| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | May 10, 2005 |
| PATENT TITLE |
Asymmetric synthesis of pregabalin |
| PATENT ABSTRACT | This invention provides a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) or a salt thereof via an asymmetric hydrogenation synthesis. Pregabalin is useful for the treatment and prevention of seizure disorders, pain, and psychotic disorders. The invention also provides intermediates useful in the production of pregabalin |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | January 11, 2001 |
| PATENT CT FILE DATE | January 11, 2001 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | August 2, 2001 |
| PATENT REFERENCES CITED |
PCT Internatinal Search Report, PCT/IB01/00024. Lin et al., "Chiral HPLC Separations for Process Development of S-(+)-isobutyl GABA, a Potential Anti-Epileptic Agent", J. Liq. Chrom. & Rel. Technol., vol. 19, No. 16, 1996, pp. 2699-2708. Serfass and Casara, "General Synthesis of 3-Substituted Alkenyl GABA as Potential Anticonvulsants", Bioorganic & Medicinial Chemistry Letters, vol. 8, 1998, pp. 2599-2602. Hoekstra et al., "Chemical Development of C1-1008, an Enantiomerically Pure Antoconvulsant", Organic Process Research & Development, vol. 1, 1997, pp. 26-38. Andruszkiewicz, et al., "A Convenient Synthesis of 3-Alkyl-4-aminobutanoic Acids", Synthesis, 1989, p. 953. Burk, et al., "Asymmetric Catalytic Synthesis of Beta-Branched Amino Acids via Highly Enantioselective Hydrogenation Reactions", J. Am. Chem. Soc., 1995, vol. 117, pp. 9375-9376. Yamamoto, et al., Bull. Chem. Soc. Jap., 1985, vol. 58, p. 3397. Yen et al., "Enantioselective synthesis of PD144723: A potent sterospecific anticonvulsant", Bioorganic & Medicinal Chemistry Letters, 1994, vol. 4, p. 823 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
1. A method for preparing an (S)-3-cyano-5-methylhexanoic acid derivative of the formula ##STR29## wherein X is CO2H or CO2¡ªY, and where Y is a cation; the method comprising asymmetric catalytic hydrogenation of an alkene of the formula ##STR30## in the presence of a chiral catalyst and solvent, wherein the chiral catalyst comprises a chiral phosphine ligand. 2. A method according to claim 1, wherein X is CO2¡ªY. 3. A method according to claim 1, wherein the chiral catalyst is a rhodium complex of an (R,R)-DuPHOS ligand, the ligand having the formula ##STR31## wherein R is alkyl. 4. A method according to claim 3, wherein the chiral catalyst is [Rh(ligand)(COD)]BF4. 5. A method according to claim 3, wherein R is methyl or ethyl. 6. A method according to claim 1, wherein the alkene is the E isomer or the Z isomer or is a mixture of said E isomer and Z isomer. 7. A method according to claim 1, wherein the cation is an alkali metal or alkaline earth metal. 8. A method according to claim 7, wherein the alkali metal is potassium. 9. A method according to claim 1, wherein the cation is a salt of a primary amine or a salt of secondary amine. 10. A method according to claim 9, wherein the amine is tert-butylamine. 11. A method according to claim 1, which further comprises first converting a carboxylic ester of the formula ##STR32## wherein R1 is alkyl, to the carboxylate salt of the formula ##STR33## where Y is a cation. 12. A method according to claim 11, wherein R1 is ethyl. 13. A method according to claim 11, wherein the carboxylate salt is isolated prior to hydrogenation. 14. A method according to claim 11, wherein the carboxylate salt is prepared in situ prior to hydrogenation. 15. A method according to claim 1, further comprising acidifying the (S)-3-cyano-5-methylhexanoic acid carboxylate salt to form (S)-3-cyano-5-methylhexanoic acid. 16. A compound of the formula ##STR34## wherein X is CO2H or CO2¡ªY, and where Y is a cation. 17. A compound of the formula ##STR35## wherein R1 is alkyl. 18. A method for preparing a compound of the formula ##STR36## wherein R1 is alkyl, the method comprising asymmetric catalytic hydrogenation of an alkene of the formula ##STR37## in the presence of a chiral catalyst and a solvent, wherein the chiral catalyst comprises a chiral phosphine ligand. 19. A method according to claim 18, wherein the chiral catalyst is a rhodium complex of an (S,S)-DuPHOS ligand, the ligand having the formula ##STR38## wherein R is alkyl. 20. A method according to claim 19, wherein the chiral catalyst is [Rh(ligand)(COD)]BF4. 21. A method according to claim 19, wherein R is methyl or ethyl. 22. A method according to claim 21, wherein R1 is ethyl. 23. A method according to claim 1, wherein the cation Y is selected from the group consisting of H+, the salt formed by reaction with a protonated primary or secondary amine, an alkaline earth metal, and an alkali metal. 24. A compound of the formula ##STR39## wherein Y is a cation. 25. A method according to claim 1, which further comprises the reduction of the cyano group to form an amino group, and when Y is other than H+, protonation by reaction with an acid to produce pregabalin. 26. A process for preparing pregabalin comprising asymmetrically hydrogenating ##STR40## where Y is a cation, in the presence of a chiral catalyst and a solvent, followed by reduction of the cyano group, and protonation to the free acid, wherein the chiral catalyst comprises a chiral phosphine ligand. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
This invention relates to a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) in an asymmetric synthesis. Pregabalin is useful for the treatment and prevention of seizure disorders, pain, and psychotic disorders. BACKGROUND OF THE INVENTION (S)-(+)-3-(Aminomethyl)-5-methylhexanoic acid is known generically as pregabalin. The compound is also called (S)-(+)-¦Â-isobutyl-¦Ã-aminobutyric acid, (S)-isobutyl-GABA, and CI-1008. Pregabalin is related to the endogenous inhibitory neurotransmitter ¦Ã-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 (¡À)-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¡ã 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 (¨Q35¡ã 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 ¦Â-substituted and ¦Â,¦Â-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¡äC¨TC (CO2Me)CH2CO2¡ªY+ 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¨TC(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. SUMMARY OF THE INVENTION The present invention provides an efficient method of preparing (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin). The method comprises asymmetric hydrogenation of a cyano substituted olefin to produce a cyano precursor of (S)-3-(aminomethyl)-5-methylhexanoic acid. The method further comprises a reaction to convert the cyano intermediate into (S)-3-(aminomethyl)-5-methylhexanoic acid. The asymmetric synthesis of (S)-3-(aminomethyl)-5-methylhexanoic acid described herein results in a substantial enrichment of pregabalin over the undesired (R)-3-(aminomethyl)-5-methylhexanoic acid. The R-enantiomer is produced only as a small percentage of the final product. The present invention offers several advantages over previous methods of making pregabalin. For example, processing to remove the undesired R-enantiomer and subsequent disposal of this waste is minimized. Because the S-enantiomer is greatly enriched in the final product, the asymmetric approach is more efficient. Furthermore, the present method does not require the use of hazardous nitro compounds, costly chiral auxiliaries, or low temperatures as required in previous methods. Moreover, unlike the classical resolution approaches or the chiral auxiliary route, which require stoichiometric amounts of the chiral agent, this synthesis utilizes sub-stoichiometric quantities of the chiral agent as a catalyst. Thus, the method of the present invention has both economic and environmental advantages. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "lower alkyl" or "alkyl" means a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The term "aryl" means an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). The aryl group may be unsubstituted or substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, ¡ªCN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, ¡ª(CH2)mCO2H, ¡ª(CH2)mCO2-alkyl, ¡ª(CH2)mSO3H, ¡ªNH alkyl, ¡ªN(alkyl)2, ¡ªCH2)mPO3H2, ¡ª(CH2)mPO3(alkyl)2, ¡ª(CH2)mSO2NH2, and ¡ª(CH2)mSO2NH-alkyl, wherein alkyl is defined as above and m is 0, 1, 2, or 3. A preferable aryl group of the present invention is phenyl. Typical substituted aryl groups include methylphenyl, 4-methoxybiphenyl, 3-chloronaphth-1-yl, and dimethylaminophenyl. The term "arylalkyl" means an alkyl moiety (as defined above) substituted with an aryl moiety (also as defined above). Examples include benzyl and 2-naphthlethyl. The disclosures in this application of all articles and references, including patents, are incorporated herein by reference. The present invention provides an efficient synthesis of (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin). This synthesis is depicted in Scheme 1, below, ##STR1## wherein R1 is lower alkyl, aryl, arylalkyl or allyl; and Y is a cation, and preferably H+, the salt of a primary or secondary amine, an alkaline earth metal, such as tert-butyl ammonium, or an alkali metal such as sodium. As illustrated in Scheme 1, a metal salt 2 (where Y is potassium, for example) of a cyano alkanoic acid may be obtained from the cyano hexenoate ester 1a or 1b by sequential asymmetric hydrogenation and ester hydrolysis to the free acid or salt. Subsequent reduction of the nitrile 2 by routine hydrogenation with a catalyst such as nickel, followed by acidification of the carboxylate salt, affords pregabalin. Alternatively, these steps can be reversed, such that the substrate for asymmetric hydrogenation is the acid or salt 4 ##STR2## where X is CO2H or CO2¡ªY, and Y is a cation. Compound 4 can exist as the individual E or Z geometric isomer, or a mixture thereof. Salts can be formed by reacting the free acid (X is CO2H) with a strong base such as a metal hydroxide, e.g., KOH. Alternatively, the salt may be formed with, for example, a counterion WH+ such as that derived from an amine (W) or a phosphine (W). Primary C1-10 alkylamines and cycloalkylamines are preferred, in particular, tert-butylamine. Tertiary amines such as triethylamine may also be used. Again, subsequent reduction of the nitrile 2 by standard methods, followed by acidification of the carboxylate salt, affords pregabalin. In the general synthesis of pregabalin according to Scheme 1, the cyano olefin compound 1a or 1b undergoes ester hydrolysis and asymmetric hydrogenation to form the desired enantiomer of a 3-cyano-5-methylhexanoic acid or the corresponding carboxylate salt 2. The olefin substrate can be the individual E or Z geometric isomer, or a mixture thereof. Subsequent reduction of the nitrile 2, followed by acidification of the carboxylate salt, affords pregabalin. The asymmetric hydrogenation step is performed in the presence of a chiral catalyst, preferably a rhodium complex of an (R,R)-DuPHOS or (S,S)-DuPHOS ligand, commercially available from Strem Chemicals, Inc. (7 Mulliken Way, Newburyport, Mass. 01950-4098) and Chirotech Technology Limited (Cambridge Science Park, Cambridge, Great Britain) (see U.S. Pat. Nos. 5,532,395 and 5,171,892). The ligand preferably has the formula ##STR3## wherein R is lower alkyl. Preferred alkyl groups for R are n-alkyl groups, such as, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl. More preferred alkyl groups for R are methyl or ethyl. Other catalysts that can be used include rhodium complexes of chiral-BPE and chiral-DIPAMP which have the formulas ##STR4## Such catalysts generally are complexed with 1,5-cyclooctadiene (COD). These agents are fully described by Burk et al. in J. Am. Chem. Soc., 1995;117:9375. The asymmetric hydrogenation reaction is carried out under a hydrogen atmosphere and preferably in a protic solvent such as methanol, ethanol, isopropanol, or a mixture of such alcohols with water. The cyano hexenoate starting materials (e.g., 1a) are readily available (Yamamoto et al., Bull. Chem. Soc. Jap., 1985;58:3397). They can be prepared according to Scheme 2, below, ##STR5## wherein R1 is as defined above in Scheme 1 and R2 is COCH3 or CO2alkyl. In the synthesis of a compound 1a according to Scheme 2, amine catalyzed addition of acrylonitrile (i.e., the Baylis-Hillman reaction) to 2-methylpropanal affords the cyano allylic alcohol. Typical amines used to catalyze the condensation include agents such as 1,4-diazabicyclo[2,2,2]octane (Dabco). The cyano allylic alcohol is subsequently converted to either an alkyl carbonate (e.g., by reaction with an alkyl halo formate such as ethyl chloro formate) or the respective acetate (by reaction with acetic anhydride or acetyl chloride). The resulting 2-(2-methylpropyl)prop-2-enenitrile is then subjected to palladium-catalyzed carbonylation to produce ethyl 3-cyano-5-methylhex-3-enoate 1a (e.g., where R1 is methyl or ethyl). In one embodiment of the invention illustrated in Scheme 3 below, asymmetric hydrogenation is first carried out on 1a (where R1 is ethyl for example) to form the (S)-3-cyano-5-ethylhexanoic acid ester 3. Use of chiral (S,S) hydrogenation catalysts from the bisphospholane series, for example [(S,S)-Me-DuPHOS]Rh(COD)+BF4- on the ester substrates (e.g., R1 is alkyl) provides products enriched in the desired S-enantiomer. The ester 3 is subsequently hydrolyzed to the acid or salt 2. Scheme 3 below shows this synthetic route. wherein Y is as defined above for Scheme 1. By switching to the catalyst [(R,R)-Me-DuPHOS]Rh(COD)+BF4-, the hydrogenation product is enriched in (R)-3-cyano-5-methylhexanoic acid ethyl ester. Typically, these hydrogenation processes provide for substrate conversion of at least 90%, and enantiomeric enrichment (e.e.) of 20% to 25%. Further enrichment of the product can be effected by selective recrystallization with a chiral resolving agent, as described below. ##STR6## A preferred embodiment of the invention is illustrated in Scheme 4, where the ester 1a is first hydrolyzed to the salt of the 3-hexenoic acid 4, (e.g., 4a as shown in Scheme 4 where Y is sodium or potassium). The cyano hexanoic acid salt 4a is then hydrogenated to the salt 2. The cyano hexanoic acid salt 4a may be isolated, or may be prepared in situ prior to hydrogenation. Scheme 4 below depicts this preferred embodiment, wherein Y is as defined above for Scheme 1. A distinctive feature of the hydrogenation of the salt 4a is that the desired S-enantiomer 2 is obtained by use of a chiral (R,R) catalyst from the bisphospholane series, for example [(R,R)-Me-DuPHOS]Rh(COD)+BF4-. This represents an unexpected switch in absolute stereochemistry when compared to hydrogenation of the ester substrate 1a (Scheme 3). In addition, the enantioselectivity achieved in the hydrogenation of the salt 4a is much higher, typically at least about 95% e.e. The choice of cation Y does not appear to be critical, since comparable enantioselectivities are observed with metallic cations (e.g., K+) and non-metallic cations (e.g., tert-butyl ammonium). Without being bound by theory, the contrasting properties of substrates 1a and 4a may derive from binding interactions between functional groups of each substrate and the rhodium center in the catalyst, which in turn may influence both the direction and degree of facial selectivity during hydrogenation of the olefin. Thus, in the hydrogenation of the ester 1a, the cyano substituent may participate in binding to the catalyst. This effect appears to be entirely overridden in hydrogenation of the salt 4a, in which binding by the carboxylate group is likely to be dominant. ##STR7## As a further embodiment, the invention provides novel compounds of the formula 4 ##STR8## wherein X is CO2H or CO2¡ªY, and where Y is a cation as described above in Scheme 1. These compounds are useful substrates in the synthesis of pregabalin. In another preferred embodiment of the invention, the final pregabalin product may be selectively recrystallized with (S)-mandelic acid to provide still further enhanced enrichment of the desired S-isomer. Thus, high levels of the (R)-enantiomer (up to at least 50%) can be removed by classical resolution via the S-mandelic acid salt (U.S. Pat. No. 5,840,956; U.S. Pat. No. 5,637,767). Suitable solvents for such selective recrystallizations include, for example, water or an alcohol (e.g., methanol, ethanol, and isopropanol, and the like) or a mixture of water and an alcohol. In general, excess mandelic acid is used. It is also noted that mandelic acid can be used in combination with another acid. Alternatively, pregabalin containing low levels (¨Q1%) of the (R)-enantiomer, can be enriched to >99.9% of the (S)-enantiomer by simple recrystallization from, for example, water/isopropyl alcohol. Pregabalin containing higher levels (up to 3.5%) of the (R)-enantiomer), can also be enriched by simple recrystallization from, for example, water/isopropyl alcohol, although successive recrystallizations are usually required to reach >99.9% of the (S)-enantiomer. "Substantially pure" pregabalin, as used herein, means at least about 95% (by weight) S-enantiomer, and no more than about 5% R-enantiomer. The following detailed examples further illustrate particular embodiments of the invention. These examples are not intended to limit the scope of the invention and should not be so construed. The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds, or prepared using well-known synthetic methods well-known to those skilled in the art of organic chemistry. Preparations of Starting Materials 3-Hydroxy-4-methyl-2-methylene pentanenitrile ##STR9## A 250 mL, three-necked, round-bottom flask with overhead stirring is charged with 0.36 g (1.6 mmol) of 2,6-di-tert-butyl-4-methylphenol, 37 g (0.33 mol) of 1,4-diazabicyclo[2,2,2]octane, 60 mL (0.66 mol) of isobutyraldehyde, 52 mL (0.79 mol) of acrylonitrile, and 7.2 mL (0.4 mol) of water. The reaction mixture is stirred at 50¡ã C. for 24 hours, cooled to 25¡ã C., and quenched into a solution of 33 mL (0.38 mol) of hydrochloric acid and 100 mL of water. The product is extracted with 120 mL of methylene chloride. The aqueous acid layer is extracted again with 25 mL of methylene chloride. The combined methylene chloride layers are concentrated by rotary evaporation to provide 79.9 g (96.7%) of 3-hydroxy-4-methyl-2-methylenepentanenitrile as a yellow oil (which may solidify to a white solid on standing), 96.7% (area under the curve) by HPLC assay, which may be used in the next step without further purification. Carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester ##STR10## A nitrogen-purged 5 L, three-necked, round-bottom flask with overhead stirring is charged with 150 g (1.2 mol) of 3-hydroxy-4-methyl-2-methylenepentanenitrile, 1.0 L of methylene chloride, and 170 mL (2.1 mol) of pyridine. The solution is cooled at 10¡ã C. to 15¡ã C. in an ice bath. Using a 1 L graduated addition funnel, a mixture of 0.5 L of methylene chloride and 200 mL (2.1 mol) of ethyl chloroformate is added slowly while maintaining the reaction temperature at 20¡ã C.¡À5¡ã C. The reaction is stirred at 22¡ã C.¡À3¡ã C. for about two additional hours. The reaction solution is poured into a 6 L separatory funnel containing 200 mL (2.3 mol) of hydrochloric acid and 1.25 L of water. The lower organic layer is washed again with a solution of 60 mL (0.7 mol) of HCl and 0.5 L of water. The organic layer is dried over anhydrous magnesium sulfate (30 g), filtered, and concentrated by rotary evaporation to provide 226 g of carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester as a yellow oil which may be used in the next step without further purification. Acetic acid 2-cyano-1-isopropyl-allyl ester (using acetyl chloride) ##STR11## A nitrogen-purged 5 L, three-necked, round-bottom flask with overhead stirring is charged with 50 g (0.4 mol) of 3-hydroxy-4-methyl-2-methylenepentanenitrile, 0.4 L of methylene chloride, and 80 mL (1 mol) of pyridine. The solution is cooled at 10¡ã C. to 15¡ã C. in an ice bath. Using a 500 mL graduated addition funnel, a mixture of 100 mL of methylene chloride and 43 mL (0.6 mol) of acetyl chloride is added slowly while maintaining the reaction temperature at 25¡ã C.¡À5¡ã C. The reaction is stirred at 22¡ã C.¡À3¡ã C. for about one additional hour. The reaction solution is poured into a 4 L separators funnel containing 85 mL (1.0 mol) of hydrochloric acid and 750 mL of water. The lower organic layer is washed again with a solution of 20 mL (0.2 mol) of HCl and 250 mL of water. The organic layer is dried over anhydrous magnesium sulfate (20 g), filtered, and concentrated by rotary evaporation to provide 66 g of acetic acid 2-cyano-1-isopropyl-allyl ester as a yellow oil which may be used in the next step without further purification. Acetic acid 2-cyano-1-isopropyl-allyl ester (using acetic anhydride) To a 500 mL, four-necked, round-bottom flask equipped with an overhead stirrer, a temperature probe, a reflux condenser, and a nitrogen inlet is charged acetic anhydride (40 mL, 0.45 mol). This solution is heated to 50¡ã C. and a solution of 3-hydroxy-4-methyl-2-methylenepentanenitrile (50 g, 0.40 mol) and 4-(dimethylamino)pyridine (1.5 g) in tetrahydrofuran (25 mL) is added over 35 minutes. A temperature of 50¡ã C. to 63¡ã C. is maintained without external heating. After the addition is complete, the reaction mixture is heated at 60¡ã C. for 75 minutes. The solution is cooled to 30¡ã C. and the cooled reaction mixture is diluted with 30 mL of tert-butylmethyl ether (MTBE) and 25 mL of water. This mixture is cooled to 10¡ã C. and a solution of 50% aqueous sodium hydroxide (37 g, 0.46 mol) diluted with 45 mL of water is added with cooling, such that the temperature is maintained at about 15¡ã C. For the final pH adjustment, 50% aqueous sodium hydroxide 9.8 g (0.12 mol) is added dropwise to a final pH of 9.4. After adding 10 mL of water and 10 to 15 mL of MTBE, the reaction mixture is phased and separated. The upper organic product layer is separated and washed with 25 mL of brine, dried over magnesium sulfate, and concentrated in vacuo to provide 63.7 g (95%) of acetic acid 2-cyano-1-isopropyl-allyl ester as a pale yellow oil. Ethyl 3-cyano-5-methyl hex-3-enoate ##STR12## A high pressure reactor with overhead stirring is charged with 3.0 g (13.4 mmol) of palladium acetate, 7.0 g (26.8 mmol) of triphenylphosphine, and 226 g (0.92 mol) of the crude oil containing carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester, and 500 mL of ethanol. Carbon monoxide is introduced at 280 to 300 psi, and the mixture is heated at 50¡ã C. overnight with stirring. The red-brown solution is filtered through celite to remove solids. The filtrate is concentrated by rotary evaporation to provide 165 g of crude yellow oily product, ethyl-3-cyano-5-methyl hex-3-enoate, which assays 84% (area) by gas chromatography (GC) as a mixture of the E and Z geometric isomers. The crude product may be used without further purification, or alternatively, is purified by vacuum distillation (0.6-1.0 mm Hg at 60¡ã C.-70¡ã C.) to give a colorless oil which assays ¨R95% (area) by GC. Ethyl 3-cyano-5-methyl hex-3-enoate (using, KBr) A high pressure reactor with overhead stirring is charged with palladium acetate (0.52 g, 2.3 mmol), triphenylphosphine (0.65 g, 2.3 mmol), potassium bromide (5.5 g, 4.8 mmol), a crude oil containing carbonic acid 2-cyano-1-isopropyl-allyl ester ethyl ester (240 g, 1.2 mole), triethylamine (2.2 g, 22 mmol), ethanol 2B (45 mL), and acetonitrile (200 mL). Carbon monoxide is introduced at 50 psi. and the mixture is heated at 50¡ã C. overnight with stirring. The pressure of the reactor is released to 10 to 15 psi after about 1, 3, and 6 hours and is refilled with carbon monoxide to 50 psi. The reaction mixture is filtered through celite to remove solids. The filtrate is concentrated in vacuo and 800 mL of hexane is added. The resulting mixture is washed twice with 500 mL of water, and the hexane is removed in vacuo to provide 147 g of crude ethyl 3-cyano-5-methyl hex-3-enoate as an oil. This crude product is purified by fractional distillation (0.7 mm Hg at 60¡ã C.-70¡ã C.). Ethyl 3-cyano-5-methyl hex-3-enoate (using NaBr) A high pressure reactor with overhead stirring is charged with 0.5 g (0.5 mmol) of tris(dibenzylideneacetone)dipalladium (0), 0.5 g (2.0 mmol) of triphenylphosphine, 0.5 g (5.0 mmol) of sodium bromide, 4.5 mL (25.0 mmol) of diisopropylethylamine, 8.35 g (50.0 mmol) of acetic acid 2-cyano-1-isopropyl-allyl ester, and 100 mL of ethanol. Carbon monoxide is introduced at 40 to 50 psi, and the mixture is heated at 50¡ã C. for 24 hours with stirring. The brown solution is filtered through celite to remove solids. The filtrate is concentrated by rotary evaporation. The concentrated reaction mixture is diluted with 150 mL of methyl tert-butyl ether and washed with water. The solvent is removed on a rotary evaporator to provide 7.7 g of crude yellow oily product, ethyl-3-cyano-5-methyl hex-3-enoate (85 area percent on GC assay). The crude product may be used without further purification or alternatively, may be purified by vacuum distillation (0.6-1.0 mm Hg at 60¡ã C.-70¡ã C.). |
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