MXPA00002031A

MXPA00002031A - Process for preparing growth hormone secretagogues

Info

Publication number: MXPA00002031A
Application number: MXPA/A/2000/002031A
Authority: MX
Inventors: Robert Busch Frank; Kwokfung Chiu Charles; Nathaniel Meltz Clifford; James Post Ronald; Robert Rose Peter
Original assignee: Pfizer Products Inc
Priority date: 1999-02-26
Filing date: 2000-02-25
Publication date: 2001-06-26

Abstract

This invention relates to improved processes for preparing compounds of Formula II, and compounds of Formula III, wherein R1, R2, R3 and Prt are defined as set forth in the specification.

Description

PROCEDURE FOR PREPARING SECRETAGOGOS OF HORMONES OF GROWTH BACKGROUND OF THE INVENTION This invention relates to an improved process for preparing compounds of Formula II, which comprises coupling a compound of Formula IV with a compound of Formula V. This invention also relates to an improved process for preparing compounds of Formula III by coupling a compound of Formula IV with a compound of Formula V and the subsequent deprotection of the resulting Prt-protected compound of Formula II. The Publication of the International Patent Application N °. WO97 / 24369, commonly assigned, hereinafter referred to as application 24369, which is incorporated herein by reference, discloses certain secretagogues of growth hormone compounds of Formula I, in which the definitions of the variables are described in this document.

As described in application 24369, said compounds have utility in the treatment, among other diseases, of osteoporosis. The compounds of Formula II, are described in the application 24369 as intermediates in a process for preparing the compounds of Formula III, ill which are within the scope of the description of said international application. The process described in application 24369 requires the coupling of a compound of Formula IV with a compound of Formula V. The first step of the coupling reaction is the reaction of a compound of Formula IV, shown below, with an organic amine for forming the free base of the compound of Formula IV and the organic amine salt of tartaric acid. The next step in the described process is a filtration step to remove the organic amine salt of tartaric acid.

This step was considered necessary to eliminate the possibility of reaction of tartaric acid with the compound of Formula IV under coupling conditions. Due to the racemization of the 3a position of the pyrazolo [4,3-cjpyridine, which occurs at room temperature, this filtration had to be performed cryogenically, that is, at reduced temperatures. When the large-scale coupling reaction is performed, cryogenic filtration presents technical problems, for example, dragging, slow filtration, the need to use additional equipment and extra handling. This causes low yields of the product. In the process of this invention, cryogenic filtration is avoided, obtaining a more simplified process and better chemical and optical yields.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to a method, called Process A, to prepare a compound of Formula II, ll in which: R1 is -alkyl (C? -C? o) optionally substituted with up to three fluorine atoms; R is phenylmethyl or 2-pyridylmethyl; R3 is -alkyl (C? -C5) -O-alkyl (Co-C5) phenyl, the phenyl substituent being in the definition of R3 optionally substituted with up to three fluorine atoms; and Prt is an amine protecting group, which comprises: a) mixing an appropriate chiral tartrate salt having the structure of Formula IV, D- or L-tartaric acid IV wherein Ri and R2 are as defined above, and an organic amine in a reaction inert solvent, at a temperature of about -68 ° C to about -40 ° C, to form a suspension; b) adding a compound of Formula V, wherein R and Prt are as defined above, said suspension to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of Formula V; and c) adding a coupling reagent to said reaction mixture to form a compound of Formula II. A preferred process within Process A, termed Process B, is a process wherein said compound of Formula IV is suspended in said solvent prior to the addition of said organic amine. A preferred process within Process B, designated Process C, is a process in which said suspension is heated to about -50 ° C before step b. Another preferred process within Process A, termed Process D, is the process in which: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is the propanephosphonic acid anhydride. A preferred process of Process D, designated Process E, is a process wherein R 1 is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process of Process E is a process in which the compound of Formula II selected from (1- (2- (1 (R) - (2,4-difluorobenzyloxymethyl) -3a-tert -butyl ester ( 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 and (1- (2- (3a (R) -benzyl-2-methyl) tert-butyl ester -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. Another preferred method of Process E is a process in which a compound of Formula NA is prepared HE HAS Another preferred method of Process E is the process in which a compound of Formula IIB is prepared.

IIB Another preferred process within Process B, called Process F, is the process in which: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propanephosphonic acid anhydride. A preferred process within Process F, designated Process G, is a process wherein R 1 is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process within Process F is a process in which the compound of Formula II selected from (1- (2- (1 (R) - (2,4-difluorobenzothioxymethyl) tert -butyl ester) is prepared. -3a (R) -p¡r'din-2-ylmethyl-2- (2,2,2-trifluoro-etiI) -3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [ 4.3-c] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-meth yl-ethyl) -carbamic acid and the tert-butyl ester of the acid (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. Another preferred process within Process F is a process in which a compound of Formula HA is prepared HA Another preferred process within Process F is a process in which a compound of Formula IIB is prepared IIB Another preferred process within Process C, designated Process H, is a process in which: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethoxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is the propanephosphonic acid anhydride. A preferred process within Process H, termed Process I, is that in which R is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process within Process I is a process in which the compound of Formula II selected from (1- (2- (1 (R) - (2,4-difluorobenzyloxymethyl) tert-butyl ester is prepared. l) -3a (R) -pyridin-2-ylmethyl-2- (2,2,2-trifluoro-etl) -3-oxo-2,3,3a, 4,6,7- hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid and tert-butyl ester of (1- (2- (3a (R)} -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo ^. S-cjpyridin-d-iO-líRJ-benzyloxymethyl ^ -oxo-ethylcarbamoi-1-methyl-ethyl ) -carbamic Another preferred process within Process I is a process in which a compound of Formula HA is prepared HE HAS Another preferred process within Process I is a process in which a compound of Formula IIB is prepared IIB This invention also relates to a process, called Process J, for preparing a compound of Formula III, III wherein: R1 is -alkyl (C? -C? o) optionally substituted with up to three fluorine atoms; R2 is phenylmethyl or 2-pyridylmethyl; and R3 is -alkyl (C? -C5) -0-alkyl (Co-C5) phenyl, the phenyl substituent being in the definition of R3 optionally substituted with up to three fluorine atoms, comprising: a) mixing a chiral tartrate salt appropriate Formula IV, • D- or L-tartaric acid IV wherein R1 and R2 are as defined above, and an organic amine in a solvent inert to the reaction at a temperature of about -68 ° C to about -45 ° C to form a suspension; b) adding a compound of Formula V, V wherein R3 and Prt are as defined above, to said suspension, to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of Formula V; c) adding a coupling reagent to said reaction mixture to form a compound of Formula II; and d) reacting said compound of Formula II with a suitable deprotective reagent to form a compound of Formula III. A preferred process within Process J, designated Process K, is a process in which said Formula IV compound is suspended in said solvent before the addition of said organic amine and the additional step of heating said suspension to a temperature of about - 50 ° C at about -40 ° C is performed before step b. A preferred process within Process K, designated Process L, is a process wherein said Prt is Boc and said Boc is removed by reacting said compound of Formula II with an acid. A preferred process within Process L, called Process M, is a process in which said acid is methanesulfonic acid. A preferred process within Process M, designated Process N, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is the propanephosphonic acid anhydride. A preferred process within Process N, designated Process O, is a process wherein R 1 is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process within Process O is a process in which said compound of formula III selected from 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2, is prepared, 3,3a, 4,6,7-hexahydro-pyrazolo- [4,3-c] pyridin-5-yl-1 (R) -benzyloxymethyl-2-oxo-etl] -isobutyramide and 2 -amino-N- (1 (R) - (2,4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-ylmethyl) -2- (2,2 , 2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-p¡razolo [4,3-c] pyridin-5-yl) -etii-2-methyl-propionamide Another preferred method within Procedure O is a process in which a compound of Formula I HA is prepared IIIA Another preferred process within Process O is a process in which a compound of Formula IIIB IIIB is prepared. Another preferred process within Process L, termed Process P, is a process in which said acid is trifluoroacetic acid. A preferred process within Process P, designated Process R, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is the propanephosphonic acid anhydride. A preferred process within Process R, designated Process S, is a process wherein R 1 is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process within Process S is a process in which said compound of Formula III selected from 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2,3 is prepared. , 3a, 4,6,7-hexahydro-p¡razolo- [4,3-c] pyridin-5-1-l (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide and 2-amino -N- (1 (R) - (2,4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-ylmethyl) -2- (2,2,2 -trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -ethyl-2-methyl-propionamide Another preferred process within the Process S is a process in which a compound of Formula IIIA is prepared IIIA Another preferred process within Process S is a process in which a compound of Formula IIIB is prepared IIIB Another preferred process within claim K, called Process T, is a process wherein said Prt is Boc and said Boc is removed by the reaction of said compound of Formula II with an acid. A preferred process within Process T, termed Process U, is a process in which said acid is methanesulfonic acid. A preferred process within Process U, designated Process V, is a process wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is the propanephosphonic acid anhydride. A preferred process within Process V, designated Process W, is a process wherein R is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process within Process W is a process wherein said compound of Formula III is selected from 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) -benzylloxymethyl-2-oxo-ethyl] -isobutyramide and 2- amino-N- (1 (R) - (2,4-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-ylmethyl) -2- (2,2, 2-trifluoro-etl) -2,3,3a, 4,6,7-hexahydro-pyrrazolo [4,3-c] pyridin-5-yl) -ethyl-2- Methyl-propionamide Another preferred process within Process W is a process in which a compound of formula IIIA is prepared IIIA Another preferred process within Process W is a process in which a compound of Formula IIIB is prepared IIIB Gnu μn cuiii uc! ??? μicici i u ucnu? uci r- | < _ »CedÍmÍent? T, designated Process X, is a process in which said acid is trifluoroacetic acid. A preferred process within Process X, designated Process Y, is a process in which: R is phenylmethyloxymethyl or 2,4-difluorophenylmethyl-oxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is the propanephosphonic acid anhydride. A preferred process within Process Y, designated Process Z, is a process wherein R 1 is methyl or 2,2,2-trifluoroethyl and R 2 is phenylmethyl or 2-pyridylmethyl. A preferred process within Process Z is a process in which said compound of Formula III selected from 2-amino-N- [2- (3a (R) -benzyl-2-methyl-3-oxo-2, is prepared, 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-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-methyl] -2- (2,2,2- trifluoroethylene) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -ethyl-2-methyl-propionamide. Another preferred process within Process Z is a process in which a compound of Formula IIIA is prepared IHB Another preferred process within Process Z is a process in which a compound of Formula 11 IB is prepared IIIB This invention also relates to a process for preparing a compound of Formula XX, XX comprising the following consecutive steps: a) reacting said hydrochloride of 4-oxo-piperidinecarboxylic acid methyl ester with di-t-butyl dicarbonate and triethylamine in isopropyl ether to form 1- (1-dimethylethyl) 3-methyl 4-oxo-1,3-piperidinedicarboxylic acid ester; b) reacting said 1- (1-dimethylethyl) 3-methyl ester of 4-oxo-1,3-piperidinedicarboxylic acid with benzyl bromide and potassium carbonate in tetrahydrofuran to form the 1- (1-dimethylethyl) 3-methyl ester of 4-oxo- (phenylmethyl) -1,3-piperidinedicarboxylic acid; c) reacting said 1- (1-dimethylethyl) 3-methyl ester of 4-oxo- (phenylmethyl) -1,3-piperidinedicarboxylic acid with methylhydrazine in acetic acid and methyl t-butyl ether to form 1,1-dimethylethyl 2,3a, 4,5,6,7-hexahydro-2-methyl-3-oxo-3a- (phenylmethyl) -5H-pyrazolo [4,3-c] pyridine-5-carboxylic acid ester; d) reacting said 1,4-dimethylethyl ester of 2,3a, 4,5,6,7-hexahydro-2-methyl-3-oxo-3a- (phenylmethyl) -5H-pyrazolo [4,3-c] pyridine-5-carboxylic acid with trifluoroacetic acid to form (3aR) -2,3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) -3H-pyrazolo [4,3-c] pyridin-3-one; and e) reacting said (3aR) -2,3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) -3H-pyrazolo [4,3-c] pyridin-3-one with acid L-tartaric in acetone and water to form said salt L-tartrate of Formula XX. This invention particularly relates to a process as indicated in the immediately preceding paragraph, wherein said L-tartaric acid is added without isolation of said (3aR) -2,3a, 4,5,6,7-hexahydro- 2-methyl-3a- (phenylmethyl) -3H-pyrrazolo [4,3-c] pyridin-3-one. In particular, the compound of formula XX is isolated as a dihydrate. The desired crystalline form is isolated after cooling in an appropriate mixture of solvents. This invention also relates to a polymorph of a dihydrate of a compound of formula XX: XX This invention particularly relates to the polymorph having the atomic coordinates and the sotropic shift coefficients equivalent to those indicated in Table 1. This invention also particularly relates to the polymorph having the X-ray crystal structure according to the Figure 1.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray crystal structure of the compound of Formula XX, collected on a Siemens R3RA? / Diffractometer. The crystal structure shows that the compound is a dihydrate of the L-tartrate salt of said compound.

DETAILED DESCRIPTION OF THE INVENTION The following schemes illustrate the synthesis of the compounds of Formulas II and III. The symbol "" indicates a stereochemical center. In the scheme, "Prt" is used to indicate any suitable amine protecting group known to those skilled in the art. In the description that follows each scheme, the amine protecting group Prt is illustrated with the preferred amine protecting group BOC, although it will be recognized that other amine protecting groups may also be used.

SCHEME 1 ACID (D) - O (L) -TARTARIC 1e Compounds of Formula IV wherein Alk is methyl or ethyl, R1, R2 and Prt are as defined above, for example, the compounds of Formula 1e, are prepared as is indicated in Scheme 1 or 1a. According to Scheme 1, step a, a compound of formula 1a is mixed with a polar aprotic solvent inert to the reaction such as acetone, methyl ethyl ketone, DMF (dimethylformamide) or preferably tetrahydrofuran, at a temperature of about 0 ° C. at room temperature, preferably at room temperature. R2-X is added to the solution, X being a leaving group such as halo or an alkyl or aryl sulfonate; a base such as potassium t-butoxide or a carbonate such as Li2C? 3, Cs2C? 3 or, preferably, potassium carbonate; and optionally a phase transfer reagent such as potassium iodide or tetrabutylammonium iodide. In the case potassium carbonate is used as the base, it is preferred not to use a phase transfer reagent. It is preferred that when R2 is benzyl, R2-X is benzyl bromide, and that when R2 is 2-pyridylmethyl, R2-X is picolyl chloride hydrochloride. After stirring at a temperature of about -20 ° C to about 70 ° C for about 2 to 16 hours, preferably at a temperature of 60 ° C to about 65 ° C for about 12 hours, the product is isolated from the mixture of reaction according to techniques well known to those skilled in the art. This step is preferably carried out as indicated in Preparation Five, Step D, shown below. According to step b, a hydrazine derivative is reacted with a compound of Formula 1b. Preferably, the hydrazine derivative is a 70% aqueous solution of CF3CH2NHNH2 (trifluoroethylhydrazine) or CH3NHNH2 (methylhydrazine) anhydrous, which is used as an aqueous solution in ethanol, water or toluene. When the 70% solution of trifluoroethylhydrazine is used, it is further preferred that the 70% aqueous solution of CF3CH2NHNH2 is extracted with toluene. To a solution of a compound of formula 1b in an organic solvent such as ethanol, toluene or, preferably, methyl t-butyl ether (MTBE), 2,2,2-trifluoroethylhydrazine or anhydrous methylhydrazine is first added, followed by acid. acetic. Preferably, MTBE is used to prevent the reaction mixture from reaching an excessively high temperature. The reaction mixture is heated to a temperature of about 50 ° C to about 110 ° C for a period of about 30 minutes to 24 hours, preferably at about 60 ° C for a period of about 12 to about 15 hours. The reaction mixture is cooled to room temperature and neutralized with an aqueous base such as NaHC 3. When used in this document, the term "room temperature" means a temperature of about 20 ° C-25 ° C. The organic layer is separated and treated using conventional procedures known in the art to produce a compound of formula 1c. This step is preferably carried out as indicated in Preparation Five, Step E, shown below. According to step c, an acid such as HCl in IPE or ethanol, trifluoroacetic acid (TFA) or an alkylsulfonic acid, such as methanesulfonic acid, is added to a solution of a compound of formula 1c, in an inert organic solvent to the reaction such as EtOH, IPE or preferably CH2Cl2. The mixture is stirred for a period of about 1 to 12 hours and then cooled to a temperature from about 0 ° C to about room temperature, preferably at room temperature. After completion of the reaction, a base such as triethylamine or NH OH is added to the mixture. The mixture is allowed to warm to room temperature, diluted with more organic solvent and treated using conventional procedures known in the art to produce a compound of formula 1d. as an alternative, and preferably, the compound of formula 1d can be used without isolation in the next step. Step c of Scheme 1 is preferably performed in combination with step d of Scheme 1 as indicated in Preparation Five, Step F, shown below. According to step d, (D) - or (L) -tartaric acid, preferably (L) -tartaric acid, is added to a compound of formula 1d in acetone / water (from about 8: 1 to about 9: 1). ) at a temperature of about room temperature. The mixture is stirred at a temperature from about room temperature to about the reflux temperature of the solvent mixture for a period of about 1 hour to one night, for example, for 18 hours, preferably 15 to 18 hours. Preferably, the compound of formula 1e is isolated in crystalline form dihydrate. Then, the solid is filtered, collected and washed with cold acetone to produce a compound of formula 1e, which is preferably the (L) -tartrate of a single enantiomer. This step is preferably carried out as indicated in Preparation Five, Step F, without isolation of the free base precursor compound.

SCHEME 1a SCHEME 2 2d The compounds of formula V wherein R is difluorobenzyloxymethyl, R 25 is alkyl, aryl or substituted aryl and Prt is an amine protecting group, for example, the compounds of formula 2d, are prepared as indicated in Scheme 2. according to step e, to a solution of N-BOC-serine, preferably N-BOC- (D) -serine, the compound of formula 2a, in THF / DMF (from about 1: 1 to about 2: 1) a At about 0 ° C, n-BuLi or a potassium urea-butoxide solution is added. The reaction mixture is stirred at about 0 ° C for about 10 to about 30 minutes, preferably for 20 minutes, and then 2,4-difluorobenzyl bromide is added. After warming to room temperature and stirring for a period of about 6 to about 24 hours, the reaction mixture is concentrated in vacuo to remove the THF and an aqueous acid such as 1 N HCl is added to adjust the mixture to a pH of about 3. The reaction mixture is then partitioned between water and an organic solvent such as methylene chloride (CH2Cl2) or IPE. The organic solution is treated using conventional procedures known in the art, yielding the compound of Formula 2b, preferably one having the R configuration at the chiral center, also known as the (D) enantiomer. According to step f, to a solution of the compound of formula 2b in an organic solvent such as THF, CH2Cl2, IPE or a mixture thereof, preferably CH2Cl2 / IPE (about 1: 1), an alkyl acid is added. or arisulfonic acid such as methanesulfonic acid. The solid is filtered and washed with a mixture of CH2Cl2 / IPE (1: 1) yielding the compound of formula 2c, preferably the one having the R configuration at the chiral center, also known as the (D) enantiomer. According to step g, to a solution of the compound of formula 2c in THF / water (approximately 4: 1) is added 2,5-dioxo-pyrrolidin-1-yl ester of 2-fer-butoxycarbonylamino- 2-methylpropionic acid and an alkylamine such as triethylamine. The reaction mixture is stirred at room temperature for about 1-24 hours and quenched with an aqueous acid such as an aqueous solution of 10% citric acid. The mixture is partitioned with an organic solvent such as ethyl acetate and the organic layer is separated and treated using conventional procedures known in the art, yielding a compound of formula 2d, preferably one having the R configuration at the chiral center, also known as enantiomer (D).

The compound of Formula V wherein R3 is benzyloxymethyl and Prt is Boc, is prepared as indicated in Preparation Three, Steps A and B, shown below. Compounds in which Prt is an amine protecting group other than Boc, are prepared by substituting the appropriate N-protected methylalanine derivative with N-t-butyloxycarbonyl-methylalanine. Appropriate N-protected methylalanine derivatives, if not commercially available, can be readily prepared from -methylalanine according to procedures well known to those skilled in the art.

SCHEME 3 ACID (D) OR (L) - TART I- ACID (L) - (+) - TARTARIC lll (3b) 3c The compounds of formulas II, III and 3c wherein R1, R2 and R3 are as defined above, are prepared according to Scheme 3. According to step h, a compound of formula IV (1e), preferably the salt (L) -tartrate of a single enantiomer is suspended at a temperature from about -68 ° C to about -45 ° C, preferably from about -68 ° C to about -60 ° C and, more preferably, about -68 ° C, with a solvent inert to the reaction, preferably ethyl acetate. An organic amine, such as diisopropylethylamine, trimethylamine or triethylamine, preferably triethylamine, is added. During the addition of the organic amine, the temperature is maintained in a range from about -68 ° C to about -45 ° C and preferably from about -68 ° C to about -60 ° C. The reaction mixture is stirred for a period of about 30 to about 120 minutes at a temperature between about -78 ° C and about -45 ° C. The resulting suspension contains a mixture of the free base of a compound of Formula IV and an organic amine salt of tartaric acid. To this suspension is added an organic amine such as diisopropylethylamine, trimethylamine or triethylamine, preferably triethylamine. During this addition, the internal temperature of the reaction mixture is maintained below -50 ° C. To this reaction mixture, which still contains an organic amine salt of tartaric acid, a compound of Formula V is added all at once, while maintaining the temperature of the reaction mixture in a range of about -68 ° C. at about -45 ° C. A coupling reagent such as propanephosphonic acid anhydride is then added over a period of about 5 minutes to about 30 minutes. During the next hour, the temperature is allowed to rise gradually to a range of about -25 ° C to about 0 ° C, preferably at about -20 ° C. The reaction mixture is treated using standard procedures known in the art, yielding a compound of Formula II, preferably with the absolute and relative configuration 3a (R), 1 (R). According to step i, to a compound of Formula II in a reaction inert solvent, such as CH 2 Cl 2, IPE or THF, an acid such as HCl in EtOH, methanesulfonic acid or trifluoroacetic acid in CH 2 Cl 2 is added at a temperature from about 0 ° C to about room temperature. The mixture is stirred for a period of about 40 minutes to about 4 hours at room temperature and then a saturated aqueous base such as Na 2 C 3 or NaHC 3 is added until the solution is at neutral pH (7.0). The organic layer is separated and treated using conventional procedures known in the art, yielding a compound of Formula III, preferably with the absolute and relative configuration 3a (R), 1 (R). According to step j, to a solution of a compound of Formula III in an alcohol such as methanol, ethanol or isopropanol, preferably sodium propane, L - (+) tartaric acid is added. When methanol or ethanol is used, the reaction mixture is stirred for a period of about 1 hour to about 12 hours, then it is filtered and the filtrate is concentrated. In any case, the crude residue is diluted with an organic solvent such as ethyl acetate, heated and allowed to cool slowly to room temperature. The solid is filtered and dried to give the L - (+) tartaric acid salt of the compound of formula 3c, preferably with the absolute and relative configuration 3a (R), 1 (R). The starting materials and reagents used in the methods of this invention can be purchased from usual vendors or prepared according to procedures well known to those skilled in the art of organic chemistry. In particular, 4-oxo- (phenylmethyl) -3-piperidinecarboxylic acid methyl ester hydrochloride can be prepared as indicated in Preparation Five, Step A, shown below or, alternatively, can be prepared as indicated in Hoffman, N. and Erinjeri, A., J. Heterocyclic Chem., 1965, 2, 326. When used herein, the term "solvent inert to the reaction" means a solvent that does not interact with the starting materials. , reagents, intermediates or products in a way that adversely affects the performance of the desired product. Said solvent inert to the reaction of step a is a solvent in which the free base of the compound of Formula IV is soluble. When used herein, the term "organic amine" means a lower alkylamine, such as triethylamine, trimethylamine or diisopropylethylamine.; or a cyclic amine such as piperidine, pyrrolidine or N-methylmorpholine. The following examples are provided for illustrative purposes only and should not be considered a limitation of the described invention. Silica gel was used for the column chromatography. The melting points were taken on a Buchi 510 apparatus and are uncorrected. The proton NMR spectra were recorded on a Varian XL-300, Bruker AC-300, Varian Unity 400 or Bruker AC-250 at 25 ° C. Those skilled in the art of organic chemistry will recognize that the NMR data obtained in the present document can also be obtained with other NMR instruments available from a variety of vendors well known to those skilled in the art. Chemical shifts are expressed in parts per million downstream of trimethylsilane.

General Procedure A: (Excision of a Boc protecting group from a Boc-protected amine using concentrated HCl): The Boc-protected amine is dissolved in a minimum volume of ethanol, the resulting solution is cooled to approximately 0 ° C, HCl is added concentrate (typically about 1 to 4 ml per mmol of Boc-protected amine) and the reaction mixture is warmed to room temperature and stirred for a period of about 1 to about 2.5 hours (or the time necessary for it to disappear). completely the starting material and a more polar product appears according to thin layer chromatography). The resulting solution or suspension is concentrated and the residue is evaporated several times together with added ethanol to produce the free amine, which is used without further purification or purified as specified.

EXAMPLE 1 (1- (2- (3a (R) -benzyl-2-methyl-3-oxo-2,3,3aA6,7-hTxahydro-pyrazoloF4,3-c1pyridin-5-yl) tert-butyl ester -1 (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic To a dry 4-neck round bottom flask, 1 liter capacity, purged with nitrogen and equipped with a mechanical stirrer, a capped nitrogen condenser, a thermocouple and an addition funnel, (L) -tartrate was added. of 3a-benzyl-2-methyl-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one (prepared according to Preparation One, Step D, 66, 09 g, 0.168 mmol, 1.12 equivalents) and ethyl acetate (660 ml, 10 volumes). A suspension formed. The suspension was stirred and cooled to an internal temperature of -68 ° C to -66 ° C. To the stirred and cooled suspension was added triethylamine (TEA, 58 ml, 42.5 g, 0.42 moles, 2.8 equivalents) via the addition funnel. The internal temperature was maintained at a temperature of -68 ° C to -66 ° C during the addition. The reaction mixture was stirred for about 1.5 hours while the internal temperature rose to about -52 ° C. To the reaction mixture (which was a suspension of the tartrate salt of triethylamine and the free base of (L) -tartrate of 3a-benzyl-2-methyl-2,3) 3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one) triethylamine (96.5 ml, 70 g, 0.69 mmol, 4.6 equivalents) was added over 5 minutes. During the addition, an internal temperature of -53 ° C to -50 ° C was maintained. To the reaction mixture was added 3-benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamino) -proponic acid (prepared according to Preparation Three, Step B, 57.07 g, 0.150 moles. , 1, 0 equivalents) all in a single portion. During the addition an internal temperature of -55 ° C to -50 ° C was maintained. To the reaction mixture was added propanophosphonic anhydride (PPAA, 180 ml, 190 g, 2.0 equivalents) as a 50% solution of propanephosphonic acid anhydride in ethyl acetate. The PPAA was added for 15 minutes and, during the addition, the internal temperature rose to about -30 ° C. The reaction mixture was stirred at about -30 ° C for about 0.5 hour. The reaction mixture was poured into a vigorously stirred mixture of diisopropyl ether (IPE, 660 ml, 10 volumes) and water (660 ml, 10 volumes). The resulting biphasic mixture was stirred for 1 hour and then the reaction mixture was allowed to settle. The aqueous portion was decanted and the organic portion was then washed sequentially with aqueous HCl (1 N, 165 ml, 2.5 volumes, 1.3 equiv.), 10% aqueous Na2C? 3 (330 ml, 5 volumes, 2, 1 equivalent) and aqueous NaCl at 15% (165 ml). The washed organic portion was concentrated in vacuo until the lowest volatile volume was obtained and IPE (300 ml, approximately 5 volumes) was added to the concentrate. The solution was again concentrated in vacuo to the smallest volatile volume. IPE (330 ml, approximately 5 volumes) was added to the concentrate and the solution was heated atmospherically to an internal temperature of approximately 67 ° C. Precipitates were observed and the suspension was cooled to an internal temperature of about 1 ° C for 1 hour with stirring. The solids were filtered and dried under vacuum at about 50 ° C yielding 54.85 g of the title compound (60.4% yield).

EXAMPLE 2 2-Amino-N-r2- (3afR) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo-4,3-clpyridin-5-yl- 1 (R) -benzHMMmethyl-2-oxo-etill-isobutyramide (salt L-ta i-trata) To a 5-liter round-bottomed flask, equipped with a mechanical stirrer, a thermocouple, a condenser and an addition funnel, were added consecutively (L) -tartrate of 3a (R) -benzyl-2- methyl-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one (prepared according to Preparation One, Step D, 60.57 g, 0.10 moles , 1.0 equivalent) and methylene chloride (400 ml, 6.7 volumes). The mixture was stirred to produce a clear solution and the solution was then cooled to an internal temperature of -10 ° C to -5 ° C. To the chilled and stirred solution was added trifluoroacetic acid (TFA, 180 ml, 3.0 volumes / 23.6 equivalents / 2.33 moles) at such a rate that the internal temperature did not exceed -5 ° C. The addition was completed in approximately 10 minutes. Then, the reaction mixture was heated slowly to 8 ° C for 1 hour. While maintaining an internal temperature of 10 ° C-20 ° C, the reaction mixture was brought to a pH higher than 8 by the slow addition of Na 2 CO 3 (1.0 N, 1200 ml, 12 equivalents / 12 moles). The reaction mixture was allowed to settle and the organic portion was decanted. The aqueous fraction was extracted with methylene chloride (2 portions of 100 ml, each of 1.65 volumes). The combined organic fractions were washed with water (100 ml). The washed organic fraction was concentrated to the smallest volatile volume by distillation at atmospheric pressure and to the concentrate was added ethyl acetate (2000 ml, 33 volumes). To the ethyl acetate solution was added a solution of L-tartaric acid (15.05 g, 0.10 mol / 1 equivalent) in methanol (60 ml, 1 volume). The reaction mixture was heated and the methanol was removed by distillation. The distillation was continued until the internal and liquefaction temperatures were 77 ° C-78 ° C and then the reaction mixture was heated to reflux for 1-2 hours. Subsequently, the reaction was cooled to about 15 ° C for several hours. The solids were filtered, washed with ethyl acetate (200 ml) and dried overnight under vacuum at about 50 ° C, yielding 60.79 g of the title compound (92.7% yield).

EXAMPLE 3 (1- (2- (1 (R) - (2,4-difluorobenzylmethyl) -3a (R) -pyridin-2-methyl-tert-butyl ester 2- (2,2,2-Trifluoro-etn-3-oxo-2,3,3a.4,6,7-hexahydro-pyrazolor-4,3-c1pyridin-5-ip-2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic To a dry round bottom flask, 0.5 liter capacity and 4 nozzles, purged with nitrogen and equipped with a mechanical stirrer, a capped nitrogen condenser, a thermocouple and an addition funnel, sequentially added (L) -tartrate 3a-pyridin-2-methyl-2 - (2,2,2-trifluoroethyl) -2,3a, 4,5,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one (prepared according to Preparation Two, Stage D, 10.35 g, 0.0224 moles, 1.12 equivalents) and ethyl acetate (110 ml, 10 volumes). A suspension formed. The suspension was stirred and cooled to an internal temperature of -68 ° C to -60 ° C. To the stirred and cooled suspension was added triethylamine (TEA, 7.75 ml, 5.66 g, 0.056 moles, 2.8 equivalents) through the editing funnel. During the addition, the internal temperature was maintained in a temperature range of -68 ° C to -60 ° C. The reaction mixture was stirred for about 1.5 hours while the internal temperature was raised to a temperature of about -62 ° C to -52 ° C. To the reaction mixture (which was a suspension of the triethylamine tartrate salt and the free base of 3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoroethyl) (L) -tartrate) -2.3a, 4,5,6,7-hexahydro-pyrazolo [4,3-c] pyridin-3-one) was added triethylamine (12.7 ml, 9.30 g, 0.092 mole, 4.6 equivalents ) for 5 minutes. During the addition, an internal temperature of -62 ° C to -50 ° C was maintained. To the reaction mixture was added 2- (2-ert-butoxycarbonylamino-2-methyl-propionylamino) -3- (2) acid., 4-difluoro-benzyloxy) -propionic (prepared according to Preparation Four, Step C, 8.34 g, 0.020 moles, 1.0 equivalents), all in one portion. During the addition, an internal temperature of -60 ° C to -58 ° C was maintained. Propanophosphonic anhydride (PPAA, 24 mL, 25.5 g, 2.0 equivalents) was diluted to a 50% solution of propanephosphonic anhydride in ethyl acetate, with ethyl acetate (24 mL, 2.2%). volumes) and the solution was cooled to about -45 ° C. The PPAA solution was then added to the reaction mixture. The PPAA was added for 15 minutes and the internal temperature was gradually raised to about -19 ° C for about 1 hour. The reaction mixture was poured into a vigorously stirred mixture of diisopropyl ether (IPE, 100 ml, 9.1 volumes) and water (100 ml, 9.1 volumes). The resulting biphasic mixture was stirred for 5 minutes and then the reaction mixture was allowed to settle. The aqueous portion was decanted and the organic portion was then sequentially washed with aqueous HCl (0.5 N, 50 ml, 4.5 volumes, 1.3 equiv.), Saturated aqueous NaHC? 3 (50 ml, 4.5 volumes, ~ 2.5 equivalents) and aqueous NaCl at 15% (50 ml). The washed organic portion was concentrated in vacuo to yield an oil. The oil was stirred with hexanes (50 ml, approximately 2.5 volumes) yielding a glassy solid, 13.75 g (96.8% crude yield). The solids were dissolved in chloroform and concentrated in vacuo to yield an oil. This procedure was repeated with hexanes. Finally, the resulting oil was stirred with hexanes for 16 hours. The resulting solids were filtered affording 10.45 g of the title compound (73.6% yield).

EXAMPLE 4 2-Amino-N- (1 (R) - (2,4-difluoro-benzyloxymethyl) -2-oxo-2-f3-oxo-3a (R) -pyridin-2-methyl l) -2- (2.2.2-trifluoro-etn-2.3.3a.4.6.7-hexahydro-pyrrazoloi4.3-clpyridn-5-yl) -ethyl-2-methyl-propionamide The (1- (2- (1 (R) - (2,4-difluorobenzyloxymethyl) -3a (R) -pyridin-2-ylmethyl-2- (2-tert -butyl) ester was deprotected. , 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 (prepared according to Example Three, 17.5 g, 25.3 mmol) according to the procedure described in General Procedure A, yielding a colorless solid. The product was triturated with diethyl ether to yield the title compound. (13.6 g, 90%): + APCI EM (Mass spectrometry by chemical ionization at atmospheric pressure) (M + H) + 591.

EXAMPLE 5 L - (+) 2-Amino-N- (1- (2,4-d-fluoro-benzyloxymethyl-p-2-oxo-2-y3-oxo-3a (R) -pyridin-) tartrate 2-methyl-2- (2,2,2-trifluoro-etn-2,3,3a, 4,6,7-hexahydro-pyrazolo-4,3-c1pyridin-5-n-ethyl | - 2-methyl-propionamide To a solution of 2-amino-N- (1 (R) - (2,4-difiuoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-ylmethyl) -2- (2,2,2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin- 5-l) -ethyl) -2-methyl-propionamide (prepared according to Example Four, 370 g, 0.6 mol) in methanol (4070 ml) in a 12-ml round bottom flask. equipped with a mechanical stirrer, L- (+) tartaric acid (90 g, 0.6 mole) was added.The reaction mixture was stirred for about 90 minutes at about 22 ° C, filtered and concentrated. it was diluted with ethyl acetate (4.560 ml), heated to about 70 ° C and allowed to cool slowly to room temperature for about 17 hours The solid was filtered and dried to give crystals white, p.p. 188-189 ° C (348.46, 76% yield). 1 H NMR (MeOH, d 4): 8.28 (d, 1 H), 7.59 (t, 1 H), 7.41-7.39 (m, 1 H), 7.18-7.13 (m , 1 H), 6.92 (t, 1 H), 5.2 (t, 1 H), 4.56 (sa, 3 H), 4.36 (s, 2 H), 4.31-4.25 (m, 1H), 4.13-4.06 (m, 1H), 3.78 (d, 2H), 3.21 (t, 1 H), 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 X-Ray Analysis of Individual Crystals. A representative crystal was examined and a data series of 1 A (maximum /: 0.5) was collected on a Siemens R3RA / V diffractometer. The atomic dispersion factors were taken from the International Tables for X-Ray Crystallography1. All crystallographic calculations were facilitated by the SHELXTL2 system. All the data of the diffractometer were collected at room temperature. In Table I shown below, the relevant adjustment, data collection and crystal parameters are summarized. A test structure was obtained by direct procedures.

This test structure was adjusted routinely. Hydrogen positions were calculated whenever possible. The methyl hydrogens and the nitrogen and oxygen hydrogens were localized by differential Fourier techniques. The hydrogen parameters were added to the structure factor calculations, but were not adjusted. The displacements calculated in the final adjustment cycle by least squares were all less than 0.1 with respect to their corresponding standard deviations. The final R index was 4.95%. A final difference of Fourier did not reveal any absence or erroneous situation of electronic density. The adjusted structure was represented using the SHELXTL representation package (Figure 1). The absolute configuration was assigned to the known configuration of L-tartaric acid. The coordinates, anisotropic temperature factors, distances and angles are provided as supplementary material, see Tables II to VI.

TABLE 1 X-ray Crystallographic Analysis of a Single Crystal A. Crystal Parameters: formula C? 4H? 8N30 + C4H5? 6".2H2? (429.4) crystallization medium acetone and water (4: 1) crystal size, mm 0.05 x 0.12 x 0.32 cell dimensions a = 8,235 (3) A b = 7,032 (2) A c = 18,106 (6) A = 90,0 ° = 99,41 (2) ° = 90,0 ° V = 1034,4 (6) A3 space group P2? Molecules / cell unit 2 calculated density, g / cm3 1, 379 linear absorption factor, mm "1 0.946 B. Adjustment parameters: number of reflections 1174.39 non-zero reflections (l> 3.0) 1025 index3 R 4.95% GOFb 1 Secondary extinction factor0, * 52 (8 'x 7 to index - R =? II Fol -I Fcl /? L Fo t b GOF == [? W (Fo2 - F < 2f (m - s)], / 2 in which w ^ ts? ÍF) - * -! gl F2] '1 and g = 0.0005 P = F [1 + 0.002? F2 / sin (2?) r1 / * TABLE II Atomic coordinates (x10) and equivalent isotropic displacement coefficients (A2 x 103) X yz U (eq) C (1 ') 7050 (7) 12045 (7) 6424 (4) 31 (1) 0 (1 A') 5715 (5) 12748 (6) 6097 (3) 41 (1) OR (1B ') 8234 (5) 12946 (6) 6748 (3) 41 (1) C (2') 7120 (6) 9881 (7) 6388 (4) 29 (1) 0 (2 ') 8733 (5) 9232 (6) 6715 (3) 37 (1) C (3 ') 6707 (7) 9167 (7) 5599 (4) 32 (1) 0 (3') 7899 (5) 9726 (6) 5160 (3) 47 (1) C (4 ') 6647 (7) 6999 (7) 5583 (4) 32 (1) 0 (4A') 5644 (5) 6263 (6) 5971 (3) 39 (1) 0 (4B ' ) 7465 (5) 6110 (7) 5213 (3) 59 (1) N (1) 5011 (6) 8379 1995 (3) 43 (1) N (2) 4317 (6) 6558 (7) 1896 (3) 40 (1) C (2A) 2623 (6) 6380 (8) 1541 (4) 55 (1) C (3) 5357 (7) 5149 (8) 2171 (4) 36 (1) 0 (3) 5039 ( 5) 3491 (6) 2188 (3) 46 (1) C (4) 6998 (6) 6172 (8) 2450 (3) 28 (1) C (5) 6515 (6) 8177 (8) 2299 (4) 33 (1) C (6) 7511 (6) 5878 (8) 3290 (4) 39 (1) N (7) 8723 (6) 7355 (7) 3591 (3) 40 (1) C (8) 8153 ( 7) 9366 (8) 3440 (4) 49 (1) C (9) 7643 (7) 9700 (8) 2603 (4) 46 (1) C (10) 8290 (6) 5440 (8) 1989 (4) 37 (1) C (11) 7862 (7) 5776 (8) 11667 (4) 43 (1) C (12) 8463 (7) 7317 (8) 853 (4) 69 (1) C (13) 8108 ( 8) 7675 (9) 76 (5) 97 (1) C (14) 7080 (*) 6405 (9) -336 (5) 96 (1) C (15) 6443 (8) 4882 (8) -59 ( 5) 81 ( 1) C (16) 6872 (7) 4533 (8) 705 (4) 75 (1) 0 (1W) 8100 (5) 6278 (7) 7609 (3) 54 (1) 0 (2W) 10828 (5 ) 8138 (7) 5099 (3) 62 (1) Sotropic Equivalent U defined as one third of the trace of the orthogonal Uy tensor hoist.

TABLE III Link lengths (A) C (1 ') - O (1A *) 1, 262 (7) C (1') - O (1B ') 1, 229 (7) (cr) -c (2') 1,525 (7) C (2 ') - 0 (2') 1.4347 (6) C (2 ') - C (3') 1,500 (9) C (3 ') - 0 (3') 1,416 (8) C (3 ') - C (4 ') 1,526 (7) C (4') - 0 (4A ') 1, 277 (8) C (4') - 0 (4B ') 1,201 (8) N (1) -N (2) 1,402 (5) N (1) -C (5) 1, 278 (7) N (2) - C (2A) 1,443 (7) N (2) - C (3) 1,350 (7) C (3) - 0 (3) 1,196 (7) C (3) -C (4) 1,541 (7) C (4) -C (5) 1,478 (7) C (4) -C (6) 1,526 (9) C (4 ) -C (10 1,544 (9) C (5) - C (9) 1,465 (7) C (6) - N (7) 1,481 (7) N (7) - C (8) 1,501 (7) C ( 8) -C (9) 1,524 (10) C (10) -C (11) 1,492 (9) C (11) -C (12) 1,355 (9) C (11) -C (16) 1, 380 ( 8) C (12) -C (13) 1,411 (12) C (13) -C (14) 1,365 (9) C (14) -C (15) 1,327 (10) C (15) -C (16) 1,393 (11) TABLE IV Linking angles (°) Table IV. Bond Angles (2) (1A ') - C (1') - 0 (1B ') 125.8 (5) 0 (1A') - C (1 ') - C (2') 114.1 (5) 0 (1B ') - C (1') - C (2-) 120.2 (5) C (V) - C (2 ') - 0 (2') 109.8 (4) C (1 ') - C (2') - C (3 ') 111.7 (5) 0 (2') - C (2 ') - C (3') 109.7 (5) C (2 ') - C (3') - 0 (3 ') 111.9 (4) C (2') - C (3 ') - C (4') 110.7 (5) 0 (3 ') - C (3') - C (4 ') 106.9 (5) C (3') - C (4 ') - 0 (4A') 114.6 (5) C (3 ') - C (4') - 0 (4B ') 120.7 (6) 0 (4A') - C (4 ') - 0 (4B') 124.6 (5) N (2) -N (1) -C (5) 107.4 (3) N (1) -N (2) -C (2A) 118.7 (4) N (1) ~ N (2) -C (3) 113.8 (4) C (2A) - N (2) - C (3) 127.5 (5) N (2) - C (3) - 0 (3) 126.6 (5) N (2) -C (3) -C (4) 104.3 (4) 0 (3) - C (3) - C (4) 129.0 (5) C (3) - C (4) - C (5) 100.9 (4) C (3) - C (4) - C (6) 110.4 (5) C (5) -C (4) -C (6) 109.6 (5) C (3) -C (4) -C (10) 108.2 (5) C (5) -C (4) -C (10) 114.0 (5) C (6) -C (4) -C (10) 113.0 (4) N (1) -C (5) -C (4) 113.4 (4) N (1) -C (5) -C (9) 126.2 (4) C (4) -C (5) -C (9) 119.5 (4) C (4) - C (6) - N (7) 109.4 (5) C (6) - N (7) - C (8) 115.0 (4) N (7) - C (8) - C (9) 110.7 (5) C (5) - C (9) - C (8) 108.4 (5) C (4) -C (10) -C (11) 114.5 (4) C (10) -C (11) -C (12) 120.2 (5) C (10) -C (11) -C (16) 121.6 (6) C (12) -C (11) -C (16) 118.3 (7) C (11) -C (12) -C (13) 122.0 (6) C (12) -C (13) -C (14) 115.9 (7) C (13) -C (14) -C (15) 124.7 (8) C (14) -C (15) -C (16) 117.8 (6) C (11) -C (16) -C (15) 121.2 (6) TABLE V Anisotropic displacement coefficients (A2 x 103) C (1 ') 32 (1 2 (1) 5 (1) -8 (1) 0 (1 A') 35 (1 -4 (1) 2 (1) 2 (1) 0 (1 B ') 35 (1 -4 (1) -2 (1) -13 (1) C (2 ') 32 (1 1 (1) -1 (1) 1 (1) 0 (2') 32 (1 4 (1) -1 (1) 0 (1) C (3 ') 41 (1 6 (1) 6 (1) -6 (1) 0 (3 ') 71 (1 -2 (1) 23 (1) 1 (1) C (4') 28 (1 2 (1) 3 (1) 2 (1) 0 (4A ') 41 (1 -7 (1) 10 (1) -9 (1) O (4B') 56 (1 7 (1) 32 (1) -2 (1) N (1 ) 39 (1 4 (1) -6 (1) 7 (1) N (2) 30 (1 2 (1) -2 (1) -4 (1) C (2A) 27 (1 -3 (1) -2 (1) -1 (1) C (3) 39 (1 8 (1) 10 (1) -7 (1) O (3) 45 (1 -3 (1) 5 (1) 1 (1) C (4) 23 (1 0 (1) 2 (1) 3 (1) C (5) 31 (1 -1 (1) 6 (1) 0 (1) C (6) 38 (1 4 (1) 1 (1) -4 (1) N (7) 39 (1 1 (1) -6 (1) -1 (1) C (8) 44 (1 -1 (1) 1 (1) -9 (1 ) C (9) 41 (1 6 (1) 2 (1) 0 (1) C (10) 37 (1 6 (1) 9 (1) 4 (1) C (11) 39 (1 10 (1) 7 (1) -2 (1) C (12) 72 (1 4 (1) 2 (1) 1 (1) C (13) 103 2 (1) 16 (1) 27 (1) C (14) 103 13 (1) 4 (1) 6 (1) C (15) 81 (1 -4 (1) -6 (1) -17 (1) C (16) 80 (1 -4 (1) 13 (1) -12 (1) 0 (1 W) 56 (1 -7 (1) 7 (1) -2 (1) 0 (2W) 58 (1 3 (1) 42 (1) 7 (1) The exponent of anisotropic displacement takes the form: -2p (has Un + 2hka b U12) TABLE VI Atomic coordinates of H (x 10) and isotropic displacement coefficients (A2 x 103) X yz UH (2 ') 6314 9385 6665 80 H (2A') 8195 (10) 8867 (10) 7105 (9) 50 H (3 ') 5656 9704 5398 80 H (3A') 8259 (10) 11720 (10 ) 5037 (9) 50 H (4A ') 5234 (10) 6488 (10) 6270 (9) 50 H (2A) 2319 5061 1512 80 H (2B) 2495 6907 1046 80 H (2C) 1928 7053 1829 80 H ( 6A) 7999 4642 3381 80 H (6B) 6562 5972 3533 80 H (7A) 9771 (10) 7980 (10) 3431 (9) 50 H (7B) 9183 (10) 7721 (10) 4160 (9) 50 H ( 8A) 7229 9605 3689 80 H (8B) 9033 10220 3630 80 H (9A) 8599 9685 2362 80 H (9B) 7101 10908 2520 80 H (10A) 8417 4095 2071 80 H (10B) 9315 6067 2166 80 H (12) 9152 8192 1169 80 H (13) 8559 8747 -149 80 H (14) 6799 6628 -864 80 H (15) 5710 4049 -375 80 H (16) 6471 3406 915 80 H (1WA) 8471 (10) 5946 (10 ) 7323 (9) 52 (1) H (1WB) 6863 (10) 5969 (10) 7529 (9) 50 H (2WA) 11347 (10) 8095 (10) 5456 (9) 50 H (2WB) 11515 (10 9176 (10) 4829 (9) 50 PREPARATION 1 Stage A. 3-Methyl and tert-butyl ester of 4-oxo-piperidine-1,3-dicarboxylic acid To a mixture of 7.00 g (36.2 mmol) of 4-oxo-piperidine-3-carboxylic acid methyl ester and 8.82 g (72.3 mmol) of 4,4-dimethylaminopyridine in 200 ml of chloride of methylene at about 0 ° C, a solution of 7.88 g (36.2 mmol) of di-tert-butyl dicarbonate in 150 ml of methylene chloride was added for about 30 minutes. The mixture was warmed to room temperature and then stirred for about 17 h. The mixture was concentrated and the residue was diluted with chloroform and washed three times with 10% aqueous HCl, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO and concentrated to give 9.18 g of a clear yellow oil.

Step B. 3- (R, S) -benzyl-4-oxo-p-per-phenyl-1,3-dicarboxylic acid 3-methyl ester and 1-tert-butyl ester To a solution c A (5.00 g, 19.4 mmol) in 1 sodium hydride (room temperature dispersion) during stirring was added via a cannula a solution of 3.32 g (19.4 mmol) of benzyl bromide in 15 ml of DMF and the mixture was stirred for about 42 hours at room temperature The mixture was diluted with ethyl acetate and washed once with water and four times with brine, dried over MgSO4 and concentrated to give 6.0 g of the title compound. from Step B in the form of a yellow oil, MS (Cl, NH3) 348 (MH +).

Step C. Tert-Butyl Ester of 3a- (R, S) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazoloyl-4,3-cl-pyridine-5 -carboxylic A mixture of the compound prepared according to Step B (4.00 g, 11.5 mmol) and 530 mg (11.5 mmol) of methylhydrazine in 100 ml of ethanol was heated at reflux for about 8 h. The mixture was concentrated and the residue was dissolved in 100 ml of toluene and heated to reflux for 17 h. The mixture was concentrated and the residue was purified by chromatography on silica gel using an elution gradient of (15:85 v / v ethyl acetate: hexane) to (75:25 v / v ethyl acetate: hexane) , giving 2.6 g of the title compound of Step C as a clear, colorless oil. MS (Cl, NH3) 344 (MH +).

Stage D. (L) -Tartrate of 3a (R) -benzyl-2-methyl-2,3.3a.4.6.7-hexahydro-pyrazolor4,3-c1pyridin-3-one A 3a- (R, S) -benzyl-2-methyl-3-oxo-tert-butyl tert-butyl ester was added sequentially to a 2 liter round bottom flask equipped with a mechanical stirrer, an addition funnel and a thermocouple. -2,3,3, a, 4,6,7-hexahydro-pyrazolo [4,3-c] -pyridine-5-carboxylic acid (prepared according to Step C, 51.5 g, 0.15 moles, 1.0 equivalents) and methylene chloride (515 ml, 10 volumes). The mixture was stirred to form a solution which was then cooled to an internal temperature of 0 ° C-5 ° C. To the cooled mixture was added trifluoroacetic acid (TFA, 130 ml, 192 g, 1.68 moles, 11.2 equivalents, 2.5 volumes). The TFA was added through the addition funnel for 15 minutes while maintaining an internal temperature of 0 ° C-5 ° C. The reaction mixture was heated to about 20 ° C for 3 hours and then the reaction mixture was cooled to 10 ° C-15 ° C. To the cooled reaction mixture was added sodium carbonate (92 g, 0.868 mol) in water (920 ml) for 20 minutes. The pH was 7.5. The reaction mixture was transferred to a 2 liter separatory funnel and allowed to settle. The organic portion was decanted and the aqueous portion was extracted with methylene chloride (130 ml, 2.5 volumes). The pooled organic portions were transferred back to the 2 liter reactor and L-tartaric acid (24.77 g, 0.165 moles, 1.1 equivalents) dissolved in acetone (354 ml, approximately 7 volumes) and water (44 ml) was added. , approximately 1 volume). The reaction mixture was stirred and heated to about 38 ° C overnight. The resulting suspension was cooled to 0 ° C-5 ° C, granulated for 1 hour and then filtered. The solids were washed with 100 ml of cold acetone and then dried under vacuum at 40 ° C-50 ° C for 16 hours, yielding 51.86 g (87.9% yield) of the title compound of step D.

PREPARATION 2 Step A. 3-Ethyl and 1-butyl-4-oxo-3-pyridin-2-yl-methyl-piperidine-1,3-dicarboxylic acid ester To a solution of 3-ethyl ester and 1-phenyl-butyl ester of 4-oxo-piperidine-1,3-dicarboxylic acid (prepared according to the process of Preparation One, Step A, 10.34 g, 38.2 mmol) in DMF (40 mL) at about 0 ° C, was added picolyl chloride hydrochloride (5.7 g, 34.7 mmol), potassium carbonate ( 14.4 g, 104.1 mmol) and potassium iodide (5.76 g, 34.7 mmoles). After stirring at about 0 ° C for about 2 hours, the ice bath was removed and DABCO (973 mg, 8.68 mmol) was added. The reaction mixture was stirred for approximately minutes and poured into a mixture of water and IPE. The organic layer was separated and washed with saturated aqueous NaHCO 3 and saturated aqueous NaCl, dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was crystallized from hexanes to give a white solid (8.19 g, 65% yield). 1H-NMR (CDCl 3) d 1, 17 (t, 3H), 1.48 (s, 9H), 1.55 (s, 2H), 2.61 (m, 1H), 2.71 (m, 1 H), 3.31-3.50 (m, 3H), 4.11 (d, 2H), 4.49 (d, 1H), 7.06 (sa, 1H), 7.17 (d, 1H), 7 , 54 (m, 1H), 8.40 (s, 1H).

Step B. 3-Oxo-3a-pyridin-2-ylmethyl-2- (2,2,2-trifluoro-etip-2,3,3a, 4,6,7-hexahydro-p, ferric-butyl ester razoloí4,3-c] pyridine-5-carboxylic acid A 70% aqueous solution of CF3CH2NHNH2 (325 mL, 1.986 moles) was extracted with toluene (3 x 1200 mL). To a solution of the compound prepared according to step A (600 g, 1.655 mole) in toluene (900 ml), first the combined toluene extracts containing the anhydrous 2,2,2-trifluoroethylhydrazine were added, followed by acetic acid (121.4 g, 1.986 moles). The reaction mixture was heated to about 70 ° C for about 2 hours, and then another 70% aqueous 2,2,2-trifluoroethyl hydrazine extract (50 g) in toluene was added. The reaction mixture was heated to about 80 ° C for about 3.5 hours, cooled to room temperature and diluted with saturated aqueous NaHC 3 (2 I). The toluene layer was separated and washed with saturated aqueous NaCl, dried over Na2SO4 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). 1 H-NMR (CDCl) d 1.50 (s, 9H), 2.53 (d, 1 H), 2.70 (sa, 2H), 2.88 (sa, 1H), 3.31 (m, 2H), 3.97 (m, 1 H), 4.19 (m, 1H), 4.46 (sa, 1 H), 4.63 (sa, 1 H), 7.06 (m, 2H) , 7.51 (m, 1 H), 8.34 (m, 1 H).

Stage C. 3a-P¡r¡d¡n-2-l-metl-2- (2,2,2-trifluoroethyl) -2.3a.4.5,6.7-hexahydro-p¡razoloF4,3 -c1pyridin-3-one Methanesulfonic acid (11.6 g, 121 mmol) was added dropwise to a solution of the compound prepared according to step B (10 g, 24.2 mmol) in CH2Cl2 (100 mL) for about 30 minutes. The reaction mixture was stirred for about 1 hour, then cooled to about 0 ° C and then triethylamine (18.6 ml, 133.1 mmol) was added through an addition funnel. The mixture was allowed to warm to room temperature for about 1 hour, diluted with more CH 2 Cl 2 and washed with saturated aqueous NaCl, dried over Na 2 SO 4, filtered and concentrated in vacuo to give the product as a white solid (7, 2 g). 1 H-NMR (CDCl 3) d: 2.51-2.72 (m, 4H), 3.35 (m, 2H), 3.49 (m, 2H), 4.03 (m, 1 H), 4 , 25 (m, 1H), 7.08 (d, 2H), 7.51 (t, 1H), 8.37 (d, 1H).

Stage D. (D) -Tarate of 3a-pyridin-2-methyl-2- (2,2,2-trifluoroethylene-2,3a, 4,5,6,7-hexahydro-pyrazolor4 3-c1pyridin-3-one In a round bottom flask, 5 I capacity, dried and purged with nitrogen, equipped with a mechanical stirrer, D - (-) tartaric acid (129 g, 0.86 mol) was added to the compound prepared in accordance with Step C (243 g, 0.78 mol) in acetone / water (9: 1, 2430 ml) at about 17 ° C. The mixture was stirred at room temperature overnight, filtered and the solid was collected, washed with cold acetone and dried in vacuo. The product was obtained in the form of a yellow solid (284 g, 78.8% yield).

PREPARATION 3 Step A. 2,5-Dioxo-pyrrolidin-1-yl ester of 2-tert-butoxycarbonylamino-2-methyl-propionic acid A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol), Nt-butoxycarbonyl-methylalanine (197 g, 0.969 mol) and 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (186 g, 0.970 mol. ) in anhydrous dichloromethane (1.4 I) was stirred at room temperature for about 18 hours under nitrogen atmosphere. The reaction mixture was washed three times with saturated sodium bicarbonate solution and then with 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 (256 g, 88%): PBEM (Particle Beam Spectrometry) ( M + 18) + 318; 1 H-NMR = 250 MHz (CDCl 3) d: 4.91 (NH, br, 1H), 2.84 (-CO (CH 2) 2 CO-, s, 4H), 1.67 (Me, s, 6H), 1, 48 (BOC, s, 9H).

Step B. 2 (R) -3-Benzyloxy-2- (2-tert-butoxycarbonylamino-2-methyl-propionylamine) -propionic acid To a solution of DO-benzyl serine (106 g, 0.532 mol) and the title compound of Step A (160 g, 0.532 mol) in water / dioxane (250/1000 mL), triethylamine (223 mL, 1 mL) was slowly added. , 60 moles) at room temperature. The reaction was heated to about 50 ° C and stirred for about 15 hours under nitrogen. The solvent was then removed under vacuum, ethyl acetate was added and the stirred mixture was acidified with aqueous solution of 10% HCl to pH 2-3. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of Step B (200 g, 99%): -APCI MS (M-1) ": 379; 1 H NMR = 300 MHz (methanol-d4) d: 7.69 (NH, d, 1H), 7.32 (Ph, m, 5H), 4.60 (CHC02H, m, 1H), 4.51 (CH2Ph, s, 2H) 3.81 (CH2Obz, m, 2H), 1.41 (Me, s, 6H), 1.40 (BOC, s, 9H).

PREPARATION 4 Stage A. Acid 2 (R) -2-ferc-butoxycarbonylamino-3- (2,4-di-fluoro-benzyloxy-propionic acid) To a solution of N-Boc- (D) -Serine (452 g, 2.2026 mol) in a mixture of THF (7 I) and DMF (3 I) at about 0 ° C, a solution of tert. potassium butoxide (515.8 g, 4.5963 moles). The reaction mixture was stirred at about 0 ° C for 30 minutes and then 2,4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After warming to room temperature, the reaction mixture was concentrated in vacuo to remove THF. The reaction mixture was partitioned between 4.5 I of H2O and 4.5 I of IPE. The layers were separated and the pH of the aqueous layer was adjusted with HCl 1 N to about 3. The aqueous layer was extracted twice with 4 I, each time, of IPE. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield a yellow waxy solid (518.0 g, yield: 70.9%). 1 H-NMR (CDC) d 1.44 (s, 9 H), 3.73 (m, 1 H), 3.94 (d, 1 H), 4.44 (sa, 1 H), 4.54 (s, 2H), .34 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 7.30 (m, 1H).

Stage B. Methanesulfonate salt of 2 (R) -2-amino-3- (2,4-difluoro-benzyloxy-propionic acid M? SOgH To a solution of the product from Step A (1.19 g, 3.59 mmol) in CH2Cl2 / IPE (1: 1, 12 mL) was added methanesulfonic acid (1.72 g, 17.95 mmol) through a syringe for approximately 10 minutes. Immediately a solid precipitated from the solution. After about 1 hour, the solid was filtered and washed with a (1: 1) mixture of CH2Cl2 / IPE, yielding 939 mg of the product (80% yield).

Step C. Acid 2 (R) -2- (2-fer-butoxycarbonylamino-2-methyl-propylamino) -3- (2,4-difluoro-benzyloxy) -propionic acid To a solution of the product from Step B (520 mg, 1.46 mmol) in THF / water (4: 1, 10 mL) was added 2,5-dioxo-pyrrolidin-1-yl ester of the 2- ferric acid. butoxycarbonylamino-2-methyl-propionic acid (438 mg, 1.46 mmol) and triethylamine (369 mg, 3.65 mmol). The reaction mixture was stirred at room temperature for about 1 hour and quenched with an aqueous solution of 10% citric acid (10 ml). After about 15 minutes, ethyl acetate (50 ml) was added and the organic layer was separated and washed with saturated aqueous NaCl, dried over Na 2 SO 4 and concentrated in vacuo to give a foam (534.1 mg, yield of 88%). %). 1 H-NMR (CD 3 OD): d 1.38 (sa, 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 5 (2R, 3R) -2.3-Dihydroxybutanedioate (3aR) -2,3aA5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) -3H-pyrazolo | 4,3-clpyridin- 3-one (1: 1) Step A: 4-Oxo-1- (phenylmethyl-P-3-piperidinecarboxylic acid methyl ester hydrochloride) A solution of 1-benzyl-4-piperidone (56.5 kg, 1.0 eq.) In toluene was prepared ( 189 I) at a temperature of 15 ° C to 25 ° C. In a second reactor were introduced toluene (659 I), potassium tert-butoxide (71.9 kg, 2.25 eq.) And dimethyl carbonate (51). 5 kg, 2.0 eq.) At a temperature of 15 ° C to 25 ° C. The resulting suspension was heated to a temperature of 80 ° C to 90 ° C. The solution of 1-benzyl-4-piperidone in toluene it was added slowly to the suspension for a period of 60 to 90 minutes.After 90 more minutes, the reaction mixture was cooled to below 15 ° C. The completed reaction was stopped with acetic acid (38.5 kg, 2, 25 eq.) And water (367 I) The two-phase mixture was separated The organic layer was filtered to remove the solids The organic filtrate was concentrated by distillation under reduced pressure to a volume of approximately 150 I. the concentrated mixture was added toluene (799 I). The addition of hydrogen chloride (gas, 11.0 kg, 1.05 eq.) Produced the hydrochloride salt in the form of a precipitate. The suspension was stirred at a temperature of 10 ° C to 15 ° C for 30 minutes. The solids were isolated by filtration, washed with hexanes (ca. 130 I) and dried using vacuum, yielding 79.4 kg of 4-oxo-1- (phenylmethyl) -3-piperidinecarboxylic acid methyl ester hydrochloride ( 97.8%). Analysis calculated for C? 4H? 7N03 HCl: C 59.3; H, 6.39; N, 4.94; found: C, 59.7; H, 6.65; N, 4.85.

Step B: 4-Oxo-1-piperidinecarboxylic acid methyl ester hydrochloride In a reactor purged with nitrogen, clean and dry, 4-oxo-1- (phenylmethyl) -3-piperidinecarboxylic acid methyl ester hydrochloride (prepared from according to Preparation Five, Stage A, 78.8 kg, 1.0 eq.), ethanol (416 I), water (340 I) and 10% palladium on carbon (catalyst, 7.88 kg, 0.1 kg / kg). The mixture was subjected to hydrogenation conditions of about 32 x 103 kg / m2 of hydrogen pressure at a temperature between 25 ° C and 35 ° C for about 18 hours. After completion of the reaction, the reaction mixture was vented with nitrogen and filtered to remove the spent catalyst. The catalyst cake was washed with ethanol (150 I). The filtrate and washing liquid were concentrated under reduced pressure to about 57 I. The product was crystallized by the slow addition of 2-propanol (227 I). The suspension was cooled to a temperature of 10 ° C to 20 ° C and stirred for about one hour. The product was isolated by filtration, rinsed with hexanes (76 I) and dried under vacuum for approximately 24 hours to give 43.2 kg of 4-oxo-1-pyridinecarboxylic acid methyl ester hydrochloride ( 80.0%). Analysis calculated for C7HnN03-HCI: C, 43.42; H 6.25; N 7.23; found: C, 43.7; H, 6.59; N, 7.19.

Step C: 1- (1, 1 -Dimethylethyl) 3-methyl ester of 4-oxo-1,3-piperidinedicarboxylic acid. In a glass-coated container, purged with nitrogen, clean and dry, isopropyl ether (IPE, 309) was introduced. I), 4-oxo-1-piperidinecarboxylic acid methyl ester hydrochloride (prepared according to Preparation Five, Step B, 42.6 kg, 1.0 eq.) And water (153 I) at a temperature of 15 at 25 ° C. The addition of triethylamine (28.9 kg, 1.3 eq.) Produced a thick white emulsion. Slow addition of di-tert-butyl dicarbonate (52.6 kg, 50 I, 1.1 eq.) To the reaction mixture, followed by a rinse with IPE, produced a clear biphasic solution. The mixture was stirred at a temperature of 15 ° C to 25 ° C for approximately 12 hours. After completion of the reaction, the aqueous layer was separated and extracted with IPE (20 L). The organic extracts were combined and washed sequentially with 1 N HCl (110 I), water (90 I) and saturated sodium chloride solution (103 I). The washed organic layer was dried over anhydrous sodium sulfate. The mixture was filtered to remove the insoluble compounds. The filtrate was concentrated using vacuum distillation to give the oil 1- (1,1-dimethylethyl) 3-methyl ester of 4-oxo-1,3-piperidinedicarboxylic acid. Approximately 49 I (53 kg) of oily product was collected (estimated yield 95%). The oil was kept in the reactor for immediate use in the next stage.

Step D: 4-Oxo-3- (phenylmethyl) -1,3-pyridinedicarboxylic acid 1- (1,4-dimethylethyl) 3-methyl ester in the purged nitrogen vessel containing approximately 1 - (1 4-oxo-1,3-piperidinedicarboxylic acid (1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step C, 53 kg, 49 I, 1.0 eq.) Were introduced tetrahydrofuran (THF, 536 l) and potassium carbonate (72 kg, 2.5 eq.). The suspension was treated with benzyl bromide (36.0 kg, 1.01 eq.) For 10 to 15 minutes. The reaction mixture was heated to the reflux temperature until the reaction was completed (generally between 12 and 18 hours). The mixture was cooled to a temperature between 20 ° C and 25 ° C, filtered to remove the salts and the filter cake was washed with THF (134 I). The THF was removed from the mixture by partial distillation in vacuo and replaced with heptanes (402 I). The resulting suspension was cooled to a temperature between -5 ° C and 5 ° C and stirred for about 1 hour. The solids were collected by filtration, washed with heptanes (57 I), cooled between 0 ° C and 10 ° C and dried under vacuum between 45 ° C and 55 ° C, giving 50.1 kg of 1 - (1 4-oxo-3- (phenylmethyl) -1,3-piperidinedicarboxylic acid, 1-dimethylethyl) 3-methyl ester (69.2% yield). The HPLC assay showed a product peak of 99.2% at about 12 minutes. HPLC conditions: Intersil C-8 column, 4.6 x 150 mm; mobile phase: 50% acetonitrile / water; aqueous phase: 1 liter of water, 3 ml of triethylamine and 1 ml of H3PO4 at pH 6.5; flow rate 1.0 ml / min; detected by UV at 210 nm.

Step E: 1, 1-Dimethylethyl ester of 2,3,3a, 4,6,7-hexahydro-2-methyl-3-oxo-3a- (phenylmethyl- (5H) -p¡razolo [ 4,3-Clpyridine-5-carboxylic acid Methylhydrazine is very toxic, it is a suspected carcinogen, it is flammable and potentially explosive, it must be handled with great care, and during handling it must have on hand evacuation equipment, drying agents, Liqua paks and Fire extinguishers: Make sure that the air hoses are long enough to escape from any emergency situation As the methylhydrazine can react with metal oxides, the reaction vessel was inspected to ensure that no metal surfaces were exposed before starting The reaction In a clean, glass-lined, nitrogen-purged vessel, 4-oxo-3- (phenylmethyl) -1,3-piperidinedicarboxylic acid (1-, 1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Stage D, 50.1 kg, 1, 0 eq.) in methyl t-butyl ether (MTBE, 208 I) at a temperature of 15 ° C to 20 ° C to form a solution. The reaction solution was charged with methylhydrazine (7.6 kg, 1.15 eq.). After stirring for about 30 minutes, acetic acid (13.0 kg, 1.5 eq.) Was added. The reaction mixture was heated slowly to reflux temperature (53 ° C to 57 ° C) and refluxed for a period of 15 to 20 hours. The reaction was cooled to a temperature of 20 ° C to 25 ° C. The reaction mixture was cooled to a temperature between 5 ° C and 10 ° C and slowly charged with 10% sodium bicarbonate solution in water (175 I). The biphasic mixture was separated and the organic layer was washed sequentially with water (175 I) and saturated sodium chloride solution (175 I). The aqueous wash layers should be combined and treated with bleach solution to destroy all residual methylhydrazine before throwing them out. The organic solution was concentrated to a volume between 130 and 170 I at partial vacuum. The addition of heptanes (174 I) to the mixture precipitated the product. The suspension was stirred for 2 hours at a temperature between 5 ° C and 10 ° C. The solids were isolated by filtration, washed with cold MTBE (34 I) and dried under vacuum at a temperature comprised between 35 ° C and 45 ° C for 24 hours, giving 47.1 kg of 1,1-dimethylethyl ester of the product. 2,3,3a, 4,6,7-hexahydro-2-methyl-3-oxo-3a- (phenylmethyl) -5H-pyrazolo [4,3-c] pyridine-5-carboxylic acid (95.1 yield) %). The HPLC assay showed a product peak of 99.1% at about 5 minutes. HPLC conditions: Intersil C-8 column, 4.6 x 150 mm; mobile phase: 50% acetonitrile / water; aqueous phase: 1 liter of water, 3 ml of triethylamine and 1 ml of H3PO4 at pH 6.5; flow rate 1.0 ml / min; detected by UV at 205 nm.

Stage F: (2R.3R) -2.3-Dihydroxybutanedioate of (3aR) -2.3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenolmethyl) -3H-p razoloí4,3-c1piridin-3-one (1: 1) It has been observed that the intermediate free amine is epimerized in solution and as an isolated solid. Therefore, the dynamic resolution stage was completed immediately after the check out stage. In a clean purged nitrogen reactor, methylene chloride (471 I) and 1,3,3a, 4,6,7-hexahydro-2-methyl-3-oxo-3a 1,1-dimethylethyl ester were introduced. - (phenylimethyl) -5H-pyrazolo [4,3-c] pyridine-5-carboxylic acid (prepared according to Preparation Five, Step E, 47.0 kg, 1.0 eq.). The mixture was stirred and cooled to a temperature between -5 ° C and 5 ° C. Trifluoroacetic acid (117 kg, 7.5 eq.) Was slowly added to the reaction mixture. The reaction mixture was heated to a temperature between 20 ° C and 30 ° C and stirred for 12 to 15 hours. The reaction mixture is quenched by the slow addition of a 10% aqueous sodium carbonate solution (486 I, 0.5 eq.) At a temperature between 5 ° C and 15 ° C. The organic layer was separated and the aqueous layer was extracted with methylene chloride (19 I). In a second reactor a mixture of acetone (456 I), water (56.4 I) and L-tartaric acid (22.6 kg, 1.1 eq.) Was prepared. The tartaric acid mixture was combined with the organic layers at a temperature between 20 ° C and 25 ° C. The resulting suspension was heated to a temperature between 35 ° C and 45 ° C and stirred for 8 to 18 hours (overnight). When the reaction was considered complete, the suspension was cooled and granulated at a temperature between 0 ° C and 10 ° C for three to four hours and filtered. The cake of the product was washed with a mixture of acetone (40 l) and water (4.5 l). The product was dried under vacuum using only mild heat (applied if the evaporation of the acetone produces refrigeration). A yield of 37.7 kg of (2R, 3R) -2,3-dihydroxybutanedioate of (3aR) -2,3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) was obtained ) -3H-pyrazolo [4,3-c] pyridin-3-one (1: 1) (yield 70.1%).

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A process for preparing a compound of formula II wherein: R1 is -alkyl (C? -C-? o) optionally substituted with up to three fluorine atoms; R2 is phenylmethyl or 2-pyridylmethyl; R3 is -alkyl (C? -C5) -0-alkyl (Co-Cdjphenyl), the phenyl substituent being in the definition of R3 optionally substituted with up to three fluorine atoms, and Prt is an amine protecting group, comprising: a ) mixing an appropriate chiral tartrate salt having the structure of formula IV, D- or L-tartaric acid IV in which Ri and R2 are as defined above, and an organic amine in a reaction-inert solvent, at a temperature from about -68 ° C to about -40 ° C, to form a suspension; b) adding a compound of formula V, wherein R and Prt are as defined above, said suspension to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of Formula V; and c) adding a coupling reagent to said reaction mixture to form a compound of Formula II.
2. A process according to claim 1, wherein said compound of Formula IV is suspended in said solvent before the addition of said organic amine.
3. A process according to claim 2, wherein said suspension is heated to about -50 ° C before step b.
4. A process according to claim 1, wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is propanephosphonic acid anhydride.
5. A process according to claim 4, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl.
6. A process according to claim 5, wherein the compound of Formula II selected from (1- (2- (1 (R) - (2,4-difluorobenzyloxymethyl) tert -butyl ester is prepared. -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 and the tert-butyl ester of (1- (2- (3a (R) -benzyl- 2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-cjpyridin-5-yl) -1 (R) -benzyloxymethyl-2-oxo-ethylcarbamoyl) -1 -methyl-etl) -carbamic.
7. A process according to claim 5, wherein a compound of Formula HA is prepared IIA 8. - A method according to claim 5, wherein a compound of Formula IIB is prepared IIB 9. - A process according to claim 2, wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is the propanephosphonic acid anhydride. 10. A process according to claim 9, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl. 11. A process according to claim 10, wherein the compound of Formula II selected from (1- (2- (1 (R) - (2,4-difluorobenzyloxymethyl) tert -butyl ester is prepared. -3a (R) -pyridin-2-ylmethyl-2- (2,2,2-trifluoro-ethyl) -3-oxo-2,3,3a, 4,6,7-hexahydro-p, razolo [4,3-c] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-ethyl) -carbamic acid and tert-butyl ester of (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. 12. A process according to claim 10, wherein a compound of Formula HA is prepared HE HAS 13. - A method according to claim 10, wherein a compound of Formula I IB is prepared IIB 14. - A process according to claim 3, wherein: in step a, said organic amine is triethylamine; in step b, R3 is phenylethyloxymethyl or 2,4-difluorophenylmethyloxymethyl and Prt is t-butyloxycarbonyl; and in step c, said coupling reagent is the propanephosphonic acid anhydride. 15. A process according to claim 14, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl. 16. A process according to claim 15 in which a compound of Formula II is prepared from between (1- (2- (1 (R) - (2,4-difluorobenzyloxymethyl) -3a-tert -butyl ester (R ) -pyridin-2-methyl-2- (2,2,2-trifluoro-ethyl) -3-oxo-2,3,3a, 4,6,7-hexahydro-pyrrazolo [4,3] -c] pyridin-5-yl) -2-oxo-ethylcarbamoyl) -1-methyl-etiI) -carbamic acid and (1- (2- (3a (R) -benzyl-2-methyl) tert -butyl ester) -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. 17. A process according to claim 15, wherein a compound of Formula HA is prepared HE HAS 18. - A method according to claim 15, wherein a compound of Formula IIB is prepared IIB 19. - A process for preparing a compound of Formula III wherein: R is -alkyl (C? -C? O) optionally substituted with up to three fluorine atoms; R2 is phenylmethyl or 2-pyridylmethyl; and R3 is -alkyl (C? -C5) -0-alkyl (Co-Csjphenyl), the phenyl substituent being in the definition of R3 optionally substituted with up to three fluorine atoms, comprising: a) mixing an appropriate chiral tartrate salt which has the structure of Formula IV, • D- or L-tartaric acid IV wherein R1 and R2 are as defined above, and an organic amine in a solvent inert to the reaction at a temperature of about -68 ° C to about -45 ° C to form a suspension; b) adding a compound of Formula V, wherein R and Prt are as defined above, said suspension to form a reaction mixture comprising the tartrate salt of the organic amine, the free base of a compound of Formula IV and a compound of Formula V; c) adding a coupling reagent to said reaction mixture to form a compound of Formula II; and d) reacting said compound of Formula II with a suitable deprotective reagent to form a compound of Formula III. 20. A process according to claim 19, wherein said Formula IV compound is suspended in said solvent before the addition of said organic amine, which comprises the additional step of heating said suspension to a temperature of about -50 ° C. at about -40 ° C before stage b. 21. A process according to claim 20, wherein said Prt is Boc and said Boc is removed by reacting said compound of Formula II with an acid. 22. A process according to claim 21, wherein said acid is methanesulfonic acid. 23. A process according to claim 22, wherein R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propanephosphonic acid anhydride. 24. A process according to claim 23, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl. 25. A process according to claim 24, wherein said compound of Formula III is selected from 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-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-methylmethyl) -2- (2,2, 2-trifluoro-etl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -etl-2-methyl- propionamide 26. A process according to claim 24, wherein a compound of formula I HA IIIA is prepared 27. - A method according to claim 24, wherein a compound of formula IB is prepared IIIB 28. - A process according to claim 21, wherein said acid is trifluoroacetic acid. 29. A process according to claim 28, wherein: R is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step c, said coupling reagent is propanephosphonic acid anhydride. 30. A process according to claim 29, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl. 31. A process according to claim 30, wherein said compound of Formula III is selected from 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-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -p¡r¡d¡n-2-ylmethyl) - 2- (2,2,2-trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -ethyl-2-methyl-propionamide 32. A process according to claim 30, wherein a compound of formula IIIA is prepared IIIA 33. - A method according to claim 30, wherein a compound of formula IIIB IIIB is prepared 34. - A method according to claim 20, wherein said Prt is Boc and said Boc is removed by the reaction of said compound of Formula II with an acid. 35.- A process according to claim 34, wherein said acid is methanesulfonic acid. 36. A process according to claim 35, wherein: R3 is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step f, said coupling reagent is propanephosphonic acid anhydride. 37. A process according to claim 36, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl. 38.- A method according to claim 37, wherein said compound of Formula III is selected from 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-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-ylmethyl) -2- (2,2 , 2-trifluoro-etiI) -2,3,3a, 4,6,7-hexahydro-p¡razolo [4,3-c] pyridin-5-yl) -ethyl-2-methyl-proponamide 39.- A method according to claim 37, wherein a compound of formula IIIA is prepared GOING 40. - A method according to claim 37, wherein a compound of formula IIIB is prepared IHB 41.- A method according to claim 34, wherein said acid is trifluoroacetic acid. 42. - A process according to claim 41, wherein: R is phenylmethyloxymethyl or 2,4-difluorophenylmethyloxymethyl; in step b, said organic amine is triethylamine; and in step f, said coupling reagent is the propanephosphonic acid anhydride. 43. A process according to claim 42, wherein R1 is methyl or 2,2,2-trifluoroethyl and R2 is phenylmethyl or 2-pyridylmethyl. 44. A process according to claim 43, wherein said compound of Formula III is selected from 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-difluoro-benzyloxymethyl) -2-oxo-2- (3-oxo-3a (R) -pyridin-2-methylmethyl) -2- (2,2,2 -trifluoro-ethyl) -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -eti-2-met L-propionamide 45. A process according to claim 43, wherein a compound of formula IIIA is prepared. IIIA 46.- A method according to claim 43, wherein a compound of formula IIIB 47 is prepared.- A process for preparing an L-tartrate salt of formula XX, comprising the following consecutive steps: a) reacting said methyl ester hydrochloride of 4-oxo-piperidinecarboxylic acid with di-t-butyl dicarbonate and triethylamine in isopropyl ether to form 1- (1-dimethylethyl) 3-methyl ester of 4-oxo-1,3-piperidinedicarboxylic acid; b) reacting said 1- (1-dimethylethyl) 3-methyl ester of 4-oxo-1,3-piperidinedicarboxylic acid with benzyl bromide and potassium carbonate in tetrahydrofuran to form 1- (1-dimethylethyl) 3-methyl ester of the 4-oxo- (phenylmethyl) -1,3-piperidionecarboxylic acid; c) reacting said 1- (1-dimethylethyl) 3-methyl ester of 4-oxo- (phenylmethyl) -1,3-piperidinedicarboxylic acid with methyldrazine in acetic acid and methyl t-butyl ether to form 1,1-dimethylethyl ester 2,3a, 4,5,6,7-hexahydro-2-methyl-3-oxo-3a- (phenylmethyl) -5H-pyrazolo [4,3-c] pyridine-5-carboxylic acid; d) reacting said 1,4-dimethylethyl ester of 2,3a, 4,5,6,7-hexahydro-2-methyl-3-oxo-3a- (phenylmethyl) -5H-pyrazolo [4,3] -c] pyridine-5-carboxylic acid with trifluoroacetic acid to form (3aR) -2,3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) -3H-pyrazolo [4,3 -c] pyridin-3-one; and e) reacting said (3aR) -2,3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) -3H-pyrrazolo [4,3-c] pyridin-3-one with L-tartaric acid in acetone and water to form said L-tartrate salt of formula XX. 48.- A method according to claim 47, wherein said L-tartaric acid is added without isolating said (3aR) -2,3a, 4,5,6,7-hexahydro-2-methyl-3a- (phenylmethyl) -3H-pyrazolo [4,3- c] pyridin-3-one. 49. A method according to claim 47, comprising the additional step of crystallizing said salt L-tartrate of formula XX in said solution of acetone and water. 50. A process according to claim 49, wherein said L-tartrate salt of formula XX is isolated as a dihydrate. 51.- A polymorph of a dihydrate of a compound of formula XX: XX 52.- A polymorph according to claim 51 having the atomic coordinates and the isotropic displacement coefficients shown in Table 1. 53.- A polymorph according to the claim 51 having the X-ray crystal structure according to Figure 1.