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WO2011086565A1 - Procédé de préparation d'acides gamma-amino énantiomériquement enrichis et/ou racémiques - Google Patents

Procédé de préparation d'acides gamma-amino énantiomériquement enrichis et/ou racémiques Download PDF

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Publication number
WO2011086565A1
WO2011086565A1 PCT/IN2010/000140 IN2010000140W WO2011086565A1 WO 2011086565 A1 WO2011086565 A1 WO 2011086565A1 IN 2010000140 W IN2010000140 W IN 2010000140W WO 2011086565 A1 WO2011086565 A1 WO 2011086565A1
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compound
reaction
process according
preparation
vila
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Bhairab Nath Roy
Girij Pal Singh
Piyush Suresh Lathi
Rangan Mitra
Manoj Kunjabihari Agrawal
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Lupin Ltd
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Lupin Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride

Definitions

  • the invention relates to a process for preparation of enantiomerically enriched and/or racemic ⁇ -amino acids, particularly those useful for preparing ⁇ -amino acids that exhibit binding affinity to the human ⁇ 2 ⁇ calcium channel subunit, including pregabalin and related compounds such as 3- «-propyl-4-aminobutyric acid.
  • pregabalin is a potent anticonvulsant.
  • pregabalin exhibits anti-seizure activity and is found to be useful for treatment of various other conditions, like pain, fibromyalgia, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, insomnia, alcoholism and various psychiatric disorders, including mania and bipolar disorder.
  • US patent No. 5,637,767 disclosed the method for synthesis of (5)-pregabalin.
  • isovaleraldehyde is reacted with diethyl malonate to obtain 2-carboxyethyl-5-methylhex-2- enoic acid ethyl ester, which is further reacted with potassium cyanide to obtain 2- carboxy ethyl 3-cyano-5-methylhexanoic acid ethyl ester.
  • Hydrogenation of 2-carboxyethyl 3-cyano-5-methylhexanoic acid ethyl ester in presence of nickel gives the racemic pregabalin, which is further resolved with (5)-mandelic acid to obtain pregabalin.
  • the above method provides the (S) -pregabalin in high optical purity, the overall yield is very poor.
  • the process uses potassium cyanide which is very toxic and hazardous, and to be avoided. Reaction scheme is depicted in Figure 1.
  • US Patent No. 5,616, 573 disclose the method for synthesis of pregabalin from 3-isobutyl glutaric acid. 3-isobutyl glutaric acid is converted to its corresponding anhydride by refluxing with acetic anhydride. Subsequent reaction with ⁇ 3 ⁇ 4 ⁇ produces the glutaric acid mono- amide, which is resolved with (7 ⁇ -a-phenylethyl amine, yielding the corresponding salt. Decomposition of salt gives the (i? -enantiomer, which on Hoffmann degradation with Br 2 /NaOH provides ⁇ -pregabalin [I].
  • the above process, as depicted in Figure 2 involves the use of hazardous chemicals such as bromine, which is not eco-friendly.
  • WO 01/55090 Al reports the asymmetric hydrogenation of a cyano intermediate to produce a cyano precursor of (3 ⁇ 4)-aminomethyl 5-methyl hexanoic acid, which is further reduced to obtain (Sj-pregabalin.
  • the disclosed method requires the use of carbon monoxide under high pressure, raising serious problem in adapting this process for production scale.
  • the application discloses the use of various C 2 symmetric bisphosphine ligands, including (R, R) Me-DUPHOS, which is very costly and the "turn over" number is not satisfactory, which creates significant impact on the final cost of the product.
  • the disclosed method requires the use of carcinogenic acrylonitrile and the use of highly toxic carbon monoxide under high pressure. Reaction scheme is depicted in Figure 5.
  • US Patent No. 6,924,377 discloses the method for synthesis of pregabalin through reductive amination of mucohalic acid and its derivatives. This process needs special cryogenic equipment to reach required operating temperature, which can be as low as -30 °C. Overall yield is poor and requires column chromatography at most of the stages to obtain pure intermediate or product. Hence it can not be a process for synthesis of pregabalin at industrial scale. Reaction scheme is depicted in Figure 8.
  • WO 2009053446 A2 discloses the method for synthesis of pregabalin from 2,2'dichloro-3- isobutylcyclobutanone. Reaction scheme is depicted in Figure 9
  • WO 2007/035890 Al, WO 2007/035789 Al and US Patent Application No. 2008/0306292 have reported the similar chemistry, such as desymmetrization of 3-isobutyl glutaric acid with (5)-phenylethylamine, which are obvious extensions of Schwartz and Carter work and devoid of any inventive merit. Further, there is sufficient teaching, suggestion and motivation in prior art for synthesis of molecule through desymmetrization. This is very similar to the KSR Int'l Co. vs. Teleflex, Inc., 550 U.S. 398 (2007) case in the Supreme Court of the United States concerning the issue of obviousness as applied to patent claims.
  • WO 2007/035890 Al reports the synthesis of pregabalin via chiral intermediate obtained through Hoffman degradation. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine. This process needs the special cryogenic equipment to reach required operating temperature, which can be as low as -60 °C. Reaction scheme is depicted in Figure 10.
  • WO 2007/035789 Al reports the synthesis of pregabalin via chiral intermediate obtained through Hoffman degradation. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine and sodium metal. This process needs the special cryogenic equipment to reach required operating temperature, which can be as low as -60 °C. Reaction scheme is depicted in Figure 1 1.
  • compound [III] is described as an impurity in the synthesis of pregabalin, however, spectral data such as IR, NMR or mass of the compound [III] are not provided neither any enablement whatsoever of compound [III] are disclosed. Also, it is very difficult to rationalize the production or generation of compound [III], as an impurity as reported in a disclosed reaction condition for obtaining pregabalin.
  • WO2009/081208A1 discloses the process for preparation of racemic pregabalin. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine. Reaction scheme is depicted in Figure 13.
  • This invention provides that.
  • the present invention is directed towards the process for preparation of enantiomerically enriched compounds of formula IV
  • Figure 14 Schematic representation of formation of compound Vila including precipitation of compounds Villa and Vlllb
  • FIG. 15 Schematic representation of formation of compound Vllb with precipitation of VHId and VIIIc
  • FIG. 16 Schematic representation of formation of compound VIIc with precipitation of VHIe and VHIf
  • FIG. 17 Schematic representation of formation of compound Vlld with precipitation of VHIh and Vlllg
  • FIG. 18 Schematic representation of formation of compound Vile with precipitation of Villi and Vlllj
  • FIG. 19 Schematic representation of formation of compound Vllf with precipitation of Vlllk and Villi
  • FIG. 23 Schematic representation of formation of compound Vila and further formation of compound X
  • the invention provides method for synthesis of enatiomerically enriched ⁇ -amino acid [IV] according to the following schemes 1 and 2.
  • the present invention provides the process for the preparation of ⁇ - amino acid [IV] from compound [V].
  • compound [V] is reacted with compound [VI] and thereafter the resulting compound [VII] is hydrogenated to obtain compound [VIII]. Further, hydrogenolysis of compound [VIII] produces the enantiomerically enriched ⁇ -amino acid [IV].
  • the present invention provides the process for the preparation of ⁇ - amino acid [IV] from compound [V].
  • compound [V] is reacted with compound [VI] and thereafter the resulting compound [VII] is hydrogenated to produces the enantiomerically enriched ⁇ -amino acid [IV].
  • the present invention provides the process for the preparation of ⁇ -amino acid [IV] from compound [V].
  • compound [V] is reacted with compound [VI] and thereafter the resulting compound [VII] is hydrogenolyzed through catalytic transfer hydrogenation in presence of ammonium formate to produce the ⁇ -amino acid [IV].
  • the present invention provides the process for the preparation of racemic ⁇ -amino acid [IV] from compound [V] where compound [V] is reacted with ammonia and thereafter the resulting compound [IX] is hydrogenated to produces the racemic ⁇ -amino acid [IV].
  • compound [VII] is synthesized by reacting compound [V] with compound [VI] which is carried out in polar and non-polar solvents.
  • Polar solvents such as, methanol, ethanol, .so-propanol, tetrahydrofuran, di-wopropyl ether etc are used and non-polar solvents such as dichloromethane, toluene are used; preferably, methanol and isopropyl alcohol and more preferably isopropyl alcohol.
  • compound [VII] is obtained by reacting compound [V] with compound [VI].
  • Compound [VI] is chiral or achiral primary amine, preferably with chiral primary amines such as (5)-(-)-or-methyl benzyl amine, ( ?)-(+)-a-methyl benzyl amine, (5)-(+)-phenyI glycinol and ( ?)-(-)-phenyl glycinol.
  • Compound [VII] is usually obtained by conducting reaction at temperature of about 25 to 80 °C.
  • the temperature maintained during the reaction is about 25 to 30 °C.
  • Alcoholic solvent may be selected from methanol, ethanol, so-propanol; preferably methanol and .so-propanol.
  • hydrogen pressure is about 1 kg/cm 2 to 5 kg/cm 2 ; preferably 3 kg/cm 2 pressure is used.
  • Noble metal catalyst can be selected from platinum oxide, palladium on carbon and palladium hydroxide on carbon; preferably the noble metal catalyst is palladium on carbon and palladium hydroxide on carbon. After the completion of reaction, reaction mixture is filtered through filtrate pad to remove the catalyst. Solvent is distilled out to obtain compound [VIII].
  • Hydrogenolysis of compound [VIII] is carried out in an alcoholic solvent and Bransted acid, in presence of a noble metal catalyst under hydrogen pressure to obtain the corresponding enantiomerically enriched ⁇ -amino acid.
  • Alcoholic solvent may be selected from methanol, ethanol, z ' so-propanol; preferably methanol.
  • hydrogen pressure is about 10 kg/cm 2 to 50 kg/cm 2 , preferably 40 kg/cm 2 pressure.
  • Noble metal catalyst may be selected from platinum oxide, palladium on carbon, palladium hydroxide on carbon; preferably the noble metal catalyst is palladium on carbon and palladium hydroxide on carbon; more preferably palladium hydroxide on carbon.
  • Bronsted acid can be selected from acetic acid, hydrochloric acid, sulfuric acid and trifluoroacetic acid; preferably acetic acid and trifluoroacetic acid; more preferably trifluoroacetic acid.
  • Compound [Villa] precipitates out from reaction, leaving compound [VHIb] dissolved in the reaction media.
  • Figure 14 gives the schematic representation.
  • the enantiomeric excess (ee) is determined by HPLC using a Shimadzu LC 2010 system equipped with a chiral column (Purosphere star RP-18e (4.6 x 150mm), 5 ⁇ ), column oven temperature 25 °C and UV visible detector (UV at 340nm). Mobile phase is buffer: acetonitrile (55 :45) with flow rate 1.0 mL "1 , injection volume 20 ⁇ .
  • the enantiomeric excess (ee) is determined by derivatized by reacting with Murphy's reagent. NM spectra are obtained at 200 and 400 MHz Bruker instruments, with CDC1 3 as solvent.
  • tt-Heptane (394 mL) and morpholine (127.5 mL) are introduced in a reactor while stirring.
  • the mixture is cooled to 0° C and glyoxylic acid (195 g, 150 mL, 50 wt % in water) is added.
  • the mixture is heated to 20° C during 1 hour and then 77-valeraldehyde (148.8 mL) is added.
  • the reaction mixture is heated at 45° C during 20 hours.
  • a 37 % aqueous solution of hydrochloric acid (196.9 mL) is slowly added to the mixture, which is then stirred during 2 hours.
  • the aqueous phase is washed three times with heptane.
  • Di- w -propyl ether is added to the aqueous phase.
  • the organic phase is removed and the aqueous phase further extracted with di-z ' so-propyl ether (2x).
  • the di-wo-propyl ether layers are combined, washed with brine and then dried under reduced pressure. After evaporation of the solvent, 100.0 g of 5-hydroxy-4- «-propyl-5H-furan-2-one are obtained as light brown oil.
  • rc-Heptane (75.0 mL) and morpholine (17.8 g) are introduced in a reactor while stirring.
  • the mixture is cooled to 0° C and glyoxylic acid (29.6 g, 50 wt% in water) is added.
  • the mixture is heated to 20° C during 1 hour and then 4-methyl valeraldehyde (20.0 g) is added.
  • the reaction mixture is heated at 45° C during 20 hours.
  • a 37 % aqueous solution of hydrochloric acid (30 mL) is slowly added to the mixture, which is then stirred during 2 hours.
  • the aqueous phase is washed three times with n-heptane.
  • Di-z ' so-propyl ether is added to the aqueous phase.
  • the organic phase is removed and the aqueous phase further extracted with di-MO-propyl ether (2x).
  • the di-zso-propyl ether layers are combined, washed with brine and then dried under reduced pressure. After evaporation of the solvent, 13.0 g of 5-hydroxy-4-wobutyl-5H-furan-2-one are obtained as light yellow oil.
  • reaction mixture is filtered and filtrate was concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 6.5 g of (i?,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid as a off-white solid obtained after vacuum filtration.
  • Filtered cake contains Pd/C and (5,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid which is suspended in methanol and stirred for 20 min to dissolve (S,iS)-3-[(l -phenyl ethylamino)- methyl] -hexanoic acid. Pd/C is separated by filtration. Filtrate is concentrated under vacuum to obtain 6.7 g of (S,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid as a white solid.
  • reaction mixture is filtered and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and ' stirred overnight to yield 6.0 g of (S',i?)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid as a off-white solid obtained after vacuum filtration.
  • Filtered cake contains Pd/C and (i?,i?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid which is suspended in methanol and stirred for 20 min to dissolve (i?,i?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid.
  • Pd/C is separated by filtration. Filtrate is concentrated under vacuum to obtain 6.7 g of (R,R)-3-[( ⁇ -phenyl ethylamino)-methyl]-hexanoic acid as white solid.
  • reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 3.5 g of 3-[(l-(5)-phenylethylamine)- methyl]- 5 -methyl -hexanoic acid as off-white solid obtained after vacuum filtration.
  • reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 3.5 g of 3-[(l-(i?)-phenylethylamine)- methyl]-5-methyl-hexanoic acid as a off-white solid obtained after vacuum filtration.
  • reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 7.5 g of 3-[(2-hydroxy-l-(S)-phenyl ethyl amino)-methyl]-hexanoic acid as a semi solid material obtained after vacuum filtration.
  • reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 6.0 g of 3-[(2-hydroxy-l -(5 -phenyl- ethylamino) methyl] -5 -methyl hexanoic acid as a semi solid obtained after vacuum filtration.
  • reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 6.0 g of 3-[(2-hydroxy-l-(5)-phenyl- ethylamino) methyl] -5 -methyl hexanoic acid as a semi solid obtained after vacuum filtration.
  • Diastereomeric mixture of [VHIg] and [VHIh] (2.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % . catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.75 g). Chiral HPLC analysis shows 60 % ee for (S) -pregabalin
  • Example 22 Synthesis of pregabalin from diastereomeric mixture of [VHIk] and [Villi] Diastereomeric mixture of [VHIk] and [Villi] (2.0 g) is dissolved in methanol (100 mL) and 10 % acetic acid in a Parr autoclave reactor followed by addition of palladium-hydroxide on carbon (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.75 g). Chiral HPLC analysis shows ( ?S,) -pregabalin
  • Example 23 Synthesis of pregabalin from diastereomeric mixture of [ VHIkJ and [Villi] Diastereomeric mixture of [VHIk] and [Villi] (2.0 g) is dissolved in methanol (100 mL) and 10 % trifluoroacetic acid in a Parr autoclave reactor followed by addition of palladium hydroxide on carbon (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.6 g). Chiral HPLC analysis shows 60 % ee for (./ ⁇ -pregabalin
  • Diastereomeric mixture of [Vlllm] and [VHIn] (3.0 g) is dissolved in methanol (100 mL) and 10% trifluoroacetic acid in a Parr autoclave reactor followed by addition of palladium hydroxide on carbon (20 % catalyst loading).
  • Reactor is purged with hydrogen gas twice and ; . then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: . methanol (9: 1)]. After 24 h reaction is stopped and chiral HPLC analysis shows racemic pregabalin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation d'acides γ-amino énantiomériquement enrichis et/ou racémiques, en particulier ceux utilisés pour préparer des acides γ-amino qui présentent une affinité de liaison avec la sous-unité du canal calcique humain α2δ comprenant la prégabaline et des composés apparentés tels que l'acide 3-n-propyl-4-aminobutyrique.
PCT/IN2010/000140 2010-01-15 2010-03-10 Procédé de préparation d'acides gamma-amino énantiomériquement enrichis et/ou racémiques Ceased WO2011086565A1 (fr)

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IN38KO2010 2010-01-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014155291A1 (fr) 2013-03-27 2014-10-02 Pfizer Ireland Pharmaceuticals Processus et intermédiaires pour la préparation de prégabaline
CN112020498A (zh) * 2018-06-20 2020-12-01 上海朴颐化学科技有限公司 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法

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US20030225149A1 (en) * 2002-04-30 2003-12-04 Blazecka Peter G. Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids
WO2006128692A2 (fr) * 2005-06-01 2006-12-07 Ucb Pharma, S.A. Derives de 2-oxo-1-pyrrolidine
WO2008118427A2 (fr) * 2007-03-22 2008-10-02 Teva Pharmaceutical Industries Ltd. Synthèse de l'acide (s)-(+)-3-(aminométhyl)-5-méthylhexanoïque
WO2008127646A2 (fr) * 2007-04-11 2008-10-23 Dsm Ip Assets B.V. Procédés à base de transaminase utilisés dans la préparation de la prégabaline
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WO2014155291A1 (fr) 2013-03-27 2014-10-02 Pfizer Ireland Pharmaceuticals Processus et intermédiaires pour la préparation de prégabaline
JP2016516744A (ja) * 2013-03-27 2016-06-09 ファイザー アイルランド ファーマシューティカルズ プレガバリンの調製のための方法および中間体
RU2628298C2 (ru) * 2013-03-27 2017-08-15 Пфайзер Айрлэнд Фармасьютикалс Способ и промежуточные соединения для получения прегабалина
EP3216863A1 (fr) 2013-03-27 2017-09-13 Pfizer Ireland Pharmaceuticals Processus et intermédiaires pour la préparation de prégabaline
CN112020498A (zh) * 2018-06-20 2020-12-01 上海朴颐化学科技有限公司 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法
CN112020498B (zh) * 2018-06-20 2024-04-02 上海朴颐化学科技有限公司 一种布瓦西坦中间体、其制备方法及布瓦西坦的制备方法

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