HK1091483A - The preparation method of pyrazolo[4,3-c]pyridine-3-one l-tartaric acid - Google Patents

Description

Preparation method of pyrazolo [4, 3-c ] pyridine-3-ketone L-tartrate

The application is a divisional application of Chinese patent application 03107552.5 filed on 25/2/2000. The invention of the original application is entitled "preparation method of pyrazolo [4, 3-c ] pyridine-3-ketone L-tartrate".

Technical Field

The invention relates to a preparation method of a compound (3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridine-3-ketone L-tartrate.

Background

International patent application publication No. WO97/24369, hereinafter the' 369 application, which is incorporated by reference, discloses certain growth hormone secretagogue compounds of the general formula I,

and the definitions of the substituents are disclosed therein. The compounds disclosed in the' 369 application are useful, among other uses, for treating osteoporosis.

A compound of the formula II

Disclosed in the' 369 application as an intermediate in the preparation of compounds of formula III,

it is also within the scope of the disclosure of said international application.

The method disclosed in the' 369 application requires coupling a compound of formula IV with a compound of formula V. The first step of the coupling reaction is the reaction of the compound of formula IV with an organic amine to form the free base of the compound of formula IV and an organic amine salt of tartaric acid. The next step in the disclosed process is a filtration step to remove the organic amine salts of tartaric acid. This step is considered necessary in order to eliminate the reaction that may occur between tartaric acid and the compound of formula IV under the coupling conditions. Since racemization occurs at the 3a position of pyrazolo [4, 3-c ] pyridine at room temperature, filtration must be performed under reduced temperature conditions, i.e., at low temperature. When the coupling reaction is carried out on a batch scale, the technical problems of reduced temperature filtration, i.e., entrainment, slow filtration, the use of additional equipment and additional processing, arise. Resulting in reduced yields. In the process of the invention, reduced temperature filtration is avoided, a more rational process and improved yields of chemical and optically active species are obtained.

Disclosure of Invention

The invention relates to a process for the preparation of a compound of the general formula II, referred to as process A,

wherein:

R¹is- (C) optionally substituted by up to three fluorine atoms₁-C₁₀) An alkyl group;

R²is phenylmethyl or 2-pyridylmethyl;

R³is- (C)₁-C₅) Alkyl-0- (C)₀-C₅) Alkylphenyl, wherein in R³Phenyl in the definition is optionally substituted with up to three fluorine atoms; and is

Prt is a protecting group for an amino group,

the method comprises the following steps:

a) a suitable chiral tartrate salt having the structure of formula IV,

wherein R is¹And R²The definition is as above-mentioned,

mixing the slurry with organic amine in a reaction inert solvent to form slurry;

b) adding a compound of formula V to the slurry,

wherein R is³And Prt is as defined above, to form a tartrate salt comprising an organic amine, a free base of a compound of formula IV and a compound of formula VA reaction mixture of the compounds; and

c) adding a coupling agent to the reaction mixture to form a compound of formula II.

A preferred method in method a, referred to as method B, is to suspend the compound of formula IV in the solvent prior to addition of the organic amine.

A preferred method in method B, referred to as method C, is to warm the slurry to-50 ℃ prior to step B).

Another preferred method in method a, referred to as method D, is a method wherein, in step a, the organic amine is triethylamine; in step b, R³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl, and Prt is tert-butoxycarbonyl; and in step c, the coupling agent is propanephosphonic anhydride.

A preferred method in Process D, referred to as Process E, is a process wherein R is¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

A preferred method in process E is to prepare a compound selected from (1- (2- (1(R) - (2, 4-difluorobenzyloxymethyl) -3a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoro-ethyl) -3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid tert-butyl ester and (1- (2-3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid tert-butyl ester compound of formula II.

In another preferred process in Process E, a compound of formula IIA is prepared,

in a further preferred process in process E, compounds of the general formula IIB are prepared,

another preferred method in Process B, referred to as Process F, is a process wherein: in step a the organic amine is triethylamine; in step b, R³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl and Prt is tert-butoxycarbonyl; and in step c, the coupling agent is propanephosphonic anhydride.

A preferred method in Process F, referred to as Process G, is a process wherein: r¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

In a preferred process of process F, a compound selected from the group consisting of (1- (2- (1(R) - (2, 4-difluorobenzyloxymethyl) -3a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid tert-butyl ester and (1- (2-3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid tert-butyl ester compound of formula II.

In another preferred process of process F, a compound of formula IIA is prepared,

in a further preferred process in process F, compounds of the general formula IIB are prepared,

another preferred method in Process C, referred to as Process H, is a process wherein:in step a the organic amine is triethylamine; in step b, R³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl and Prt is tert-butoxycarbonyl; and in step c, the coupling agent is propanephosphonic anhydride.

A preferred method of Process H, referred to as Process I, is one in which: r¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

In a preferred process of process I, a compound selected from the group consisting of (1- (2- (1(R) - (2, 4-difluorobenzyloxymethyl) -3a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid tert-butyl ester and (1- (2-3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid tert-butyl ester compound of formula II.

In another preferred process of process I, a compound of formula IIA is prepared,

in a further preferred process in process I, compounds of the general formula IIB are prepared,

the invention also relates to a process for the preparation of a compound of formula III, designated process J,

wherein:

R¹at most, is(C) optionally substituted by three fluorine atoms₁-C₁₀) An alkyl group;

R²is phenylmethyl or 2-pyridylmethyl;

R³is- (C)₁-C₅) alkyl-O- (C)₀-C₅) Alkylphenyl, wherein in R³Phenyl in the definition is optionally substituted with up to three fluorine atoms;

the method comprises the following steps:

a) a suitable chiral tartrate salt having the structure of formula IV,

wherein R is¹And R²The definition is as above-mentioned,

mixing the slurry with organic amine in a reaction inert solvent to form slurry;

b) adding a compound of formula V to the slurry,

wherein R is³And Prt is as defined above, forming a reaction mixture comprising a tartrate salt of an organic amine, a free base of the compound of formula IV, and the compound of formula V;

c) adding a coupling agent to the reaction mixture to form a compound of formula II; and

d) reacting said compound of formula II with a suitable deprotecting reagent to form a compound of formula III.

A preferred method in method J, designated method K, is to suspend the compound of formula IV in the solvent prior to addition of the organic amine, and to perform an additional step of raising the temperature of the slurry to about-50 ℃ to about-40 ℃ prior to step b.

A preferred method in process K, referred to as process L, is a process wherein Prt is Boc and the Boc is removed by reacting the compound of general formula II with an acid.

A preferred process in Process L, referred to as Process M, is a process wherein the acid is methanesulfonic acid.

A preferred method in Process M, referred to as Process N, is a process wherein R³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl, and in step b the organic amine is triethylamine; and in step c), the coupling agent is propanephosphonic anhydride.

A preferred method of Process N, referred to as Process O, is a process wherein R¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

In a preferred process of Process O, a compound selected from the group consisting of 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethyl ] -isobutyramide and 2-amino-N- ((1(R) - (2, 4-difluorobenzyloxymethyl) -2-oxo-2- (3-oxo-3 a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -ethyl-2-methyl-propionamide.

In another preferred process of Process O, a compound of formula IIIA is prepared,

in a further preferred process in process O, compounds of the general formula IIIB are prepared,

another preferred process in process L, referred to as process P, is a process wherein the acid is trifluoroacetic acid.

A preferred method in Process P, referred to as Process R, is a process wherein R is³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl; in step b, the organic amine is triethylamine; and in step c, the coupling agent is propanephosphonic anhydride.

A preferred method of Process R, referred to as Process S, is a process wherein R¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

In a preferred process of process S, a compound selected from the group consisting of 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethyl ] -isobutyramide and 2-amino-N- ((1(R) - (2, 4-difluorobenzyloxymethyl) -2-oxo-2- (3-oxo-3 a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, a compound of formula III of 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -ethyl-2-methyl-propionamide.

In a further preferred process in process S, a compound of the general formula IIIA is prepared,

in a further preferred process of process S, compounds of the general formula IIIB are prepared,

another preferred process in process K, referred to as process T, is a process wherein Prt is Boc and the Boc is removed by reacting the compound of general formula II with an acid.

A preferred process in Process T, designated Process U, is a process wherein the acid is methanesulfonic acid.

A preferred method of Process U, referred to as Process V, is a process wherein: r³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl, and in step b the organic amine is triethylamine; and in step c), the coupling agent is propanephosphonic anhydride.

A preferred method of Process V, referred to as Process W, is a process wherein R¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

In a preferred process of process W, a compound selected from the group consisting of 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethyl ] -isobutyramide and 2-amino-N- ((1(R) - (2, 4-difluorobenzyloxymethyl) -2-oxo-2- (3-oxo-3 a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, a compound of formula III of 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -ethyl-2-methyl-propionamide.

In another preferred process of process W, a compound of formula IIIA is prepared,

in another preferred process of process W, a compound of formula IIIB is prepared,

another preferred process in process T, designated process X, is a process wherein the acid is trifluoroacetic acid.

A preferred method in Process X, referred to as Process Y, is a process wherein: r³Is phenylmethoxymethyl or 2, 4-difluorophenylmethoxymethyl; in step b), the organic amine is triethylamine; and isIn step c, the coupling agent is propanephosphonic anhydride.

A preferred method of Process Y, referred to as Process Z, is a process wherein R is¹Is methyl or 2, 2, 2-trifluoroethyl and R²Is phenylmethyl or 2-pyridylmethyl.

In a preferred process of process Z, a compound selected from the group consisting of 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethyl ] -isobutyramide and 2-amino-N- ((1(R) - (2, 4-difluorobenzyloxymethyl) -2-oxo-2- (3-oxo-3 a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, a compound of formula III of 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -ethyl-2-methyl-propionamide.

In another preferred process of process Z, a compound of formula IIIA is prepared,

in a further preferred process in process Z, compounds of the general formula IIIB are prepared,

the invention also relates to a process for the preparation of compounds of general formula XX,

comprises the following steps:

a) reacting said methyl 4-oxo-piperidinecarboxylate hydrochloride with di-tert-butyl dicarbonate and triethylamine in isopropyl ether to form 1- (1-dimethylethyl) 3-methyl 4-oxo-1, 3-piperidinedicarboxylate;

b) reacting the 1- (1-dimethylethyl) 3-methyl 4-oxo-1, 3-piperidinedicarboxylate with benzyl bromide and potassium carbonate in tetrahydrofuran to form 1- (1-dimethylethyl) 3-methyl 4-oxo- (phenylmethyl) -1, 3-piperidinedicarboxylate;

c) reacting the 1- (1-dimethylethyl) 3-methyl 4-oxo- (phenylmethyl) -1, 3-piperidinedicarboxylic acid with methylhydrazine in acetic acid and methyl tert-butyl ether to form 1, 1-dimethylethyl 2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c ] pyridine-5-carboxylate; and

d) reacting the 1, 1-dimethylethyl 2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c ] pyridine-5-carboxylate with trifluoroacetic acid to form (3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one;

e) reacting the (3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one with L-tartaric acid in acetone and water to form the L-tartrate salt of the general formula XX.

The invention especially relates to a process as described in the previous paragraph wherein the addition of said L-tartaric acid does not require isolation of said (3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one. In particular, the compound of formula XX is isolated as the dihydrate. The desired crystalline form can be isolated from a suitable solvent mixture by cooling.

The invention also relates to dihydrate polymorphs of the compound of formula XX:

the invention particularly relates to polymorphs having the atomic valences (atomic coordinates) and the isotropic equivalent substitution coefficients (equivalent isotropic substitutions) listed in table 1. The invention also relates in particular to polymorphs having the X-ray crystal structure shown in figure 1.

FIG. 1 is a diagram of an X-ray crystal structure of a compound of formula XX, collected by a Siemens R3Ra/v diffractometer. The crystal structure shows that it is a dihydrate of the L-tartrate salt of the compound.

The following schemes illustrate the synthesis of compounds of formula II and III. The symbol "+" refers to a stereochemical center. In the schemes "Prt" refers to any suitable amino protecting group known to those skilled in the art. In the description of each scheme, the amino protecting group Prt is exemplified by the preferred amino protecting group BOC, although other amino protecting groups may be used.

Scheme 1

A compound of the formula IV in which Alk is methyl or ethyl, R¹，R²And Prt are as defined above, e.g., compounds of formula 1e, can be prepared according to scheme 1 or 1a above. According to scheme 1, step a, a compound of formula 1a is mixed with a reaction inert polar aprotic solvent such as acetone, methyl ethyl ketone, DMF (dimethylformamide) or preferably tetrahydrofuran at about 0 deg.C to room temperature, preferably at room temperature. Adding R to the solution²-X, wherein X is a leaving group such as halogen or alkyl-or aryl-sulfonate; bases such as potassium tert-butoxide or carbonates such as Li₂CO₃，Cs₂CO₃Or preferably potassium carbonate; and optionally a phase transfer agent such as potassium iodide or tetrabutylammonium iodide. When potassium carbonate is used as the base, it is preferred not to use a phase transfer reagent. Preferably wherein R is²Is benzyl, R²-X is benzyl bromide and wherein R²Is 2-pyridylmethyl, R²-X is picolyl chloride hydrochloride. After stirring at about-20 ℃ to about 70 ℃ for about 2 to 16 hours, preferably 60 ℃ to about 65 ℃ for 12 hours, the product is isolated from the reaction mixture using techniques known to those skilled in the art. This step is preferably carried out in accordance withThis was done as in preparation example 5, step D, below.

According to step b, a hydrazine derivative is used to react with the compound of formula 1 b. A preferred hydrazine derivative is CF₃CH₂NHNH₂(Trifluoroethylhydrazine) in 70% aqueous solution or aqueous CH₃NHNH₂(methylhydrazine), an aqueous solution thereof in ethanol, water or toluene is used. When a 70% solution of trifluoroethylhydrazine is used, the CF is preferably extracted with toluene₃CH₂NHNH₂70% aqueous solution. To a solution of the compound of formula 1b in an organic solvent such as ethanol, toluene or preferably methyl tert-butyl ether (MTBE) is added anhydrous 2, 2, 2-trifluoroethylhydrazine or methylhydrazine followed by acetic acid. Preferably, MTBE is used to prevent the reaction mixture from reaching dangerously high temperatures. The reaction mixture is heated at about 50 ℃ to about 110 ℃ for about 30 minutes to 24 hours, preferably at about 60 ℃ for about 12 to 15 hours. The reaction mixture is cooled to room temperature and washed with an aqueous base such as NaHCO₃And (4) neutralizing. As used herein, the term "room temperature" refers to a temperature of about 20 deg.C to about 25 deg.C. The organic layer is separated and treated using standard methods known in the art to provide compounds of formula 1 c. This step is preferably carried out as described in preparation 5, step E, below.

According to step c, compounds of the formula 1c are reacted in a reaction-inert organic solvent such as EtOH, IPE or preferably CH₂Cl₂To the solution in (a) is added an acid such as HCl in IPE or ethanol, trifluoroacetic acid (TFA) or an alkyl sulfonic acid such as methanesulfonic acid. The compound is stirred for about 1 to 12 hours and then cooled to about 0 ℃ to about room temperature, preferably to room temperature. After completion of the reaction, a base such as triethylamine or NH is added to the reaction mixture₄And (5) OH. The reaction mixture is warmed to room temperature, diluted with an organic solvent and worked up using standard methods known to those skilled in the art to give compounds of formula 1 d. Alternatively and preferably, the compound of formula 1d is used directly in the next step without isolation. Step c of scheme 1 is preferably performed in combination with step d of scheme 1 according to the method described in preparation 5, step F, below.

According to step D, (D) -or (L) -tartaric acid, preferably (L) -tartaric acid, is added to a solution of the compound of formula 1D in acetone/water (about 8: 1 to about 9: 1) at room temperature. The reaction mixture is stirred at about room temperature to the reflux temperature of the mixed solvent for about 1 hour to overnight, for example, 18 hours, preferably 15 to 18 hours. The compound of formula 1e is preferably isolated in crystalline form as the dihydrate. The solid is then filtered, collected and washed with cold acetone to give the compound of formula 1e, which is preferably the (L) -tartrate salt of the single enantiomer. This step is preferably carried out according to preparation 5, step F, below, without isolation of the precursor free base compound.

Scheme 1a

Scheme 2

A compound of the formula V, wherein R³Is difluorobenzyloxymethyl, R²⁵Is alkyl, aryl or substituted aryl and Prt is an amino protecting group, e.g., a compound of formula 2d, prepared according to the method described in scheme 2. According to step e, a solution of N-BuLi or potassium tert-butoxide is added to a solution of N-BOC-serine, preferably N-BOC- (D) -serine, of the compound of formula 2a in THF/DMF (about 1: 1 to about 2: 1) at about 0 ℃. The reaction mixture is stirred at 0 ℃ for about 10 minutes to about 30 minutes, preferably about 20 minutes, and then 2, 4-difluorobenzyl bromide is added. After warming to room temperature and stirring for about 6 to about 24 hours, the reaction mixture is concentrated in vacuo to remove THF and the pH of the mixture is adjusted to about 3 by the addition of an aqueous acid such as 1N HCl. The reaction mixture is dissolved in water and an organic solvent such as dichloromethane (CH)₂Cl₂) Or between IPEs. The organic solution is treated by standard methods known to the person skilled in the art to give the compound of the general formula 2b, preferably having the R configuration in the stereogenic center and already havingKnown as the (D) -enantiomer.

According to step f, the compound of formula 2b is reacted in an organic solvent such as THF, CH₂Cl₂IPE or mixtures thereof, preferably CH₂Cl₂To the solution in/IPE (about 1: 1) is added an alkyl-or arylsulfonic acid such as methanesulfonic acid. The solid was filtered and combined with CH₂Cl₂the/IPE (about 1: 1) mixture is washed to give the compound of the formula 2c, preferably having the R configuration in the stereocenter and known as the (D) -enantiomer.

To a solution of the compound of formula 2c in THF/water (ca. 4: 1) was added 2-tert-butoxycarbonylaza-2-methylpropan-2, 5-dioxopyrrolidin-1-yl ester and an alkylamine such as triethylamine according to step g. The reaction mixture is stirred at room temperature for about 1-24 hours and quenched with an aqueous acid such as 10% aqueous citric acid. The reaction mixture is partitioned in an organic solvent such as ethyl acetate, the organic layer is separated and treated by standard methods known to those skilled in the art to give compounds of formula 2D, preferably having the R configuration at the stereocenter and known as the (D) -enantiomer.

A compound of the formula V, wherein R³The compound which is benzyloxymethyl and Prt is Boc can be prepared according to the procedure described in preparation 3, Steps A and B below. Compounds in which Prt is an amino protecting group other than Boc are prepared by replacing N-tert-butoxycarbonyl-alpha-methylalanine with a substituted appropriate N-protected alpha-methylalanine derivative. Suitable N-protected α -ylalanine derivatives, if not commercially available from the manufacturer, can be readily prepared from α -methylalanine according to methods known to those skilled in the art.

Scheme 3

Compounds of the general formulae II, III and 3c, in which R¹，R²And R³As defined above, can be according toThe method of scheme 3. According to step h, the compound of formula IV (1e), preferably the (L) -tartrate salt of a single enantiomer, is homogenized with a reaction inert solvent, preferably ethyl acetate, at about-68 deg.C to about-45 deg.C, preferably at about-68 deg.C to about-60 deg.C, and most preferably at about-68 deg.C. To this organic amine, such as diisopropylethylamine, trimethylamine or triethylamine, preferably triethylamine, is added. During the addition of the organic amine, the temperature is maintained at about-68 ℃ to about-45 ℃, preferably at about-68 ℃ to about-60 ℃. The reaction mixture is stirred at about-78 ℃ to about-45 ℃ for about 30 to about 120 minutes. The resulting slurry contains the free base of the compound of formula IV and an organic amine salt of tartaric acid. To this slurry is added an organic amine, such as diisopropylethylamine, trimethylamine or triethylamine, preferably triethylamine. During the addition, the temperature of the reaction mixture was maintained below-50 ℃. The compound of formula V is added in one portion to the reaction mixture also containing the organic amine salt of tartaric acid while maintaining the temperature of the reaction mixture at about-68 ℃ to about-45 ℃. The coupling reagent, such as propanephosphonic acid anhydride, is then added over a period of about 5 minutes to about 30 minutes. The reaction temperature is allowed to slowly rise to about-25 ℃ to about 0 ℃, preferably to-20 ℃ over about 1 hour. The reaction mixture is worked up by standard methods known to the person skilled in the art to give compounds of the general formula II, preferably having the absolute and relative 3a (R), 1(R) configuration.

According to step i, the compound of formula II is reacted in a reaction inert solvent such as CH at about 0 ℃ to room temperature₂Cl₂Addition of an acid such as HCl in EtOH, or methanesulfonic acid or trifluoroacetic acid in CH to a solution of IPE or THF₂Cl₂The solution of (1). The mixture is stirred at room temperature for about 40 minutes to 4 hours, and then a saturated base such as Na is added₂CO₃Or NaHCO₃The aqueous solution was allowed to stand until the solution reached a neutral (7.0) pH. The organic layer is separated and treated by standard methods known to those skilled in the art to provide compounds of formula III, preferably having the absolute and relative 3a (R), 1(R) configurations.

According to step j, L- (+) tartaric acid is added to a solution of the compound of formula III in an alcohol such as methanol ethanol or isopropanol, preferably isopropanol. When methanol or ethanol is used, the reaction mixture is stirred for about 1 to about 12 hours, then filtered and the filtrate is concentrated. In both cases, the crude residue is diluted with an organic solvent such as ethyl acetate, heated and slowly cooled to room temperature. The solid is filtered and dried to give the L- (+) -tartrate salt of the compound of formula 3c, preferably having the absolute and relative 3a (R), 1(R) configuration.

The starting materials and reagents used in the process of the invention are either commercially available from the general manufacturer or can be prepared according to methods known to those skilled in the art of organic chemistry. In particular, methyl 4-oxo- (phenylmethyl) -3-piperidinecarboxylate hydrochloride may be prepared as described in preparation 5, step a, below, or alternatively, as described in Hoffman, n. and Erinjeri, a.

The term "reaction-inert solvent" as used herein means a solvent which does not react with the starting materials, reagents, intermediates or products of the reaction in a manner which would adversely affect the yield of the desired product. The reaction inert solvent in step a is a free base soluble solvent for the compound of formula IV.

The term "organic amine" as used herein means a lower alkylamine such as triethylamine, trimethylamine or diisopropylethylamine; or a cyclic amine, such as piperidine, pyrrolidine or N-methylmorpholine.

Detailed Description

The following examples are intended to further illustrate the invention and are not intended to limit the disclosure of the invention.

Silica gel was used for column chromatography. Melting points were determined using a Buchi 510 instrument and were uncorrected. Proton NMR spectra were recorded at 25 ℃ using either Varian XL-300, Bruker AC-300, Varian Unity 400 or Bruker AC-250. Those skilled in the art of organic chemistry will appreciate that the NMR data obtained herein may also be obtained using other NMR instruments available from different manufacturers known to those skilled in the art. Chemical shifts are expressed in parts per million below the magnetic field of the trimethylsilane.

General procedure a: (removal of Boc-protecting group in Boc-protected amine using concentrated HCl): the Boc-protected amine was dissolved in a minimum volume of ethanol and the resulting solution was cooled to 0 ℃ to which concentrated hydrochloric acid was added

(typically about 1 to 4ml per mmol of Boc-protected amine) and the reaction mixture is warmed to room temperature and stirred for about 1 to about 2.5 hours (or time required for complete disappearance of starting material to polar product as judged by thin layer chromatography). The resulting solution or suspension is concentrated and the residue is co-evaporated several times with ethanol to give the free amine without further or special purification.

Example 1

(1- (2- (3a (R) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c)]Pyridine- 5-Yl) -1(R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) carbamic acid tert-butyl Esters

To a dry, nitrogen-purged 1 liter 4-neck round bottom flask equipped with a mechanical stirrer, nitrogen-terminated condenser, thermocouple, and addition funnel was added 3 a-benzyl-2-methyl-2, 3, 3a, 4, 6, 7-hexahydropyrazolo [4, 3-c ] through the addition funnel]Pyridin-3-one (L) -tartrate (prepared as per preparation 1, step D, 66.09g, 0.168 moles, 1.12 equivalents) and ethyl acetate (660ml, 10 volumes). A slurry is formed. The slurry was stirred and the internal temperature was cooled to-68 ℃ to-66 ℃. To the cold slurry was added triethylamine (TEA, 58ml, 42.5g, 0.42 mole, 2.8 equivalents) via an addition funnel with stirring. During the addition, the internal temperature was maintained at-68 ℃ to-66 ℃. The reaction mixture was stirred for about 1.5 hours while the internal temperature rose to about-52 ℃. To the reaction mixture (which is triethylamine tartrate and 3 a-benzyl-2-methyl-2, 3, 3a, 4, 6, 7-hexahydropyrazoleAnd [4, 3-c ]]Slurry of pyridin-3-one (L) -tartrate) was added triethylamine (96.5ml, 70g, 0.69 moles, 4.6 equivalents) over 5 minutes, maintaining an internal temperature of-53 ℃ to-50 ℃ during the addition. To the reaction mixture was added 3-benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -propionic acid (prepared according to preparation 3, step B, 57.07g, 0.150 mol, 1.0eq) in one portion. The internal temperature was maintained between-55 ℃ and-50 ℃ during the addition. To the reaction mixture was added propanephosphonic anhydride (PPAA, 180ml, 190g, 2.0 equiv) as a 50% solution of propanephosphonic anhydride in ethyl acetate. The PPAA was added over 15 minutes, and during the addition, the internal temperature was raised to about-30 ℃. The reaction mixture was stirred at-30 ℃ for about 0.5 hour. The reaction mixture was poured into a vigorously stirred mixture of isopropyl ether (IPE, 660ml, 10 vol.) and water (660ml, 10 vol.). The resulting biphasic mixture was stirred for 1 hour and the reaction mixture was allowed to settle on standing. The aqueous phase was decanted and the organic phase was successively washed with aqueous HCl (1N, 165ml, 2.5 vol, 1.3 eq), 10% Na₂CO₃Aqueous (330ml, 5 vol, 2.1 equiv), and 15% aqueous NaCl (165 ml). The washed organic phase was concentrated in vacuo to the lowest stirrable volume. IPE (330ml, about 5 volumes) was added to the concentrate. Again concentrated in vacuo to the lowest stirrable volume. IPE (330ml. about 5 volumes) was added to the concentrate and the solution was heated to an internal temperature of 67 ℃ at atmospheric pressure. When precipitation was observed, the slurry was cooled to an internal temperature of about 1 ℃ over 1 hour with stirring. The solid was filtered and dried under vacuum at about 50 ℃ to give 54.85g of the title compound (yield, 60.4%).

Example 2

2-amino-N- [2- (3a (r) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c)] Pyridin-5-yl) -1(R) -benzyloxymethyl-2-oxo-ethyl]Isobutyramide (L-tartrate)

To a 5 liter 4-neck round bottom flask equipped with a mechanical stirrer, thermocouple, condenser and addition funnel was added 3a (R) -benzyl-2-methyl-2, 3, 3a, 4, 6, 7-hexahydropyrazolo [4, 3-c ] continuously]Pyridin-3-one (L) -tartrate (prepared as per preparation 1, step D, 60.57g, 0.10 moles, 1.0 equiv) and dichloromethane (400ml, 6.7 volumes). The mixture was stirred to a clear solution and the solution was cooled to an internal temperature of about-10 ℃ to-5 ℃. Trifluoroacetic acid (TFA, 180ml, 3.0 vol/23.6 eq/2.33 mol) was added to the cooled stirred solution at a rate that maintained the internal temperature at no more than-5 ℃. The addition took about 10 minutes to complete, and the reaction mixture was then slowly warmed to 8 ℃ over about 1 hour. While maintaining the internal temperature at 10 ℃ to 20 ℃, Na was slowly added to the reaction mixture₂CO₃(1.0N, 1200ml, 12 equivalents/12 moles) to achieve a pH of the reaction mixture of greater than 8. The reaction mixture was allowed to stand and the organic phase was decanted off. The aqueous phase was extracted with dichloromethane (2X 100ml, 1.65 volumes each). The combined organic phases were washed with water (100 ml). The washed organic phase is concentrated by distillation at atmospheric pressure to the lowest stirrable volume. To the concentrate was added ethyl acetate (2000ml, 33 vol). To the ethyl acetate solution was added a solution of L-tartaric acid (15.05g, 0.1 mol/eq) in methanol (60ml, 1 volume). The reaction mixture was heated and the methanol was distilled off. Distillation was continued until the internal and overhead temperatures were 77 ℃ to 78 ℃ and the reaction mixture was refluxed for 1 to 2 hours. After several hours the reaction mixture was cooled to about 15 ℃. The solid was filtered, washed with ethyl acetate (200ml) and dried under vacuum at about 50 ℃ overnight to give 60.79g of the title compound (92.7% yield).

Example 3

(1- (2- (1(R) - (2, 4-Difluorobenzoxymethyl) - (3a (R)) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoro-l-methyl) Ethyl) -3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c]Pyridin-5-yl) -2-oxo-ethylamino Formyl) -1-methyl-ethyl) carbamic acid tert-butyl ester

To a dry, nitrogen purged, 0.5 liter, 4-necked round bottom flask equipped with a mechanical stirrer, nitrogen-capped condenser, thermocouple, and addition funnel was added 3 a-pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3a, 4,5, 6, 7-hexahydropyrazolo [4, 3-c ] continuously]Pyridin-3-one (L) -tartrate (prepared according to preparation 2, step D, 10.35g, 0.0224 mol, 1.12 equiv) and ethyl acetate (110ml, 10 vol). A slurry is formed. The slurry was stirred and cooled to an internal temperature of-68 ℃ to-60 ℃. To the cooled stirred slurry was added triethylamine (TEA, 7.75ml, 5.66g, 0.056 mol, 2.8 eq) via an addition funnel. The internal temperature was maintained between-68 ℃ and-60 ℃ during the addition. The reaction mixture was stirred for about 1.5 hours while the internal temperature rose to about-62 ℃ to-52 ℃. To the reaction mixture (which is triethylamine tartrate and 3 a-pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3a, 4,5, 6, 7-hexahydropyrazolo [4, 3-c)]Slurry of pyridin-3-one (L) -tartrate) was added triethylamine (12.7ml, 9.30g, 0.092 moles, 4.6 equivalents) over 5 minutes, maintaining an internal temperature of-62 ℃ to-50 ℃ during the addition. To the reaction mixture was added 2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -3- (2, 4-difluorobenzyloxy) -propionic acid (prepared according to preparation 4, step C, 8.34g, 0.020 mole, 1.0eq) in one portion. The internal temperature was maintained between-60 ℃ and-58 ℃ during the addition. Propane phosphonic anhydride (PPAA, 24ml, 25.5g, 2.0 equiv.) was diluted with ethyl acetate (24ml, 2.2 vol) to make a 50% solution of propane phosphonic anhydride in ethyl acetate and cooled to about-45 ℃. The PPAA solution was added to the reaction mixture. The PPAA was added to the reaction mixture for 15 minutes, and the internal temperature was slowly raised to-19 ℃ over 1 hour. The reaction mixture was poured into a vigorously stirred mixture of isopropyl ether (IPE, 100ml, 9.1 vol) and water (100ml, 9.1 vol). The resulting biphasic mixture was stirred for 5 minutes and the reaction mixture was allowed to settle on standing. Decanting the aqueous and organic phasesSuccessively with aqueous HCl (0.5N, 50ml, 4.5 vol, 1.3 eq), NaHCO₃Saturated aqueous solution (50ml, 4.5 vol, ca. 2.5 eq), and 15% aqueous NaCl (50 ml). The washed organic phase was concentrated in vacuo to give an oil. The oil was stirred with hexanes (50ml, ca. 2.5 vol.) to give a glassy solid, 13.75g (96.8% crude yield). The solid was dissolved in chloroform and concentrated in vacuo to give an oil. The process was repeated with hexane. Finally, the resulting oil was stirred with hexane for 16 hours. The resulting solid was filtered to give 10.45g of the title compound (73.6% yield).

Example 4

2-amino-N- (1(R) - (2, 4-difluorobenzyloxymethyl) -2-oxo-2- (3-oxo-3 a (R) -pyridin-2-ylmethyl -2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c]Pyridin-5-yl) -ethyl 2-methylpropionamide

Mixing (1- (2- (1(R) - (2, 4-difluorobenzyloxymethyl) -3a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c)]Pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-ethyl) carbamic acid tert-butyl ester (prepared as in example 3, 17.5g, 25.3mmol) is deprotected as described in general procedure a to give a colorless solid. The product was triturated with ether to give the title compound (13.6g, 90%): + Apcl MS (M + H)⁺591。

Example 5

2-amino-N- {1- (2, 4-difluoro)Benzyloxymethyl) -2-oxo-2- [ 3-oxo-3 a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c]Pyridin-5-yl) -ethyl- 2-methylpropionamide L- (+) tartrate

To a solution of 2-amino-N- (1(R) - (2, 4-difluorobenzyloxymethyl) -2-oxo-2- (3-oxo-3 a (R) -pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -ethyl) -2-methylpropanamide (prepared according to the procedure of example 4, 370g, 0.6mol) in methanol (4,070ml) in a 12L round-bottomed flask equipped with a mechanical stirrer was added L- (+) -tartaric acid (90g, 0.6 mol). The reaction mixture was stirred at 22 ℃ for 90 minutes, filtered and concentrated. The crude residue was diluted with ethyl acetate (4,560ml), heated at about 70 ℃ and allowed to cool slowly to room temperature over about 17 hours. The solid was filtered and dried to give white crystals, mp 188- & 189 deg.C (348.46g, 76% yield).

¹H NMR(MeOH，d4)δ：8.28(d，1H)，7.59(t，1H)，7.41-7.39(m，1H)，7.18-7.13(m，1H)，6.92(t，1H)，5.2(t，1H)，4.56(bs，3H)，4.36(s，2H)，4.31-4.25(m，1H)，4.13-4.06(m，1H)，3.78(d，2H)，3.21(t，1H)，3.18-2.96(m，2H)，2.65-2.55(m，2H)，1.57(d，6H).MS：MH+611.[a]⁵⁸⁹+22.03(c＝11.9，MeOH).

Example 6

Single crystal X-ray analysis. Representative crystals were measured and 1_ data set (max. theta./lambda. 0.5) was collected on a Siemens (Siemens) R3RA/V diffractometer. Atomic scattering coefficients were obtained from table 1 of international X-ray crystallography. All crystallographic calculations were performed using SHELXTL²Provided is a system. All diffractometer data were collected at room temperature. The Pertinent crystallization, data collection, and refinement parameters are all summarized in table I below.

The test structures were obtained in a direct manner. The test structure is corrected (refined) according to the conventional method. The hydrogen position is calculated at all times. The hydrogen and oxygen on the methyl hydrogen and nitrogen atoms are located using the differential Fourier technique. The hydrogen parameters were added to the structure coefficient calculations, but not corrected. The displacement calculations at the last cycle of the least power correction are all less than their respective standard deviations of 0.1. The final R-index was 4.95%. The final difference fourier analysis showed no missing or misplaced electron density.

The corrected structure was plotted using the SHELXTL plotting software package (fig. 1). The absolute configuration is determined according to the known configuration of L-tartaric acid. Coordinated, anisotropic temperature coefficients, distances and angles are available as supplementary materials, see tables II to VI.

TABLE I analysis of single crystal X-ray crystallography

A. Crystal parameters:

molecular formula	C14H18N3O+C4H5O6 -·2H2O(429.4)
		Crystal size of crystallization medium, calculated value of mm empty cell size spacer molecule/unit empty cell density, g/cm3Linear absorption coefficient, mm-1B. Correcting parameters: number of reflections	Acetone and water (1: 1)0.05 × 0.12 × 0.32a ═ 8.235(3) _ b ═ 7.032(2) _ c ═ 18.106(6) _ α ═ 90.0 ° β ═ 99.41(2) ° γ ═ 90.0 ° V ═ 1034.4(6) \\ u { (3) } b } 99.032 (2) } c ═ 18.106(6) } α } 99.0 ° β ° V ═ 903P2121.3790.9461174.39

Non-zero (nonzero) reflection (1 > 3.0 sigma) R-indexaGOFbSecondary extinction coefficientc，χ

10254.95％152(8)×10-4

R-index ═ Σ | Fo | - | Fc |/∑ Fo |

GOF＝[∑w(Fo²-Fc²)²/(m-s)]^1/2

Wherein ═ σ²(F)+|g|F²]^-1And g ═ 0.0005

F^*＝F[1+0.002χF²/sin(2θ)]^-1/4

TABLE II atomic coordination (× 10)⁴) And the equivalent isotropic substitution coefficient (\ u)²×10³)

	x	y	z	U (equivalent)
					C(1’)O(1A’)O(1B’)C(2’)O(2’)C(3’)O(3’)C(4’)O(4A’)O(4B’)N(1)N(2)C(2A)C(3)O(3)C(4)C(5)	7050(7)5715(5)8234(5)7120(6)8733(5)6707(7)7899(5)6647(7)5644(5)7465(5)5011(6)4317(6)2623(6)5357(7)5039(5)6998(6)6515(6)	12045(7)12748(6)12946(6)9881(7)9232(6)9167(7)9726(6)6999(7)6263(6)6110(7)83796558(7)6380(8)5149(8)3491(6)6172(8)8177(8)	6424(4)6097(3)6748(3)6388(4)6715(3)5599(4)5160(3)5583(4)5971(3)5213(3)1995(3)1896(3)1541(4)2171(4)2188(3)2450(3)2299(4)	31(1)41(1)41(1)29(1)37(1)32(1)47(1)32(1)39(1)59(1)43(1)40(1)55(1)36(1)46(1)28(1)33(1)

C(6)N(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)C(15)C(16)O(1W)O(2W)

7511(6)8723(6)8153(7)7643(7)8290(6)7862(7)8463(7)8108(8)7080(*)6443(8)6872(7)8100(5)10828(5)

5878(8)7355(7)9366(8)9700(8)5440(8)5776(8)7317(8)7675(9)6405(9)4882(8)4533(8)6278(7)8138(7)

3290(4)3591(3)3440(4)2603(4)1989(4)11667(4)853(4)76(5)-336(5)-59(5)705(4)7609(3)5099(3)

39(1)40(1)49(1)46(1)37(1)43(1)69(1)97(1)96(1)81(1)75(1)54(1)62(1)

Equivalent isotropic U is defined as orthogonal U_ijTensor trace 3/1

Table iii bond length (_)

C(1’)-O(1A’)	1.262(7)	C(1’)-O(1B’)	1.229(7)
				(C1’)-C(2’)C(2’)-C(3’)C(3’)-C(4’)C(4’)-O(4B’)N(1)-C(5)N(2)-C(3)C(3)-C(4)C(4)-C(6)C(5)-C(9)N(7)-C(8)C(10)-C(11)C(11)-C(16)C(13)-C(14)C(15)-C(16)	1.525(7)1.500(9)1.526(7)1.201(8)1.278(7)1.350(7)1.541(7)1.526(9)1.465(7)1.501(7)1.492(9)1.380(8)1.365(9)1.393(11)	C(2’)-O(2’)C(3’)-O(3’)C(4’)-O(4A’)N(1)-N(2)N(2)-C(2A)C(3)-O(3)C(4)-C(5)C(4)-C(10)C(6)-N(7)C(8)-C(9)C(11)-C(12)C(12)-C(13)C(14)-C(15)	1.4347(6)1.416(8)1.277(8)1.402(5)1.443(7)1.196(7)1.478(7)1.544(9)1.481(7)1.524(10)1.355(9)1.411(12)1.327(10)

Table iv. key angle: (°)

O(1A’)-C(1’)-O(1B’)	125.8(5)	O(1A’)-C(1’)-C(2’)	114.1(5)
				O(1B’)-C(1’)-C(2’)C(1’)-C(2’)-C(3’)C(2’)-C(3’)-O(3’)O(3’)-C(3’)-C(4’)C(3’)-C(4’)-O(4B’)N(2)-N(1)-C(5)N(1)-N(2)-C(3)N(2)-C(3)-O(3)O(3)-C(3)-C(4)C(3)-C(4)-C(6)C(3)-C(4)-C(10)C(6)-C(4)-C(10)N(1)-C(5)-C(9)C(4)-C(6)-N(7)N(7)-C(8)-C(9)C(4)-C(10)-C(11)C(10)-C(11)-C(16)C(11)-C(12)-C(13)C(13)-C(14)-C(15)C(11)-C(16)-C(15)	120.2(5)111.7(5)111.9(4)106.9(5)120.7(6)107.4(3)113.8(4)126.6(5)129.0(5)110.4(5)108.2(5)113.0(4)126.2(4)109.4(5)110.7(5)114.5(4)121.6(6)122.0(6)124.7(8)121.2(6)	C(1’)-C(2’)-O(2’)O(2’)-C(2’)-C(3’)C(2’)-C(3’)-C(4’)C(3’)-C(4’)-O(4A’)O(4A1)-C(4’)-O(4B’)N(1)-N(2)-C(2A)C(2A)-N(2)-C(3)N(2)-C(3)-C(4)C(3)-C(4)-C(5)C(5)-C(4)-C(6)C(5)-C(4)-C(10)N(1)-C(5)-C(4)C(4)-C(5)-C(9)C(6)-N(7)-C(8)C(5)-C(9)-C(8)C(10)-C(11)-C(12)C(12)-C(11)-C(16)C(12)-C(13)-C(14)C(14)-C(15)-C(16)	109.8(4)109.7(5)110.7(5)114.6(5)124.6(5)118.7(4)127.5(5)104.3(4)100.9(4)109.6(5)114.0(5)113.4(4)119.5(4)115.0(4)108.4(5)120.2(5)118.3(7)115.9(7)117.8(6)

Table v. anisotropic substitution coefficient (\ u)²×10³)

	U11	U22	U33	U12	U13	U23
							C(1’)O(1A’)O(1B’)C(2’)O(2’)C(3’)O(3’)C(4’)O(4A’)O(4B’)N(1)N(2)C(2A)C(3)O(3)C(4)C(5)C(6)N(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)C(15)C(16)O(1W)O(2W)	32(1)35(1)35(1)32(1)32(1)41(1)71(1)28(1)41(1)56(1)39(1)30(1)27(1)39(1)45(1)23(1)31(1)38(1)39(1)44(1)41(1)37(1)39(1)72(1)103(1)103(1)81(1)80(1)56(1)58(1)	26(1)19(1)26(1)17(1)33(1)18(1)33(1)27(1)32(1)35(1)48(1)39(1)66(1)40(1)27(1)34(1)32(1)38(1)42(1)46(1)42(1)46(1)55(1)85(1)108(1)108(1)93(1)88(1)45(1)48(1)	34(1)67(1)60(1)36(1)43(1)37(1)41(1)39(1)45(1)92(1)37(1)47(1)68(1)30(1)65(1)26(1)36(1)38(1)34(1)54(1)52(1)29(1)37(1)49(1)82(1)73(1)63(1)58(1)60(1)91(1)	2(1)-4(1)-4(1)1(1)4(1)6(1)-2(1)2(1)-7(1)7(1)4(1)2(1)-3(1)8(1)-3(1)0(1)-1(1)4(1)1(1)-1(1)6(1)6(1)10(1)4(1)2(1)13(1)-4(1)-4(1)-7(1)3(1)	5(1)2(1)-2(1)-1(1)-1(1)6(1)23(1)3(1)10(1)32(1)-6(1)-2(1)-2(1)10(1)5(1)2(1)6(1)1(1)-6(1)1(1)2(1)9(1)7(1)2(1)16(1)4(1)-6(1)13(1)7(1)42(1)	-8(1)2(1)-13(1)1(1)0(1)-6(1)1(1)2(1)-9(1)-2(1)7(1)-4(1)-1(1)-7(1)1(1)3(1)0(1)-4(1)-1(1)-9(1)0(1)4(1)-2(1)1(1)27(1)6(1)-17(1)-12(1)-2(1)7(1)

The anisotropic substitution index takes the form:

-2π²(h²a*²U₁₁+…+2hka*b^*U₁₂)

TABLE VI H-atom coordination (× 10)⁴) And isotropic substitution coefficient (\ u)²×10³)

	x	y	z	U
					H(2’)H(2A’)H(3’)H(3A’)H(4A’)H(2A)H(2B)H(2C)H(6A)H(6B)H(7A)H(7B)H(8A)H(8B)H(9A)H(9B)H(10A)H(10B)H(12)H(13)H(14)H(15)H(16)H(1WA)H(1WB)H(2WA)H(2WB)	63148195(10)56568259(10)5234(10)231924951928799965629771(10)9183(10)722990338599710184179315915285596799571064718471(10)6863(10)11347(10)11515(10)	93858867(10)970411720(10)6488(10)506169077053464259727980(10)7721(10)96051022096851090840956067819287476628404934065946(10)5969(10)8095(10)9176(10)	66657105(9)53985037(9)6270(9)151210461829338135333431(9)4160(9)3689363023622520207121661169-149-864-3759157323(9)7529(9)5456(9)4829(9)	805080505080808080805050808080808080808080808052(1)505050

Preparation example 1

And A.4-Oxopiperidine-1, 3-dicarboxylic acid 1-tert-butyl 3-methyl ester

A mixture of 7.00g (36.2mmol) of methyl 4-oxo-piperidine-3-carboxylate hydrochloride and 8.82g (72.3mmol) of 4, 4-dimethylaminopiperidine in 200ml of dichloromethane is taken over about 30 minutes at about 0 DEG.CTo this was added a solution of 7.88g (36.2mmol) of di-tert-butyl carbonate in 150ml of dichloromethane. The mixture was warmed to room temperature and stirred for about 17 hours. The mixture was concentrated, and the residue was diluted with chloroform and washed three times with 10% aqueous HCl, saturated aqueous sodium bicarbonate and brine, respectively, over MgSO₄Drying and concentration gave 9.18g of a clear yellow oil.

And B, step B.3- (R, S) -benzyl-4-oxo-piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

To a solution of the compound prepared in step A (5.00g, 19.4mmol) in 10mL DMF was added 745mg (7.4mmol) sodium hydride (60%, oil dispersion) and the mixture was stirred at room temperature for about 15 minutes. To the stirred solution was added a solution of 3.32g (19.4mmol) of benzyl bromide in 15ml of DMF through a cannula, and the mixture was stirred at room temperature for 42 hours. The mixture was diluted with ethyl acetate and washed once with water, 4 times with brine, and MgSO₄Drying and concentration gave 6.0g of the title compound of step B as a yellow oil. MS (Cl, NH)₃)348(MH⁺)。

And C, performing step C.3a (R, S) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c)]Pyridine compound -5-Carboxylic acid tert-butyl ester

A mixture of the compound prepared according to step B (4.00g, 11.5mmol) and 530mg (11.5mmol) of methylhydrazine in 100ml of ethanol is heated under reflux for about 8 hours. The mixture was concentrated and the residue was dissolved in 100ml of toluene and heated under reflux for 17 hours. The mixture was concentrated and the residue was chromatographed on silica gel using a gradient (15: 85v/v ethyl acetate: hexane) to (75: 25v/v ethyl acetate: hexane) to give 2.6g of the title compound of step C as a clear colorless oil. MS (Cl, NH)₃)344(MH⁺)。

And D, step D.3a (R) -benzyl-2-methyl-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c]Pyridin-3-ones (L) -tartrate salt

To a 2L round bottom flask equipped with a mechanical stirrer, addition funnel, and thermocouple was added 3a (R, S) -benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-C ] pyridine-5-carboxylic acid tert-butyl ester (prepared as in step C, 51.5g, 0.15 moles, 1.0 equivalent) and dichloromethane (515ml, 10 volumes) in that order. The mixture was stirred to form a solution and cooled to an internal temperature of 0-5 ℃. To the cooled mixture was added trifluoroacetic acid (TFA, 130ml, 192g, 1.68 mol, 11.2 eq, 2.5 vol). TFA was added over 15 minutes through the addition funnel while maintaining an internal temperature of 0-5 ℃. The reaction mixture was warmed to 20 ℃ over 3 hours and then cooled to 10 ℃ to 15 ℃. To the cooled reaction mixture was added a solution of sodium carbonate (92g, 0.868 moles) in water (920ml) over 20 minutes. The pH was 7.5. The reaction mixture was transferred to a 2L separatory funnel and allowed to settle by standing. The organic layer was decanted and the aqueous layer was extracted with dichloromethane (130ml, 2.5 vol). The organic layers were combined and transferred back to a 2L reactor to which was added L-tartaric acid (24.77g, 0.165 moles, 1.1 equivalents) dissolved in acetone (354ml, about 7 volumes) and water (44ml, about 1 volume). The reaction mixture was stirred and heated overnight at about 38 ℃. The resulting slurry was cooled to 0 ℃ to 5 ℃, granulated for 1 hour, and then filtered. The solid was washed with 100ml cold acetone and dried under vacuum at 40 deg.C-50 deg.C for 16 hours to give 51.86g (87.9% yield) of the title compound of step D.

Preparation example 2

And A.4-oxo-3-pyridin-2-ylmethyl-piperazine1-tert-butyl 3-ethyl pyridine-1, 3-dicarboxylate

To a solution of 4-oxo-piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (prepared according to preparation 1, step A, 10.34g, 38.2mmol) in DMF (40ml) was added picolyl chloride hydrochloride (5.7g, 34.7mmol), potassium carbonate (14.4g, 104.1mmol) and potassium iodide (5.76g, 34.7mmol) at about 0 ℃. After stirring at 0 ℃ for about 2 hours, the ice bath was removed and DABCO (973mg, 8.68mmol) was added. The reaction mixture was stirred for 30 minutes and poured into a mixture of water and IPE. The organic layer was separated with saturated NaHCO₃Washing with aqueous solution and saturated aqueous NaCl solution, and adding Na₂SO₄Dried and concentrated in vacuo. The crude residue was crystallized from hexane to give a white solid (8.19g, 65% yield).¹H-NMR(CDCl₃)δ1.17(t，3H)，1.48(s，9H)，1.55(s，2H)，2.61(m，1H)，2.71(m，1H)，3.31-3.50(m，3H)，4.11(d，2H)，4.49(d，1H)，7.06(br s，1H)，7.17(d，1H)，7.54(m，1H)，8.40(s，1H).

And B, step B.3-oxo-3 a-pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3, 3a, 4, 6, 7-hexahydro Pyrazolo [4, 3-c]Pyridine-5-carboxylic acid tert-butyl ester

CF is prepared by₃CH₂NHNH₂A70% aqueous solution (325ml, 1.986mol) was extracted with toluene (3X 1200 ml). To a solution of the compound prepared according to step A (600g, 1.655mol) in toluene (900ml) was added first the combined toluene extracts containing anhydrous 2, 2, 2-trifluoroethylhydrazine, followed by acetic acid (121.4g, 1.986 mol). The reaction mixture was heated at about 70 ℃ for about 2 hours, and then a 70% aqueous toluene extract of 2, 2, 2-trifluoroethylhydrazine (50g) was further added thereto. Mixing the reaction mixtureHeating at about 80 deg.C for about 3.5 hours, cooling to room temperature and adding saturated NaHCO₃(2L) dilution with an aqueous solution. The toluene layer was separated, washed with saturated aqueous NaCl and Na₂SO₄Dried and concentrated in vacuo to give an oil (754.8 g). Crystallization from methanol/water gave the desired product as a white solid (609.5 g).

¹H-NMR(CDCl₃)δ1.50(s，9H)，2.53(d，1H)，2.70(br s，2H)，2.88(br s，1H)，3.31(m，2H)，3.97(m，1H)，4.19(m，1H)，4.46(br s，1H)，4.63(br s，1H)，7.06(m，2H)，7.51(m，1H)，8.34(m，1H).

And C, performing step C.3 a-pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3a, 4,5, 6, 7-hexahydro-pyrazolo [4，3-c]Pyridin-3-ones

To the compound prepared according to step B (10g, 24.2mmol) in CH₂Cl₂To a solution (100ml) was added methanesulfonic acid (11.6g, 121mmol) dropwise over 30 minutes. The reaction mixture was stirred for 1 hour, then cooled to about 0 ℃ and triethylamine (18.6mL, 133.1mmol) was added via an addition funnel. The mixture was allowed to warm to room temperature over about 1 hour and CH was added₂Cl₂Diluted and washed with saturated NaCl, Na₂SO₄Drying, filtration and concentration in vacuo gave the product as a white solid (7.2 g).

¹H-NMR(CDCl₃)δ：2.51-2.72(m，4H)，3.35(m，2H)，3.49(m，2H)，4.03(m，1H)，4.25(m，1H)，7.08(d，2H)，7.51(t，1H)，8.37(d，1H).

And D, step D.3 a-pyridin-2-ylmethyl-2- (2, 2, 2-trifluoroethyl) -2, 3a, 4,5, 6, 7-hexahydro-pyrazole And [4, 3-c ]]Pyridin-3-one (D) -tartrate salt

To a solution of compound prepared according to step C (243g, 0.78mol) in acetone/water (9: 1, 2430ml) was added D- (-) tartaric acid (129g, 0.86mol) at about 17 deg.C in a dry and nitrogen purged 5L round bottom flask equipped with a mechanical stirrer. The mixture was stirred at room temperature overnight, filtered, the solid collected and washed with cold acetone and dried in vacuo. The product was obtained as a yellow solid (284g, 78.8% yield).

Preparation example 3

And A.2, 5-Dioxo-pyrrolidin-1-yl 2-Boc-amino-2-methylpropionate

A solution of N-hydroxysuccinimide (112g, 0.973mol), N-t-butoxycarbonyl- α -methylalanine (197g, 0.969mol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (186g, 0.970mol) in dry dichloromethane (1.4L) was stirred at room temperature under a nitrogen atmosphere for about 18 hours. The reaction mixture was washed three times each with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of step a as a white solid (256g, 88%).

PBMS(M+18)⁺318；¹H NMR＝250MHz(CDCl₃)δ：4.91(NH，br s，1H)，2.84(-CO(CH₂)₂CO-，s，4H)，1.67(Me，s，6H)，1.48(BOC，s，9H).

And B, step B.2(R) -3-benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -propionic acid

To a solution of D-O-benzylserine (106g, 0.532mol) and the title compound of step a (160g, 0.532mol) in water/dioxane (250/1000ml) was slowly added triethylamine (223ml, 1.60mol) at room temperature. The reaction mixture was heated to about 50 ℃ and stirred under nitrogen for about 15 hours. The solvent was then removed in vacuo, ethyl acetate was added, the mixture was stirred and acidified to pH2-3 with 10% aqueous HCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of step B (200g, 99%).

-Apcl MS(M-1)^-379；¹H NMR 300MHz (methanol-d)₄)δ：7.69(NH，d，1H)，7.32(Ph，m，5H)，4.60(CHCO₂H，m，1H)，4.51(CH₂Ph，s，2H)，3.81(CH₂Obz，m，2H)，1.41(Me，s，6H)，1.40(BOC，s，9H).

Preparation example 4

And A.2(R) -2-tert-Butoxycarbonylamino-3- (2, 4-difluoro-benzyloxy) propionic acid

To a solution of N-Boc- (D) -serine (452g, 2.2026mol) in a mixture of THF (7L) and DMF (3L) was added potassium tert-butoxide solution (515.8g, 4.5963mol) at about 0 ℃. The reaction mixture was stirred at about 0 ℃ for about 30 minutes, then 2, 4-difluorobenzyl bromide (456.5g, 2.2051mol) was added. After warming to room temperature, the reaction mixture was concentrated in vacuo to remove THF. The reaction mixture was heated to 4.5L H₂Split between O and 4.5L IPE. The layers were separated and the pH of the aqueous layer was adjusted to about 3 with 1N HCl. The aqueous layer was extracted twice with 4L IPE each time. Na for organic solution₂SO₄Dried and concentrated in vacuo to give a yellow waxy solid (518.0g, 70.9% yield).

70.9％).¹H-NMR(CDCl₃)δ1.44(s，9H)，3.73(m，1H)，3.94(d，1H)，4.44(brs，1H)，4.54(s，2H)，5.34(m，1H)，6.78(m，1H)，6.84(m，1H)，7.30(m，1H).

And B, step B.2(R) -2-amino-3- (2, 4-difluoro-benzyloxy) -propionic acid, methanesulfonate salt

To the product of step A (1.19g, 3.59mmol) in CH over about 10 minutes by syringe₂Cl₂To a solution of/IPE (1: 1, 12ml) was added methanesulfonic acid (1.72g, 17.95 mmol). A solid precipitated immediately in solution. After about 1 hour, the solid was filtered and washed with CH₂Cl₂Washing with the mixture/IPE (1: 1) gave 939mg of product (80% yield).

And C, performing step C.2(R) -2- (2-tert-Butoxycarbonylamino-2-methyl-propionylamino) -3- (2, 4-difluorobenzyloxy) propane Acid(s)

To a solution of the product of step B (520mg, 1.46mmol) in THF/water (4: 1, 10mL) was added 2-tert-butoxycarbonylamino-2-methylpropanoic acid-2, 5-dioxo-pyrrolidin-1-yl ester (438mg, 1.46mmol) and triethylamine (369mg, 3.65 mmol). The reaction mixture was stirred at room temperature for about 1 hour, and then quenched with 10% aqueous citric acid (10 ml). After about 15 minutes, ethyl acetate (50ml) was added and the organic layer was separated, washed with saturated aqueous NaCl and Na₂SO₄Dried and concentrated in vacuo to give a foamy mass (534.1mg, 88% yield).

¹H-NMR(CD₃OD)：δ1.38(br s，15H)，3.77(d，1H)，3.92(d，1H)，4.52(m，3H)，6.92(m，1H)，7.41(m，1H)，7.58(d，1H).

Preparation example 5

(3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c]Pyridine- 3-keto, (2R, 3R) -2, 3-dihydroxysuccinate (1: 1)

Step A:4-oxo-1- (phenylmethyl) -3-piperidinecarboxylic acid methyl ester hydrochloride

A solution of 1-benzyl-4-piperidone (56.5kg, 1.0 eq.) in toluene (189L) was prepared at 15 ℃ to 25 ℃. Toluene (659L), potassium tert-butoxide (71.9kg, 2.25 equivalents) and dimethyl carbonate (51.5kg, 2.0 equivalents) were placed in a separate reactor at 15 deg.C to 25 deg.C. The resulting slurry was warmed to 80 to 90 ℃. A solution of 1-benzyl-4-piperidone in toluene was slowly added to the slurry over a period of 60 to 90 minutes. After a further 90 minutes, the reaction mixture was cooled to below 15 ℃. The reaction was quenched by the addition of acetic acid (38.5kg, 2.25 equivalents) and water (367L). The two-phase mixture was separated. The organic layer was filtered to remove solids. The organic filtrate was concentrated by distillation under reduced pressure to a volume of about 150L. Toluene (799L) was added to the concentrated mixture. Hydrogen chloride (gas, 11.0kg, 1.05 eq.) was added to give the hydrochloride as a precipitated solid. The slurry was stirred at 10 ℃ to 15 ℃ for 30 minutes. The solid was isolated by filtration, washed with hexane (130L), and dried under vacuum to give 79.4Kg of methyl 4-oxo-1- (phenylmethyl) -3-piperidinecarboxylate hydrochloride (97.8% yield). C₁₄H₁₇NO₃Elemental analysis of HCl, theoretical value: c59.3; h6.39; n4.94; measured value: c59.7; h6.65; and N4.85.

And B, step B.4-oxo-1-piperidinecarboxylic acid methyl ester hydrochloride

To a clean, dry nitrogen purged reactor was charged methyl 4-oxo-1- (phenylmethyl) -3-piperidinecarboxylate hydrochloride (prepared according to preparation 5, step a, 78.8kg,1.0eq), ethanol (416L), water (340L), and 10% palladium on carbon (catalyst, 7.88kg, 0.1 kg/kg). The mixture was placed under hydrogenation conditions at about 45psig (32X 10)³kg/m²) Hydrogen pressure, hydrogenation at a temperature of 25 ℃ to 35 ℃ for about 18 hours. After completion of the reaction, the reaction mixture was replaced with nitrogen and filtered to remove the spent catalyst. The catalyst cake was washed with ethanol (150L). The filtrate and washings were concentrated under reduced pressure to about 57L. The product was crystallized by slow addition of 2-propanol (227L). The slurry was cooled to 10 ℃ to 20 ℃ and stirred for about 1 hour. The product was isolated by filtration, washed with hexane (76L), and dried under vacuum for about 24 hours to give 43.2kg (yield 80.0%) of methyl 4-oxo-1-piperidinecarboxylate hydrochloride. C₇H₁₁NO₃Elemental analysis of HCl, theoretical value: c43.42; h6.25; n7.23; measured value: c43.7; h6.59; and (7) N7.19.

And C, performing step C.4-oxo-1, 3-piperidinecarboxylic acid 1- (1, 1-dimethylethyl) 3-methyl ester

A clean, dry, nitrogen purged glass-lined vessel was charged with isopropyl ether (IPE, 309L), methyl 4-oxo-1-piperidinecarboxylate hydrochloride (prepared according to preparation 5, step B, 42.6kg, 1.0 eq.), and water (153L) at 15 ℃ to 25 ℃. Triethylamine (28.9kg, 1.3 equivalents) was added to give a viscous white emulsion. Di-tert-butyl dicarbonate (52.6kg, 50L, 1.1 eq) was slowly added to the reaction mixture, which was then washed with IPE to give a clear biphasic solution. The mixture was stirred at 15 ℃ to 25 ℃ for about 12 hours. After completion of the reaction, the aqueous layer was separated and extracted with IPE (20L). The combined organic extracts were washed successively with 1N HCl (110L), water (90L), and saturated sodium chloride solution (103L). The washed organic layer was dried over anhydrous sodium sulfate. The mixture was filtered to remove insoluble material. The filtrate was concentrated by vacuum distillation to give 1- (1, 1-dimethylethyl) 3-methyl 4-oxo-1, 3-piperidinecarboxylate as an oil. About 49L (53kg) of oily product was collected (assuming a 95% yield). The oil was left in the reactor to be used directly in the next step.

And D, step D.4-oxo-3- (phenylmethyl) -1, 3-piperidinedicarboxylic acid 1- (1, 1-dimethylethyl) 3-methyl ester

To a nitrogen purged vessel containing 1- (1, 1-dimethylethyl) 3-methyl 4-oxo-1, 3-piperidinecarboxylate (prepared according to preparation 5, step C, 53kg, 49L, 1.0eq) were added tetrahydrofuran (THF, 536L) and potassium carbonate (72kg, 2.5 eq). The slurry was treated with benzyl bromide (36.0kg, 1.01 eq) for about 10 to 15 minutes. The reaction mixture is heated at reflux temperature until the reaction is complete (typically between 12 and 18 hours). The mixture was cooled to 20 ℃ to 25 ℃, the salts were removed by filtration, and the filter cake was washed with THF (134L). The THF in the mixture was removed by partial vacuum distillation and replaced with heptane (402L). The resulting slurry was cooled to-5 ℃ to 5 ℃ and stirred for about 1 hour. The solid was collected by filtration, washed with heptane (57L) cooled to 0 ℃ to 10 ℃ and dried under vacuum at 45 ℃ to 55 ℃ to give 50.1kg of 1- (1, 1-dimethylethyl) 3-methyl 4-oxo-3- (phenylmethyl) -1, 3-piperidinedicarboxylate (69.2% yield). HPLC analysis showed a 99.2% peak of the product at about 12 minutes. HPLC conditions: intersil C-8 column, 4.6X 150 mm; mobile phase: 50% acetonitrile/water; aqueous phase: 1L of water, 3ml of triethylamine and 1ml of H₃PO₄pH 6.5; the flow rate was 1.0 ml/min; UV detection at 210 nm.

Step E:2, 3, 3a, 4, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c] Pyridine-5-carboxylic acid 1, 1-dimethylethyl ester

Methylhydrazine is highly toxic, may be a carcinogen, is flammable and may explode. The application requires extra care. During operation, the hands must have the color of the leakage treatment, the desiccant, the liquification packs (liqua packs) and the fire extinguisher. It is ensured that the air hose is long enough to escape any accident site. Since methylhydrazine can react with metal oxides, inspection of the reaction vessel ensures that no metal surfaces are exposed prior to initiating the reaction. 4-oxo-3- (phenylmethyl) -1, 3-piperidinedicarboxylic acid 1- (1, 1-dimethylethyl) 3-methyl ester (prepared according to preparation 5, step D, 50.1kg, 1.0eq) was dissolved in methyl tert-butyl ether (MTBE, 208L) at 15 ℃ to 20 ℃ in a clean, glass-lined, nitrogen-purged vessel to prepare a solution. Adding methylhydrazine (A) to the reaction solution7.6g, 1.15 eq). After stirring for about 30 minutes, acetic acid (13.0kgm 1.5 eq) was added. The reaction mixture was slowly heated to reflux temperature (53 ℃ to 57 ℃) and kept at reflux for 15 to 20 hours. The reaction mixture was cooled to 20 ℃ to 25 ℃. The reaction mixture was cooled to 5 ℃ to 10 ℃ and 10% aqueous sodium bicarbonate solution (175L) was slowly added. The biphasic mixture was separated and the organic phase was washed successively with water (175L) and saturated sodium chloride solution (175L). The combined aqueous wash layers were treated with a bleaching solution to destroy any remaining methylhydrazine before being discarded. The organic solution was concentrated under partial vacuum to a volume of 130 to 170L. Heptane (174L) was added to the mixture to precipitate the product. The slurry was stirred between 5 ℃ and 10 ℃ for 2 hours. The solid was isolated by filtration, washed with cold MTBE (34L) and dried under vacuum between 35 deg.C and 45 deg.C for 24 hours to give 2, 3, 3a, 4, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c]47.1kg of 1, 1-dimethylethyl pyridine-5-carboxylate (yield 95.1%). HPLC analysis showed a 99.1% peak of the product at about 5 minutes. HPLC conditions: intersil C-8 column, 4.6X 150 mm; mobile phase: 50% acetonitrile/water; water phase: 1L of water, 3ml of triethylamine and 1ml of H₃PO₄pH 6.5; the flow rate was 1.0 ml/min; UV detection at 205 nm.

Step F:(3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c] Pyridin-3-one, (2R, 3R) -2, 3-dihydroxysuccinate (1: 1)

The intermediate free amine has been observed to epimerize in solution and separate as a solid. Thus, the dynamic resolution step can be completed immediately after the deprotection step. To a clean, nitrogen purged reactor was added dichloromethane (471L) and 2, 3, 3a, 4, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c ] pyridine-5-carboxylic acid 1, 1-dimethyl ester (prepared according to preparation 5, step E, 47.0kg, 1.0 eq). The mixture was stirred and cooled to-5 ℃ to 5 ℃. Trifluoroacetic acid (117kg, 7.5 equivalents) was slowly added to the reaction mixture. The reaction mixture was warmed to 20 to 30 ℃ and stirred for 12 to 15 hours. The reaction was quenched by slow addition of 10% aqueous sodium carbonate (486L, 0.5 equiv.) at 5 ℃ to 15 ℃. The organic layer was separated and the aqueous layer was extracted with dichloromethane (19L).

A mixture of acetone (456L), water (56.4L) and L-tartaric acid (22.6kg, 1.1 equiv.) was prepared in another reactor. The tartaric acid mixture was mixed with the organic layer at 20 ℃ to 25 ℃. The resulting slurry was heated to 35 ℃ to 45 ℃ and stirred for 8 to 18 hours (over). When the reaction was judged to be complete, the slurry was cooled and granulated at 0 ℃ to 10 ℃ for 3 to 4 hours and filtered. The product cake was washed with a mixture of acetone (40L) and water (4.5L). The product was dried under vacuum using only moderate heating (if acetone evaporated resulting in cooling). 37.7kg (3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one, (2R, 3R) -2, 3-dihydroxysuccinate (1: 1) were obtained (yield 70.1%).

Claims (6)

1. A process for the preparation of the L-tartrate salt of formula XX,

comprises the following steps:

a) reacting said methyl 4-oxo-piperidinecarboxylate hydrochloride with di-tert-butyl dicarbonate and triethylamine in isopropyl ether to form 1- (1-dimethylethyl) 3-methyl 4-oxo-1, 3-piperidinedicarboxylate;

b) reacting the 1- (1-dimethylethyl) 3-methyl 4-oxo-1, 3-piperidinedicarboxylate with benzyl bromide and potassium carbonate in tetrahydrofuran to form 1- (1-dimethylethyl) 3-methyl 4-oxo-3- (phenylmethyl) -1, 3-piperidinedicarboxylate;

c) reacting the 1- (1-dimethylethyl) 3-methyl 4-oxo-3- (phenylmethyl) -1, 3-piperidinedicarboxylic acid with methylhydrazine in acetic acid and methyl tert-butyl ether to form 1, 1-dimethylethyl 2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c ] pyridine-5-carboxylate;

d) reacting the 1, 1-dimethylethyl 2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3-oxo-3 a- (phenylmethyl) -5H-pyrazolo [4, 3-c ] pyridine-5-carboxylate with trifluoroacetic acid to form (3a) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one; and

e) reacting said (3a) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one with L-tartaric acid in acetone and water to form the L-tartrate salt of the general formula XX, wherein the addition of said L-tartaric acid does not require isolation of said (3aR) -2, 3a, 4,5, 6, 7-hexahydro-2-methyl-3 a- (phenylmethyl) -3H-pyrazolo [4, 3-c ] pyridin-3-one.

2. A process according to claim 1 comprising the additional step of crystallizing said L-tartrate salt of formula XX from said acetone and aqueous solution.

3. A process according to claim 2 wherein the L-tartrate salt of formula XX is isolated in the form of the dihydrate.

4. A polymorph of a dihydrate of compound of formula XX:

5. the polymorph of claim 4 having an X-ray crystal structure as shown in figure 1.

6. The polymorph of claim 4 having the atomic coordination and equivalent isotropic substitution coefficients set forth in Table II:

TABLE II atomic coordination (x 10)⁴) And the equivalent isotropic substitution coefficient (\ u)²×10³) x y z U (equivalent) C(1’)O(1A’)O(1B’)C(2’)O(2’)C(3’)O(3’)C(4’)O(4A’)O(4B’)N(1)N(2)C(2A)C(3)O(3)C(4)C(5) 7050(7)5715(5)8234(5)7120(6)8733(5)6707(7)7899(5)6647(7)5644(5)7465(5)5011(6)4317(6)2623(6)5357(7)5039(5)6998(6)6515(6) 12045(7)12748(6)12946(6)9881(7)9232(6)9167(7)9726(6)6999(7)6263(6)6110(7)83796558(7)6380(8)5149(8)3491(6)6172(8)8177(8) 6424(4)6097(3)6748(3)6388(4)6715(3)5599(4)5160(3)5583(4)5971(3)5213(3)1995(3)1896(3)1541(4)2171(4)2188(3)2450(3)2299(4) 31(1)41(1)41(1)29(1)37(1)32(1)47(1)32(1)39(1)59(1)43(1)40(1)55(1)36(1)46(1)28(1)33(1) C(6)N(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)C(15)C(16)O(1W)O(2W) 7511(6)8723(6)8153(7)7643(7)8290(6)7862(7)8463(7)8108(8)7080(*)6443(8)6872(7)8100(5)10828(5) 5878(8)7355(7)9366(8)9700(8)5440(8)5776(8)7317(8)7675(9)6405(9)4882(8)4533(8)6278(7)8138(7) 3290(4)3591(3)3440(4)2603(4)1989(4)11667(4)853(4)76(5)-336(5)-59(5)705(4)7609(3)5099(3) 39(1)40(1)49(1)46(1)37(1)43(1)69(1)97(1)96(1)81(1)75(1)54(1)62(1)