GB2431641A

GB2431641A - Alternative synthesis of aryl-octanoyl amide compounds

Info

Publication number: GB2431641A
Application number: GB0521723A
Authority: GB
Inventors: Stuart John Mickel
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-10-25
Filing date: 2005-10-25
Publication date: 2007-05-02
Also published as: GB0521723D0

Abstract

An alternative synthesis of certain 2(S), 4(S), 5(S), 7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide compounds or pharmaceutically acceptable salts thereof which uses the synthetic pathway detailed in Schemes 1-4. Novel intermediates are used in the preparation of the above target compound.

Description

PC/4-34597P I 1 2431641 Organic Compounds The present invention

provides new methods for preparing certain 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives, or pharmaceutically acceptable salts thereof. The present invention further relates to novel intermediates useful in the manufacture of the same.

More specifically, the 2(S) ,4(S) ,5(S) ,7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives to which the methods of the present invention apply are any of those having renin inhibitory activity and, therefore, pharmaceutical utility, e.g., those disclosed in U.S. Patent No. 5,559,111.

Surprisingly, it has now been found that 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoyl amide derivatives are obtainable in high diastereomeric and enantiomeric purity using a benzene derivative of formula (I) as the starting material.

In particular, the present invention provides a method for the preparation of a compound of the formula ::xI?420R5 (A) wherein R1 is halogen, C16halogenalkyl, C1alkoxy-C1alkyIoxy or C16alkoxy-C1aIkyl; R2 is halogen, C14alkyl or C14alkoxy; R3 and R4 are independently branched Calkyl; and R5 is cycloalkyl, C1..6alkyl, C16hydroxyalkyl, C1alkoxy-C1alkyl, C1alkanoyIoxy-C1alkyl, C16aminoalkyl, C16alkylamino-C16alkyl, C1.6dialkylamino-C16aIkyl, C1alkanoylamino-C16a1ky1, HO(O)C-C16a1ky1, C1alkyl-O-(O)C-C1alkyl, H2N-C(O)-C1alkyl, C1alkyl-HN-C(O)-C16alkyl or (C16alkyl)2N-C(O)-C16alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting with compounds (I) and (Ila) of Schemes I and 2 and compound (lIb) of Scheme 3 and following reaction steps as outlined in Schemes I to 4 to obtain a compound of formula (A).

PC/4-34597P I Scheme I: O\POR6 07R3' R3 OR6 (Ia) (Ib) (Ic) (Id) I, I

OH OH O 0

HO _____ R3 HO R3 R3 (Ila) (If) (le) R1 R1jL1,c1 R2X R (I) (III) ,OR OR R2 (I) (IV) Scheme 2: (ha) R1 R2L R2 R3 (I) (VI) R1 R2 R2 R3 (VIII) (VII) PC/4-34597P I Scheme 3: R4 R4 R4 HO..L..j(NHR5.-H1(NHR5. RO._....._'L1(NHR5 (IX) (X) (Xl) 1' R4 R4 HOjf0H RO_.L1(N HR5 (lIb) (XII) Scheme 4: RO..J CJR4 R4 R1 R3 R 0 + H'L.,_1f/NHR5 (X) R1 (IV) or ________ R2 R3 (XIII) 0 H R4 R1 + ROJL__*......_*Lr.NHR5 R2) R3 R4 OH NHR5 (VIII) (XII) (A) In the Schemes 1 -4 the substituents R1 to R5 have meanings as defined for formula (A), and R represents C120a1ky1 or C1..6halogenalkyl.

Compounds of formulae (IV), (V), (VII), (VIII), (X), (XII) and (XIII) are key intermediates in the methods of the present invention.

PC/4-34597P I Other objects, features, advantages and aspects of the present invention will become apparent to those skilled in the art from the following description and appended claims. It should be understood, however, that the description, appended claims, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following.

A conventional resolution of a compound of formula (le) wherein R3 has a meaning as defined herein above, to yield a compound of formula (Ila) may be used to resolve the enantiomers of compound (le), e.g., via reaction with (R)-or (S)-phenylethylamine. The undesired enantiomer may be recycled. As illustrated in Scheme 1, a compound (le) may be obtained from a lactone of formula (Ia) by (i) addition of a dialkyl phosphate group, (ii) a subsequent Wittig reaction, (iii) reduction of the resulting olefin, followed by (iv) hydrolysis.

Reaction (i) may utilize, e.g., LDA in THF at about -78 C followed by treatment with CIP(O)(OR)2 in which R has a meaning as defined herein above, or alternatively by treatment with CIP(O)(OR)2, and oxygen; the Wittig reaction (ii) may utilizes, e.g., NaH and acetone; the reduction (iii) may be performed, e.g., using hydrogen in the presence of a suitable palladium catalyst; and the hydrolysis may be conducted, e.g., in aqueous alcoholic NaOH.

Reduction (iii) may also be conducted stereoselectively, e.g., in the presence of a chiral phosphine ligand such as BINAP, which approach after hydrolysis gives the desired stereoisomer (Ila) directly.

As illustrated in Scheme 1, the reaction of the compound of formula (I) wherein R1 and R2 have meanings as defined herein above, with a compound of formula (ha) wherein R3 has a meaning as defined herein above, to yield a compound of formula (Ill) wherein R1 to R3 have meanings as defined herein above, may be carried out according to methods which are well-known in the art, e.g., in the presence of, e.g., SOd2 and AlCl3 in the absence or presence of a suitable solvent, such as toluene and the like, the temperature being preferably from about room temperature to about reflux temperature.

Phosphorylation of a resulting compound of formula (Ill) to yield a compound of formula (IV) wherein R1 to R3 have meanings as defined herein above, may be carried out by treatment with, e.g., P(OR)3 wherein R has a meaning as defined herein above, at about 100 C.

The conversion of a resulting compound of formula (IV) to yield a compound of formula (V) wherein R, R1, R2 and R3 have meanings as defined herein above, involves the removal of the carbonyl oxygen present in a compound of formula (IV) which may be carried out by well-P0/4-34597 P1 known methods such as, e.g., hydrogenation in the presence of a suitable catalyst, such as Pd/C and the like, and in the presence of, e.g., an aromatic solvent such as toluene and an acid such as hydrochloric acid, glacial acetic acid, the temperature being conveniently from room temperature to about 10000.

As illustrated in Scheme 2, the reaction of a compound of formula (I) with a compound of formula (lla) to yield a compound of formula (VI) wherein R, R1, R2 and R3 have meanings as defined herein above, can be carried out in a similar way as the aforementioned reaction of a compound of formula (I) with a compound of formula (ha) to yield a compound of formula (III) according to Scheme 1, and any chloro substituent present in the product thus obtained thereby having to be replaced with a hydroxy group which can be brought about by methods which are readily available to those skilled in the art.

Reduction of the carbonyl group of a resulting compound of formula (VI) to yield a compound of formula (VII) wherein R, R1, R2 and R3 have meanings as defined herein above, may be carried out using well- known methods such as, e.g., hydrogenation in the presence of a suitable catalyst, such as Pd/C and the like, and in the presence of, e.g., an aromatic solvent such as toluene and an acid such as hydrochloric acid, glacial acetic acid, the temperature being conveniently from room temperature to about 100 C.

The conversion of a resulting compound of formula (VII) to yield a compound of formula (VIII) wherein R, R1, R2 and R3 have meanings as defined herein above, involves an oxidation of a primary alcohol to yield a corresponding aldehyde of formuls (VIII) may be brought about by methods readily available to those skilled in the art, e.g., by treatment with sodium hypochlorite and TEMPO in the presence of potassium bromide, potassium acetate, water, dichloromethane, or using Swern oxidation and the like.

As illustrated in Scheme 3, a compound of formula (lib) wherein R4 has a meaning as defined herein above, obtainable analogously as illustrated in Scheme I for a compound of formula (ha), may be converted a compound of formula (IX) wherein R5 has a meaning as defined herein above, by reaction with a primary amine of formula R5NH2 in which R5 has a meaning as defined herein above, using methods well known in the art, e.g., in the presence of a coupling agent such as DCC and a polar solvent such as DMF.

The conversion of a resulting compound of formula (IX) to yield a compound of formula (X) wherein R4 and R5 have meanings as defined herein above, may be carried out by known PC/4-34597P I methods, e.g., as illustrated in Scheme 2 for the conversion of a compound of formula (VII) to yield a compound of formula (VIII).

The phosphorylation of a resulting compound of formula (X) to yield a compound of formula (Xl) wherein R, R4 and R5 have meanings as defined herein above, may be carried out by known methods, e.g., by using P(OR)3 at about 100 C.

The removal of the hydroxyl group of a resulting compound of formula (Xl) to yield a compound of formula (XII) wherein R, R4 and R5 have meanings as defined herein above, may be carried out by known methods, e.g., (i) reaction with SOd2, followed by (ii) reaction with Bu3SnH, AIBN in an aromatic solvent such as toluene.

As illustrated in Scheme 4, a compound of formula (V) may be reacted with a compound of formula (X), or a compound of formula (VIII) may be reacted with a compound of formula (XII), to afford a compound of formula (XIII) wherein R, R1, R2, R3, R4 and R5 have meanings as defined herein above, under conditions of Wittig reaction, e.g., by generating the phosphonate anion using sodium hydride in toluene, or an organolithium base or sodium or potassium hexamethyldisilazide in tetrahydrofuran, optionally in the presence of a crown ether, followed by addition of the aldehyde of formula (X) or formula (VIII), preferably at a temperature ranging from about -78 C to about room temperature. Variations of the conditions just explained which are appropriate for achieving the desired result will be readily apparent to those skilled in the art.

A resulting compound of formula (XIII) wherein R, R1, R2, R3, R4 and R5 have meanings as defined herein above, may then be reacted, e.g., (i) with Na104, RuCI3 sulphuric acid and ethyl acetate, acetonitrile and water at about 0 C, (ii) with NH2OH and ethanol, and (iii) a catalytic hydrogenation with e.g. Pd/C and BINAP, to afford a compound of formula (A).

Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.

As an alkyl, R1 may be linear or branched and preferably comprise 1 to 6 C atoms, especially I or 4 C atoms. Examples are methyl, ethyl, n-and i-propyl, n-, i-and t-butyl, pentyl and hexyl.

PC/4-34597P1 As a halogenalkyl, R1 and R may be linear or branched and preferably comprise I to 4 C atoms, especially I or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R1 and R2 may be linear or branched and preferably comprise I to 4 C atoms.

Examples are methoxy, ethoxy, n-and i-propyloxy, n-, i-and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyl group preferably comprises I to 4 C atoms.

Examples are methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 6-methoxyhexyl, ethoxymethyl, 2ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl, butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

As a C16alkoxy-C1alkyloxy, R1 may be linear or branched. The alkoxy group preferably comprises I to 4 and especially I or 2 C atoms, and the alkyloxy group preferably comprises I to 4 C atoms. Examples are methoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy, 4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy, ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy, 5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.

In a preferred embodiment, R1 is methoxy-or ethoxy-C14alkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula (A), wherein R1 is 3-methoxypropyloxy and R2 is methoxy.

As a branched alkyl, R3 and R4 preferably comprise 3 to 6 C atoms. Examples are i-propyl, i-and t-butyl, and branched isomers of pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula (A) are in each case i-propyl.

As a cycloalkyl, R5 may preferably comprise 3 to 8 ring-carbon atoms, 3 or 5 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl may optionally be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl and the like.

PC/4-34597P I As an alkyl, R5 may be linear or branched in the form of alkyl and preferably comprise I to 6 C atoms. Examples of alkyl are listed herein above. Methyl, ethyl, n-and i-propyl, n-, i-and t-butyl are preferred.

As a C1hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms.

Some examples are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-, 3-or 4-hydroxybutyl, hydroxypentyl and hydroxyhexyl.

As a C16alkoxy-C1.6alkyl, R5 may be linear or branched. The alkoxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-, 3-or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl, 3-ethoxypropyl, and 2-, 3-or 4-ethoxybutyl.

As a C1.6alkanoyloxy-C1.6alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

As a C1aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms.

Some examples are 2-aminoethyl, 2-or 3-aminopropyl and 2-, 3-or 4-aminobutyl.

As C1.6alkylamino-C16alkyl and C1.6dialkylamino-C16a1ky1, R5 may be linear or branched. The alkylamino group preferably comprises C1alkyl groups and the alkyl group has preferably 2 to 4 C atoms. Some examples are 2-methylaminoethyl, 2-dimethylaminoethyl, 2- ethylaminoethyl, 2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C-C1.6alkyl, R5 may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

As a C16a1ky1-O-(O)C-C16alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another I to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4- methoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and 4-ethoxycarbonylbutyl.

PC/4-34597P I As a H2N-C(O)-C16alkyI, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoethyl, 2- carbamido-2,2-dimethylethyl, 2-or 3-carbamidopropyl, 2-, 3-or 4-carbamidobutyl, 3- carbamido-2-methylpropyl, 3-carbamido-I,2-dimethylpropyl, 3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4-or 5-carbamidopentyl, 4-carbamido-3,3-or -2,2-dimethylbutyl.

As a C16alkyl-HN-C(O)-C16alkyl or (C16a1ky1)2N-C(O)-C16alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises I to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined herein above, whose N atom is substituted, with one or two methyl, ethyl, propyl or butyl.

As an alkyl, R may be linear or branched and comprise preferably I to 12 C atoms, I to 8 C atoms being especially preferred. Particularly preferred is a linear C14alkyl. Some examples are methyl, ethyl and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl. Especially preferred are methyl and ethyl.

In a preferred embodiment, R is methyl.

Accordingly, preferred are the methods of the present invention, wherein a compound of formula (A) has the formula ::ioN NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

Further preferred are the methods of the present invention, wherein a compound of formula (B) is (2S,4S, 5S, 7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy) -benzyl]-8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate, also known as aliskiren.

The invention is inclusive of the following intermediates: PC/4-34597P I A compound of the formula

OR 0 OR (IV)

wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C16aIkyIoxy or C1aIkoxy-C1aIkyI; R2 is halogen, C14a1ky1 or C14aIkoxy; R3 is branched C3.6alkyl; and R is C1.20alkyl or C16halogenalkyl.

A compound of the formula lOR R1 OR R2 wherein R1 is halogen, C16halogenalkyl, C1alkoxy-C1alkyIoxy or C1aIkoxy-C1alkyl; R2 is halogen, C1alkyl or C1..4alkoxy; R3 is branched Calkyl; and R is C120alkyl or C16halogenalkyl.

A compound of the formula (VII) wherein R1 is halogen, C16halogenalkyl, C1alkoxy-C1alkyloxy or C1alkoxy-C1alkyl; R2 is halogen, C14alkyl or C14alkoxy; and R3 is branched Calkyl.

A compound of the formula

R

)ti I (VIII) R2 3 wherein R1 is halogen, C1halogenalkyl, C16alkoxy-C16alkyloxy or C,6alkoxy-C16a1ky1; R2 is halogen, C14alkyl or C14alkoxy; and R3 is branched C6alkyl.

A compound of the formula P0/4-34597 P1 R4 (XI) wherein R4 is branched C3alkyl; R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C1alkoxy- C16a1kyl, C16alkanoyloxy-C16a1ky1, C1.6aminoalkyl, C16alkylamino-C16aIkyI, C16dialkylamino- C1.6alkyl, C16alkanoylamino-C16alky1, HO(O)C-C1alkyl, C16a1ky1-O-(O)C-C16alky1, H2N-C(O)-C16a1kyl, C16alkyI-H N-C(O)-C16aIkyI or (C1.6aIkyI)2N-C(O)-C1aIkyI; and R is C120alky1 or C16halogenalkyl.

A compound of the formula R4 0 I RO..(N5 (XII) / RO 0 wherein R4 is branched C3.6aIkyI; R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C1aIkoxy-C16a1ky1, C1aIkanoyloxy-C16aIkyI, C1aminoaIkyI, C16aIkyIamino-C1aIkyl, C1diaIkyIamino-C16aIkyI, C16aIkanoylamino-C1aIkyl, HO(O)C-C1aIkyl, C1aIkyl-O-(O)C-C16aIkyl, H2N-C(O)-C16a1ky1, C1alkyl-H N-C(O)-C16a1ky1 or (C1aIkyI)2N-C(O)-C1aIkyl; and R is C1.20aIkyI or C1haIogenaIkyI.

A compound of the formula :;R4ONHR5 (XIII) where R1 is halogen, C16halogenalkyl, C16aIkoxy-C16aIkyIoxy or C16aIkoxy-C1aIkyI; R2 is halogen, C14aIkyI or C14aIkoxy; R3 and R4 are independently branched C3aIkyI; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C1aIkoxy-C1..6aIkyI, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16aIkyIamino-C1aIkyl, C16dialkylamino-C1.6aIkyI, C1aIkanoyIamino-C16a1ky1, HO(O)C-C1aIkyI, C16a1ky1-O-(O)C-C16aIkyI, H2N-C(O)-C1alkyI, C1aIkyI-HN-C(O)-C1.6aIkyI or (C1.6aIkyI)2N-C(O)-C16a1ky1.

Preferably in the above wherever applicable R1 is 3-methoxypropyloxy, R2 is methoxy, R3 and R4 are isopropyl, and R5 is 2-carbamoyl-2-methyl-propyl.

PC/4-34597P I As indicated herein above, compounds of the present invention can be converted into acid addition salts. The acid addition salts may be formed with mineral acids, organic carboxylic acids or organic sulfonic acids, e.g., hydrochloric acid, fumaric acid and methanesulfonic acid, respectively.

In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The present invention further includes any variant of the above process, in which an inter-mediate product obtainable at any stage thereof is used as the starting material, and the remaining steps are carried out, or in which the reaction components are used in the form of their salts.

When required, protecting groups may be introduced to protect the functional groups present from undesired reactions with reaction components under the conditions used for carrying out a particular chemical transformation of the present invention. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (amino, hydroxyl, thiol etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in McOmie, "Protective Groups in Organic Chemist,'/', Plenum Press, London, NY (1973); Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure.

Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, PC/4-34597P I benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n-or i-propanol, n-, i-or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine, N-methylpyr-rolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

The processes described herein above are preferably conducted under inert atmosphere, more preferably under nitrogen atmosphere.

Compounds of the present invention may be isolated using conventional methods known in the art, e.g., extraction, crystallization and filtration, and combinations thereof.

Claims

PC/4-34597P I What is claimed is: 1. A method for preparing a compound

of the formula (A) where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C1alkoxy-C1alkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched Calkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C16alkoxy-C16a1ky1, C16alkanoyloxy-C1alkyl, C1aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C1alkyl, C1alkanoylamino- C1.6alkyl, HO(O)C-C16a1ky1, C16alkyl-O-(O)C-C16a1ky1, H2N-C(O)-C1alkyl, C16a1ky1-H N-C(O)-C16a1ky1 or (C16a1ky1)2N-C(O)-C1.6alkyl; or a pharmaceutically acceptable salt thereof; which method comprises starting with compounds I and Ila of Scheme I and 2 respectively llb of Scheme 3 and following reaction steps as outlined in Schemes I to 4 to obtain a compound of formula (A).

2. A method according to claim 1, wherein a compound of formula (A) has the formula ::EoN NH2 (B) wherein R1 is 3-methoxypropyloxy; R2 is methoxy; and R3 and R4 are isopropyl; or a pharmaceutically acceptable salt thereof.

3. A method according to claim 2, wherein a compound of formula (B) is (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3(3-methoxy-propoxy)-benzyl] -8-methyl-nonanoic acid (2-carbamoyl-2-methyl-propyl)-amide hemifumarate.

PC/4-34597P1 4. A compound of the formula

OR 0 OR (IV)

wherein R1 is halogen, C1..6halogenalkyl, C1.6aIkoxy-C1aIkyIoxy or C16aIkoxy-C1aIkyI; R2 is halogen, C14a1ky1 or C14aIkoxy; R3 is branched C3alkyI; and R is C120a1ky1 or C1halogenaIkyI.

5. A compound of the formula

IIOR R1 OR xq R2

wherein R1 is halogen, C16halogenalkyl, C1aIkoxy-C16alkyloxy or C1alkoxy-C1aIkyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 is branched C3alkyl; and R is C120a1kyl or C16halogenalkyl.

6. A compound of the formula (VII) wherein R1 is halogen, C1.6halogenalkyl, C1alkoxy-C16alkyloxy or C1alkoxy-C1alkyI; R2 is halogen, C14alkyI or C1..4alkoxy; and R3 is branched C36a1ky1.

7. A compound of the formula R1 (VIII) R2 R3 wherein R1 is halogen, C16halogenalkyl, C16alkoxy-C1alkyloxy or C16alkoxy-C1alkyl; R2 is halogen, C1.4aIkyI or C14alkoxy; and R3 is branched C3alkyl.

8. A compound of the formula PC/4-34597P1 R4 (XI) wherein R4 is branched C6aIkyl; R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C1aIkoxy-C16alky1, C16alkanoyloxy-C16a1ky1, C16aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino- C16a1ky1, C16alkanoylamino-C16alkyl, HO(O)C-C1.6aIkyI, C16alkyl-O-(O)C-C1aIkyI, H2N-C(O)-C1.6alkyI, C16alkyl-H N-C(O)-C16alky1 or (C1.6alkyl)2N-C(O)-C16a1ky1; and R is C120a1kyl or C1haIogenaIkyI.

9. A compound of the formula R4 RO__._L(NHR5 (Xli) wherein R4 is branched C3.6alkyl; R5 is cycloalkyl, C16a1ky1, C1hydroxyalkyl, C1alkoxy-C1.6aikyI, C1.6alkanoyloxy-C16alkyI, C1aminoalkyl, C16alkylamino-C16alkyl, C16dialkylamino-C16a1ky1, C16alkanoylamino-C16aikyl, HO(O)C-C1aIkyl, C1.6alkyl-O-(O)C-C16alkyI, H2N-C(O)-C16a1ky1, C16alkyi-HN-C(O)-C1alkyl or (C16alkyl)2N-C(O)-C1alkyl; and R is C1..20aIkyi or C16halogenalkyl.

10. A compound of the formula :;R4oR5 (Xlii) where R1 is halogen, C16halogenalkyl, C16alkoxy-C16alkyloxy or C16alkoxy-C1aikyl; R2 is halogen, C14a1ky1 or C14alkoxy; R3 and R4 are independently branched C36alkyl; and R5 is cycloalkyl, C16a1ky1, C16hydroxyalkyl, C1aikoxy-C16alkyl, C16aikanoyloxy-C16alkyl, C16aminoalkyl, C16alkylamino-C16a1ky1, C16dialkylamino-C16aikyl, C16alkanoylamino-C1aIkyl, HO(O)C-C16a1ky1, C16a1ky1-O-(O)C-C16a1ky1, H2N-C(O)-C1aIkyI, C1alkyl-H N-C(O)-C16alkyi or (C16alkyl)2N-C(O)-C16a1ky1.

11. A compound according to any one of claims 4 to 7, wherein R1 is 3-methoxypropyloxy, R2 is methoxy and R3 is isopropyl.

PC/4-34597P I 12. A compound according to claims 8, 9 or 10, wherein R5 is 2-carbamoyl-2-methyl-propyl; and R4 is isopropyl.

13. A compound according to claim 10, wherein R1 is 3-methoxypropyloxy; R2 is methoxy, R3 and R4 are isopropyl; and R5 is 2-carbamoyl-2-methyl-propyl.