| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 24, 1998 |
| PATENT TITLE |
Method of making (S)-3-(Aminomethyl)-5-Methylhexanoic acid |
| PATENT ABSTRACT |
A method of making (.+-.)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with ##STR1## to form primarily ##STR2## reacting the ##STR3## with a cyanide source to form ##STR4## decarboxylating the ##STR5## to form ##STR6## hydrolyzing the ##STR7## with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (.+-.)-3-(aminomethyl)-5-methylhexanoic acid, wherein R.sub.1 and R.sub.2 are the same or different and are hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, benzyl, or C.sub.3 -C.sub.6 cycloalkyl. The present invention also provides a method of making (.+-.)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with ##STR8## to form primarily ##STR9## reacting the ##STR10## with a cyanide source to form ##STR11## decarboxylating the ##STR12## to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (.+-.)-3-(aminomethyl)-5-methylhexanoic acid. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 6, 1997 |
| PATENT REFERENCES CITED |
Elderfield, J. Am. Chem. Soc., vol. 77, pp. 4819-4822, 1955. Lange, Syn. Comm., vol. 23, pp. 1371-1377, 1993. Carruthers, et al., Bioorganic & Medicinal Chemistry Letters, vol. 5, No. 3, pp. 237-240 (1995). Andruszkiewicz, et al., Synthesis, pp. 953-955 (1989). Jung, et al., Biochemistry, vol. 17, No. 13, pp. 2628-2632 (1978). PCT Search Report, Dec. 9, 1996 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. The compound having the formula ##STR52## wherein M is sodium or potassium. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION 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. BACKGROUND OF THE INVENTION 3-(Aminomethyl)-5-methylhexanoic acid, which is also called .beta.-isobutyl-y-aminobutyric acid or isobutyl-GABA, is a potent anticonvulsant. Isobutyl-GABA is related to the endogenous inhibitory neurotransmitter .gamma.-aminobutyric acid or GABA, which is involved in the regulation of brain neuronal activity. It is thought that convulsions can be controlled by controlling the metabolism of the neurotransmitter .gamma.-aminobutyric 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 excessive unsynchronized neuronal activity that disrupts normal function. 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 concentrations of GABA, as the concentrations of GAD and GABA 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, the compound (.+-.)-3-(aminomethyl)-5-methylhexanoic acid, a GAD activator, has the ability to suppress seizures while avoiding the undesirable side effect of ataxia. It has been discovered that the anticonvulsant effect of isobutyl-GABA is stereoselective. That is, the S-stereoisomer 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. 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 temperatures (.ltoreq.-35.degree. C.) under carefully controlled conditions. These synthetic routes include the use of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to introduce the stereochemical configuration needed in the final product. See, for example, U.S. Ser. 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. 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 intermediate 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.degree. C. The present method does not use nitro compounds, require low temperatures, or require strongly basic conditions. The present invention provides an efficient synthesis of isobutyl-GABA and provides for the resolution of racemic isobutyl-GABA to obtain the S-stereoisomer of isobutyl-GABA that avoids the above-identified problems. SUMMARY OF THE INVENTION The present invention provides the compounds ##STR13## where R.sub.1 and R.sub.2 are the same or different and are hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, benzyl or C.sub.3 -C.sub.6 cycloalkyl; ##STR14## where M is hydrogen, an alkali metal, or an alkaline earth metal; ##STR15## where R.sub.1 is defined above; and ##STR16## The present invention provides a method of making (.+-.)-3-(aminomethyl)-5-methylhexanoic acid which comprises condensing isovaleraldehyde with ##STR17## to form primarily ##STR18## reacting the ##STR19## with a cyanide source to form ##STR20## decarboxylating the ##STR21## to form ##STR22## hydrolyzing the ##STR23## with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (.+-.)-3-(aminomethyl)-5-methylhexanoic acid, wherein R.sub.1 and R.sub.2 are the same or different and are hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, benzyl, or C.sub.3 -C.sub.6 cycloalkyl. A preferred method of making (.+-.)-3-(aminomethyl)-5-methylhexanoic acid comprises condensing isovaleraldehyde with ##STR24## to form primarily ##STR25## reacting the ##STR26## with a cyanide source to form ##STR27## decarboxylating the ##STR28## to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (.+-.)-3-(aminomethyl)-5-methylhexanoic acid. The present invention also provides a method for obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid from (.+-.)-3-(aminomethyl)-5-methylhexanoic acid which comprises combining (.+-.)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol or a mixture of water and an alcohol; allowing a precipitate to form; introducing the precipitate into a polar aprotic solvent or a mixture of polar aprotic solvent and water to form a slurry; and collecting the solid from the slurry. DETAILED DESCRIPTION OF THE INVENTION In accordance with Scheme I below, the present invention provides an efficient synthesis of racemic isobutyl-GABA and a method for obtaining (S)-isobutyl-GABA from racemic isobutyl-GABA. ##STR29## wherein R.sub.1 and R.sub.2 are the same or different and are hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, benzyl or C.sub.3 -C.sub.6 cycloalkyl; and M is hydrogen, an alkali metal, or an alkaline earth metal. Scheme I illustrates a method of making (.+-.)-3-(aminomethyl)-5-methylhexanoic acid (VII or racemic 3-(aminomethyl)-5-methylhexanoic acid), the method comprising condensing isovaleraldehyde (I) with (II) to form (III); reacting (III) with a cyanide source to form (IV); decarboxylating (IV) to form (V); hydrolyzing (V) with an alkali metal or alkaline earth metal hydroxide to form (VI); and hydrogenating (VI) to form (.+-.)-3-(aminomethyl)-5-methylhexanoic acid (VII). In a preferred embodiment of the present method, (.+-.)-3-(aminomethyl)-5-methylhexanoic acid can be made by condensing isovaleraldehyde (I) with (II) to form (III); reacting (III) with a cyanide source to form (IV); hydrolyzing and decarboxylating (IV) to form (VI); and hydrogenating (VI) to form (.+-.)-3-(aminomethyl)-5-methylhexanoic acid (VII). Also provided by the present invention is a method for obtaining (S)-3-(aminomethyl)-5-methylhexanoic acid (IX) from (.+-.)-3-(aminomethyl)-5-methylhexanoic acid (VII), the method comprising combining (.+-.)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid in water, an alcohol or a mixture of water and an alcohol; allowing a precipitate to form; introducing the precipitate into a polar aprotic solvent, or a polar aprotic solvent and water, to form a slurry; and collecting the solid from the slurry. In one step of the present method for making (.+-.)-3-(aminomethyl)-5-methylhexanoic acid, isovaleraldehyde is condensed with ##STR30## wherein R.sub.1 and R.sub.2 are the same or different and are hydrogen C.sub.1 -C.sub.6 alkyl, aryl, benzyl, or C.sub.3 -C.sub.6 cycloalkyl. This type of reaction is known to those skilled in the art as a Knoevenagel Condensation, and the conditions under which a Knoevenagel Condensation can be carried out are well known to those skilled in the art. For example, the condensation can be achieved using a catalytic amount of a base such as di-n-propylamine. Other suitable catalysts are known in the literature. See for example, Tietze L. F., and Beifuss U. in Comprehensive Organic Synthesis, 1991;2:341-394 (Trost B. M., ed.), Pergamon Press. Representative examples of suitable catalysts include pyrrolidine, .beta.-alanine, ammonium acetate, di-isoproplylamine, and di-n-propylamine. These basic catalysts can also be used in combination with an acid such as p-toluene sulfonic acid or acetic acid. A preferred catalyst system in the present method is di-n-propylamine and acetic acid. In general, the reaction is run in a refluxing hydrocarbon solvent including, but not limited to, toluene, hexane, heptane, methyl tert-butyl ether or cyclohexane, with the azeotropic removal of water. A preferred solvent is hexane. It is noted that olefin regioisomers can also be formed in the reaction, but are converted to the desired product in a subsequent step in the reaction sequence. Representative examples of C.sub.1 -C.sub.6 alkyl groups include methyl ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl. Representative examples of C.sub.3 -C.sub.6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Representative examples of aryl groups include phenyl and substituted phenyl, naphthyl, pridinyl, and the like. The aryl moiety may be substituted with one or more substituents, which can be the same or different. Examples of such groups include C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and halogen. Preferably, R.sub.1 and R.sub.2 are ethyl. In general, the isovaleraldehyde and ##STR31## are added to the solvent along with the catalyst, and refluxed with azeotropic removal of water. It is also contemplated that additional catalyst may be added when the rate of azeotropic water collection slows. The progress of the condensation reaction may be monitored by methods well known in the art. A preferred monitoring method is gas chromatography (GC). In another step of the present method, ##STR32## is reacted with a cyanide source to form ##STR33## In general, ##STR34## is reacted with a cyanide source in a polar protic solvent such as ethanol, methanol, n-propanol, isopropanol, a mixture of water and alcohols, or polar aprotic solvents such as dimethylsulfoxide (DMSO) or DMSO/water, and then treated with an acid. Examples of suitable cyanide sources include, but are not limited to, hydrogen cyanide, acetone cyanohydrin or an alkali metal or alkaline earth metal cyanide, such as sodium cyanide, potassium cyanide, or magnesium cyanide. The ##STR35## in this step may be used in the next step without purification, i.e. in crude form, or it may be purified. Examples of suitable acids are acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, benzoic acid, mandelic acid, p-toluenesulfonic acid, and the like. The ##STR36## can be decarboxylated to form ##STR37## by heating ##STR38## in a solvent with a salt. Examples of suitable solvents include mixtures of water and a polar solvent such as ethanol or dimethylsulfoxide (DMSO). Examples of suitable salts include alkali metal and alkaline earth metal halides such as sodium chloride and alkali metal and alkaline earth metal cyanides such as sodium cyanide, magnesium cyanide, and the like. The ##STR39## can be hydrolyzed with an alkali metal hydroxide or an alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt. The alkali or alkaline earth metal hydroxide can be any alkali or alkaline earth metal hydroxide known to those skilled in the art. Examples of suitable alkali metal hydroxides include sodium hydroxide, lithium hydroxide, and potassium hydroxide. Examples of suitable alkaline earth metal hydroxides include calcium hydroxide and magnesium hydroxide. The reaction is usually run in a suitable protic solvent such as water or a mixture of water and a polar protic solvent such as methanol, ethanol, or isopropanol. The carboxylate salt can be reduced to give the alkali or alkaline earth metal salt of (.+-.)-3-(aminomethyl)-5-methylhexanoic acid. The carboxylate salt can be protonated with mineral acids or carboxylic acids to give the carboxylic acid and then the nitrile group of the carboxylic acid can be reduced. Conversely, the nitrile group of the carboxylate salt can be reduced, and subsequently protonated to form the carboxylic acid. The salt can be treated with mineral acids or carboxylic acids to give (.+-.)-3-(aminomethyl)-5-methylhexanoic acid. Those skilled in the art are familiar with the reduction of nitrile functional groups. One common method of reducing a nitrile uses a hydrogenation catalyst, such as sponge nickel, in the presence of hydrogen. Other catalysts include palladium, platium, rhodium, cobalt, and nickel. In general, the reaction is run in a solvent system such as a mixture of water and a polar protic solvent. The amino carboxylate formed after nitrile reduction can be obtained in the acid form by treating the amino carboxylate with an acid. The mineral acids such as hydrochloric acid can be used. Carboxylic acids, such as acetic acid, can also be used. Preferably, the acid is acetic acid, as a byproduct formed by the reaction is MOAc where M is an alkali metal ion (Na, K, and the like), and OAc is an acetate ion. The salt MOAc is more soluble in aqueous alcoholic solvents than inorganic salts such as sodium chloride, potassium chloride, and the like. Thus, isolation of the product is simplified, and the need for ion exchange treatment to remove excess salts is avoided. The cyano acid may also be reduced using a suitable hydrogenation catalyst, such as sponge nickel and hydrogen, in a polar solvent such as methanol, ethanol, or isopropanol in combination with ammonia or a mixture of ammonia and water. Examples of other suitable hydrogenation catalysts include palladium, platium, rhodium, cobalt, and nickel. In a preferred method ##STR40## is taken to (.+-.)-3-(aminomethyl)-5-methylhexanoic acid without isolation of intermediates. For example, ##STR41## can be hydrolyzed using an alkali or alkaline earth metal hydroxide such as potassium hydroxide or sodium hydroxide in an alcohol solvent, which promotes decarboxylation. Further hydrolysis using an alkali or alkaline earth metal hydroxide in water, an alcohol, or a mixture of water and an alcohol, gives carboxylate (VI), which can be reduced with a hydrogenation catalyst followed by treatment with a mineral acid to give racemic 3-(aminomethyl)-5-methylhexanoic acid. Racemic 3-(aminomethyl)-5-methylhexanoic acid can be resolved, i.e., the enantiomers separated, by selective crystallization with (S)-mandelic acid. Racemic 3-(aminomethyl)-5-methylhekanoic acid and (S)-mandelic acid can be combined in a solvent such as water or an alcohol or a mixture of water and an alcohol to form a salt. Examples of suitable alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and the like. In general, the S,S salt precipitates from the solution, and the diastereomer, the R,S salt, stays in solution. Diasteriomeric purity of the S,S salt can be enhanced by further crystallizations. Additional (S)-mandelic acid can be included in the recrystallizations to enhance diastereomeric enrichment. In general, an excess of mandelic acid is used. It is also noted that mandelic acid can be used in combination with another acid in accordance with the "Pope-Peachy" method known in the art. Removal of (S)-mandelic acid from the salt to give enriched (S)-3-(aminomethyl)-5-methylhexanoic acid can be done using a polar aprotic solvent such as dimethylsulfoxide or mixtures of dimethylsulfoxide and water or tetrahydrofuran and water, at temperatures typically in the range of about 0.degree. C. to about 100.degree. C. Trituration to obtain the S-enantiomer has the advantage that it is operationally simple and more economical than traditional acid/base or ion exchange methods. Alternatively, (S)-3-(aminomethyl)-5-methyl-hexanoic acid can be obtained by combining (.+-.)-3-(aminomethyl)-5-methylhexanoic acid with (R)-mandelic acid to give the R,R salt which crystallizes out of the solution leaving the solution enriched in (S)-3-(aminomethyl)-5-methylhexanoic acid which can then be isolated from the solution by methods well known to those skilled in the art. The (R)-mandelic salt of (S)-3-(aminomethyl)-5-methylhexanoic acid can be isolated as an intermediate, treated with a polar aprotic solvent or mixture of water and a polar aprotic solvent to give the (S)-3-(aminomethyl)-5-methylhexanoic acid. It is also possible to obtain (S)-3-(aminomethyl)-5-methylhexanoic acid from racemic isobutyl-GABA by standard methods of resolution known to those skilled in the art. It is noted that the isolated solids may be dried at each stage in the resolution or carried on to the next step as solvent-wet solids with comparable results. Also provided by the present invention are the novel compounds ##STR42## where R.sub.1 and R.sub.2 are the same or different and are hydrogen, C.sub.1 -C.sub.6 alkyl, aryl, benzyl or C.sub.3 -C.sub.6 cycloalkyl; ##STR43## where M is hydrogen, an alkali metal, or an alkaline earth metal; ##STR44## where R.sub.1 is a defined above; and ##STR45## It is also contemplated that the compounds of the present method can be found or isolated in the form of hydrates or solvates, which are considered to fall within the scope of the present invention |
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