USOO5637767A United States Patent (19) 11 Patent Number: 5,637,767 Grote et al. 45) Date of Patent: Jun. 10, 1997 54 METHOD OF MAKING (S)-3- with a cyanide source to form (AMINOMETHYL)-5-METHYLEHEXANOIC AC) 75 Inventors: Todd M. Grote; Brian K. Huckabee, both of Holland; Thomas Mulhern, R1O2C CO2R2 Hudsonville; Denis M. Sobieray, Holland, all of Mich.; Robert D. Titus, decarboxylating the Indianapolis, Ind. 73) Assignee: Warner-Lambert Company, Morris Plains, N.J. r CN RO2C CO2R2 21) Appl. No.: 474,874 to form 22 Filed: Jun. 7, 1995 (51 int. C. m. C07L 205/00 52 U.S. C. ..... 562/553: 562/401 Sri CN (58) Field of Search .................................. 562/401,553 CO2R1 56 References Cited hydrolyzing the U.S. PATENT DOCUMENTS 5,132,451 7/1992 Jennings et al. ........................ 562/507 r CN CO2R1 OTHER PUBLICATIONS with an alkali or alkaline earth metal hydroxide to form an Carruthers, et al., Bioorganic & Medicinal Chemistry Let alkali or alkaline earth metal carboxylate salt; and hydro ters, vol. 5, No. 3, pp. 237-240 (1995) Andruszkiewicz, et genating the alkali or alkaline earthmetal carboxylate salt to al., Synthesis, pp. 953-955 (1989). form (E)-3-(aminomethyl)-5-methylhexanoic acid, wherein RandR are the same or different and are hydrogen, C-C, Jung, et al., Biochemistry, vol. 17, No. 13, pp. 2628-2632 alkyl, aryl, benzyl, or C-C cycloalkyl. The present inven (1978). tion also provides a method of making (E)-3-(aminomethyl) -5-methylhexanoic acid that comprises condensing isoval Primary Examiner-Michael L. Shippen eraldehyde with Attorney, Agent, or Firm-Todd M. Crissey CO2R1 57 ABSTRACT CO2R2 A method of making (+)-3-(aminomethyl)-5- methylhexanoic acid that comprises condensing isovaleral to form primarily dehyde with CO2R1. Sco.CO2R1 21 COR; to form primarily reacting the CO2R CO2R1 21 coR; N~. CO2R2 reacting the with a cyanide source to form CO2R1 N~so rROC COR2 5,637,767 Page 2 decarboxylating the to forman alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate r salt to form (E)-3-(aminomethyl)-5-methylhexanoic acid. ROC CO2R2 20 Claims, No Drawings 5,637,767 1. 2 METHOD OF MAKING (S)-3- 1989;953. The synthesis described therein uses potentially (AMINOMETHYL)-5-METHYLHEXANOIC unstable nitro compounds, including nitromethane, and an ACD intermediate containing a nitro functional group, which is reduced to an amine in a potentially exothermic and haz FIELD OF THE INVENTION ardous reaction. The synthesis also uses lithium bis This invention relates to a method of making (E)-3- (trimethylsilylamide) at -78°C. The present method does (aminomethyl)-5-methylhexanoic acid and to a method of not use nitro compounds, require low temperatures, or obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from require strongly basic conditions. (E)-3-(aminomethyl)-5-methylhexanoic acid. 10 The present invention provides an efficient synthesis of BACKGROUND OF THE INVENTION isobutyl-GABA and provides for the resolution of racemic 3-(Aminomethyl)-5-methylhexanoic acid, which is also isobutyl-GABA to obtain the S-stereoisomer of isobutyl called B-isobutyl-y-aminobutyric acid or isobutyl-GABA, is GABA that avoids the above-identified problems. a potent anticonvulsant. Isobutyl-GABA is related to the 15 endogenous inhibitory neurotransmittery-aminobutyric acid SUMMARY OF THE INVENTION or GABA, which is involved in the regulation of brain neuronal activity. The present invention provides the compounds It is thought that convulsions can be controlled by con trolling the metabolism of the neurotransmitter 20 y-aminobutyric acid. When the concentration of GABA diminishes below a threshold level in the brain, convulsions rROC COR2 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” where RandR are the same or different and are hydrogen, means excessive unsynchronized neuronal activity that dis C-C alkyl, aryl, benzyl or C-C cycloalkyl; rupts normal function. Because of the importance of GABA as an inhibitory neurotransmitter, and its effect on convulsive states and 30 Sr. CN other motor dysfunctions, a variety of approaches have been COM 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 where M is hydrogen, an alkali metal, or an alkaline earth trations of GABA, as the concentrations of GAD and GABA 35 metal; vary in parallel and increased GAD concentrations result in increased GABA concentrations (Janssens de Varebeke P, et al., Biochem. Pharmacol, 1983:32:2751-2755; Loscher W., Biochem. Pharmacol, 1982:31:837-842; Phillips N., et al., Biochem. Pharmacol., 1982:31:2257-2261). For example, rCO2R1 the compound (E)-3-(aminomethyl)-5-methylhexanoic acid, a GAD activator, has the ability to suppress seizures while avoiding the undesirable side effect of ataxia. where R is defined above; It has been discovered that the anticonvulsant effect of isobutyl-GABA is stereoselective. That is, the 45 NH OH S-stereoisomer of isobutyl-GABA shows better anticonvul and OC sant 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 CO2H efficient process for the synthesis of the S-stereoisomer of 50 isobutyl-GABA. The present invention provides a method of making Presently, (S)-3-(aminomethyl)-5-methylhexanoic acid (E)-3-(aminomethyl)-5-methylhexanoic acid which com has been prepared by two synthetic routes. These routes each prises condensing isovaleraldehyde with use reactions that require n-butyllithium, and both routes 55 contain a step that must be carried out at low temperatures CO2R1 (s-35° C) under carefully controlled conditions. These synthetic routes include the use of (4R,5S)-4-methyl-5- CO2R2 phenyl-2-oxazolidinone as a chiral auxiliary to introduce the stereochemical configuration needed in the final product. 60 to form primarily See, for example, U.S. Ser. No. 08/064285, which is hereby incorporated by reference. Although these routes provide the COR target compound in high enantiomeric purity, they are dif ficult to conduct on large-scale and use expensive reagents 21 COR; which are difficult to handle. 65 In addition, (E)-isobutyl GABA can be synthesized in accordance with Andruszkiewicz, et al., Synthesis, 5,637,767 4 reacting the to form primarily CO2Ri CO2R1 N~so N~. COR2; with a cyanide source to form reacting the 10 CO2R1. R1O2C CO2R2 N~. CO2R2 15 decarboxylating the with a cyanide source to form 20 rR1O2C CO2R-2 R1O2C CO2R2 to form decarboxylating the 25 Sri CN CO2R1 r CN ROC COR2 30 hydrolyzing the to forman alkalioralkaline earthmetal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (E)-3-(aminomethyl)-5-methylhexanoic acid. 35 The present invention also provides a method for obtain rCO2R ing (S)-3-(aminomethyl)-5-methylhexanoic acid from (E)- 3-(aminomethyl)-5-methylhexanoic acid which comprises with an alkali or alkaline earth metal hydroxide to forman combining (E)-3-(aminomethyl)-5-methylhexanoic acid and alkali or alkaline earth metal carboxylate salt; and hydro (S)-mandelic acid in water, an alcohol or a mixture of water genating the alkali or alkaline earthmetal carboxylate salt to 40 and an alcohol; allowing a precipitate to form; introducing form (E)-3-(aminomethyl)-5-methylhexanoic acid, wherein the precipitate into a polar aprotic solvent or a mixture of R and R2 are the same or different and are hydrogen, C-C, polar aprotic solvent and water to form a slurry; and col alkyl, aryl, benzyl, or C-C cycloalkyl. lecting the solid from the slurry. A preferred method of making (E)-3-(aminomethyl)-5- methylhexanoic acid comprises condensing isovaleralde 45 DETALED DESCRIPTION OF THE hyde with INVENTION CO2R In accordance with Scheme Ibelow, the present invention provides an efficient synthesis of racemic isobutyl-GABA COR2 50 and a method for obtaining (S)-isobutyl-GABA from race mic isobutyl-GABA. Scheme I COR COR CN Sra.<:2. -G Yo -> inR1O2C COR2 -1 5,637,767 5 -continued Scheme I NH2 CN C- rt COM C COM VI rCO2R1 W (S)-mandelic acid NH3+ OH OC -Ge. CO2H wherein R and R are the same or different and are resentative examples of suitable catalysts include hydrogen, C-C alkyl, aryl, benzyl or C-C cycloalkyl; pyrrollidine, 3-alanine, ammonium acetate, and M is hydrogen, an alkali metal, or an alkaline earth di-isoproplylamine, and di-n-propylamine. These basic cata metal. 25 Scheme I illustrates a method of making (E)-3- lysts can also be used in combination with an acid such as (aminomethyl)-5-methylhexanoic acid (VII or racemic p-toluene sulfonic acid or acetic acid. A preferred catalyst 3-(aminomethyl)-5-methylhexanoic acid), the method com system in the present method is di-n-propylamine and acetic prising condensing isovaleraldehyde (I) with (II) to form acid. (III); reacting (III) with a cyanide source to form (TV); 30 In general, the reaction is run in a refluxing hydrocarbon decarboxylating (IV) to form (V); hydrolyzing (V) with an solvent including, but not limited to, toluene, hexane, alkalimetal or alkaline earth metal hydroxide to form (VI); heptane, methyl tert-butyl ether or cyclohexane, with the and hydrogenating (VI) to form (E)-3-(aminomethyl)-5- azeotropic removal of water. A preferred solventis hexane. methylhexanoic acid (VTI). It is noted that olefin regioisomers can also be formed in the In a preferred embodiment of the present method, (E)-3- 35 reaction, but are converted to the desired product in a (aminomethyl)-5-methylhexanoic acid can be made by con subsequent step in the reaction sequence.