treatment.

Synthesis of example 40

7A and 7B (0.051g) were dissolved in hydrochloric acid (2mL of 6N solution) and the mixture was refluxed for 4 hours. After cooling, the solvent was evaporated under reduced pressure to give the acid as a white solid. It was recrystallized from ethyl acetate/methanol to afford pure example 40(0.046g, 0.21mmol, 81%); delta_H(400MHz；D₂O)：3.3(2H，[AB]q)，2.7(2H，[AB]q)，2(2H，m)，1.35-1.85(8H，m)；δ_C(400MHz；D₂O)：174.8，47.50，46.59，44.28，43.61，41.64，38.37，38.09，25.88。

m/z(ES+)184(M+H，100％)。

EXAMPLE 41

(1 α, 3 β, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride

Synthesis of Compound (2)

Dibromide 1(5.7g, 22.3mmol), ethyl cyanoacetate (4.8mL, 44.5mmol) and potassium carbonate (6.15g, 44.5mmol) were stirred together in DMF (100mL) for 48 h. Dilute hydrochloric acid (100mL) was added and the mixture was extracted with ether (3X 100 mL). The combined organic extracts were washed with brine and dried (MgSO)₄) The solvent was evaporated under reduced pressure. Chromatography of the residue (SiO) ₂Heptane-ethyl acetate, 98: 2) to give cyanoester 2(4.3g, 100%) whose diastereoisomeric mixture was 68: 32: rf (heptane-ethyl acetate, 9: 1) 0.28; v. of_max(film)/cm^-12241(CN), 1741(C ═ O); major diastereomer: Δ H (400 MHz; CDCl)₃)4.30(2H，q，J 7.1，CO₂CH₂Me), 2.98(2H, m), 2.56-2.22(6H, m), 1.70(2H, m), 1.35(3H, t, J7.1, Me); minor diastereomer: Δ H (400 MHz; CDCl)₃)4.26(2H，q，J 7.1，CO₂CH₂Me)，3.05(2H，m)，2.56-2.22(6H，m)，1.99(2H，m)，1.33(3H，t，J 7.1，Me)。

Synthesis of Compound (3)

Cyano ester 2(0.76g, 3.91mmol), water (0.14mL, 7.82mmol) and lithium chloride (0.66g, 15.6mmol) were heated in DMSO (40mmL) to 150 ℃ for 22 hours. The mixture was cooled, diluted with water (150mL) and extracted with ether (3X 50 mL). The combined ether extracts were washed with brine and dried (MgSO)₄) The solvent was evaporated under reduced pressure. Chromatography of the residue (SiO)₂Heptane-ethyl acetate, 95: 5) to give cyanide 3(0.21g, 44%) whose diastereomer mixture was 60: 40; rf (heptane-ethyl acetate, 9: 1) 0.44; v. of_max(film)/cm^-12238 (CN); major diastereomer: Δ H (400 MHz; CDCl)₃)2.97(1H, m), 2.87(2H, m), 2.32-2.18(2H, m), 2.10-1.96(3H, m), 1.92-1.78(2H, m), 1.48-1.38(1H, m); minor diastereomer: Δ H (400 MHz; CDCl) ₃)3.13(1H，m)，2.87(2H，m)，2.32-2.18(2H，m)，2.10-1.96(3H，m)，1.92-1.78(2H，m)，1.48-1.38(1H，m)。

Synthesis of Compound (4)

A solution of cyanide 3(0.86g, 7.1mmol) in THF (30mL) was added dropwise to a stirred solution of lithium hexamethyldisilazide (7.8mL of 1M solution in THF, 7.8mmol) in THF (40mL) at-78 deg.C under argon. The mixture was heated to-40 ℃ and stirred for 2 hours. The mixture was cooled to-78 deg.C, then dimethylallyl bromide (1.3mL, 10.6mmol) was added. The mixture was stirred at-78 ℃ for a further 2 hours and then warmed to room temperature overnight. Saturated ammonium chloride (20mL) was added and the mixture was diluted with ether (50mL) and then eluted with hydrochloric acid (30 mL). The aqueous layer was further extracted with ether (2X 50mL) and the combined organic extracts were washed with brine and dried (MgSO)₄) The solvent was evaporated under reduced pressure. Chromatography of the residue (SiO)₂Heptane-ethyl acetate, 98: 2) to give cyanoalkene 4 as a colorless oil (0.96g, 72%); rf (heptane-ethyl acetate, 95: 5) 0.38; v. of_max(film)/cm^-1 2230(CN)，1673(C＝C)；δH(400MHz；CDCl₃)5.27(1H，tt，J 7.6，1.3，CHCMe₂)，2.89(2H，m)，2.30-2.22(4H，m)，2.10(2H，d，J 14.2)，1.94(2H，m)，1.84-1.62(2H，m)，1.65(3H，s，Me)，1.55(3H，s，Me)；m/z(AP+)190(M+H，100％)。

Synthesis of Compound (5)

Cyanoolefin 4(0.96g, 5.1mmol) and sodium hydroxide (10.2 mL)2.5M methanol solution, 25.5mmol) were stirred together in dichloromethane (80mL) at-78 ℃. The mixture turned orange immediately by passing ozone through it. After 2 hours, the mixture turned green and the solution was purged with oxygen for 5 minutes, followed by purging with nitrogen. To the stirring mixture was added diethyl ether (100mL) and water (100mL) to dilute, and then warmed to room temperature overnight. The aqueous layer was further extracted with ether (2X 50mL) and the combined organic extracts were washed with brine and dried (MgSO) ₄) The solvent was evaporated under reduced pressure. Chromatography of the residue (SiO)₂Heptane-ethyl acetate, 95: 5) to give cyano ester 5 as a yellow oil (0.70g, 71%); rf (heptane-ethyl acetate, 8: 2) 0.36; v. of_max(film)/cm^-1 2233(CN)，1740(C＝O)；δH(400MHz；CDCl₃)3.75(3H，s，OMe)，2.94(2H，m)，2.63(2H，s，CH₂CO₂Me)，2.35-2.21(4H，m)，2.00(2H，m)，1.86(2H，m)；m/z(AP+)194(M+H，95％)。

Synthesis of Compound (6)

A solution of the cyanoester 5(0.81g, 4.2mmol) in methanol (100mL) was shaken over a catalytic amount of a sponge nickel catalyst under a hydrogen atmosphere (60Psi, 30 ℃ C.) for 6 hours. The mixture was filtered and the solvent was evaporated under pressure to give lactam 6 as a white solid (0.64g, 92%); v. of_max(film)/cm^-1 1692(C＝O)；δH(400MHz；CDCl₃)5.52(1H，br s，NH)，3.54(2H，s，CH₂NH)，2.80(2H，m)，2.26(2H，m)，2.16(2H，s，CH₂CO)，1.93(2H，ddd，J 13.4，8.1，2.4)，1.74(2H，dd，J 13.0，3.2)，1.64(2H，m)。

Synthesis of (1. alpha., 3. beta., 5. alpha.) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride (example 41)

Lactam 6(0.64g, 3.87mmol) was dissolved in 1, 4-dioxane (4mL) and hydrochloric acid (16mL of 6N solution) and the mixture refluxed for 6 hours. After cooling, the mixture was diluted with water (20mL) and washed with dichloromethane (2X 15 mL). Evaporation of the aqueous layer under pressure gave acid 7 as a white solid (0.67g, 79%). With ethyl acetateRecrystallization from methanol gave pure example 41(0.26 g); Δ H (400 MHz; d)₆-DMSO)7.98(2H，br s，NH₂)，3.13(2H，s，CH₂NH₂) 2.70(2H, s), 2.17-2.14(4H, m), 1.85(2H, dd, J13.3, 8.0), 1.63(2H, m), 1.55(2H, dd, J12.9, 5.1); m/z (ES +)184(M + H, 100%); LCMS (Prodigy C18, 50mm × 4.6mmid column, 5-50% acetonitrile/water) retention time 2.40 min, 98% purity.

The following compounds were prepared by at least one of the methods of examples 34-41.

(1 alpha, 5 beta) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1. alpha., 5. beta.) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 alpha, 5 beta) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid,

(1 α, 6 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 β) (2-aminomethyl-decahydro-azulene-2-yl) -acetic acid,

(1 alpha, 5 beta) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1. alpha., 5. beta.) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 alpha, 5 beta) (2-aminomethyl-octahydro-pentalen-2-yl) -acetic acid,

(1 α, 6 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1 alpha, 3 alpha, 5 alpha) (3-aminomethyl-bicyclo [3.1.0] hex-3-yl) -acetic acid,

(1 α, 3 α, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 α, 6 α, 8 α) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 alpha, 7 alpha, 9 alpha) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

(1 α, 3 β, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid,

(1 α, 6 α, 8 β) (2-aminomethyl-octahydro-inden-2-yl) -acetic acid,

(1 α, 7 α, 9 β) (2-aminomethyl-decahydro-azulen-2-yl) -acetic acid,

((1R, 3R, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3S, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3S, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3R, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3R, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1R, 3S, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3S, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3R, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((3. alpha. R, 5S, 7. alpha. S) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3. alpha. S, 5S, 7. alpha. R) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3. alpha. S, 5R, 7. alpha. R) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((2S, 4. alpha. R, 8. alpha. S) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4. alpha. R, 8. alpha. S) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4. alpha. S, 9. alpha. R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2S, 4. alpha. R, 9. alpha. S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2R, 4. alpha. R, 9. alpha. S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((1R, 3R, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3S, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3S, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1S, 3R, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) -acetic acid,

((1R, 3R, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1R, 3S, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3S, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((1S, 3R, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) -acetic acid,

((3. alpha. R, 5S, 7. alpha. R) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3. alpha. S, 5S, 7. alpha. S) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((3. alpha. S, 5R, 7. alpha. S) -5-aminomethyl-octahydro-inden-5-yl) -acetic acid,

((2. alpha., 4. alpha. R, 8. alpha. R) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4. alpha. S, 8. alpha. R) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2R, 4. alpha. S, 8. alpha. S) -2-aminomethyl-decahydro-naphthalen-2-yl) -acetic acid,

((2S, 4. alpha. R, 9. alpha. R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2S, 4. alpha. S, 9. alpha. S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid,

((2R, 4. alpha. S, 9. alpha. S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) -acetic acid.

The following procedure relates in particular to the preparation of example 42, ((1 α, 3 α, 5 α) -3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid.

Method 1

Nitromethane and a base, such as potassium carbonate, sodium carbonate or cesium carbonate, are added to a solution of an unsaturated ester, such as dimethyl sulfoxide or N, N-dimethylformamide thereof, at a temperature of from 0 ℃ to 120 ℃. This process allows to obtain high yields of nitro esters while reducing the yield of the deconjugated esters compared to the previous route.

Method 2A

a) Alkyl cyanoacetates, such as ethyl cyanoacetate, are added to a cycloheptanone mixture of formula (1) dissolved in a solvent selected from toluene, benzene, xylene, or n-heptane, to which acetic acid and alpha-alanine or ammonium acetate, or pyridine are also added. Stirring the mixture at a temperature of from 0 ℃ to 150 ℃ and removing the water by using, for example, a dean-Stark trap or an activated molecular sieve to give an olefin of the general formula (2);

b) adding the product of step a) above to a mixture containing benzylmagnesium chloride or bromide or iodide dissolved in an anhydrous solvent selected from tetrahydrofuran, 1, 4-dioxane, n-heptane, toluene, diethyl ether, or tert-butylethyl ether at a temperature of-100 ℃ to 110 ℃ to give an addition product of general formula (3);

c) adding the product of step b) above to a mixture of bases containing potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent selected from 1, 2-ethylene glycol, 2-methoxyethyl ether, 1, 4-dioxane, or diethylene glycol at a temperature of 25 ℃ to 250 ℃ to give a carboxylic acid of formula (4);

d) adding the product of step c) above to a mixture containing methyl iodide dissolved in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1, 4-dioxane, to which a base such as 1, 8-diazobicyclo [5.4.0] undecane-7-ene (DBU), triethylamine, or 1, 5-diazobicyclo [4.3.0] non-5-ene (DBN) is also added, followed by stirring at a temperature of-40 ℃ to 110 ℃ to give an ester of formula (5); or adding the product of step c) above to a mixture containing methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature of 0 ℃ to 100 ℃; or adding the product of the step c) into a benzene solution or a toluene solution of trimethylsilylazidomethane and methanol at a temperature of-40 ℃ to 100 ℃; or adding the product of step c) above to a solution of diazomethane in a solvent such as benzene, toluene, dichloromethane, or diethyl ether at a temperature of-40 ℃ to 40 ℃;

e) Adding the product of step d) to a mixture containing carbon tetrachloride or ethyl acetate and acetonitrile, to which are also added water, sodium periodate and ruthenium (III) chloride, followed by stirring at a temperature of-40 ℃ to 80 ℃ to give a carboxylic acid of the general formula (6);

f) adding the product of step e) above to a mixture containing a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylene, tetrahydrofuran, diethyl ether, or n-heptane, to which is also added diphenylphosphoryl azide (DPPA), followed by stirring at a temperature of 0 ℃ to 150 ℃ to obtain an isocyanate of general formula (7); or adding the product of step e) above to a solution of ethyl or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or in acetone or in diethyl ether at a temperature of-40 ℃ to 78 ℃, followed by addition of a solution of sodium azide in water and tetrahydrofuran or acetone, followed by addition of toluene or benzene under reflux; then the

g) Adding the product of the above step f) to a solvent selected from toluene, benzene, xylene, or n-heptane, to which methanol or t-butanol is also added, to obtain (8), and then adding (8) to an aqueous hydrochloric acid solution at a concentration of 0.01M to 12M in the presence or absence of a solvent such as 1, 4-dioxane, acetic acid, or water, to obtain an amino acid (9); or the product of step f) is added to a solvent selected from toluene, benzene, xylene or n-heptane to which benzyl alcohol is also added to give (8), then (8) is hydrogenated with nickel or palladium or platinum to give a lactam which is then hydrolyzed again in aqueous hydrochloric acid at a concentration of 0.01M to 12M in the presence or absence of a solvent such as 1, 4-dioxane, acetic acid or water to give example 42.

Method 2B

a) Adding the cyano ester (2) to a solution of alkylmagnesium chloride or alkylmagnesium bromide or 2-butenyl magnesium chloride in an anhydrous solvent selected from tetrahydrofuran, 1, 4-dioxane, n-heptane, toluene, diethyl ether, or tert-butylethyl ether at a temperature of-100 ℃ to 110 ℃ to give an addition product of the general formula (10);

b) adding the product of step a) above to a mixture of bases containing potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent selected from 1, 2-ethylene glycol, 2-methoxyethyl ether, 1, 4-dioxane, or diethylene glycol at a temperature of 25 ℃ to 250 ℃ to give a carboxylic acid of general formula (11);

c) adding the product of the above step b) to a mixture containing methyl iodide dissolved in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1, 4-dioxane, to which a base such as 1, 8-diazobicyclo [5.4.0] undecane-7-ene (DBU), triethylamine, or 1, 5-diazobicyclo [4.3.0] non-5-ene (DBN) is further added, followed by stirring at a temperature of-40 ℃ to 110 ℃ to obtain an ester of the general formula (11); or adding the product of step b) above to a mixture containing methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature of 0 ℃ to 100 ℃; or adding the product of the step c) into a benzene solution or a toluene solution of trimethylsilylazidomethane and methanol at a temperature of-40 ℃ to 100 ℃; or adding the product of step b) above to a solution of diazomethane in a solvent such as benzene, toluene, dichloromethane, or diethyl ether at a temperature of-40 ℃ to 40 ℃; then d) the product of step c) above is added to a mixture containing carbon tetrachloride or ethyl acetate and acetonitrile, to which is also added water, sodium periodate and ruthenium (III) chloride, followed by stirring at a temperature of-40 ℃ to 80 ℃ to give example 42.

Method 2C

Example 42

a) Adding an organometallic reagent such as a solution of vinylmagnesium chloride or vinylmagnesium bromide dissolved in a solvent such as tetrahydrofuran or diethyl ether at a temperature of-100 ℃ to 0 ℃ to the cyano ester (2) to obtain (13);

b) adding the product of step a) above to a mixture of bases containing potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent selected from 1, 2-ethylene glycol, 2-methoxyethyl ether, 1, 4-dioxane, or diethylene glycol at a temperature of 25 ℃ to 250 ℃ to give a carboxylic acid of formula (14);

c) adding the product of the above step b) to a mixture containing methyl iodide dissolved in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1, 4-dioxane, to which a base such as 1, 8-diazobicyclo [5.4.0] undecane-7-ene (DBU), triethylamine, or 1, 5-diazobicyclo [4.3.0] non-5-ene (DBN) is further added, followed by stirring at a temperature of-40 ℃ to 110 ℃ to obtain an ester of the general formula (15); or adding the product of step b) above to a mixture containing methanol and a concentrated acid such as sulfuric acid or hydrochloric acid at a temperature of 0 ℃ to 100 ℃; or adding the product of the step b) into a benzene solution or a toluene solution of trimethylsilylazidomethane and methanol at a temperature of-40 ℃ to 100 ℃; or adding the product of step b) above to a solution of diazomethane in a solvent such as benzene, toluene, dichloromethane, or diethyl ether at a temperature of-40 ℃ to 40 ℃;

d) Ozonolysis of the product of step c) above in a solvent such as chloroform or dichloromethane or methanol followed by addition of a quencher such as triphenylphosphine or dimethylsulfide at a temperature of-100 ℃ to 0 ℃ to give (16);

e) reacting the product of step d) above with an aqueous ammonia solution or ammonia gas in a solvent such as methanol or ethanol, followed by reduction with sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or in the presence of, for example, nickel, palladium or platinum to give (17); then the

f) Example 42 was obtained by hydrolysis of the product of step e) above with aqueous hydrochloric acid at a concentration of 0.01M to 12M, in the presence or absence of a solvent such as 1, 4-dioxane, acetic acid, or water.

Method 3

Stirring the unsaturated ester and benzyl thioisocyanate in a solvent mixture consisting of tetrahydrofuran, diethyl ether, or 1, 4-dioxane, a coordinating solvent such as HMPA or DMPU, and an alcohol such as t-butanol, with samarium iodide at a temperature of-100 ℃ to 0 ℃; the resulting ester is hydrogenated at a temperature of 20 ℃ to 100 ℃ in a solvent such as methanol, ethanol, ethyl acetate with a catalyst such as nickel, palladium, platinum, or rhodium to give the amino ester.

Method 4A

a) Mixing a chloride or bromide of, for example, vinyllithium or vinylmagnesium with dimethylzinc, zinc chloride, copper (I) iodide, copper (I) bromide dimethylsulfide complex, or copper (I) cyanide in the presence of a solution of a Lewis acid, such as boron trifluoride-diethyl ether complex or aluminum chloride, in a solvent such as tetrahydrofuran or diethyl ether at a temperature of-100 ℃ to 0 ℃ and then adding the unsaturated ester (1) to obtain an addition product (2);

b) ozonolysis of the product of step a) above in a solvent such as chloroform or dichloromethane or methanol followed by addition of a quencher such as triphenylphosphine or dimethylsulfide at a temperature of-100 ℃ to 0 ℃ to give (3);

c) reacting the product of the step b) with an aqueous ammonia solution or ammonia gas in a solvent such as methanol or ethanol, followed by reduction with sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or reduction in the presence of, for example, nickel, palladium or platinum to give (4); then the

d) Example 42 was obtained by hydrolysis of the product of step c) above with aqueous hydrochloric acid at a concentration of 0.01M to 12M, in the presence or absence of a solvent such as 1, 4-dioxane, acetic acid, or water.

Method 4B

a) Mixing, for example, alkylmagnesium chloride or benzylmagnesium bromide with dimethylzinc, zinc chloride, copper (I) iodide, copper (I) bromide dimethylsulfide complex, or copper (I) cyanide in the presence of a solution of a Lewis acid, such as boron trifluoride-diethyl ether complex or aluminum chloride, in a solvent such as tetrahydrofuran or diethyl ether at a temperature of-100 ℃ to 0 ℃ and then adding the unsaturated ester (1) to give an addition product (6); or mixing, for example, benzylmagnesium chloride or bromide with dimethylzinc, zinc chloride, copper (I) iodide, copper (I) bromide dimethylsulfide complex, or copper (I) cyanide in the presence of a solution of a Lewis acid, such as boron trifluoride-diethyl ether complex or aluminum chloride, in a solvent such as tetrahydrofuran or diethyl ether at a temperature of-100 ℃ to 0 ℃ and then adding the unsaturated ester (1) to give an addition product (7);

b) adding the product of step a) to a mixture containing carbon tetrachloride or ethyl acetate and acetonitrile, to which water, sodium periodate and ruthenium (III) chloride are also added, followed by stirring at a temperature of-40 ℃ to 80 ℃ to give a carboxylic acid of the general formula (8);

c) Adding the product of step b) above to a mixture containing a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylene, tetrahydrofuran, diethyl ether, or n-heptane, to which is also added diphenylphosphoryl azide (DPPA), followed by stirring at a temperature of 0 ℃ to 150 ℃ to obtain an isocyanate of general formula (9); or adding the product of step b) above to a solution of ethyl or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or in acetone or in diethyl ether at a temperature of-40 ℃ to 78 ℃, followed by addition of a solution of sodium azide in water and tetrahydrofuran or acetone, followed by addition of toluene or benzene under reflux;

d) adding the product of the above step c) to a solvent selected from toluene, benzene, xylene, or n-heptane, to which methanol or t-butanol is further added, to obtain (10), and then adding (10) to an aqueous hydrochloric acid solution having a concentration of 0.01M to 12M in the presence or absence of a solvent such as 1, 4-dioxane, acetic acid, or water, to obtain an amino acid (5); or the product of step c) is added to a solvent selected from toluene, benzene, xylene or n-heptane to which benzyl alcohol is also added to give (10) which is then hydrogenated with nickel or palladium or platinum to give the lactam which is then hydrolyzed again in aqueous hydrochloric acid at a concentration of 0.01M to 12M in the presence or absence of a solvent such as 1, 4-dioxane, acetic acid or water to give example 42.

Method 5

a) Refluxing compound (1) with potassium cyanide or sodium cyanide and water and ethanol or methanol together, removing water by using, for example, a dean-stark trap to give (2);

b) stirring the product of step a) with ethanol or toluene or benzene and saturating the solution with gaseous hydrochloric acid at a temperature of-30 ℃ to 40 ℃ to obtain (3);

c) hydrogenating the product of step b) above in methanol, ethanol, or ethyl acetate at a temperature of 15 ℃ to 60 ℃ with a catalyst such as nickel, palladium, platinum, or rhodium to give (4); then the

The following examples describe pharmaceutical compositions of the invention comprising an alpha delta ligand in an amount effective to treat tinnitus and a pharmaceutically acceptable carrier, diluent, or excipient. These examples are merely representative and are not to be construed as limiting any aspect of the present invention.

Formulation example 1

Tablet formulation:

the component dosage (mg)

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride 25

Lactose 50

Corn starch (for blending) 10

Corn starch (paste) 10

Magnesium stearate (1%) 5

Total 100

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, lactose and corn starch (for mixing) were mixed well. The corn starch (paste) was suspended in 200mL of water, heated and stirred to form a paste. The paste was used to granulate the mixed powder. The wet granulation was screened through a No. 8 hand sieve and dried at 80 ℃. The dried granules were lubricated with 1% magnesium stearate and compressed into tablets. The tablet can be administered to human for treating tinnitus 1-4 times per day.

Formulation example 2

Coating tablets:

the tablets of formulation example 1 were coated with sucrose, potato starch, mica, tragacanth gum and a coloring agent according to a conventional method.

Formulation example 3

Injection vial:

the pH of the solution containing 500g of gabapentin and 5g of disodium hydrogen phosphate was adjusted to pH6.5 with 2M hydrochloric acid in 3L of redistilled water. The solution is sterile filtered, the filtrate is filled into injection vials, lyophilized under sterile conditions, and then aseptically packaged. Each injection vial contained 25mg of gabapentin.

Formulation example 4

Suppository:

a compound containing 25g of (1 α, 3 α, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride, 100g of soybean lecithin, and 1400g of cocoa butter was melted, injection molded, and then allowed to cool. Each suppository contains 25mg of (1. alpha., 3. alpha., 5. alpha.) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride.

Formulation example 5

Solution preparation:

1g of 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4]Oxadiazole-5-one hydrochloride, 9.38g NaH₂PO₄·12H₂O、28.48g Na₂HPO₄·12H₂O, and 0.1g of algaecide were dissolved in 940mL of redistilled water to prepare a solution. The pH of the solution was adjusted to pH6.8 with 2M hydrochloric acid. The solution was diluted to 1.0L with redistilled water and sterilized by irradiation. 25mL volume of solution contained 25mg of 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4 ]-oxadiazole-5-one hydrochloride.

Preparation 6

Ointment:

500mg of 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride are mixed with 99.5g of vaseline under sterile conditions. Each 5g portion of ointment contained 25mg of 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride.

Preparation 7

And (3) capsule preparation:

according to the conventional method, 2kg of 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride are filled into hard gelatin capsules, each of which contains 25mg of 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride.

Formulation example 8

An ampoule agent:

2.5kg of gabapentin solution was dissolved in 60L of redistilled water. The solution is sterile filtered and the filtrate is filled into ampoules. The ampoule is lyophilized under aseptic conditions and aseptically packaged. Each ampoule contained 25mg gabapentin.

As noted above, the methods of the present invention provide significant advantages over existing methods of treating diseases, including tinnitus, which alleviate the affliction or secondary symptoms, but do not have disease modifying effects. Gabapentin, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, 3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, 3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, 3- (2-amino-1-cyclopentyl-ethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride, or (1 α, 3 α, 5 α) (3-aminomethyl-bicyclo [3.2.0] hept-3-yl) -acetic acid hydrochloride in MIA mice, alpha 2 delta ligands are useful for preventing or treating tinnitus.

Having described the method of the invention, various embodiments of the invention are claimed.

Claims

1. A method of treating tinnitus in a mammal suffering therefrom comprising administering a therapeutically effective amount of an α 2 δ ligand other than gabapentin or tiagabine, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the α 2 δ ligand is a compound of formula I

And pharmaceutically acceptable salts thereofWherein R is₁Is hydrogen or straight chain or branched lower alkyl, and n is an integer of 4 to 6.

3. The method according to claim 1, wherein the α 2 δ ligand is a compound of formula II

And pharmaceutically acceptable salts thereof, wherein:

R₁is a linear or branched unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted phenyl group or an unsubstituted cycloalkyl group having 3 to 6 carbon atoms;

R₂is hydrogen or methyl; and

R₃hydrogen, methyl or carboxyl.

4. A method according to claim 3, wherein the α 2 δ ligand is pregabalin.

5. The method according to claim 1, wherein the α 2 δ ligand is a compound of the formula

OrOr

Or a pharmaceutically acceptable salt thereof, wherein:

n is an integer of 0 to 2;

m is an integer of 0 to 3;

r is a sulfonamide,

the acid amide,

the amount of phosphonic acid present,

a heterocyclic ring,

sulfonic acid, or

Hydroxamic acid;

R₁-R₁₄each independently selected from hydrogen or a linear or branched alkyl group containing 1 to 6 carbon atoms, an unsubstituted or substituted benzyl or phenyl group, wherein the substituents are selected from halogen, alkyl, alkoxy, hydroxy, carboxy, alkoxycarbonyl, trifluoromethyl and nitro;

A' is a bridged ring selected from:

and

wherein

Is a connecting point;

Z₁-Z₄each is independently selected from hydrogen and methyl;

o is an integer of 1 to 4; and

p is an integer of 0 to 2, with the proviso that in formula 1 when m is 2 and n is 1, R is not-SO₃H。

6. A process according to claim 5, wherein the α 2 δ ligand is a compound of formula III

And pharmaceutically acceptable salts thereof, wherein:

m is an integer of 0 to 2;

p is an integer of 0 to 3; and

r is a sulfonamide,

the acid amide,

the amount of phosphonic acid present,

a heterocyclic ring,

sulfonic acid, or

A hydroxamic acid.

7. The method according to claim 5, wherein the α 2 δ ligand is selected from the group consisting of

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one,

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride,

3- (1-aminomethyl-cycloheptylmethyl) -4H- [1, 2, 4] oxadiazol-5-one hydrochloride,

C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine,

(1-aminomethyl-cyclohexylmethyl) -phosphonic acid,

(2-aminomethyl-4-methyl-pentyl) -phosphonic acid,

N- [2- (1-aminomethyl-cyclohexyl) -ethyl ] -methanesulfonamide,

C- [1- (1H-tetrazol-5-ylmethyl) cyclohexyl ] -methylamine,

4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine and

c- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine,

And pharmaceutically acceptable salts thereof.

8. The method according to claim 1, wherein the α 2 δ ligand is a compound of formula IV

Or a pharmaceutically acceptable salt thereof, wherein:

R²is a straight or branched chain alkyl group having 1 to 8 carbon atoms,

straight-chain or branched alkenyl groups having 2 to 8 carbon atoms,

a cycloalkyl group having 3 to 7 carbon atoms,

an alkoxy group having 1 to 6 carbon atoms,

-an alkyl cycloalkyl group,

-an alkyl-alkoxy group,

-an alkyl group OH,

-an alkyl-phenyl group,

-an alkyl-phenoxy group,

-phenyl or substituted phenyl; and is

9. The method according to claim 1, wherein the α 2 δ ligand is a compound of formula (1A) or (1B)

Or

Or a pharmaceutically acceptable salt thereof, wherein:

n is an integer of 0 to 2;

r is a sulfonamide,

the acid amide,

the amount of phosphonic acid present,

a heterocyclic ring,

sulfonic acid, or

Hydroxamic acid;

a is hydrogen or methyl; and

b is

A straight-chain or branched alkyl group having 1 to 11 carbon atoms, or

-(CH₂)_1-4-Y-(CH₂)_0-4-phenyl, wherein Y is-O-, -S-, -NR'₃Wherein

R’₃Is alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-8 carbon atoms; benzyl or phenyl, wherein benzyl or phenyl can be unsubstituted or substituted with 1-3 substituents, each substituent independently selected from alkyl, alkoxy, heteroaryl, and heteroaryl, Halogen, hydroxy, carboxy, alkoxycarbonyl, trifluoromethyl and nitro.

10. The method according to claim 9, wherein the compound of formula (1A) or (1B) is selected from the group consisting of:

4-methyl-2- (1H-tetrazol-5-ylmethyl) -pentylamine;

3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4] oxadiazole-5-thione;

(2-aminomethyl-4-methyl-pentyl) -phosphonic acid;

3- (3-amino-2-cyclopentyl-propyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (3-amino-2-cyclopentyl-propyl) -4H- [1, 2, 4] thiadiazol-5-one;

2-cyclopentyl-3- (2-oxo-2, 3-dihydro-2 λ 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -propylamine;

3- (3-amino-2-cyclobutyl-propyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (2-aminomethyl-4-methyl-pentyl) -4H- [1, 2, 4] oxadiazol-5-one;

3- (3-amino-2-cyclobutyl-propyl) -4H- [1, 2, 4] thiadiazol-5-one;

2-cyclobutyl-3- (2-oxo-2, 3-dihydro-2 λ 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -propylamine;

((2R, 4 α R, 8 α S) -2-aminomethyl-decahydro-naphthalen-2-yl) acetic acid;

((2R, 4 α S, 9 α R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid;

((2S, 4 α S, 9 α R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid;

((2S, 4 α R, 9 α S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid;

((2R, 4 α R, 9 α S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid;

((1R, 3R, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) acetic acid;

((1R, 3S, 6S) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) acetic acid;

((1S, 3S, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) acetic acid;

((1S, 3R, 6R) -3-aminomethyl-bicyclo [4.1.0] hept-3-yl) acetic acid;

((1R, 3R, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) acetic acid;

((1R, 3S, 6R) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) acetic acid;

((1S, 3S, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) acetic acid;

((1S, 3R, 6S) -3-aminomethyl-bicyclo [4.2.0] oct-3-yl) acetic acid;

((3 α R, 5R, 7 α R) -5-aminomethyl-octahydro-inden-5-yl) acetic acid;

((3 α R, 5S, 7 α R) -5-aminomethyl-octahydro-inden-5-yl) acetic acid;

((3 α S, 5S, 7 α S) -5-aminomethyl-octahydro-inden-5-yl) acetic acid;

((3 α S, 5R, 7 α S) -5-aminomethyl-octahydro-inden-5-yl) acetic acid;

((2 α, 4 α R, 8 α R) -2-aminomethyl-decahydro-naphthalen-2-yl) acetic acid;

((2S, 4 α S, 8 α R) -2-aminomethyl-decahydro-naphthalen-2-yl) acetic acid;

((2S, 4 α R, 8 α S) -2-aminomethyl-decahydro-naphthalen-2-yl) acetic acid;

((2R, 4 α S, 8 α S) -2-aminomethyl-decahydro-naphthalen-2-yl) acetic acid;

((2R, 4 α R, 9 α R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid;

((2S, 4 α R, 9 α R) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid;

(1 α, 3 α, 5 α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) acetic acid;

((2S, 4 α S, 9 α S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid; and

((2R, 4. alpha. S, 9. alpha. S) -2-aminomethyl-decahydro-benzocyclohepten-2-yl) acetic acid.

11. The method according to claim 1, wherein the α 2 δ ligand is a compound of the formula

Or a pharmaceutically acceptable salt thereof, wherein:

r is hydrogen or lower alkyl;

R₁is hydrogen or lower alkyl;

R₂is composed of

A straight-chain or branched alkyl group having 7 to 11 carbon atoms, or

-(CH₂)_(1-4)-X-(CH₂)_(0-4)-phenyl, wherein

X is-O-, -S-, -NR₃-, wherein

wherein phenyl and benzyl may be unsubstituted or substituted with 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, alkoxycarbonyl, trifluoromethyl, amino and nitro.

12. The method according to claim 1, wherein the α 2 δ ligand is a compound of formula (1), (2), (3), (4), (5), (6), (7) or (8)

And

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁-R₁₀each independently selected from hydrogen or a linear or branched alkyl group containing 1 to 6 carbon atoms, benzyl or phenyl;

m is an integer of 0 to 3;

n is an integer of 1 to 2;

o is an integer of 0 to 3;

p is an integer of 1 to 2;

q is an integer of 0 to 2;

r is an integer of 1-2;

s is an integer of 1 to 3;

t is an integer of 0 to 2; and

u is an integer of 0 to 1.

13. The method according to claim 1, wherein the α 2 δ ligand is selected from the group consisting of the following compounds and pharmaceutically acceptable salts thereof:

3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one;

(S, S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) acetic acid;

(R, S) -3-aminomethyl-5-methyl-octanoic acid;

(S, R) -3-aminomethyl-5-methyl-octanoic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) acetic acid;

(3-aminomethyl-bicyclo [3.2.0] hept-3-yl) acetic acid, wherein the cyclobutyl ring is in the trans-position of the methylamino group; and

c- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine.