# Patent

## Title
Chiral 3-carbamoylmethyl-5-methyl hexanoic acids, key intermediates for the synthesis of (S)-Pregabalin

## Abstract

The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. provisional application Ser. Nos. 60/718,689, filed Sep. 19, 2005; 60/754,392, filed Dec. 27, 2005; 60/763,593, filed Jan. 30, 2006; 60/752,434, filed Dec. 20, 2005; 60/753,220, filed Dec. 21, 2005; 60/763,696, filed Jan. 30, 2006; and 60/839,947, filed Aug. 23, 2006, herein incorporated by reference.


FIELD OF THE INVENTION
The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.
BACKGROUND OF THE INVENTION
(S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,




is also known as γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, marketed under the trade name LYRICA®, has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.

Several processes for the synthesis of (S)-Pregabalin are known. For example, see DRUGS OF THE FUTURE, 24 (8), 862-870 (1999). One such process is illustrated in scheme 1.




In Scheme 1,3-isobutyl glutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the R enantiomer, compound 6. Finally, a Hoffmann degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that it requires separating the two enantiomers, thereby resulting in the loss of half the product, such that the process cost is high.
Several stereoselective processes for the synthesis of (S)-Pregabalin have been disclosed. For example, U.S. Pat. No. 5,599,973 discloses the preparation of (S)-Pregabalin using stoichiometric (+)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. In general, however, that route is of limited use for scale-up, principally due to the low temperature required for the reactions, the use of pyrophoric reagent, such as, butyl lithium, to side reactions, and due to a low overall yield.
Another process is disclosed in U.S. Patent Application Publication No. 2003/0212290, which discloses asymmetric hydrogenation of a cyano-substituted olefin, compound 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid, compound 8, as seen in scheme 2.




Subsequent reduction of the nitrile in compound 8 by catalytic hydrogenation produces (S)-Pregabalin. The cyano hexenoate starting material, compound 7, is prepared from 2-methyl propanal and acrylonitrile (Yamamoto et al, Bull. Chem. Soc. Jap., 58, 3397 (1985)). However, the disclosed method requires carbon monoxide under high pressure, raising serious problems in adapting this scheme for production scale processes.
A process published by G. M. Sammis, et al., J. Am. Chem. Soc., 125(15), 4442-43 (2003), takes advantage of the asymmetric catalysis of cyanide conjugate addition reactions. The method discloses the application of aluminum salen catalysts to the conjugate addition of hydrogen cyanide to αβ-unsaturated imides as shown in scheme 3. Reportedly, TMSCN is a useful source of cyanide that can be used in the place of HCN. This process is not practicable for large scale production due to the use of highly poisonous reagents. Moreover, the last reductive step requires high pressure hydrogen, which only adds to the difficulties required for adapting this scheme for a production scale process.




In 1989, Silverman reported a convenient synthesis of 3-alkyl-4-amino acids compounds in SYNTHESIS (1989, 955). Using 2-alkenoic esters as a substrate, a series of GABA analogs were produced by Michael addition of nitromethane to αβ-unsaturated compounds, followed by hydrogenation at atmospheric pressure of the nitro compound to amine moiety as depicted in scheme 4.




Further resolution of compound 14 may be employed to resolve Pregabalin. This, of course, results in the loss of 50 percent of the product.
Recent studies have indicated that cinchona alkaloids are broadly effective in chiral organic chemistry. A range of nitroalkenes were reportedly treated with dimethyl or diethyl malonate in tetrahydrofuran in the presence of cinchona alkaloids to provide high enantiomeric selectivity of compound 15,




and its analogues. For example, see H. Li, et al., J. Am. Chem. Soc., 126(32), 9906-07 (2004). These catalysts are easily accessible from either quinine or quinidine, and are reportedly highly efficient for a synthetically C—C bond forming asymmetric conjugate addition as shown in scheme 5.





R3 represents several alkyl and aryl groups. The scope of the reaction has been extended to other nitroolefins and applied to prepare ABT-546 employing bis(oxazoline)Mg(OTf)2. See, for example, D. M. Barnes, et al., J. Am. Chem. Soc., 124(44), 13097-13105 (2002).
Other groups have investigated a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. See T. Okino, et al., J. Am. Chem. Soc., 127(1), 119-125 (2005). On the basis of a catalytic Michael addition to the nitroolefin with enantiomeric selectivity, they were able to prepare a series of analogues of compound 15.
Thus, there is a need in the art for new processes for the preparation of (S)-Pregabalin that do not suffer from the disadvantages mentioned above.
SUMMARY OF THE INVENTION
In one embodiment, the invention encompasses a compound of formula 24




wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.

Where Ar is phenyl and R is methyl, the compound of formula 24 corresponds to (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid of formula 24A




In another embodiment, the invention encompasses the compound of formula 24A in crystalline form.
In another embodiment, the invention encompasses a process for preparing the compound of formula 24 comprising: combining a chiral amine of formula 23,




an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture; cooling the mixture to a temperature of about 10° C. to about −70° C.; adding to the mixture 3-isobutyl glutaric anhydride of formula 22,





to obtain the compound of formula 24; and recovering the compound of formula 24 from the mixture, wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.

In another embodiment, the invention encompasses a process for preparing (S)-pregabalin comprising: combining a chiral amine of formula 23,




an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture; cooling the mixture to a temperature of about 10° C. to about −70° C.; adding to the mixture 3-isobutyl glutaric anhydride of formula 22;





to obtain the compound of formula 24; recovering the compound of formula 24 from the mixture; combining the recovered compound of formula 24, water, an ether, ammonia and an alkali metal, at a temperature of about 10° C. to about −78° C. to obtain a mixture; recovering the compound of formula 25 from the mixture;





combining the recovered compound of formula 25 with bromine, water, and an alkaline hydroxide to obtain a basic mixture; heating the basic mixture to a temperature of about 60° C. to about 85° C.; adding to the basic mixture a strong mineral acid to obtain an acidic mixture; reacting the acidic mixture with a base to obtain (S)-Pregabalin, and





recovering (S)-Pregabalin; wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.

In another embodiment, the invention encompasses a process for preparing (S)-Pregabalin comprising: combining a chiral amine of formula 23,




an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base to obtain a mixture; cooling the mixture to a temperature of about 10° C. to about −70° C.; adding to the mixture 3-isobutyl glutaric anhydride of formula 22;





to obtain the compound of formula 24; recovering the compound of formula 24 from the mixture; combining the compound of formula 24 with concentrated sulfuric acid to obtain a mixture; maintaining the mixture at a temperature of about 0° C. to about 50° C., for about 10 hours to about 30 hours; recovering the compound of formula 25 from the mixture;





combining the recovered compound of formula 25 with bromine, water, and an alkaline hydroxide to obtain a basic mixture; heating the basic mixture to a temperature of about 60° C. to about 85° C.; adding to the basic mixture a strong mineral acid to obtain an acidic mixture; reacting the acidic mixture with a base to obtain (S)-Pregabalin, and





recovering (S)-Pregabalin; wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.




BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates an 1H-NMR spectrum of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.
FIG. 2 illustrates a 13C-NMR spectrum of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.
FIG. 3 illustrates an IR spectrum of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.
FIG. 4 illustrates a powder X-ray diffraction pattern of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid.



DETAILED DESCRIPTION OF THE INVENTION
The invention provides a stereoselective synthesis of (S)-Pregabalin according to the following scheme:




The invention encompasses (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-aryl-alkyl]amino}ethyl)hexanoic acids of formula 24,




wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl, and R is a straight or branched C1-4 alkyl, ester, or carboxylic acid. Preferably, Ar is phenyl. Preferably, R is a straight or branched C1-4 alkyl, more preferably, methyl.

Preferably, the substituted phenyl is a phenyl group substituted with at least one of alkoxy, halogen, alkyl, carboxylic acid, or ester. A preferred alkoxy phenyl is methoxyphenyl. Preferred halogenated phenyls are chlorobenzene, bromobenzene, and fluorobenzene. Preferred alkylated phenyls are either toluene or ethylbenzene.
Preferably, the C1-4 alkyl is methyl, ethyl, isopropyl, n-butyl, isobutyl or t-butyl. More preferably, the C1-4 alkyl is methyl or ethyl, most preferably, methyl.
Preferably, the carboxylic acid substituent is —COOH, —CH2COOH, —CH(CH3)COOH or —C(CH3)2COOH. Preferably the ester is a methylester, ethylester, isopropylester, n-butylester, isobutyl or t-butyl derivative of one of the above-listed carboxylic acid substituents.
When Ar is phenyl and R is methyl, the compound of formula 24 is (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid 24A




which may be characterized by data selected from a .sup.13C-NMR spectrum (CDCl3, 75 MHz) having carbon chemical shifts at about 21.74, 22.15, 22.61, 24.12, 24.87, 30.85, 38.1, 40.47, 43.38, 48.88, 126.0, 127.2, 128.49, 143.00, 172.02 and 176.66 ppm; an 1H-NMR spectrum (CDCl3, 300 MHz) having hydrogen chemical shifts at about 0.84, 1.19, 1.44-1.46, 1.63, 2.27, 5.09, 6.89-6.91, 7.28 and 11.65 ppm; an IR spectrum having peaks at about 3323, 3318.8, 2955, 1691.98, 1638, 1617, 1566 and 761 cm−1. The compound of formula 24A may further be characterized by data selected from a 13C-NMR spectrum substantially as depicted in FIG. 2; a 1H-NMR spectrum substantially as depicted in FIG. 1; and an IR spectrum substantially as depicted in FIG. 3.

The invention also encompasses isolated (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}-ethyl)hexanoic acid 24A, preferably in a crystalline form. The crystalline form of 24A may be characterized by a powder X-ray diffraction (“PXRD”) pattern having peaks at about 4.3°, 6.2°, 6.8°, 7.3°, 10.3°, and 17.4° 2θ±0.2° 2θ. The crystalline form of 24A may be further characterized by X-ray powder diffraction peaks at about 7.7°, 8.2°, 9.7°, 11.3°, 12.8°, 13.9°, 15.1°, 15.7°, 18.6°, 19.1°, 19.6°, 20.9°, 21.8°, 22.4°, and 23.3° 2θ±0.2° 2θ. The crystalline form of 24A may be even further characterized by a powder X-ray diffraction pattern substantially as depicted in FIG. 4. Moreover, the crystalline form of 24A may have a melting range of about 95° C. to about 97° C.
The invention also encompasses (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid 24A having an optical purity of at least about 80 percent area by HPLC, preferably of at least about 93 percent area by HPLC, more preferably of about 99 percent to about 100 percent area by HPLC.
The compound of formula 24 may be prepared by combining a chiral amine of formula 23,




wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl, and R is a straight or branched C1-4 alkyl, ester, or carboxylic acid, an organic solvent selected from at least one of aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, esters, alkanes, and ketones, and a base, to obtain a mixture; cooling the mixture to a temperature of about 0° C. to about −70° C.; and adding 3-isobutyl glutaric anhydride of formula 22





to the mixture to obtain the compound of formula 24,





which is then recovered from the mixture.

The 3-isobutyl glutaric anhydride of formula 22 may be prepared according to the process disclosed in U.S. Pat. No. 5,616,793.
The chiral amine of formula 23 is commercially available, and is, preferably, a primary amine. Preferably, the primary amine is selected from a group consisting of IR,2S-ephedrine, naphthyl-α-methyl ethylamine, glycine methylester, α-methylbenzylamine or a chiral amino acid derivative. Preferably, the primary amine α-methylbenzylamine, and more preferably (R)-α-methylbenzylamine.
Preferably, the aromatic hydrocarbon is a C6-8 aromatic hydrocarbon. Preferably, C6-8 aromatic aromatic hydrocarbon is toluene, xylene, ethylbenzene, or cumene, more preferably, toluene. Preferably, the ether is a C3-6 ether. Preferably, the C3-6 ether is tert-butyl methyl ether, tetrahydrofuran, diisopropylethyl, or diethyl ether, more preferably, tetrahydrofuran. Preferably, the halogenated carbon is a C1-2 halogenated hydrocarbon. Preferably, the C1-2 halogenated hydrocarbon is dichloroethane, carbon tetrachloride, or chloroform, more preferably, dichloromethane. Preferably, the alcohol is a C1-4 alcohol. Preferably, the C1-4 alcohol is isopropyl alcohol, ethanol, methanol or n-butanol, more preferably, n-butanol. Preferably, the ester is a C3-6 ester. Preferably, the C3-6 ester is ethyl acetate, isopropyl acetate, or isobutyl acetate, more preferably, ethyl acetate. Preferably, the alkane is a straight, branched or cyclic C5-7 alkane, more preferably, hexane, heptane, or cyclohexane, most preferably, heptane. Preferably, the ketone is a C3-6 ketone. Preferably, the C3-6 ketone is acetone, methyl isobutyl ketone, or methyl ethyl ketone, most preferably, acetone. The more preferred organic solvent is toluene.
Preferably, the base is an organic base. Preferably, the organic base is a C1-12 amine. Preferably, the C1-12 amine is selected from the group consisting of diethyl amine, triethyl amine, di-n-propyl amine, di-isopropyl amine, tert-butylamine, tri-n-butylamine, morpholine, piperidine, pyridine, and 4-dimethyl aminopyridine, more preferably, the C1-12 amine is 4-dimethyl aminopyridine.
Preferably, the mixture is cooled to a temperature of about 0° C. to about −60° C. before adding the 3-isobutyl glutaric anhydride of formula 22. Preferably, the mixture is maintained at a temperature of about 0° C. to about −60° C. for at least about one hour, more preferably for about one hour to about two hours, before adding the 3-isobutyl glutaric anhydride of formula 22.
The order of combining the reacting substances when preparing the compound of formula 24 may influence the purity and the yield of the final product. Preferably, the chiral amine of formula 23 is combined with the base, prior to the addition of the 3-isobutylglutaric anhydride of formula 22.
The compound of formula 24 may be recovered by any method known to the skilled artisan. Such methods include, but are not limited to, extracting the organic phase with an aqueous basic solution to convert the acidic product to a salt, and acidifying the aqueous phase with a mineral acid to obtain back the acid product.
The compound of formula 24, obtained by the above-described process, has an optical purity of at least about 80 percent area by HPLC, preferably of at least about 93 percent area by HPLC, more preferably of about 99 percent to 100 percent area by HPLC.
The compound of formula 24 may optionally be further purified by crystallization from an organic solvent selected from at least one of esters, nitrites, ethers, C4-6 straight, branched, or cyclic hydrocarbons, and C6-10 aromatic hydrocarbons. Preferably, the ester is a C3-6 ester. Preferably, the C3-6 ester is ethyl acetate or isopropyl acetate. Preferably, the nitrile is a C2 nitrile. Preferably, the C2 nitrile is acetonitrile. Preferably, the ether is a C3-6 ether. Preferably, the C3-6 ether is methyl t-butyl ether. Preferably, the C6-10 aromatic hydrocarbon is a C7-9 aromatic hydrocarbon. Preferably, the C7-9 aromatic hydrocarbon is toluene or xylene. Preferably, the C4-6 straight, branched or cyclic hydrocarbon is cyclohexane or hexane, more preferably, cyclohexane. Preferred mixtures are that of xylene and ethyl acetate, hexane and ethyl acetate, cyclohexane and ethyl acetate and toluene and ethyl acetate. The most preferred mixture is that of toluene and ethyl acetate. Most preferably, the solvent is toluene.
The invention further encompasses a process for preparing (S)-Pregabalin by the following scheme:




The process comprises preparing a compound of formula 24, converting the compound of formula 24 into a compound of the following formula 25;





converting the compound of formula 25 into (S)-Pregablin; and recovering the (S)-Pregabalin.

Preferably, the compound of formula 24 is prepared by the processes described above.
The compound of formula 24 may be converted into the compound of formula 25 by a process comprising combining the compound of formula 24, water, an ether, ammonia, and an alkali metal at a temperature of about 10° C. to about −78° C. to obtain a mixture; and recovering the compound 25 from the mixture.
Preferably, the compound of formula 24, water, and ether are combined to form a first mixture, to which ammonia and the alkali metal are then added. Preferably, combining the compound of formula 24, water and ether provides a first mixture. Preferably, ammonia and the alkali metal, are then added to the first mixture. Preferably, the compound of formula 24, water, and ether are combined at a temperature of about 10° C. to about −78° C. Preferably, the mixture containing the compound of formula 24, water, and ether is combined with ammonia and an alkali metal at a temperature of about −40° C. to about 50° C.
Preferably, the ether is a C3-6 ether. Preferably, the C3-6 ether is tetrahydrofuran or dioxane.
Preferably, the ammonia is provided in an aqueous solution, i.e., ammonium hydroxide.
The preferred alkali metal is either lithium or sodium.
Preferably, the reaction mixture is maintained for about 2 to about 10 hours, more preferably for about 6 to about 10 hours.
Alternatively, the compound of formula 24 may converted into the compound of formula 25 by a process comprising combining the compound of formula 24 with concentrated sulfuric acid to obtain a mixture; maintaining the mixture at a temperature of about 0° C. to about 50° C. for about 10 hours to about 30 hours, and recovering the compound of formula 25 from the mixture.
Preferably, the concentrated sulfuric acid contains about 96 percent to about 100 percent volume of sulfuric acid and about 0 percent to about 4 percent volume of water, more preferably, about 100 percent volume of sulfuric acid.
The preferred amount of the concentrated sulfuric acid is about 2 to about 70 mole equivalents, more preferably, about 15 to about 25 mole equivalents, and most preferably, about 15 mole equivalents per mole equivalent of the compound of formula 24.
Preferably, the reaction is maintained at a temperature of about 0° C. to about 50° C., when the amount of the concentrated sulfuric acid is about 2 to about 70 mole equivalents per mole equivalent of the compound of formula 24. More preferably, the reaction is maintained at a temperature of about 25° C. to about 45° C., when the amount of the concentrated sulfuric acid is about 15 to about 25 mole equivalents per mole equivalent of the compound of formula 24, and most preferably, the reaction is maintained at a temperature of about 35° C. to about 40° C., when the amount of the concentrated sulfuric acid is about 15 mole equivalents per mole equivalent of the compound of formula 24.
The compound of formula 25 may be recovered by any method known to the skilled artisan. Such methods include, but are not limited to extraction, followed by drying over anhydrous sodium sulfate.
The compound of formula 25 may optionally be purified by crystallization from a polar organic solvent selected from the group consisting of esters, straight and branched C1-4 alcohols, and ethers. Preferably, the ester is a C3-6 ester. Preferably, the C3-6 ester is ethyl acetate. Preferably, the straight or branched C1-4 alcohol is ethanol, methanol, isopropanol, or butanol, more preferably, isopropanol, or n-butanol, and most preferably, n-butanol. Preferably, the ether is a C3-6 ether. Preferably, the C3-6 ether is tetrahydrofuran or dioxane. The most preferred polar organic solvent is ethyl acetate.
The (R)-3-(carbamoylmethyl)-5-methyl hexanoic acid 25 is obtained by the above crystallization process having an optical purity of at least about 80 percent area by HPLC, preferably of at least about 93 percent area by HPLC, and more preferably of about of about 99 percent to about 100 percent area by HPLC.
The (R)-3-(carbamoylmethyl-5-methyl hexanoic acid 25 may be converted into (S)-Pregabalin by a process comprising combining the (R)-3-(carbamoylmethyl)-5-methyl hexanoic acid 25 with bromine, water, and an alkali hydroxide to form a basic mixture; heating the basic mixture to a temperature of about 60° C. to about 85° C.; adding a strong mineral acid to the basic mixture to obtain an acidic mixture; adding a base to the acidic mixture; and recovering (S)-Pregabalin.
Preferably, the alkali hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide, more preferably, sodium hydroxide.
Preferably, the alkali hydroxide and water are combined, first, to obtain a solution, followed by addition of compound 25 and bromine.
Preferably, compound 25 is added to the solution at a temperature of about 5° C. to about 10° C. After the addition of compound 25, bromine is added, preferably, at a temperature of about 5° C. to about 10° C.
Preferably, a C4-8 alcohol is added to the basic mixture prior to the addition of the strong mineral acid. Preferably, the C4-8 alcohol is selected from the group consisting of butanol, iso-butanol, 2-butanol, pentanol and iso-pentanol, more preferably, iso-butanol.
Preferably, the strong mineral acid is selected from a group consisting of H2SO4, HCl, HBr and H3PO4, more preferably, HCl. Preferably, the addition of the strong mineral acid provides a two-phase system, comprising an organic phase and an aqueous phase.
Preferably, the base is added to the organic phase. The base may be an organic base. The preferred organic base is a secondary or tertiary amine. Preferably, the secondary amine is diisopropylamine or dipropylamine, more preferably, diisopropylamine. Preferably, the tertiary amine is tributyl amine or triethyl amine, more preferably, tributyl amine.
The base may be an inorganic base. Preferably, the inorganic base is an alkali hydroxide or an alkali carbonate. Preferred alkali hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide. More preferably, the alkali hydroxide is sodium hydroxide. Preferred alkali carbonates include, but are not limited to, sodium carbonate, sodium bicarbonate, and potassium carbonate. More preferably, the alkali carbonate is sodium carbonate. The more preferred inorganic base is alkali carbonate, most preferably, sodium carbonate.
The addition of the base induces the precipitation of S-Pregabalin. The precipitate of S-Pregabalin may be recovered by any method known to the skilled artisan. Such methods include, but are not limited to, filtering the precipitate, followed by drying.
(S)-Pregabalin is obtained by the above process having an optical purity of about 93 percent to about 100 percent area by HPLC, preferably of about 99 percent to about 100 percent area by HPLC.
Further, 3-isobutyl glutaric anhydride 22 can be regenerated by a process comprising combining the filtrate obtained from the recovery of (S)-Pregabalin with an acid, to obtain a first mixture; heating the first mixture to obtain 3-isobutyl glutaric acid of the following formula;




combining the 3-isobutylglutaric acid with acetic anhydride to obtain a second mixture; heating the second mixture to obtain 3-isobutyl glutaric anhydride 22; and recovering the 3-isobutyl glutaric anhydride 22.

Preferably, the acid is a strong mineral acid, more preferably either 6N to 12N hydrochloric acid or 20 percent to 80 percent sulfuric acid.
Preferably, the first mixture is heated at a temperature of about 100° C. to about 125° C. Preferably, when the mineral acid is hydrochloric acid, the first mixture is maintained at temperature of about 100° C. to about 105° C. Preferably, when the mineral acid is sulfuric acid, the first mixture is maintained at a temperature of about 120° C. to about 125° C.
Preferably, the second mixture of 3-isobutylglutaric acid and acetic anhydride is heated at a temperature of about 135° C. to about 155° C., more preferably at a temperature about 135° C. to about 145° C.
3-isobutyl glutaric anhydride of formula 22 may be recovered by any method known to the skilled artisan. Such methods include, but are not limited to, distilling the excess of acetic anhydride and cooling.
The following non-limiting examples are merely illustrative of the preferred embodiments of the present invention, and are not to be construed as limiting the invention, the scope of which is defined by the appended claims.
EXAMPLES










Chiral HPLC analysis


















Instrument:
Waters-2487



Column:
CHIRAL PACK AD-H, 250 × 4.6 mm, 5 μn



Mobile phase:
2% TFA in n-Hexane/Ethanol −95/5



Flow:
0.5 ml/minute



Temperature:
30° C.



Wavelength:
210 nm/UV visible spectrophotometer




















1H-NMR analysis








F2-Acquisition parameters
F2-Processing parameters













Instrument
dpx 300




Probhd
5 mm Dual Z5
SI
32768


Pulprog
zg
SF
300.1300069 MHz


TD
16384
WDW
EM


Solvent
CDCl3
SSB
0


NS
8
LB
0.01 Hz


DS
0
GB
0


SWH
8992.806 Hz
PC
1.4


FIDRES
0.548877 Hz


AQ
0.9110004 sec


RG
16


DW
55.600 μsec


DE
4.50 μsec


TE
300.0 K


D1
5 seconds


P1
11.35 μsec


SFO1
300.1342018 MHz


NUC1
1 H


PL1
0 dB



















13C-NMR analysis












F2-Acquisition parameters

F2-Processing parameters
















Instrument
dpx 300





Probhd
5 mm Dual Z5
SI
16384



Pulprog
zgdc
SF
75.4677595 MHz



TD
16384
WDW
EM



Solvent
CDCl3
SSB
0



NS
4959
LB
10.00 Hz



DS
0
GB
0



SWH
18832.393 Hz
PC
1.4



FIDRES
1.149438 Hz



AQ
0.4350452 sec



RG
9195.2



DW
26.550 μsec



DE
4.50 μsec



TE
300.0 K



D11
0.03 second



PL12
17.8 Db



Cpdprg2
waltz 16



PCPD2
90.00 μsec



SFO2
300.1330013 MHz



NUC2
1 H



PL2
0 dB



D1
1 second



P1
9.4 μsec



DE
4.5 μsec



SFO1
75.4767751 MHz



NUC1
13 C



PL1
0 dB




















IR analysis


















KBr pellets




Number of sample scans
16



Number of background scans
16



Scanning parameters
4000-500 cm−1



Resolution
4



Sample gain
8



Mirror velocity
0.6329



Aperture
100




















X-ray analysis


















Instrument
SIEMENS “Model: D-5000



Copper radiation
1.5406 A



Scanning parameters
2-50° 2θ.



Step scan
0.03°



Step time
0.5 second










Example 1
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with toluene (400 ml), (R)-(+)-phenylethylamine (38.59 g, 0.0.319 mole) and 4-dimethylaminopyridine (0.358 g, 0.0029 mole). The mixture was cooled to a temperature of −50° C. to −60° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (50 g, 0.294 mole) in toluene (100 ml), over a period of 45-60 minutes, and stirring for additional 1.5-2 hours, at a temperature of −50° C. to −60° C. The mixture was then extracted with 3.5-4.0 percent aqueous solution of NaOH (1000 ml), and the aqueous phase was washed with toluene (1×250 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution hydrochloric acid (1-12N). The aqueous phase was further extracted with ethyl acetate (1×300 ml and 1×100 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 66 g (77.2 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.91 percent, as measured by chiral HPLC.
Example 2
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and mechanical stirrer, was charged with ethyl acetate (100 ml), (R)-(+)-phenylethylamine (26.69 g, 0.0.22 mole) and 4-dimethylaminopyridine (2.69 g, 0.15.mole). The mixture was cooled to a temperature of −50° to −60° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in ethyl acetate (50 ml), over a period of 25-30 minutes, and stirring for additional 1.5-2 hours, at a temperature of −50 to −60° C. The mixture was then extracted with 5-4 percent aqueous solution of NaOH (500 ml), and the aqueous phase was separated. The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution hydrochloric acid (1-12N). The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×100 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvent to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 35.43 g (82.87 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.4 percent, as measured by chiral HPLC.
Example 3
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with toluene (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.294 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in toluene (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0°-5° C. The mixture was then extracted with 2.5-3.0 percent aqueous solution of NaHCO3 solution (500 ml), and the aqueous phase was washed with toluene (1×100 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 28.4 g (66.4 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.6 percent, as measured by chiral HPLC.
Example 4
Preparation of (3R)-5-methyl-3-(2-oxo-2 {[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer), was charged with tert-butyl methyl ether (100 ml), (R)-(+)-phenylethylamine (43.05 g, 0.355 mole) and 4-dimethylaminopyridine (0.258 g, 0.0021 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (40 g, 0.235 mole) in tert-butyl methyl ether (100 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The mixture was then extracted with 5 percent aqueous solution of NaHCO3 solution (700 ml), and the aqueous phase was washed with tert-butyl methyl ether (1×100 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×200 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 44.5 g (70 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.19 percent, as measured by chiral HPLC.
Example 5
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methylene chloride (100 ml), (R)-(+)-phenylethylamine (53.38 g, 0.44 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in methylene chloride (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution Of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 26.2 g (61.3 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.41 percent, as measured by chiral HPLC.
Example 6
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with IPA (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g 0.147 mole) in IPA (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and'stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 25.2 g (58.9 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.34 percent, as measured by chiral HPLC.
Example 7
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with ethyl acetate (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in ethyl acetate (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12 N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 26.6 g (61.5 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.3 percent, as measured by chiral HPLC.
Example 8
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with acetone (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in acetone (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 24 g (56 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.32 percent, as measured by chiral HPLC.
Example 9
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with hexane (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0.147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in hexane (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 22.2 g (51.9 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.27 percent, as measured by chiral HPLC.
Example 10
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with a mixture of cyclohexane and toluene (100 ml) in a-ratio of 1 to 1, (R)-(+)-phenylethylamine (35.58 g, 0.147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in mixture of cyclohexane and toluene (100 ml) in a ratio of 1 to 1, (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and the aqueous phase was washed with toluene (1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 28.7 g (67 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.34 percent, as measured by chiral HPLC.
Example 11
Preparation of (3R)-5-methyl-3-(2-oxo-2 {[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methyl isobutyl ketone (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0,147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in methyl isobutyl ketone (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 25.2 g (58.9 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.3 percent, as measured by chiral HPLC.
Example 12
Preparation of (3R)-5-methyl-3-2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with toluene (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0,147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in toluene (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The mixture was then extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and the aqueous phase was washed with toluene (1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 29.3 g (68.5 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.34 percent, as measured by chiral HPLC.
Example 13
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methanol (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0,147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in methanol (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaHCO3 solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 22.2 g (51.76 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(IR)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.1 percent, as measured by chiral HPLC.
Example 14
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with ethanol (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0,147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in ethanol (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml), followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 22.7 g (53.09 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.17 percent, as measured by chiral HPLC.
Example 15
Preparation of (3R)-5-methyl-3-(2-oxo-2{[(1 R)-1-phenylethyl]amino}ethyl)hexanoic acid compound (24)
A three-neck-flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with n-butanol (100 ml), (R)-(+)-phenylethylamine (35.58 g, 0,147 mole) and 4-dimethylaminopyridine (0.18 g, 0.00147 mole). The mixture was cooled to a temperature of 0-5° C., followed by addition of a solution of 3-isobutyl glutaric anhydride (25 g, 0.147 mole) in n-butanol (25 ml), over a period of 15-20 minutes, and stirring for additional 1.5-2 hours, at a temperature of 0-5° C. The solvent was stripped off and the residue was extracted with 2.5-3 percent aqueous solution of NaOH solution (500 ml), and diluted with water (1000 ml) followed by washing the aqueous phase with toluene (1×100 ml and 1×50 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a 1-12N solution of hydrochloric acid. The aqueous phase was further extracted with ethyl acetate (1×150 ml and 1×50 ml);followed by drying the combined ethyl acetates extracts over anhydrous sodium sulfate, and stripping off the solvents, to obtain a residue. The residue was crystallized from ethyl acetate and toluene mixture to get 23.1 g (54.03 percent yield) of a white solid of (3R)-5-methyl-3-(2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)hexanoic acid with an optical purity of 99.16 percent, as measured by chiral HPLC.
Example 16
Preparation of (R)-3-carbamoylmethyl-5methyl hexanoic acid compound (25)
A 2 liter four-necked flask, equipped with a mechanical stirrer, thermometer pocket and a liquid ammonia inlet, was charged with 24 (7.5 g, 0.0257 mole) from examples 1-13, tetrahydrofuran (112.5 ml) and water (7.5 ml). The reaction mixture was cooled to −40° C. and liquid ammonia (700 ml) was added followed by addition of small pieces of sodium metal (2.5 g). The resultant reaction mixture was stirred vigorously for 6-10 hours until the ammonia had evaporated. Water (100 ml) was added to the reaction mass under N2 atmosphere at 5-10° C., followed by separating the phases. The pH of the aqueous phase was adjusted to 1.5-1.7 using hydrochloric acid, followed by extractions with methylene dichloride (2×250 ml). The combined methylene dichloride layers were dried over anhydrous sodium sulfate and the solvent was stripped off. The residue was crystallized from ethyl acetate to get 1.89 g (39.37 percent yield) of (R)-3-carbamoylmethyl-5-methylhexanoic acid with optical purity of 99.81 percent as measured by chiral HPLC.
Compound 25 is characterized by: 1. IR (KBr):3436.17, 1712.53, 1644.29 cm−1. 2. 1H NMR (CDCl3): δ 0.89-0.90 (d, 6H), 1.24-1.26 (t, 2H), 1.63-1.72 (septet, 1H 2.04-2.11 (d, 2H), 2.26-2.32 (d, 2H), 6.50 (s,1H), 6.94 (s,1H). 3. 13C NMR (CDCl3): δ 21.79, 22.02, 22.61, 24.27, 29.62, 37.86, 38.82, 39.48, 42.71, 174.39, 174.83.
Example 17
Preparation of (R)-3-carbamoylmethyl-5methyl hexanoic acid compound (25)
A 2 liter four neck-flask, equipped with a mechanical stirrer, thermometer pocket and a liquid ammonia inlet, was charged with 24 (7.0 g, 0.024 mole) from examples 1-13, tetrahydrofuran (70 ml) and water (5 ml). The reaction mixture was cooled to −40° C. and liquid ammonia (400 ml) was added followed by addition of small pieces of lithium metal (0.667 g, 0.0962 mole). The resultant reaction mixture was stirred vigorously for 6-10 hours until the ammonia had evaporated. Water (50 ml) was added to the reaction mass under N2 atmosphere at 5-10° C., followed by separating the phases. The pH of the aqueous phase was adjusted to 1.5-1.7 using hydrochloric acid, followed by extractions with ethyl acetate (1×150 ml and 1×100 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate and the solvent was stripped off. The residue was crystallized from ethyl acetate to get 2.66 g (59.37 percent yield) of (R)-3-carbamoylmethyl-5-methylhexanoic acid with optical purity of 99.8 percent as measured by chiral HPLC.
Example 18
Preparation of (R)-3-carbamoylmethyl-5methyl hexanoic acid compound (25)
A 250 ml four-necked flask, equipped with thermometer pocket and drying tube, was charged concentrated sulfuric acid (36.4 g, 0.37 mole) and 24 (2.0 g, 0.0068 mole). The reaction mixture was stirred over night at 25-30° C., and then quenched with crushed ice (150 g) and stirred. The aqueous phase was extracted with ethyl acetate (1×150 ml and 1×150 ml), followed by washing the ethyl acetate layer with water, and finally drying over anhydrous sodium sulfate. The solvent was stripped off, and the product was crystallized from ethyl acetate obtaining 0.5 g (39 percent yield) of (R)-3-carbamoylmethyl-5-methylhexanoic acid with optical purity of 99.5 percent as measured by chiral HPLC.
Example 19
Regeneration of 3-isobutylglutaric acid
A 0.5 liter four necked-flask, equipped with a mechanical stirrer, thermometer pocket, and condenser, was charged with a residue of the secondary amide after crystallization (5 g) from examples 1-13 and concentrated hydrochloric acid (100 ml). The reaction mixture was refluxed at 100-105° C. for 20-24 hours, and then cooled to 20-25° C. The pH of the mixture was adjusted to 10-11 with a 20 percent solution of sodium hydroxide. The aqueous layer was extracted with toluene (2×50 ml) and the pH of the aqueous layer was adjusted to 1.5-2 with concentrated hydrochloric acid, followed by extractions with methylene chloride (2×50 ml). The combined methylene chloride layers were dried over anhydrous sodium sulfate and the solvent was stripped off to obtain 3-isobutyl glutaric acid (3.39 g) in purity of 88.48 percent as measured by GC.
3-isobutylglutaric acid is characterized by: 1. IR (KBr): 1713.27 cm−1. 2. 1H NMR (CDCl3): δ 0.89-0.92 (d, 6H), 1.25 (t, 2H), 1.6-1.69 (septet, 1H), 2.42 (s, 4H), 11.96 (s,2H). 3. 13C NMR (CDCl3): δ 6 22.39, 25.06, 28.11, 29.50, 38.45, 43.38, 179.17.
Example 20
Regeneration of 3-isobutylglutaric acid
A 0.5 liter four-necked flask, equipped with a mechanical stirrer, thermometer pocket and a condenser, was charged with the residue of the secondary amide after crystallization (5 g) from example 1-13, and 70 percent of sulfuric acid (100 ml). The reaction mixture was refluxed at 120-125° C. for 1-2 hours, and then it was cooled to 20-25° C., followed by adjusting the pH to 10-11 with a 20 percent solution of sodium hydroxide solution. The aqueous layer was extracted with toluene (2×50 ml) and the pH of the aqueous layer was adjusted to 1.5-2 with concentrated. Hydrochloric acid, and then it was extracted with methylene chloride 92×50 ml). The combined methylene dichloride layers were dried over anhydrous sodium sulfate and the solvent was stripped off to obtain 3-isobutyl glutaric acid (3.3 g).
Example 21
Converting 3-isobutylglutaric acid to 3-isobutylglutaric anhydride, compound 22
A 1 liter four-necked flask equipped with a mechanical stirrer, thermometer pocket and condenser, was charged with 3-isobutyl glutaric acid (250 g) and acetic anhydride (62.7 g). The reaction mixture was refluxed at 135°-145° C. for 2.5-3 hours, followed by distilling out the unreacted acetic anhydride at 147°-155° C., and then the distillation was continued under vacuum to ensure removal of traces of unreacted acetic anhydride. The residue was cooled to 25°-30° C. to obtain 220-225 g of 3-isobutylglutaric anhydride.
Example 22
Preparation of (S)-Pregabalin
A 0.2 liter reactor was loaded with 60 ml of water and 17.65 g of NaOH. The solution was cooled to from 10° to 15° C., and 15 g of 25 were added. Then, 15 g of Br2 were added drop-wise over a period of 15 minutes, while maintaining the temperature at less than 20° C. The mixture was heated to 80° C. for 15 minutes, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 32 percent solution of HCl was added in an amount sufficient to provide a pH of 1. The solution was then divided to two portions.
Portion I was extracted with 37 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 71 percent yield. Optical purity: 97.2 percent area by HPLC.
Portion II was extracted with 37 ml of pentanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of pentanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 73 percent yield. Optical purity: 93.1 percent area by HPLC.
Example 23
Preparation of (S)-Pregabalin
A 0.1 liter reactor was loaded with 60 ml of water and 17.6 g of NaOH. The solution was cooled to from 10° to 15° C., and 15 g of 25 were added. The mixture was stirred, and 15 g of Br2 were added drop-wise over a period of 45 minutes, while maintaining the temperature at less than 20° C. The mixture was heated to 85° C. for 15 minutes, and then was cooled to about 20 to about 25° C. Then, 12.4 ml of H2SO4 were added drop-wise in an amount sufficient to lower the pH to 1, and the resulting solution was divided to two portions.
Portion I was extracted with 37 ml of iso-butanol. The organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4, precipitating (S)-Pregabalin, which was filtered, and washed with 10 ml of iso-butanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 63 percent yield. Optical purity: 99.1 percent area by HPLC.
Portion II was extracted with 37 ml of pentanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The precipitated (S)-Pregabalin was filtered, and washed with 10 ml of pentanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 61 percent yield. Optical purity: 96.6 percent area by HPLC.
Example 24
Preparation of (S)-Pregabalin
A 0.2 liter reactor was loaded with 60 ml of water and 17.65 g of NaOH. The resulting solution was cooled to from 10° to 15° C., and 15 g of 25 were added. Then, 15 g of Br2 were added drop-wise over 15 minutes, while maintaining the temperature at less than 20° C. The mixture was heated to 80° C. for 15 minutes, and then cooled to room temperature, i.e., about 20 to about 25° C. Then, 75 ml of iso-butanol were added, and an aqueous 32 percent solution of HCl was added in an amount sufficient to provide a pH of 2. The organic phase was separated, and (S)-Pregabalin was precipitated after the addition of 14 ml of Bu3N. The mixture was cooled to 2° C., and the solid was filtered, washed, and dried at 55° C. under vacuum, providing a 61 percent yield. Optical purity: 98.7 percent area by HPLC.
Example 25
Preparation of (S)-Pregabalin
A 0.2 liter reactor was loaded with 60 ml of water and 17.65 g of NaOH. The solution was cooled to from 100 to 15° C., and 15 g of 25 were added. Then, 15 g of Br2 were added drop-wise over 15 minutes, while maintaining the temperature at less than 20° C. The mixture was heated to 80° C. for 15 minutes, arid then cooled to room temperature, i.e., about 20 to about 25° C. Then 75 ml of pentanol were added, followed by an aqueous 32 percent of HCl in an amount sufficient to provide a pH of 2. The organic phase was separated, and (S)-Pregabalin was precipitated after the addition of 14 ml of Bu3N. The mixture was then cooled to 2° C., and the solid was filtered, washed, and dried at 55° C. under vacuum, providing a 52 percent yield. Optical purity: 96.9 percent area by HPLC.
Example 26
Preparation of (S)-Pregabalin
A 0.2 liter reactor was loaded with 110 ml of water and 27.65 g of NaOH. The solution was cooled to from 100 to 15° C., and 23.5 g of 25 were added. Then, 23.5 g of Br2 were added drop-wise over 15 minutes, while maintaining the temperature at less than 20° C. The mixture was heated to 80° C. for 15 minutes, and then cooled to room temperature, i.e., about 20 to about 25° C. An aqueous 32 percent solution of HCl was added in an amount sufficient to provide a pH of 2. The mixture was then extracted with 138 ml of iso-butanol, and the organic phase was separated. (S)-Pregabalin precipitated after the addition of diisopropylethyl amine in an amount sufficient to provide a pH of 4. The mixture was cooled to 2° C., and the solid was filtered, washed, and dried at 55° C. under vacuum, providing a 43 percent yield. Optical purity: 98.4 percent area by HPLC.
Example 27
Preparation of (S)-Pregabalin
A reactor (0.2 liter) was loaded with water (50 ml), NaOH (14.7 g). The solution was cooled to 10-15° C. and 25 (12.5 g) was added. Br2 (12.5 g) was added dropwise (15 min) while keeping the temperature below 20° C. The mixture was heated to 80° C. for 15 and then cooled to room temperature. Iso-butanol was added (75 ml) then a 66 percent solution of H2SO4 was added to obtain a pH of 2. The organic phase was separated, distilled (to a volume of 50 ml), (S)-Pregabalin was precipitated after addition of Bu3N (11.6 ml). The mixture was cooled to 2° C., and then the solid was filtered, washed, and dried at 55° C. under vacuum, providing a 81 percent yield. Optical purity: 98.9 percent area by HPLC.
While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.

## Claims

1. A compound of formula 24




wherein Ar is a C6-10 aromatic group selected from the group consisting of naphthyl, phenyl, and substituted phenyl and R is straight or branched C1-4 alkyl, ester or carboxylic acid.

2. The compound according to claim 1, wherein the C6-10 aromatic group is phenyl.

3. The compound according to claim 1, wherein R is a straight or branched C1-10 alkyl.

4. The compound according to claim 3, wherein the straight or branched C1-4 alkyl is methyl, ethyl, isopropyl, n-butyl, isobutyl or t-butyl.

5. The compound according to claim 4, wherein the C1-4 alkyl is either methyl or ethyl.

6. The compound according to claim 3, wherein the straight or branched C1-4 alkyl is methyl.

7. The compound according to claim 1, wherein the substituted phenyl is a phenyl group substituted with at least one of alkoxy, halogen, alkyl, carboxylic acid, or ester.

8. The compound according to claim 7, wherein the alkoxy substituted phenyl is methoxyphenyl.

9. The compound according to claim 7, wherein the halogen substituted phenyl is chlorobenzene, bromobenzene or fluorobenzene.

10. The compound according to claim 7, wherein the alkyl substituted phenyl is toluene or ethylbenzene.

11. The compound according to claim 7, wherein the carboxylic acid is —COOH, —CH2COOH, —CH(CH3)COOH or —C(CH3)2COOH.

12. The compound according to claim 7, wherein the ester is a methylester, ethylester, isopropyester, n-butylester, isobutyl ester, or t-butyl ester derivative of —COOH, —CH2COOH, —CH(CH3)COOH or —C(CH3)2COOH.

13. The compound according to claim 1, having optical purity of at least about 93% area by HPLC.

14. The compound according to claim 13, having optical purity of about 99% to 100% area by HPLC.

15. The compound according to claim 1, wherein Ar is phenyl and R is methyl.

16. The compound according to claim 15, wherein the compound is characterized by data selected from a group consisting of: a 13C-NMR spectrum (CDCl3, 75 MHz) having carbon chemical shifts at about 21.74, 22.15, 22.61, 24.12, 24.87, 30.85, 38.1, 40.47, 43.38, 48.88, 126.0, 127.2, 128.49, 143.00, 172.02 and 176.66 ppm; a 13C-NMR spectrum substantially as depicted in FIG. 2; an 1H-NMR spectrum (CDCl3, 300 MHz) having hydrogen chemical shifts at about 0.84, 1.19, 1.44-1.46, 1.63, 2.27, 5.09, 6.89-6.91, 7.28 and 11.65 ppm; a 1H-NMR spectrum substantially as depicted in FIG. 1; an IR spectrum having peaks at about 3323, 3318.8, 2955, 1691.98, 1638, 1617, 1566 and 761 cm−1; and an IR spectrum substantially as depicted in FIG. 3.

17. The compound according to claim 15, wherein the compound is in crystalline form.

18. The compound according to claim 17, characterized by a PXRD pattern having peaks at about 4.3°, 6.2°, 6.8°, 7.3°, 10.3°, and 17.4° 2θ±0.2° 2 θ.

19. The compound according to claim 18, further characterized by data selected from a group consisting of: a PXRD pattern having peaks at about X-ray powder diffraction peaks at about 7.7°, 8.2°, 9.7°, 11.3°, 12.8°, 13.9°, 15.1°, 15.7°, 18.6°, 19.1°, 19.6°, 20.9°, 21.8°, 22.4°, and 23.3° 2θ±0.2° 2 θ.; a PXRD pattern substantially as depicted in FIG. 4; and a melting range of about 95° C. to about 97° C.