Process intermediates and methods for the preparation of process intermediates for the synthesis of argatroban monohydrate

Abstract

Methods are provided for the synthesis of key intermediates for the synthesis of Argatroban monohydrate, ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl. Such intermediates are also provided.

1 - 35 . (canceled) 
     
     
         36 . An ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate comprising in an amount HCl between about 1 mol/mol and about 2 mol/mol. 
     
     
         37 . A solvate of the compound of  claim 36  having an organic solvent or water content of at least 0.5 mol/mol. 
     
     
         38 . A dihydrochloride form of the compound of  claim 36  having a weight/weight chloride content between about 12 and about 16%. 
     
     
         39 . A dihydrochloride form of the compound of  claim 36 , wherein said compound is solvated by ethanol and has a weight/weight chloride content between about 11 and about 15%. 
     
     
         40 . A Method for obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, comprising exposing a mixture of ethyl (2R,4R)-1-[(2S)-2-amino-5[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate and ethyl (2S,4S)-1-[(2S)-2-amino-5[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, to an organic or aqueous solvent or to a mixture thereof, followed by the selective precipitation and isolation of ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated. 
     
     
         41 . The method of  claim 40  comprising:
 a) exposing a mixture of ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, and ethyl (2S,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, to an organic solvent between 0° C. and the reflux temperature; 
 b) selective precipitation of ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated; 
 c) optionally, diluting the suspension obtained in step b) with an ester or alcohol or with an ester/alcohol mixture and, optionally, heating before or after said dilution at a temperature between 40° C. and the reflux temperature between 1 and 4 hours; 
 d) cooling the suspension at a temperature between about 0 and about 25° C.; 
 e) filtering the suspension; 
 f) drying the wet solid product obtained in step e) at a temperature between about 20 and about 100° C. 
 
     
     
         42 . A method for obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, comprising:
 1) exposing a mixture of ethyl (2R,4R)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate and ethyl (2S,4S)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate to an organic solvent, to a temperature between 0° C. and the reflux temperature;   2) optionally, triggering a reaction of the solution with ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated; 3) maintaining the mixture between 1 and 40 hours at a temperature between 0° C. and the reflux temperature;   4) optionally, diluting the suspension obtained in 3) with an ester or alcohol or with an ester/alcohol mixture at a temperature between 40° C. and the reflux temperature between 1 and 4 hours;   5) cooling the suspension at a temperature between about 0 and about 25° C. and filtering it;   6) drying the wet solid product obtained in step 5) at a temperature between about 20 and about 100° C.   
     
     
         43 . The method of  claim 42 , wherein said mixture of ethyl (2R,4R)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate and ethyl (2S,4S)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate has a water content lower than 40%. 
     
     
         44 . The method of  claim 41 , wherein said alcohol is selected from among ethanol, methanol, n-propanol, isopropanol, preferably it is ethanol and said ester is preferably an alkyl acetate, preferably selected from among ethyl acetate, isopropyl acetate or butyl acetate, preferably it is isopropyl acetate. 
     
     
         45 . The method of  claim 41 , wherein said organic solvent or the solvent mixture in said steps a), 1) and 4) is in a solvent volume/mixture weight ratio between about 5/1 and about 25/1. 
     
     
         46 . The method of  claim 42  wherein in said step 1) said HCl is added as gaseous HCl by bubbling or as an HCl solution in a solvent, in an amount between 1 and 4 equivalents of HCl. 
     
     
         47 . The method of  claim 40  wherein said method produces a final product having a content of ethyl (2S,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopenthyl]-4-methylpiperidine-2-carboxylate diastereoisomeric salt lower than 5%. 
     
     
         48 . The method of  claim 42 , wherein said
 mixture of ethyl (2R,4R)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate and ethyl (2S,4S)-1-[(2S)-2-[[(1,1-dimethyletoxy)carbonyl]amino]-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate is obtained according to a method comprising:   a) dissolving 2-chloro-4,6-dimethoxy-1,3,5-triazine CDMT in an organic solvent;   b) adjusting the temperature of the solution obtained in step a) at a temperature between about −20 and about +25° C.;   c) adding N-methylmorpholine NMM, wherein said adding operation is carried out while maintaining the mixture at a temperature between about −10 and about +25° C., and letting said mixture react for a period of time between 0.5 and 4 hours;   d) adding N-Boc-N′-nitro-L-arginine and letting the mixture react between 0.5 and 4 hours at a temperature between about −10 and about +25° C.;   e) adding racemic ethyl trans-(±)-4-methylpiperidine-2-carboxylate ester or hydrochloride thereof or, alternatively, a mixture of ethyl (2R,4R)-4-methylpiperidine-2-carboxylate and ethyl (2S,4S)-4-methylpiperidine-2-carboxylate, enriched with ethyl (2R,4R)-4-methylpiperidine-2-carboxylate or pure ethyl (2R,4R)-4-methylpiperidine-2-carboxylate, letting the mixture react between 2 and 20 hours, at a temperature between about −10 and about +25° C.;   f) optionally, filtering the precipitate, followed by one or more panel washing operations with an organic solvent;   g) subsequent washings of the organic solution with aqueous solutions;   h) optionally, partial or total concentration of the organic phase by distillation at atmospheric or reduced pressure.   
     
     
         49 . The method of  claim 48 , wherein said organic solvent is used in a solvent volume/weight ratio with respect to CDMT between about 5/1 and about 25/1. 
     
     
         50 . The method of  claim 48 , wherein said organic solvent is selected from the group consisting of: esters, ethers, chlorinated solvents and alkyl nitriles. 
     
     
         51 . The method of  claim 50  wherein said organic solvent is selected from the group consisting of: ethyl acetate, isopropyl acetate, butyl acetate, methyl terbutyl ether, isopropyl ether, butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and acetonitrile. 
     
     
         52 . The method of  claim 48 , wherein N-Boc-N′-nitro-L-arginine is used in a molar ratio with respect to ethyl trans-(±)-4-methylpiperidine-2-carboxylate or hydrochloride thereof between about 0.8 and about 1.3 and the molar ratios of CDMT and NMM with respect to ethyl trans-(±)-4-methylpiperidine-2-carboxylate or hydrochloride thereof are between about 0.8 and about 3. 
     
     
         53 . The method of  claim 48 , wherein the term ester is used to indicate a ratio between ethyl (2R,4R)-4-methylpiperidine-2-carboxylate and ethyl (2S,4S)-4-methylpiperidine-2-carboxylate equal to 97/3 or higher. 
     
     
         54 . The method of  claim 48 , wherein in said aqueous washings carried out in step g) water is employed or basic aqueous solutions, acid aqueous solutions and/or saturated saline aqueous solutions are employed; said basic aqueous solution is preferably 5% sodium bicarbonate, said acid solution is selected from among a 5% tartaric or citric acid solution or a diluted hydrochloric acid solution, said saturated aqueous saline solution is preferably water saturated with sodium chloride. 
     
     
         55 . The method of  claim 48 , wherein said base and/or hydrochloride ethyl trans-(±)-4-methylpiperidine-2-carboxylate are obtained according to a method comprising:
 A) preparing a solution of trans-(±)-4-methylpiperidine-2-carboxylic hydrochloride acid with an organic polar solvent, maintaining said thermostated solution at a temperature between 0 and 30° C.; 
 B) adding HCl to the solution obtained in step A); 
 C) heating the mass obtained in step b) at a temperature between 50° C. and reflux temperature and maintaining said temperature between 3 and 24 hours; 
 C′) optionally, the mixture is filtered, washing the panel with an organic solvent and rejoining the washing solution with the first filtrate; 
 D) concentrating the mixture obtained in step C), or the rejoined filtrates obtained in step C′) by distillation at reduced or atmospheric pressure and, optionally, recovering it one or more times with an organic solvent and concentrating it at reduced or atmospheric pressure; 
 E) diluting the residue with an organic solvent; 
 F) optionally filtering said mixture obtained in step E) and obtaining hydrochloride salt; 
 F′) alternatively, to obtain ethyl trans-(±)-4-methylpiperidine-2-carboxylate as a base, said mixture obtained in step E) is thermostated at a temperature between about 0 and about 30° C. and then treated with basic aqueous solution obtaining a biphasic solution which is left under stirring between 30 and 120 minutes; 
 G′) separating the organic phase from said biphasic solution; 
 H′) concentrating said organic phase and two or more organic phases obtained in G′) by distillation at reduced or atmospheric pressure, obtaining the ethyl trans-(±)-4-methylpiperidine-2-carboxylate product. 
 
     
     
         56 . The method of  claim 55 , wherein said HCl is added as an HCl solution in ethanol or as gaseous HCl by bubbling, using 1-3 equivalents of HCl, preferably about 2 equivalents. 
     
     
         57 . The method of  claim 48 , wherein said ethyl trans-(±)-4-methylpiperidine-2-carboxylate is obtained according to a method comprising:
 A) preparing a solution of the trans-(+)-4-methylpiperidine-2-carboxylic hydrochloride acid with an organic polar solvent maintaining said thermostated solution at a temperature between about 0 and about 30° C.; 
 B) adding SOCl 2  to the solution obtained in step a) maintaining the temperature between about 0 and about 30° C.; 
 C) heating the mass obtained in step b) at a temperature between about 50° C. and the reflux temperature and maintaining said temperature between 2 and 24 hours; 
 D) concentrating the mixture by distillation at reduced or atmospheric pressure; 
 E) diluting the residue with an organic solvent; 
 F′) adjusting the temperature to between about 0 and about 30° C. and subsequently treating the residue with basic aqueous solution obtaining a biphasic solution left under stirring between 30 and 120 minutes; 
 G′) separating the organic phase from said biphasic solution and, optionally, one or more further extractions of said aqueous phase with an organic solvent; 
 H′) concentrating said organic phase and two or more organic phases obtained in G′) by distillation at reduced or atmospheric pressure, obtaining the ethyl trans-(±)-4-methylpiperidine-2-carboxylate product. 
 
     
     
         58 . The method of  claim 57  wherein, in said step B), SOCl 2  is added using between about 0.5 and about 0.9 equivalents of SOCl 2 . 
     
     
         59 . The method of  claim 55 , wherein in said step A), said organic polar solvent is selected from the group consisting of: absolute ethanol and denatured ethanol free of methanol or other alcohols. 
     
     
         60 . The method of  claim 55 , wherein said organic solvent in step A) is used in a volume/weight ratio of said trans-(±)-4-methylpiperidine-2-carboxylic hydrochloride acid between about 1/1 and about 10/1. 
     
     
         61 . The method of  claim 55 , wherein said organic solvent in steps D), E), F), F′), G′) and H′) is selected from the group consisting of: esters, ethers, chlorinated solvents, alkyl nitriles, aromatic hydrocarbons and ketones. 
     
     
         62 . The method of  claim 61  wherein said organic solvent is selected from the group consisting of: ethyl acetate, isopropyl acetate, butyl acetate, methyl terbutyl ether, isopropyl ether, butyl ether, 2-methyltetrahydrofuran, dichloromethane, toluene and methyl ethyl ketone. 
     
     
         63 . A method for purifying ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, comprising:
 1) resuspending or dissolving said compound in an alcohol/ester mixture and heating at a temperature between 20° C. and reflux temperature between 0.5 and 4 hours;   2) cooling said mixture at a temperature between about 0 and about 25° C. and filtering it, optionally followed by one or more filter washings with an ester or alcohol or with an ester/alcohol mixture;   3) drying the wet solid product obtained in step 2) at a temperature between about 20 and about 100° C. obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, having a content of ethyl (2S,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopenthyl]-4-methylpiperidine-2-carboxylate diastereoisomeric salt lower than about 1%.   
     
     
         64 . The method for purifying ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, according to  claim 40  comprising purifying the compound obtained after said steps e), f), 5) or 6) by:
 7) resuspending or dissolving said compound in an alcohol/ester mixture and heating at a temperature between 20° C. and reflux temperature between 0.5 and 4 hours; 
 8) cooling said mixture at a temperature between about 0 and about 25° C. and filtering it, optionally followed by one or more filter washings with an ester or alcohol or with an ester/alcohol mixture; 
 9) drying the wet solid product obtained in step 8) at a temperature between about 20 and about 100° C. to obtain ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl, solvated or unsolvated, having a content of ethyl (2S,4S)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopenthyl]-4-methylpiperidine-2-carboxylate diastereoisomeric salt lower than about 1%. 
 
     
     
         65 . The method of  claim 63 , wherein said alcohol/ester mixture comprises absolute ethanol and ethyl acetate in approximately 1:1 ratio. 
     
     
         66 . The method of  claim 63 , wherein the washing step is repeated at least once using ethyl acetate. 
     
     
         67 . The method for obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate dihydrochloride ethanol solvate according to  claim 41 , wherein the alcohol is ethanol and the drying of said wet solid product comprises exposure to a temperature between about 40 and about 50° C. 
     
     
         68 . The method for obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate dihydrochloride according to  claim 41  comprising drying the wet solid product by exposure to a temperature between about 75 and about 100° C. between 4 and 24 hours. 
     
     
         69 . A method for obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate dihydrochloride from ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate compounded with HCl solvate comprising exposing said compound to a temperature between about 75 and about 100° C. between 4 and 48 hours. 
     
     
         70 . A method for obtaining ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate dihydrochloride (3) from ethyl (2R,4R)-1-[(2S)-2-amino-5-[[imino(nitroamino)methyl]amino]-1-oxopentyl]-4-methylpiperidine-2-carboxylate dihydrochloride ethanol solvate, comprising exposing said compound to a temperature between about 75 and about 100° C. between 4 and 48 hours.