普瑞巴林的15种合成路线解析

pregabalin Chemical Name (+)-(S)-3-Isobutyl-GABA|(+)-4-Amino-3(S)-isobutylbutyric acid|3(S)-(Aminomethyl)-5-methylhexanoic acid CAS Registry No. 148553-50-8 Structure Image Organic Synthesis Pathways: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Pathway 1 Pathway 1 Commentary 1) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with benzyl bromoacetate (V) by means of LDA in THF affords the (S)-adduct (VI) with >95% e.e. purity. The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (VII), which is reduced with BH3/SMe2 in THF, yielding compound (VIII). The reaction of (VIII) with tosyl chloride in pyridine yields the tosylate (IX), which is treated with sodium azide in DMSO, affording the azide (X). Finally, this compound is reduced and debenzylated with H2 over Pd/C in THF (1-3). Related Information Intermediates (2S)-2-[2-(benzyloxy)-2-oxoethyl]-4-methylpentanoic acid (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 4-methylpentanoic acid (CAS#646-07-1) 4-methylpentanoyl chloride (CAS#38136-29-7) benzyl (3S)-3-(azidomethyl)-5-methylhexanoate benzyl (3S)-3-(hydroxymethyl)-5-methylhexanoate benzyl (3S)-5-methyl-3-({[(4-methylbenzene)sulfonyl]oxy}methyl)hexanoate benzyl (3S)-5-methyl-3-{[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl}hexanoate benzyl 2-bromoacetate (CAS#5437-45-6) Reagents 4-methylbenzene-1-sulfonyl chloride (CAS#98-59-9) Butyllithium (CAS#109-72-8) Lithium diisopropylamide (CAS#4111-54-0) Sodium trinitride (CAS#26628-22-8) azidosodium (CAS#26628-22-8) Dimethyl sulfideborane (CAS#13292-87-0) Lithium hydroxide (CAS#1310-65-2) Thionyl dichloride (CAS#7719-09-7) Borane dimethylsulfide (CAS#13292-87-0) Hydrogen peroxide (CAS#7722-84-1) Sodium azide (CAS#26628-22-8) Literature Bioorg Med Chem Lett 1994, 4(6): 823 Drugs Fut 1999, 24(8): 862 Med Res Rev 1999, 19(2): 149 Org Process Res Dev 1997, 1(1): 26 2. Pathway 2 Pathway 2 Commentary 2) The reaction of 4-methylpentanoic acid (I) with SOCl2 in refluxing chloroform gives the acyl chloride (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi in THF, yielding the corresponding N-acyl derivative (IV). The regioselective alkylation of (IV) with tert-butyl bromoacetate (XI) by means of LDA in THF affords the (S)-adduct (XII). The elimination of the chiral auxiliary with LiOH and H2O2 gives the glutaric acid monoester (XIII), which is reduced with BH3/SMe2 in THF, yielding compound (XIV). The reaction of (XIV) with tosyl chloride in pyridine yields the tosylate (XV), which is treated with sodium azide in DMSO, affording the azide (XVI). The hydrolysis of the tert-butyl group of (XVI) affords the free acid (XVII), which is reduced with H2 over Pd/C. Related Information Intermediates (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid (3S)-3-(azidomethyl)-5-methylhexanoic acid (4R,5S)-4-methyl-3-(4-methylpentanoyl)-5-phenyl-1,3-oxazolidin-2-one (4R,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one 2-Bromoacetic acid tert-butyl ester (CAS#5292-43-3) 4-methylpentanoic acid (CAS#646-07-1) 4-methylpentanoyl chloride (CAS#38136-29-7) tert-butyl (3S)-3-(azidomethyl)-5-methylhexanoate tert-butyl (3S)-3-(hydroxymethyl)-5-methylhexanoate tert-butyl (3S)-5-methyl-3-({[(4-methylbenzene)sulfonyl]oxy}methyl)hexanoate tert-butyl (3S)-5-methyl-3-{[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]carbonyl}hexanoate Reagents 4-methylbenzene-1-sulfonyl chloride (CAS#98-59-9) Butyllithium (CAS#109-72-8) Lithium diisopropylamide (CAS#4111-54-0) Sodium trinitride (CAS#26628-22-8) azidosodium (CAS#26628-22-8) Dimethyl sulfideborane (CAS#13292-87-0) Lithium hydroxide (CAS#1310-65-2) Thionyl dichloride (CAS#7719-09-7) Borane dimethylsulfide (CAS#13292-87-0) Hydrogen peroxide (CAS#7722-84-1) Sodium azide (CAS#26628-22-8) Literature Drugs Fut 1999, 24(8): 862 Org Process Res Dev 1997, 1(1): 26 Pathway 3 Pathway 3 Commentary 3) The reaction of diethyl malonate (XVIII) with 3-methylbutanal (XIX) by means of dipropylamine in acetic acid gives the corresponding 2-(3-methylbutylidene)malonate derivative (XX), which is treated with KCN to yield the corresponding addition compound (XXI). The decarboxylative hydrolysis of (XXI) with KOH affords 3-cyano-5-methylhexanoic acid (XXII), which is reduced with H2 over Ni to yield racemic pregabalin (XXIII). Finally, this racemate is submitted to optical resolution with (S)-(+)-mandelic acid (1,2). Related Information Intermediates 1,3-diethyl 2-(3-methylbutylidene)propanedioate 2-(1-cyano-3-methylbutyl)propanedioic acid diethyl ester 3-(Aminomethyl)-5-methylhexanoic acid (CAS#128013-69-4) 3-cyano-5-methylhexanoic acid 3-methylbutanal (CAS#590-86-3) 4-Amino-3-isobutylbutyric acid (CAS#128013-69-4) Malonic acid diethyl ester (CAS#105-53-3) Reagents 2(S)-2-Hydroxy-2-phenylacetic acid (CAS#17199-29-0) Potash (CAS#1310-58-3) Potassium hydroxide (CAS#1310-58-3) Caustic potash (CAS#1310-58-3) Potassium carbonitrile (CAS#151-50-8) dipropylamine (CAS#142-84-7) Potassium cyanide (CAS#151-50-8) Patents WO-1996040617 Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid Literature Drugs Fut 1999, 24(8): 862 Med Res Rev 1999, 19(2): 149 Pathway 4 Pathway 4 Commentary 4) The deamination of L-leucine (XXIV) with NaNO2, NaBr and H2SO4 gives 2(S)-bromo-4-methylpentanoic acid (XXV), which is esterified with tert-butyl acetate and BF3.AcOH to yield the tert-butyl ester (XXVI). The condensation of (XXVI) with the sodium salt of diethyl malonate affords the substituted malonic ester (XXVII), which is selectively hydrolyzed at the tert-butyl ester group with formic acid, giving the monoacid (XXVIII). The decarboxylative reduction of (XXVIII) with BH3 and SMe2 provides 3(S)-isobutylbutano-4-lactone (XXIX). Lactone (XXIX) is submitted to ring opening by treatment with trimethylsilyl iodide in ethanol, yielding 3(S)-(iodomethyl)-5-methylhexanoic acid ethyl ester (XXX). The reaction of (XXX) with sodium azide yields azide (XXXI), which is hydrolyzed with KOH in ethanol/water to afford the free acid (XVII). Finally, this compound is reduced to pregabalin by treatment with H2 over Pd/C. Related Information Intermediates (3S)-3-(azidomethyl)-5-methylhexanoic acid (4S)-4-(2-methylpropyl)oxolan-2-one 1-tert-butyl 2,2-diethyl (1S)-1-(2-methylpropyl)ethane-1,2,2-tricarboxylate 2(S)-Amino-4-methylpentanoic acid (CAS#61-90-5) ethyl (3S)-3-(azidomethyl)-5-methylhexanoate ethyl (3S)-3-(iodomethyl)-5-methylhexanoate tert-butyl (2S)-2-bromo-4-methylpentanoate (2S)-2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-methylpentanoic acid (2S)-2-bromo-4-methylpentanoic acid Reagents 1,3-diethyl 2-sodiopropanedioate azidosodium (CAS#26628-22-8) Boron trifluoride (CAS#7637-07-2) Ethanoic acid (CAS#64-19-7) Iodotrimethylsilane (CAS#16029-98-4) Sanibrom S (CAS#7647-15-6) Sodium bromide (CAS#7647-15-6) Sulfuric Acid (CAS#7664-93-9) Acetic acid (CAS#64-19-7) Borane dimethylsulfide (CAS#13292-87-0) Caustic potash (CAS#1310-58-3) Ethanol (CAS#1516-08-1) Potash (CAS#1310-58-3) Sanibrom (CAS#7647-15-6) Sodium nitrite (CAS#7632-00-0) Trimethyliodosilane (CAS#16029-98-4) Wellbrom (CAS#7647-15-6) Acetic acid tert-butyl ester (CAS#540-88-5) Boron fluoride (CAS#7637-07-2) Dimethyl sulfideborane (CAS#13292-87-0) formic acid (CAS#64-18-6) Potassium hydroxide (CAS#1310-58-3) Sodium azide (CAS#26628-22-8) Sodium trinitride (CAS#26628-22-8) Trimethylsilyl iodide (CAS#16029-98-4) Vinegar Acid (CAS#64-19-7) Literature Drugs Fut 1999, 24(8): 862 Org Process Res Dev 1997, 1(1): 26 Pathway 5 Pathway 5 Commentary 5) The condensation of 3-methylbutanal (XIX) with cyanoacetic acid ethyl ester (XXXII) or cyanoacetamide (XXXIII) by means of dipropylamine in refluxing hexane, followed by treatment with refluxing 6N HCl, gives 3-isobutylglutaric acid (XXXIV). This compound is converted into the corresponding anhydride (XXXV) by treatment with refluxing acetic anhydride. The reaction of the anhydride (XXXV) with NH4OH affords the glutaramic acid (XXXVI), which is submitted to optical resolution with (R)-(+)-1-phenylethylamine (1,2), ephedine or norephedrine (3), yielding the (S)-enantiomer (XXXVII). Finally, this compound is submitted to a Hoffmann degradation with Br2/NaOH (1,2). Related Information Intermediates (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid 2-cyanoacetamide (CAS#107-91-5) 3-(2-methylpropyl)pentanedioic acid 3-(carbamoylmethyl)-5-methylhexanoic acid 3-methylbutanal (CAS#590-86-3) 4-(2-methylpropyl)oxane-2,6-dione Cyanoacetic acid ethyl ester (CAS#105-56-6) Reagents (-)-1(R)-Phenylethan-1-amine (CAS#3886-69-9) acetyl acetate (CAS#108-24-7) Aqueous Ammonia (CAS#1336-21-6) Hydrochloric acid (CAS#7647-01-0) 1(R)-Phenylethylamine (CAS#3886-69-9) Ammonia water (CAS#1336-21-6) Bromine (CAS#7726-95-6) Hydrogen chloride (CAS#7647-01-0) Acetic anhydride (CAS#108-24-7) Ammonium hydroxide (CAS#1336-21-6) dipropylamine (CAS#142-84-7) Sodium hydroxide (CAS#1310-73-2) Patents EP-01879854 Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid WO-1996038405 Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid WO-2006122259 Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid Literature Drugs Fut 1999, 24(8): 862 Org Process Res Dev 1997, 1(1): 26 Pathway 6 Pathway 6 Commentary An asymmetric synthesis of pregabalin has been reported: Condensation of isobutyraldehyde (I) with acrylonitrile (II) by means of DBU and 2,6-di-tert-butyl-4- methylphenol (DBP) gives 3-hydroxy-4-methyl-2-methylenepentanenitrile (III), which is acylated with AcCl or Ac2O and pyridine to yield the acetate (IV). The carboxylation of (IV) by means of Pd(OAc)2, PPh3, CO and EtOH affords 3-cyano-4-methyl-3-hexenoic acid ethyl ester (Va-b), which is hydrolyzed with KOH in THF/water to provide the corresponding carboxylic acid potassium salt (VIa-b). Acidification of (VIa-b) with HCl, followed by reaction with tert-butylamine gives the corresponding salt (VIIa-b), which is reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)Me DUPHOS]Rh(COD)BF4 in THF/water to yield (S)-3-cyano-5-methylhexanoic acid butylammonium salt (VIII). Finally, the CN group of (VIII) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol. Alternatively, intermediate (VIa-b) can be reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid potassium salt (IX). Finally, the CN group of (IX) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol. Related Information Intermediates (3E)-3-cyano-5-methylhex-3-enoate; 2-methylpropan-2-aminium (3S)-3-cyano-5-methylhexanoate; 2-methylpropan-2-aminium 1-cyano-3-methyl-1-methylidenebutan-2-yl acetate 2-methylpropanal (CAS#78-84-2) 3-hydroxy-4-methyl-2-methylidenepentanenitrile Acrylonitrile (CAS#107-13-1) ethyl (3E)-3-cyano-5-methylhex-3-enoate potassium (3S)-3-cyano-5-methylhexanoate potassium (3Z)-3-cyano-5-methylhex-3-enoate prop-2-enenitrile (CAS#107-13-1) Reagents 1,8-Diazabicyclo[5.4.0]undec-7-ene (CAS#6674-22-2) 2,6-Bis(1,1-dimethylethyl)-4-methylphenol (CAS#128-37-0) 2-methylpropan-2-amine (CAS#75-64-9) acetyl acetate (CAS#108-24-7) Butylated hydroxytoluene (CAS#128-37-0) Caustic potash (CAS#1310-58-3) Palladium (II) diacetate (CAS#3375-31-3) Potassium hydroxide (CAS#1310-58-3) Triphenylphosphane (CAS#603-35-0) 2,[6]-DI-TERT-BUTYL-P-CRESOL (CAS#128-37-0) 2,6-Di-tert-butyl-4-methylphenol (CAS#128-37-0) 4-Methyl-2,6-di-tert-butylphenol (CAS#128-37-0) Acetyl chloride (CAS#75-36-5) Butylhydroxytoluol (CAS#128-37-0) Hydrochloric acid (CAS#7647-01-0) Palladium diacetate (CAS#3375-31-3) 2,3,4,6,7,8,9,10-O (CAS#6674-22-2) 2,6-Di-tert-butyl- Acetic anhydride ( butyl hydroxy tolu Carbon monoxide (C Hydrogen chloride Potash (CAS#1310-5 tert-Butylamine (C Rhodium catalyst Triphenylphosphine (CAS#603-35-0) Patents JP-2009073841 Asymmetric synthesis of pregabalin WO-2001055090 Asymmetric synthesis of pregabalin Pathway 7 Pathway 7 Commentary The enzymatic resolution of racemic 2-(1-cyano-3-methylbutyl)malonic acid diethyl ester (I) by means of Lipolase 100L, type EX gives a mixture of the (R)-diester (II) and the (S)-monoester potassium salt (III) that are easily separated. The cyano group of the desired (S) enantiomer (III) is hydrogenated by means of H2 over RaNi in water to yield (S)-4-isobutyl-2-oxopyrrolidine-3-carboxylic acid (IV), which is finally hydrolyzed with HCl in water/AcOH to afford the target Pregabalin. The undesired (R) enantiomer (II) is recovered and racemized by means of a treatment with NaOEt in hot ethanol. Related Information Intermediates 2-[1(R)-Cyano-3-methylbutyl]propanedioic acid diethyl ester (4S)-4-(2-methylpropyl)-2-oxopyrrolidine-3-carboxylic acid potassium (3S)-3-cyano-2-(ethoxycarbonyl)-5-methylhexanoate Reagents Candida cylindracea (CAS#9001-62-1) Hydrogen chloride (CAS#7647-01-0) Rhizopus delemar lipase (CAS#9001-62-1) Ethanol sodium salt (CAS#141-52-6) Lipase (CAS#9001-62-1) Sodium ethanolate (CAS#141-52-6) Hydrochloric acid (CAS#7647-01-0) Lypase (candida cylindracea) (CAS#9001-62-1) Sodium ethoxide (CAS#141-52-6) Patents EP-01831154 Preparation of pregabalin and related compounds JP-2008088191 Preparation of pregabalin and related compounds JP-2008133289 Preparation of pregabalin and related compounds JP-2008504252 Preparation of pregabalin and related compounds JP-2009022272 Preparation of pregabalin and related compounds US-2005283023 Preparation of pregabalin and related compounds WO-2006000904 Preparation of pregabalin and related compounds Pathway 8 Pathway 8 Commentary This compound has been obtained by three related ways: 1.- The reaction of 3-isobutyl-4-carboxxybutyramide (I) with Br2 and NaOH gives 4-amino-3-isobutylbutyric acid sodium salt (II), which is treated with HCl to obtain the target Pregabalin (1). 2.- The reduction of the nitro group of diethyl 2-(1-isobutyl-2-nitroethyl)malonate (III) by means of H2 over Pd/C gives the corresponding amino derivative (IV), which is finally submitted to a decarboxylative hydrolysis by means of Cu2O in hot ethanol/acetonitrile to obtain the target Pregabalin (2). 3.- The reductive cyclization of diethyl 2-(1-isobutyl-2-nitroethyl)malonate (III) by means of NaBH4 and NiCl2 in methanol gives 4-isobutyl-2-oxopyrrolidine-3-carboxylic acid ethyl ester (V), which is submitted to a decarboxylative hydrolysis by means NaOH in ethanol to yield 4-isobutylpyrrolidin-2-one (VI). Finally this compound is treated with 6N aq. HCl at 125? C to obtain the target Pregabalin (2). Related Information Intermediates (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid (4S)-4-(2-methylpropyl)pyrrolidin-2-one 1,3-diethyl 2-[(2S)-1-amino-4-methylpentan-2-yl]propanedioate 1,3-diethyl 2-[(2S)-4-methyl-1-nitropentan-2-yl]propanedioate ethyl (4S)-4-(2-methylpropyl)-2-oxopyrrolidine-3-carboxylate sodium (3S)-3-(aminomethyl)-5-methylhexanoate Reagents Bromine (CAS#7726-95-6) Hydrochloric acid (CAS#7647-01-0) Sodium borohydride (CAS#16940-66-2) Copper (I) oxide (CAS#1317-39-1) Hydrogen chloride (CAS#7647-01-0) Sodium hydroxide (CAS#1310-73-2) Copper Oxide (CAS#1317-39-1) Nickel (II) chloride (CAS#7718-54-9) Sodium tetrahydridoborate (CAS#16940-66-2) Patents WO-2006110783 Process for making (S)-pregabalin WO-2006110783 Process for making (S)-pregabalin WO-2006122258 Method for the preparation of pregabalin and salts thereof EP-01768950 Process for making (S)-pregabalin EP-01879851 Method for the preparation of pregabalin and salts thereof Pathway 9 Pathway 9 Commentary The reaction of 3-isobutylglutaric anhydride (I) with (R)-(+)-1-phenylethylamine (II) by means of DMAP in methanol affords the chiral carboxamide (III) as the major product, which is treated with Na or Li in liquid ammonia to yield the carboxamide (IV). Finally this compound was submitted to Hofmann rearrangement by means of NaOH and Br2 in water at 80?C to obtain the target compound (1). Alternatively, (S)-Pregabalin is obtained by treatment of cabamic acid methyl ester derivative (V) with H2SO4 at 115-120?C or HBr in refluxing H2O followed by Bu3N (2,3). Related Information Intermediates (-)-1(R)-Phenylethan-1-amine (CAS#3886-69-9) (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid (3R)-5-methyl-3-({[(1R)-1-phenylethyl]carbamoyl}methyl)hexanoic acid 1(R)-Phenylethylamine (CAS#3886-69-9) 4-(2-methylpropyl)oxane-2,6-dione N-[2(S)-Isopropyl-3-[[1(S)-phenylethyl]carbamoyl]propyl]carbamic acid methyl ester Reagents Ammonia (CAS#7664-41-7) Lithium (CAS#7439-93-2) Sodium (CAS#7440-23-5) Tri-n-butylamine (CAS#102-82-9) Bromine (CAS#7726-95-6) N,N-Dibutyl-1-butanamine (CAS#102-82-9) Sodium hydroxide (CAS#1310-73-2) Tributylamine (CAS#102-82-9) Hydrobromic acid (CAS#10035-10-6) N,N-dimethylpyridin-4-amine (CAS#1122-58-3) Sulfuric Acid (CAS#7664-93-9) Patents CA-02619473 An asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid EP-01802568 Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the new synthesis of (S)-pregabalin EP-01841726 An asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid EP-02021318 Synthesis of (S)-(+)-3-(aminomethyl)-5-methyl hexanoic acid US-07446220 An asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid US-2007191636 Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the new synthesis of (S)-pregabalin US-2007197827 An asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid WO-2007035789 Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the new synthesis of (S)-pregabalin WO-2007035890 An asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid WO-2008118427 Synthesis of (S)-(+)-3-(aminomethyl)-5-methyl hexanoic acid Pathway 10 Pathway 10 Commentary The pregabalin intermediate, the 3-isobutyl-glutaric acid (VI) has been obtained by three related methods. 1.- The reaction of isovaleraldehyde (I) with ethyl cyanoacetate (II) by means of diisopropylamine in refluxing cyclohexane gives 2-cyano-5-methyl-2-hexenoic acid ethyl ester (III), which is condensed with diethyl malonate (IV) by means of diisopropylamine to yield the adduct (V). Finally this compound is hydrolyzed with aq. HBr at 100-125 C to obtain the target intermediate 3-isobutyl-glutaric acid (VI). 2. - The condensation of isovaleraldehyde (I) with diethyl malonate (IV) gives 2-(3-methylbutylidene)malonic acid diethyl ester (VII), which is condensed with Meldrum?s acid (VIII) by means of diisopropylamine to yield the adduct (IX). Finally this compound is hydrolyzed by means of aq. HBr at 100-125 C to obtain the target intermediate 3-isobutyl-glutaric acid (VI). 3.- The condensation of isovaleraldehyde (I) with Meldrum?s acid (VIII) by means of diisopropylamine gives the 3-methylbutylidene derivative (X), which is condensed with a second Meldrum?s aci