(S)-(+)-3-(Aminomethyl)-5-methylhexanoic acid is known generically as pregabalin. The compound is also called (S)-(+)-β-isobutyl-γ-aminobutyric acid, (S)-isobutyl-GABA, and CI-1008. Pregabalin is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid or GABA, which is involved in the regulation of brain neuronal activity. Pregabalin has anti-seizure activity, as described by Silverman et al., U.S. Pat. No. 5,563,175. Other indications for pregabalin are also currently being pursued (see, for example. Guglietta et al., U.S. Pat. No. 6,127,418, and Singh et al., U.S. Pat. No. 6,001,876).
A seizure is defined as excessive unsynchronized neuronal activity that disrupts normal brain function. It is thought that seizures can be controlled by regulating the concentration of the GABA neurotransmitter. When the concentration of GABA diminishes below a threshold level in the brain, seizures result (Karlsson et al., Biochem. Pharmacol. 1974:23:3053); when the GABA level rises in the brain during convulsions, the seizures terminate (Havashi. Physiol. (London), 1959;145:570).
Because of the importance of GABA as a 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 the concentration of GABA, as the concentrations of GAD and GABA vary in parallel, and increased GAD concentrations result in increased GABA concentrations (Janssens de Varebeke et al., Biochem. Pharmacol., 1983;32:2751; Loscher, Biochem. Pharmacol., 1982;31:837; Phillips et al., Biochem. Pharmacol., 1982;31:2257). For example, the racemic compound (±)-3-(aminomethyl)-5-methylhexanoic acid (racemic isobutyl-GABA), which is a GAD activator, has the ability to suppress seizures while avoiding the undesirable side effect of ataxia.
The anticonvulsant effect of racemic isobutyl-GABA is primarily attributable to the S-enantiomer (pregabalin). That is, the S-enantiomer of isobutyl-GABA shows better anticonvulsant activity than the R-enantiomer (see, for example, Yuen et al., Bioorganic & Medicinal Chemistry Letters, 1994;4:823). Thus, the commercial utility of pregabalin requires an efficient method for preparing the S-enantiomer substantially free of the R-enantiomer.
Several methods have been used to prepare pregabalin. Typically, the racemic mixture is synthesized and then subsequently resolved into its R- and S-enantiomers (see U.S. Pat. No. 5,563,175 for synthesis via an azide intermediate). Another method uses potentially unstable nitro compounds, including nitromethane, and an intermediate that is reduced to an amine in a potentially exothermic and hazardous reaction. This synthesis also uses lithium bis(trimethylsilylamide) in a reaction that must be carried out at −78° C. (Andruszkiewicz et al., Synthesis, 1989:953). More recently, the racemate has been prepared by a “malonate” synthesis, and by a Hofmann synthesis (U.S. Pat. Nos. 5,840,956; 5,637,767; 5,629,447; and 5,616,793). The classical method of resolving a racemate is used to obtain pregabalin according to these methods. Classical resolution involves preparation of a salt with a chiral resolving agent to separate and purify the desired S-enantiomer. This involves significant processing, and also substantial additional cost associated with the resolving agent. Partial recycle of the resolving agent is feasible, but requires additional processing and cost, as well as associated waste generation. Moreover, the undesired R-enantiomer cannot be efficiently recycled and is ultimately discarded as waste. The maximum theoretical yield of pregabalin is thus 50%, since only half of the racemate is the desired product. This reduces the effective throughput of the process (the amount that can be made in a given reactor volume), which is a component of the production cost and capacity.
Pregabalin has been synthesized directly via several different synthetic schemes. One method includes use of n-butyllithium at low temperatures (≦35° C.) under carefully controlled conditions. This synthetic route requires the use of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to introduce the stereochemical configuration desired in the final product (U.S. Pat. No. 5,563,175). Thus, although these general strategies provide the target compound in high enantiomeric purity, they are not practical for large-scale synthesis because they employ costly reagents which are difficult to handle, as well as special cryogenic equipment to reach the required operating temperatures.
Because pregabalin is being developed as a commercial pharmaceutical product, the need exists for an efficient, cost effective, and safe method for its large-scale synthesis. In order to be viable for commercial manufacturing, such a process needs to be highly enantioselective, for example, where the product is formed with a substantial excess of the correct enantiomer. An object of this invention is to provide such a process, namely an asymmetric hydrogenation process.
Asymmetric hydrogenation processes are known for some compounds. Burk et al., in WO 99/31041 and WO 99/52852, describe asymmetric hydrogenation of β-substituted and β,β-disubstituted itaconic acid derivatives to provide enantiomerically enriched 2-substituted succinic acid derivatives. The itaconic substrates possess two carboxyl groups, which provide the requisite steric and electronic configuration to direct the hydrogenation to produce an enriched enantiomer. The disclosures teach that salt forms of the formula RR′C═C (CO2Me)CH2CO2—Y+ are required to obtain hydrogenated products having at least 95% enantiomeric excess.
According to U.S. Pat. No. 4,939,288, asymmetric hydrogenation does not work well on substrates having an isobutyl group. We have now discovered that an isobutyl cyano carboxy acid, salt or ester substrate, of the formula iPrCH═C(CN)CH2CO2R, can be selectively hydrogenated to provide an enantiomerically enriched nitrile derivative, which can be subsequently hydrogenated to produce substantially pure pregabalin. This selectivity is particularly surprising given the dramatic differences in steric configuration and inductive effects of a nitrile moiety compared to a carboxy group. Indeed, there is no teaching in the prior art of the successful asymmetric hydrogenation of any cyano substituted carboxy olefin of this type.