WO2007075630A1 - Method for producing 3-aminopiperidine diastereomer - Google Patents

Method for producing 3-aminopiperidine diastereomer Download PDF

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Publication number
WO2007075630A1
WO2007075630A1 PCT/US2006/048350 US2006048350W WO2007075630A1 WO 2007075630 A1 WO2007075630 A1 WO 2007075630A1 US 2006048350 W US2006048350 W US 2006048350W WO 2007075630 A1 WO2007075630 A1 WO 2007075630A1
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Prior art keywords
aminopiperidine
diastereomer
tartaric acid
dibenzoyl
resolving agent
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PCT/US2006/048350
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French (fr)
Inventor
Helen J. Samuel
Graham A. Meek
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Dow Global Technologies Inc.
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Publication of WO2007075630A1 publication Critical patent/WO2007075630A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms

Definitions

  • Hydrogenation of pyridine compounds and/or resolution of mixtures of racemic piperidine compounds by the formation of diastereomers are known in the art.
  • H. Nienburg, Chemische Berichte, (1937), 7OB, 635-8 describes the hydrogenation of 3-aminopyridine using a PtO 2 catalyst in an acid medium.
  • JP07330732 describes the resolution of 3-amino-l-benzylpiperidine by forming a diastereomer with dibenzoyl-D-tartaric acid.
  • WO 2004/083181 Al describes the catalytic hydrogenation of 2- aryl-3-amino-pyridines using platinum, on carbon in an acid medium.
  • WO9311110 describes the hydrogenation of 2-aryl-3-aminopyridines followed by resolution of the subsequent piperidines by forming a diastereomer with mandelic acid.
  • 3-Aminopiperidine enantiomers are useful, for example, as raw materials for making pharmaceutical agents.
  • the present invention provides such a method to resolve racemic 3- aminopiperidine or to obtain a composition with an increased excess of the desired stereoisomer.
  • the invention is a method for increasing the enantiomeric purity of a desired enantiomer of 3-aminopiperidine comprising: providing a composition containing (Z?)-3-aminopiperidine and (5)-3-aminopiperidine; combining the composition with a resolving agent selected from the gro ⁇ p consisting of dibenzoyl-D-tartaric acid; di(ortho- tolyl)-D-tartarie acid; N-acetyl-D-phenylalanine; mixtures of two or more of dibenzoyl-D- tartaric acid, di(ortho-tolyl)-D-tartaric acid, and iV-acetyl-D-phenylalanine; dibenzoyl-L- tartaric acid; di(ortho-tolyl)-L- tartaric acid; J
  • the present invention is a method for producing a crystalline diastereomeric salt having a mole ratio of (i?)-3- aminopiperidine diastereoisomer to (iS)-3-aminopi ⁇ eridine diastereoiorner greater than one, comprising the step of: mixing racemic 3-aminopiperidine with a resolving agent selected from the group consisting of dibenzoyl-D-tartaric acid, di(ortho-tolyl)-D-tartaric acid, N- acetyl-D-phenylalanine and mixtures thereof, in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt.
  • a resolving agent selected from the group consisting of dibenzoyl-D-tartaric acid, di(ortho-tolyl)-D-tartaric acid, N- acetyl-D-phenylalanine and mixtures thereof
  • the instant invention is a method for producing a crystalline diastereomeric salt having a mole ratio of (iS)-3-arninopiperid ⁇ ne diastereoisomer to (iO-S-aminopiperidme diastereoisomer greater than one, comprising the step of: mixing racemic 3-amino ⁇ iperidine with a resolving agent selected from the group consisting of dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid, iV-acetyl-L-phenylalanine and mixtures thereof, in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt.
  • a resolving agent selected from the group consisting of dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid, iV-acetyl-L-pheny
  • the instant invention is a method for producing a crystalline diastereomeric salt having a mole ratio of the desired 3-aminopiperidine diastereoisomer to the undesired 3- aminopiperidine diastereoisomer of greater than one, preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8.
  • the starting 3-aminopiperidine material is typically and preferably a racemic mixture but the method of this invention may also be used to increase the excess of a desired diastereoisomer in the resulting composition relative to the amount of that desired diastereoisomer in the starting composJtion.
  • the solvent used should be effective in dissolving both the initial 3- aminopiperidine material and the resolving agent.
  • the solvent is preferably ethanol or methanol or mixtures thereof.
  • the concentration of initial 3-aminopiperidine material (which is preferably a racemic mixture) is preferably in the range of from 5 to 22 weight percent of the mixture.
  • the mole ratio of initial 3-aminopiperidine material (which is preferably a racemic mixture) to resolving agent is preferably in the range of from 2:1 to 1:2.
  • the temperature is preferably initially in the range of from 35 to 70 degrees Celsius and then reduced to a temperature the range of from 0 to 20 degrees Celsius to initiate or speed crystallization.
  • the resolving agent is preferably dibenzoyl-D-tartaric acid.
  • (i?)-3-aminopiperidine is the preferred diastereoisomer.
  • the resolving agent is preferably dibenzoyl-L-tartaric acid.
  • the instant invention can further comprise the steps of combining the crystalline diastereomeric salt with a second solvent and then reacting the diastereomeric salt with an acid to produce a protonated 3-aminopiperidine product having a mole ratio of the desired protonated 3-aminopiperidine diastereoisomer to the undesired protonated 3- aminopiperidine greater than one, preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8.
  • Such second solvent is preferably selected from the group consisting of ethers, hydrocarbons and mixtures thereof. Tert-butyl methyl ether and hydrogen chloride are preferred as the solvent and acid.
  • the preferred racemic 3-aminopiperidine used in the invention is preferably made by hydrogenating racemic 3-aminopyridine using a hydrogenation catalyst such as a supported rhodium catalyst without the use of an acid.
  • the support is preferably selected from the group consisting of alumina and carbon. Not using an acid medium for the hydrogenation has the important advantage of producing 3-aminopiperidine in the free base form.
  • the mole ratio of (R)-3- aminopiperidine diastereomer to (S)-3 -aminopiperidine diastereomer produced according to the method of the instant invention is preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8.
  • the mole ratio of (S)-3 -aminopiperidine diastereomer to (i?)-3 -aminopiperidine diastereomer produced by this alternative embodiment of the instant invention is preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8.
  • Racemic 3-aminopiperidine is screened against 20 potential resolving agents to determine if any produce suitable diastereomeric salt crystals. Initially, 0.2 g of racemate is dissolved in 2ml MeOH, 1 mole eq of the resolving agent is added and any crystals obtained are isolated after stirring at room temperature for 24 hours. Where crystals do not form, the solvent is removed and replaced with a mixture of ethanol, isopropanol and ethyl acetate in an attempt to produce crystals of diastereomeric salts.
  • a Parr pressure vessel is charged with 3-aminopyridine (100 g), 5 wt% rhodium on alumina (10 g) and methanol (1 litre). The vessel is charged with nitrogen to a pressure of 10 bar, stirred for 15 minutes and vented. This process is repeated three times. The vessel is then charged with hydrogen to a pressure of 10 bar and subsequently vented without the mixture being stirred. This process is repeated three times. The vessel is then charged with hydrogen to a pressure of 15 bar, and heated to 80 0 C and stirred. Once the temperature is ' attained, the hydrogen pressure is increased to 20 bar. After 17 hours, the vessel is cooled to room temperature and the hydrogen is vented.
  • the vessel is then charged with nitrogen to a pressure of 10 bar and the mixture stirred for 10 minutes and then vented. This process is repeated three times.
  • the contents of the vessel are filtered through a pad of celite and washed with fresh methanol (300 ml). Analysis of an aliquot (0.1 ml) reveals the conversion to be >98% as determined by proton NMR comparing the integrals associated with 3-aminopyridine and 3- aminopiperidine.
  • the hydrogenation is undertaken 3 times. Each batch is diluted to 3.6L with methanol and heated to 40 0 C in a jacketed vessel with overhead stirring.
  • Dibenzoyl- D-tartaric acid (371.7g:leq) is then added via a solids addition funnel and the vessel is heated to 60 0 C with vigorous stirring for lhr, during which time crystallization occurred. The temperature is then reduced to 20 0 C over 2 hours and the reaction stirred for a further 16 hours. The crystals are then filtered, washed with methanol (300ml) and dried to give a 40-44% yield with 88-91 % diastereomeric excess (%de). These batches of material are then combined (59Og) and slurried in methanol (4L) at 50 0 C for 16 hours, cooled to 22 0 C over 1 hour and stirred for a further 1 hour.
  • a glass liner is charged with 3-aminopyridine (500 mg, 5.31 mmol), 5% Rh/C (Engelhard type 44966, 56% water content)) (113 mg) and methanol (5 ml).
  • the liner is secured in an Argonaut EndeavorTM multi-well pressure reactor.
  • the reactor is charged is charged with nitrogen to a pressure of 10 bar, stirred for 15 minutes and vented. This process is repeated three times.
  • the reactor is then charged with hydrogen to a pressure of 10 bar and subsequently vented without the mixture being stirred. This process is repeated two times.
  • the reactor is then charged with hydrogen to a pressure of 20 bar, heated to 80 C and stirred at 1000 rpm.
  • the pressure of hydrogen is maintained at 20 bar for 17 hours.
  • the reactor is vented and the reaction mixture analysed without concentration. Analysis of an aliquot (0.1 ml) reveals the conversion to be 94% as determined by proton NMR comparing the integrals associated with 3-aminopyridine and 3-aminopi ⁇

Abstract

A method for increasing the enantiomeric purity of a desired enantiomer of 3- aminopiperidine comprising: providing a composition containing (i?)-3-arninopiperidine and (jS)-3-aminopiperidine; combining the composition with a resolving agent selected from the group consisting of dibenzoyl-D-tartaric acid; di(ortho-tolyl)-D-tartaric acid; 7V-acetyl-D- phenylalanine; mixtures of two or more of dibenzoyl-D-tartaric acid, di(ortho-tolyl)-D- tartaric acid, and iV-acetyl-D-phenylalanine; dibenzoyl-L-tartaric acid; di(ortho-tolyl)-L- tartaric acid; iV-acetyl-L-phenylalanine; and mixtures of two or more of dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid; and iV-acetyl-L-phenylalanine in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt, which is enriched in either the (i?)-3-aminopiperidine diastereomer or the (-S)-3-aminopiperidine diastereomer.

Description

METHOD FOR PRODUCINCr 3-AMINOPIPERIDINE DIASTEREOMER
FIELD OF THE INVENTION This invention is in the field of methods for producing enantiomers and more specifically the instant invention is in the field of producing 3-aminopiperidine enantiomers in the form of a crystalline diastereomeric salt. BACKGROUND OF THE INVENTION
Hydrogenation of pyridine compounds and/or resolution of mixtures of racemic piperidine compounds by the formation of diastereomers are known in the art. For example, H. Nienburg, Chemische Berichte, (1937), 7OB, 635-8 describes the hydrogenation of 3-aminopyridine using a PtO2 catalyst in an acid medium. JP07330732 describes the resolution of 3-amino-l-benzylpiperidine by forming a diastereomer with dibenzoyl-D-tartaric acid. WO 2004/083181 Al describes the catalytic hydrogenation of 2- aryl-3-amino-pyridines using platinum, on carbon in an acid medium. WO9311110 describes the hydrogenation of 2-aryl-3-aminopyridines followed by resolution of the subsequent piperidines by forming a diastereomer with mandelic acid.
3-Aminopiperidine enantiomers are useful, for example, as raw materials for making pharmaceutical agents. However, there remains a need for an effective method to resolve racemic 3-aminopiperidine or to obtain a composition with an increased excess of the desired enantiomer.
SUMMARY OF THE INVENTION
The present invention provides such a method to resolve racemic 3- aminopiperidine or to obtain a composition with an increased excess of the desired stereoisomer. Thus, the invention is a method for increasing the enantiomeric purity of a desired enantiomer of 3-aminopiperidine comprising: providing a composition containing (Z?)-3-aminopiperidine and (5)-3-aminopiperidine; combining the composition with a resolving agent selected from the groυp consisting of dibenzoyl-D-tartaric acid; di(ortho- tolyl)-D-tartarie acid; N-acetyl-D-phenylalanine; mixtures of two or more of dibenzoyl-D- tartaric acid, di(ortho-tolyl)-D-tartaric acid, and iV-acetyl-D-phenylalanine; dibenzoyl-L- tartaric acid; di(ortho-tolyl)-L- tartaric acid; JV-acetyl-L-phenylalanine; and mixtures of two or more of dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid; and N-acetyl-L- phenylalanine in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt, which is enriched in either the (i?)-3-aminopiperidine diastereomer or the (S)-3-aminopiperidine diastereomer. Thus, according to a first preferred embodiment, the present invention is a method for producing a crystalline diastereomeric salt having a mole ratio of (i?)-3- aminopiperidine diastereoisomer to (iS)-3-aminopiρeridine diastereoiorner greater than one, comprising the step of: mixing racemic 3-aminopiperidine with a resolving agent selected from the group consisting of dibenzoyl-D-tartaric acid, di(ortho-tolyl)-D-tartaric acid, N- acetyl-D-phenylalanine and mixtures thereof, in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt.
In another embodiment, the instant invention is a method for producing a crystalline diastereomeric salt having a mole ratio of (iS)-3-arninopiperidϊne diastereoisomer to (iO-S-aminopiperidme diastereoisomer greater than one, comprising the step of: mixing racemic 3-aminoρiperidine with a resolving agent selected from the group consisting of dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid, iV-acetyl-L-phenylalanine and mixtures thereof, in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt.
DETAILED DESCRIPTION
The instant invention is a method for producing a crystalline diastereomeric salt having a mole ratio of the desired 3-aminopiperidine diastereoisomer to the undesired 3- aminopiperidine diastereoisomer of greater than one, preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8.
The starting 3-aminopiperidine material is typically and preferably a racemic mixture but the method of this invention may also be used to increase the excess of a desired diastereoisomer in the resulting composition relative to the amount of that desired diastereoisomer in the starting composJtion. The solvent used should be effective in dissolving both the initial 3- aminopiperidine material and the resolving agent. The solvent is preferably ethanol or methanol or mixtures thereof. The concentration of initial 3-aminopiperidine material (which is preferably a racemic mixture) is preferably in the range of from 5 to 22 weight percent of the mixture. The mole ratio of initial 3-aminopiperidine material (which is preferably a racemic mixture) to resolving agent is preferably in the range of from 2:1 to 1:2. The temperature is preferably initially in the range of from 35 to 70 degrees Celsius and then reduced to a temperature the range of from 0 to 20 degrees Celsius to initiate or speed crystallization. When (i?)-3-aminopiperidine is the desired diastereoisomer, the resolving agent is preferably dibenzoyl-D-tartaric acid. (i?)-3-aminopiperidine is the preferred diastereoisomer. When 0S)-3 -aminopiperidine diastereoisomer is desired the resolving agent is resolving agent is preferably dibenzoyl-L-tartaric acid.
The instant invention can further comprise the steps of combining the crystalline diastereomeric salt with a second solvent and then reacting the diastereomeric salt with an acid to produce a protonated 3-aminopiperidine product having a mole ratio of the desired protonated 3-aminopiperidine diastereoisomer to the undesired protonated 3- aminopiperidine greater than one, preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8. Such second solvent is preferably selected from the group consisting of ethers, hydrocarbons and mixtures thereof. Tert-butyl methyl ether and hydrogen chloride are preferred as the solvent and acid.
The preferred racemic 3-aminopiperidine used in the invention is preferably made by hydrogenating racemic 3-aminopyridine using a hydrogenation catalyst such as a supported rhodium catalyst without the use of an acid. The support is preferably selected from the group consisting of alumina and carbon. Not using an acid medium for the hydrogenation has the important advantage of producing 3-aminopiperidine in the free base form.
When (R)-3-aminoρiperidine is desired, the mole ratio of (R)-3- aminopiperidine diastereomer to (S)-3 -aminopiperidine diastereomer produced according to the method of the instant invention is preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8. When (i!>)-3-aminopiperidine diastereomer is desired, the mole ratio of (S)-3 -aminopiperidine diastereomer to (i?)-3 -aminopiperidine diastereomer produced by this alternative embodiment of the instant invention is preferably greater than two, more preferably greater than 3, more preferably still greater than 5, yet more preferably greater than 6, and most preferably greater than 8. EXAMPLES
Racemic 3-aminopiperidine is screened against 20 potential resolving agents to determine if any produce suitable diastereomeric salt crystals. Initially, 0.2 g of racemate is dissolved in 2ml MeOH, 1 mole eq of the resolving agent is added and any crystals obtained are isolated after stirring at room temperature for 24 hours. Where crystals do not form, the solvent is removed and replaced with a mixture of ethanol, isopropanol and ethyl acetate in an attempt to produce crystals of diastereomeric salts. The salts and liquors are recovered, cracked to liberate 3-aminopiρeridine free base and the enantiomeric excess (ee) of the 3-aminopiperidine from Crystals and in the mother liquors (ML) is determined as well as the Yield of Crystals. Results are shown in the Table below.
Figure imgf000005_0001
The data in the table above indicate that dibenzoyltartric acid, di(ortho-tolyl)tartaric acid, and iV-acetylphenylalanine are surprisingly suitable for use as resolving agents.
A Parr pressure vessel is charged with 3-aminopyridine (100 g), 5 wt% rhodium on alumina (10 g) and methanol (1 litre). The vessel is charged with nitrogen to a pressure of 10 bar, stirred for 15 minutes and vented. This process is repeated three times. The vessel is then charged with hydrogen to a pressure of 10 bar and subsequently vented without the mixture being stirred. This process is repeated three times. The vessel is then charged with hydrogen to a pressure of 15 bar, and heated to 80 0C and stirred. Once the temperature is ' attained, the hydrogen pressure is increased to 20 bar. After 17 hours, the vessel is cooled to room temperature and the hydrogen is vented. The vessel is then charged with nitrogen to a pressure of 10 bar and the mixture stirred for 10 minutes and then vented. This process is repeated three times. The contents of the vessel are filtered through a pad of celite and washed with fresh methanol (300 ml). Analysis of an aliquot (0.1 ml) reveals the conversion to be >98% as determined by proton NMR comparing the integrals associated with 3-aminopyridine and 3- aminopiperidine. The hydrogenation is undertaken 3 times. Each batch is diluted to 3.6L with methanol and heated to 40 0C in a jacketed vessel with overhead stirring. Dibenzoyl- D-tartaric acid (371.7g:leq) is then added via a solids addition funnel and the vessel is heated to 60 0C with vigorous stirring for lhr, during which time crystallization occurred. The temperature is then reduced to 20 0C over 2 hours and the reaction stirred for a further 16 hours. The crystals are then filtered, washed with methanol (300ml) and dried to give a 40-44% yield with 88-91 % diastereomeric excess (%de). These batches of material are then combined (59Og) and slurried in methanol (4L) at 50 0C for 16 hours, cooled to 22 0C over 1 hour and stirred for a further 1 hour. The solid is then filtered, washed with methanol (5 x 100ml) and dried to give 543.5g of white solid, 92.1% yield and 96.4 %de. This solid is reslurried in methanol (3.75L) at 60 °C for 2 hours, cooled to 22 0C and stirred for 16 hours. The solid is then filtered, washed with methanol (5 x 100ml) and dried to give 511.83g of white solid, 94.2% yield and 98.1 %de.495g of this material is then slurried in 3L of methyl t-butyl ether (MTBE) and HCI (3eq) in MTBE (IL) is added slowly over 2 hours with stirring. This material is then heated to 50 0C for 1 hour, cooled to 5 0C and stirred over night. The solid is then filtered, washed with MTBE and dried to give 179.5g of white solid, 96% yield. This material, the hydrochloride salt of (i?)-3-aminopiperidine, is analysed by chiral HPLC and determined to be of >99% chemical purity and >98%ee.
A glass liner is charged with 3-aminopyridine (500 mg, 5.31 mmol), 5% Rh/C (Engelhard type 44966, 56% water content)) (113 mg) and methanol (5 ml). The liner is secured in an Argonaut Endeavor™ multi-well pressure reactor. The reactor is charged is charged with nitrogen to a pressure of 10 bar, stirred for 15 minutes and vented. This process is repeated three times. The reactor is then charged with hydrogen to a pressure of 10 bar and subsequently vented without the mixture being stirred. This process is repeated two times. The reactor is then charged with hydrogen to a pressure of 20 bar, heated to 80 C and stirred at 1000 rpm. The pressure of hydrogen is maintained at 20 bar for 17 hours. The reactor is vented and the reaction mixture analysed without concentration. Analysis of an aliquot (0.1 ml) reveals the conversion to be 94% as determined by proton NMR comparing the integrals associated with 3-aminopyridine and 3-aminopiρeridine.
CONCLUSION
While the instant invention has been described above according to its preferred embodiments, it can be modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the instant invention using the general principles disclosed herein. Further, the instant application is intended to cover such departures from the present disclosure as come within the known or customary practice in the art to which ithis invention pertains and which fall within the limits of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method for increasing the enantiomeric purity of a desired enantiomer of 3-aminopiperidine comprising: providing a composition containing (R)-3- aminopiperidine and (5)-3-aminopiperidine; combining the composition with a resolving agent selected from the group consisting of dibenzoyl-D-tartaric acid; di(ortho-tolyl)-D- tartaric acid; JV-acetyl-D-phenylalanine; mixtures of two or more of dibenzoyl-D-tartaric acid, di(ortho-tolyl)-D-tartaric acid, and N-acetyl-D-phenylalanine; dibenzoyl-L-tartaric acid; di(ortho-tolyl)-L-tartaric acid; iV-acetyl-L-phenylalanine; and mixtures of two or more of dibenzoyl-L-tartaric acid, di(ortho-tolyl)-L-tartaric acid; and iV-acetyl-L-phenylalanine in a solvent effective to dissolve the racemic 3-aminoρiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt, which is enriched in either the (i?)-3- aminopiperidine diastereomer or the (Λy3-aminopiperidine diastereomer.
2. The method of claim 1 comprising the step of: mixing racemic 3- aminopiperidine with a resolving agent selected from the group consisting of dibenzoyl-D- tartaric acid, di(ortho-tolyl)-D-tartaric acid, JV-acetyl-D-phenylalanine and mixtures thereof, in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt having a mole ratio of (i?)-3- aminopiperidine diastereomer to (5)-3 -aminopiperidine diastereomer greater than one.
3. The method of claim 1, comprising the step of: mixing racemic 3- aminopiperidine with a resolving agent selected from the group consisting of dibenzoyl-L- tartaric acid, di(ortho-tolyl)-L-tartaric acid, TV-acetyl-L-phenylalanine and mixtures thereof, in a solvent effective to dissolve the racemic 3-aminopiperidine and the resolving agent, and to crystallize the crystalline diastereomeric salt having a mole ratio of (iS)-3-aminopiperidine diastereomer to (R)-3-aminopiperidine diastereomer greater than one.
4. The method of any one of Claims 1-3, wherein the solvent is selected from the group consisting of ethanol, methanol and mixtures thereof.
5. The method of any one of Claims 1-4, wherein the initial concentration of 3-aminopiperidine is in the range of from 5 to 22 weight percent of the mixture, wherein the mole ratio of racemic 3-aminopiperidine to resolving agent is in the range of from 2: 1 to 1 :2 and wherein the temperature is initially in the range of from 35 to 70 degrees Celsius and then reduced to a temperature in the range of from 0 to 20 degrees Celsius.
6. The method of any one of Claims 1-5, wherein the solvent consists essentially of methanol.
7. The method of either one of Claims 1 or 2, wherein the resolving agent is dibenzoyl-D-tartaric acid.
8. The method of any of Claims 1, 2, or 4-7, further comprising the steps of combining the crystalline diastereomeric salt with a solvent and then reacting the diastereomeric salt with an acid to produce a protonated 3-arninopiperidine product having a mole ratio of protonated (i?)-3-aminopiperidine to protonated (5)-3-aminopiperidine greater than one.
9. The method of either one of Claims 1 or 3, wherein the resolving agent is dibenzoyl-L-tartaric acid.
10. The method of any of Claims 1, 3-6, or 9, further comprising the steps of combining the crystalline diastereomeric salt with a solvent and then reacting the diastereomeric salt with an acid to produce a protonated 3-aminopiperidine product having a mole ratio of protonated (iS)-3-aminop:iperidine to protonated (/?)-3 aminopiperidine greater than one.
11. The method of either of Claims 8 or 10, wherein the solvent is selected from the group consisting of ethers, hydrocarbons and mixtures thereof.
12. The method of Claim 11 , wherein the solvent is essentially tert-butyl methyl ether and wherein the acid is essentially hydrogen chloride.
13. The method of any of Claims 2-12, wherein the racemic 3- aminopiperidine is made by hydrogenating 3-aminopyridine using a hydrogenation catalyst.
14. The method of Claim 13, wherein the hydrogenation catalyst is a supported rhodium catalyst.
15. The method of Claim 14, wherein the support is selected from the group consisting of alumina and carbon.
16. The method of any of Claims 1 -2, 4-8, or 11 - 15., wherein the mole ratio of (i?)-3-aminopiperidine diastereomer to 0S)-3-aminopiperidine diastereomer in the crystallized diastereromer salt is greater than three.
17. The method of Claim 16, wherein the mole ratio of (R)-3- aminopiperidine diastereomer to
Figure imgf000009_0001
diastereomer is greater than eight.
18. The method of any of Claims 1, 3-6, or 9- 15, wherein the mole ratio of (5}-3-aminopiperidine diastereomer to (i?)-3-aminopiperidine diastereomer in the crystallized diastereomer salt is greater than three.
19. The method of Claim 18, wherein the mole ratio of (-S)-3- aminopiperidine diastereomer to (i?)-3 -aminopiperidine diastereomer is greater than eight.
PCT/US2006/048350 2005-12-22 2006-12-19 Method for producing 3-aminopiperidine diastereomer WO2007075630A1 (en)

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* Cited by examiner, † Cited by third party
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WO2009107571A1 (en) 2008-02-27 2009-09-03 住友化学株式会社 Method for optical resolution of alkylpiperidin-3-yl carbamate and intermediate therefor
WO2009119700A1 (en) 2008-03-26 2009-10-01 住友化学株式会社 Manufacturing method for a piperidine-3-ylcarbamate compound and optical resolution method therefor
JP2011057619A (en) * 2009-09-10 2011-03-24 Tokai Univ Method for producing optically active amine compound, and diastereomer salt and method for producing the same
WO2011160037A3 (en) * 2010-06-17 2012-04-05 Dr. Reddy's Laboratories Ltd. Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride
CN103319399A (en) * 2013-05-29 2013-09-25 威海迪素制药有限公司 Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride
WO2014128139A1 (en) 2013-02-20 2014-08-28 Reuter Chemische Apparatebau Kg Process for the preparation of enantiomerically enriched 3-aminopiperidine
EP2457899A4 (en) * 2009-07-21 2015-06-03 Sumitomo Chemical Co Process for production of optically active nipecotamide
CN108689914A (en) * 2018-07-03 2018-10-23 湖北华世通生物医药科技有限公司 A method of chipal compounds are prepared using intermediate
CN113234012A (en) * 2021-06-01 2021-08-10 青岛化赫医药科技有限公司 Preparation method of 3-methylamino pyridine and derivatives or salts thereof
CN114591219A (en) * 2022-03-22 2022-06-07 汉瑞药业(荆门)有限公司 Preparation method of S-3-aminopiperidine dihydrochloride

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027966A1 (en) * 1993-05-28 1994-12-08 Pfizer Inc. Process for preparing and resolving 2-phenyl-3-aminopiperidine
EP1457487A1 (en) * 2001-12-21 2004-09-15 Toray Fine Chemicals Co., Ltd. Process for production of optically active cis-piperidine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027966A1 (en) * 1993-05-28 1994-12-08 Pfizer Inc. Process for preparing and resolving 2-phenyl-3-aminopiperidine
EP1457487A1 (en) * 2001-12-21 2004-09-15 Toray Fine Chemicals Co., Ltd. Process for production of optically active cis-piperidine derivatives

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009227665A (en) * 2008-02-27 2009-10-08 Sumitomo Chemical Co Ltd Method for optical resolution of alkylpiperidin-3-yl carbamate and intermediate therefor
EP2248803A1 (en) * 2008-02-27 2010-11-10 Sumitomo Chemical Company, Limited Method for optical resolution of alkylpiperidin-3-yl carbamate and intermediate therefor
EP2248803A4 (en) * 2008-02-27 2012-03-28 Sumitomo Chemical Co Method for optical resolution of alkylpiperidin-3-yl carbamate and intermediate therefor
WO2009107571A1 (en) 2008-02-27 2009-09-03 住友化学株式会社 Method for optical resolution of alkylpiperidin-3-yl carbamate and intermediate therefor
WO2009119700A1 (en) 2008-03-26 2009-10-01 住友化学株式会社 Manufacturing method for a piperidine-3-ylcarbamate compound and optical resolution method therefor
JP2009256298A (en) * 2008-03-26 2009-11-05 Sumitomo Chemical Co Ltd Optical resolution method for piperidin-3-ylcarbamate compound, and its intermediate
EP2471775A1 (en) 2008-03-26 2012-07-04 Sumitomo Chemical Co., Ltd. Manufacturing method for a piperidine-3-ylcarbamate compound and optical resolution method therefor
EP2457899A4 (en) * 2009-07-21 2015-06-03 Sumitomo Chemical Co Process for production of optically active nipecotamide
JP2011057619A (en) * 2009-09-10 2011-03-24 Tokai Univ Method for producing optically active amine compound, and diastereomer salt and method for producing the same
WO2011160037A3 (en) * 2010-06-17 2012-04-05 Dr. Reddy's Laboratories Ltd. Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride
US20130172562A1 (en) * 2010-06-17 2013-07-04 Dr. Reddy's Laboratories, Inc. Process for the preparation of a single enantiomer of 3-aminopiperidine dihydrochloride
EP3653607A2 (en) 2013-02-20 2020-05-20 Reuter Chemische Apparatenbau e.K. Process for the preparation of enantiomerically enriched 3-aminopiperidine
WO2014128139A1 (en) 2013-02-20 2014-08-28 Reuter Chemische Apparatebau Kg Process for the preparation of enantiomerically enriched 3-aminopiperidine
US10464898B2 (en) 2013-02-20 2019-11-05 Reuter Chemische Apparatebau Kg Process for the preparation of enantiomerically enriched 3-aminopiperidine
US11472770B2 (en) 2013-02-20 2022-10-18 Reuter Chemische Apparatebau Kg Process for the preparation of enantiomerically enriched 3-aminopiperidine
EP4289819A2 (en) 2013-02-20 2023-12-13 Reuter Chemische Apparatebau e.K. Process for the preparation of enantiomerically enriched 3-aminopiperidine
US11897843B2 (en) 2013-02-20 2024-02-13 Reuter Chemische Apparatebau Kg Process for the preparation of enantiomerically enriched 3-aminopiperidine
CN103319399A (en) * 2013-05-29 2013-09-25 威海迪素制药有限公司 Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride
CN108689914A (en) * 2018-07-03 2018-10-23 湖北华世通生物医药科技有限公司 A method of chipal compounds are prepared using intermediate
CN113234012A (en) * 2021-06-01 2021-08-10 青岛化赫医药科技有限公司 Preparation method of 3-methylamino pyridine and derivatives or salts thereof
CN114591219A (en) * 2022-03-22 2022-06-07 汉瑞药业(荆门)有限公司 Preparation method of S-3-aminopiperidine dihydrochloride

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