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Method of Making 3-(Aminomethyl)-5-Methylhexanoic Acid

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Method of Making 3-(Aminomethyl)-5-Methylhexanoic Acid Europäisches Patentamt *EP000830338B1* (19) European Patent Office Office européen des brevets (11) EP 0 830 338 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07C 229/08, C07C 255/19, of the grant of the patent: C07C 255/22, C07C 227/04 12.12.2001 Bulletin 2001/50 (86) International application number: (21) Application number: 96914618.2 PCT/US96/06819 (22) Date of filing: 13.05.1996 (87) International publication number: WO 96/40617 (19.12.1996 Gazette 1996/55) (54) Method of making 3-(aminomethyl)-5-methylhexanoic acid Verfahren zur Herstellung von 3-(Aminomethyl)-5-Methylhexansäure Procédé de preparation de l’acide 3-(aminométhyl)-5-méthylhexanoique (84) Designated Contracting States: • SOBIERAY, Denis, Martin AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC Holland, MI 49424 (US) NL PT SE • TITUS, Robert, Daniel Designated Extension States: Indianapolis, IN 46227 (US) LT LV SI (74) Representative: Mansmann, Ivo et al (30) Priority: 07.06.1995 US 474874 Warner-Lambert Company, Legal Division, (43) Date of publication of application: Legal Department, 25.03.1998 Bulletin 1998/13 c/o Gödecke AG 79090 Freiburg (DE) (73) Proprietor: WARNER-LAMBERT COMPANY Morris Plains New Jersey 07950 (US) (56) References cited: EP-A- 0 100 019 EP-A- 0 450 577 (72) Inventors: WO-A-93/23383 • GROTE, Todd, Michel Holland, MI 49424 (US) • SYNTHESIS, no. 12, December 1989, NEW • HUCKABEE, Brian, Keith YORK, US, pages 953-5, XP002011378 R. Holland, MI 49424 (US) ANDRUSZKIEWICZ ET. AL.: "A Convenient • MULHERN, Thomas Synthesis of 3-Alkyl-4-Aminobutanioc Acids" Hudsonville, MI 49426 (US) cited in the application Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 830 338 B1 Printed by Jouve, 75001 PARIS (FR) EP 0 830 338 B1 Description [0001] This invention relates to a method of making (±)-3-(aminomethyl)-5-methylhexanoic acid and to a method of obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (±)-3-(aminomethyl)-5-methylhexanoic acid. 5 BACKGROUND OF THE INVENTION [0002] 3-(Aminomethyl)-5-methylhexanoic acid, which is also called β-isobutyl-γ-aminobutyric acid or isobutyl-GABA, is a potent anticonvulsant. Isobutyl-GABA is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid 10 or GABA, which is involved in the regulation of brain neuronal activity. [0003] It is thought that convulsions can be controlled by controlling the metabolism of the neurotransmitter γ-ami- nobutyric acid. When the concentration of GABA diminishes below a threshold level in the brain, convulsions result (Karlsson A., et al., Biochem. Pharmacol., 1974;23:3053-3061), and when the GABA level rises in the brain during convulsions, the seizures terminate (Hayashi T., Physiol. (London), 1959;145:570-578). The term "seizure" means 15 excessive unsynchronized neuronal activity that disrupts normal function. [0004] Because of the importance of GABA as an inhibitory neurotransmitter, and its effect on convulsive states and other motor dysfunctions, a variety of approaches have been taken to increase the concentration of GABA in the brain. In one approach, compounds that activate L-glutamic acid decarboxylase (GAD) have been used to increase concen- trations of GABA, as the concentrations of GAD and GABA vary in parallel and increased GAD concentrations result 20 in increased GABA concentrations (Janssens de Varebeke P., et al., Biochem. Pharmacol., 1983;32:2751-2755; Lo- scher W., Biochem. Pharmacol., 1982;31:837-842; Phillips N., et al., Biochem. Pharmacol., 1982;31:2257-2261). For example, the compound (±)-3-(aminomethyl)-5-methylhexanoic acid, a GAD activator, has the ability to suppress sei- zures while avoiding the undesirable side effect of ataxia. [0005] It has been discovered that the anticonvulsant effect of isobutyl-GABA is stereoselective. That is, the S-ster- 25 eoisomer of isobutyl-GABA shows better anticonvulsant activity than the R-stereoisomer. See, for example, Yuen, et al., in Bioorganic & Medicinal Chemistry Letters, 1994;4(6):823-826. Thus, it would be beneficial to have an efficient process for the synthesis of the S-stereoisomer of isobutyl-GABA. [0006] Presently, (S)-3-(aminomethyl)-5-methylhexanoic acid has been prepared by two synthetic routes. These routes each use reactions that require n-butyllithium, and both routes contain a step that must be carried out at low 30 temperatures (≤-35°C) under carefully controlled conditions. These synthetic routes include the use of (4R,5S)-4-me- thyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to introduce the stereochemical configuration needed in the final product. See, for example, United States Serial No. 08/064,285, which is hereby incorporated by reference. Although these routes provide the target compound in high enantiomeric purity, they are difficult to conduct on large-scale and use expensive reagents which are difficult to handle. 35 [0007] In addition, (±)-isobutyl GABA can be synthesized in accordance with Andruszkiewicz, et al., Synthesis, 1989; 953. The synthesis described therein uses potentially unstable nitro compounds, including nitromethane, and an in- termediate containing a nitro functional group, which is reduced to an amine in a potentially exothermic and hazardous reaction. The synthesis also uses lithium bis(trimethylsilylamide) at -78°C. The present method does not use nitro compounds, require low temperatures, or require strongly basic conditions. 40 [0008] In Ullmann's Encyclopedia of Industrial Chemistry Vol. 18 A (1991) page 182/183 and in Römpp-Chemie- Lexikon Vol. 4 (1991) page 2623 the resolution of certain optically pure enantiomers has been described. These doc- uments, however, do not mention the resolution of γ-amino acids. Furthermore the processes disclosed require the protection of the amino acids by additional process steps. [0009] The present invention provides an efficient synthesis of isobutyl-GABA and provides for the resolution of 45 racemic isobutyl-GABA to obtain the S-stereoisomer of isobutyl-GABA that avoids the above-identified problems. [0010] The present invention provides a method of making (±)-3-(aminomethyl)-5-methylhexanoic acid and its S- form, (S)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising: a. condensing isovaleraldehyde with 50 55 to form primarily 2 EP 0 830 338 B1 5 b. reacting the 10 15 with a cyanide source to form 20 25 c. decarboxylating the 30 35 to form 40 45 d. hydrolyzing the 50 55 3 EP 0 830 338 B1 with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; e. hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid, wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl, or C3-C6 cycloalkyl, and 5 f. optionally resolving the obtained (±)-3-(aminomethyl)-5-methylhexanoic acid to obtain (S)-3-(aminomethyl)- 5-methylhexanoic acid by standard methods of resolution. [0011] In a preferred method decarboxylating and hydrolyzing steps c.) and d.) are combined to form the carboxylate salt. 10 [0012] The present invention also provides for a method wherein the resolution step comprises: a. combining (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol; b. allowing a precipitate to form; 15 c. introducing the precipitate into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry; and d. collecting the solid from the slurry. [0013] The present invention also provides for a method wherein the resolution step comprises: 20 a. combining (±)-3-(aminomethyl)-5-methylhexanoic acid and (R)-mandelic acid in water, an alcohol, or a mixture of water and an alcohol to give the (R,R)-salt; b. crystallizing the salt out of the solution; c. isolating the (S)-3-(aminomethyl)-5-methylhexanoic acid from the solution. 25 [0014] Preferred is a resolution method wherein the (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)- or (R)- mandelic acid are combined in a 3% v/v solution of water in isopropyl alcohol. [0015] Also preferred is a method wherein the (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)- or (R)-mandelic acid are combined in methanol or isopropanol. Preferred polar solvents are dimethylsulfoxide and tetrahydrofuran. 30 [0016] The invention further provides a compound having the formula 35 wherein R1 and R2 are the same or different and are hydrogen, C1-C6 alkyl, aryl, benzyl or C3-C6 cycloalkyl, 40 preferably a compound wherein R1 and R2 are ethyl. [0017] The invention further provides a compound having the formula 45 50 wherein M is hydrogen, an alkali metal, or an alkaline earth metal and R1 is C1-C6 alkyl, aryl, benzyl, or C3-C6 cycloalkyl, preferred is a compound wherein M is sodium or potassium. [0018] Preferred are the mandelic acid salts of 3-(aminomethyl)-5-methylhexanoic acid wherein the mandelic acid is (S)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (S)-3-(aminomethyl)-5-methylhexanoic acid or 55 wherein the mandelic acid is (R)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (R)-3-(aminomethyl)-5-methylhexanoic acid or wherein the mandelic acid 4 EP 0 830 338 B1 is (R)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (S)-3-(aminomethyl)-5-methylhexanoic acid or wherein the mandelic acid is (S)-mandelic acid and the 3-(aminomethyl)-5-methylhexanoic acid is (R)-3-(aminomethyl)-5-methylhexanoic acid.
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