DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of R,S-ester formula (I) using proline or substituted proline. The present invention further provides an improved process for the preparation of Pregabalin using R,S-ester formula (I), obtained by a process described herein.

BACKGROUND OF THE INVENTION

Pregabalin chemically known as 3-(S)-aminomethyl-5-methyl hexanoic acid, is used to treat several central nervous system disorders that include epilepsy, neuropathic pain, anxiety and social phobia.

The International (PCT) publication no. WO2008062460 A2 and U.S. Patent No. 6,046,353 discloses a method for preparation of Pregabalin via. an intermediate recemic R,S-ester (ethyl-3-cyano-5-methyl-hexanoate) by reacting diethyl malonate and isovaleraldehyde which on hydrolysis, hydrogenation and subsequent resolution provide pregabalin. The process scheme is as depicted below.

US patent no.10,023,885 B2 discloses the process for the preparation of Pregabalin as depicted in below scheme, wherein the R,S-ester is obtained by reacting isovaleraldehyde and alkyl -2-cyanoacetate via. an intermediate 2-isobutylsuccinonitrile and the R,S-ester further converted into Pregabalin.

From above patent / patent application it seems that R,S-ester is one of the key strategic intermediates in the commercialization of Pregabalin API. The research article ACS Catalysis Vol. 1, Iss. 9, 1010-1013discloses a method for producing R,S-ester (ethyl 3-substituted-3- cyanopropionate) in three steps: i) by reacting diethyl malonate and isovaleraldeyhde in presence of piperidine, acetic acid and hydrocarbon solvent such as n-heptane at reflux temperature for 16-23 hours; ii) treating with potassium cyanide in presence of ethanol;and iii) by enzymatic resolution using lipase enzyme in presence of water and potassium phosphate buffer at 30°C for 22hours.The above reaction involved piperidine which is a flammable, explosive, toxic reagent, costly lipase enzyme for enzymatic resolution and costly solvents n-heptane. The process may also createhazardous waste which required further treatment thus, the overall process set to become expensive and cumbersome in nature and makes process non-feasible on commercial scale.

International (PCT) publication no.WO 2010070593 A2 (henceforth '593) discloses a method for preparation of R,S-ester (ethyl-(3R)-3-cyano-5-methylhexanoate) in four steps: i) by reacting diethyl malonate and isovaleraldehyde in presence of dipropylamine, acetic acid and hydrocarbon solvent such as cyclohexane at reflux temperature for 3 hours; ii) treating with potassium cyanide or sodium cyanide in presence expensive N-(4-Trifluoromethylbenzyl) cinchoninium bromide catalyst in a methyl tert-butyl ether solvent for overnight; iii) by treating with potassium hydroxide in presence of water and ethanol at 30°C for overnight; and iv) by treating with acetic acid in presence of ethanol, at reflux temperature for 10 hours.The above reaction involved expensive catalyst, reagents and solvents. The above reaction also involved extensive reaction conditions and long cycle time; thus, it increases overall cost of production.

Indian patent IN 262797 (henceforth '797) discloses a method for preparation of R,S-ester (ethyl-3-cyano-5-methylhexanoate) in three steps: i) by reacting diethyl malonate with isovaleraldehyde in presence of morpholine, acetic acid, chlorinated solvent such as dichloromethane at 50°C for 5 hours; ii) treating with sodium cyanide in presence acetic acid, ethanol, n-heptane solvent(s); and iii) by treating with sodium chloride in presence of water and dimethylsulfoxide for 2 hours. The above reaction involved flammable, corrosive base such as morpholine, corrosive solvent such as dichloromethane. The above reaction also involved multiple solvents and reagent which involved additional cost for distillation, isolation and removal of effluent which increases overall cost of production.

International (PCT) publication no.WO 2006128706A2 (henceforth '706) discloses a method for preparation of (5s,6s)-6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylic acid (2,3-CHA).The'706 patent, also discloses the process for preparation of compound dimethyl2-(3-methylbutylidene) malonateby reacting with dimethyl malonate and isovaleraldehyde in presence of L-Proline, in a dimethyl sulfoxide solvent for overnight and resulting compound is isolated by using multiple isolation and extraction technique. The above process involved skin irritant, corrosive and high boiling dimethyl sulfoxide solvent which required additional purification and vacuum distillation technique for its removal. Moreover, the present process required longer cycle time for completion of reaction, which makes process non-suitable on commercial scale.

Although several processes have been reported for the preparation of R,S-ester, they suffer from one or more drawbacks such as use of hazardous regents like piperidine, morpholine, expensive N-(4-Trifluoromethylbenzyl) cinchoninium bromide catalyst and corrosive, toxic solvents such as dimethyl sulfoxide, dichloromethane etc, also involving a number of isolation and purification steps. Hence, there is still a need for simple, cost effective and industrially viable process to produce R,S-ester.

To overcome the existing limitations, the inventors of instant invention has developed a process for the preparation of recemic R,S-ester by using commercially available reagent, and solvents. The instant invention provides R,S ester in a simple two-step process with short cycle time in a cost effective and industrially viable manner.

OBJECTIVES OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of R,S-ester of formula (I), using proline or substituted prolinein an alcoholic solvent.

Another objective of the present invention is to provide a process for the preparation of Pregabalin by using R,S-ester of formula (I)which is obtained by a process of an instant invention.

SUMMARY OF THE INVENTION

In one aspect of the present invention provides an improved process for the preparation of R,S-ester of formula (I), which comprises the steps of:

a) reacting compound of formula (II) with isovaleraldehyde (III) to obtain compound of formula (IV) in presence of proline or substituted proline in analcoholic solvent;

wherein R1 and R2 are same or different and selected from linear or branched C1 to C4 alkyl;
b) reacting compound of formula (IV) with a cyanide source to obtain racemic cyano diester compound of formula (V) in presence or absence of acid catalyst in alcoholic solvent;

c) converting racemic cyano diester compound of formula (V) to cyano acid of formula (VI) wherein M is hydrogen, in presence of base, alcoholic solvent;

d) converting an acid group of formula (VI) to racemic R,S-ester compound of formula (I) in presence of an acid catalystin alcoholic solvent.

The above process is illustrated in the following general synthetic scheme.

wherein R1, R2 and M as given above.

In another aspect of the present invention provides an improved process for the preparation of R,S-ester of formula (I), which comprises the steps of:

a) reacting compound of formula (II) with isovaleraldehyde (III) to obtain compound of formula (IV) in presence of proline or substituted proline in an alcoholic solvent;

wherein R1 and R2 are same or different and selected from linear or branched C1 to C4 alkyl;
b) obtaining compound of formula (I) by inherent reaction transformation of compound formula (IV): wherein first compound of formula (IV) reacting with cyanide source in presence or absence of acid catalyst in alcoholic solvent, resulting recemic compound of formula (V) reacting with base in alcoholic solvent, and finally compound of formula (VI) reacting with alcoholic solvent in presence of an acid catalyst.

In another embodiment of the present invention provides an improved process for the preparation of compound of formula (I), where R is methyl.

In another embodiment of the present invention provides an improved process for the preparation of compound of formula (I), where R is ethyl.

In another aspect of the present invention provides an improved process for the preparation of Pregabalin using racemic R,S-ester of formula (I) obtained by a process described herein, where the process for preparation of Pregabalin is followed by a person skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive. As used in the specification, and in the appended claims, indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular indicates otherwise. The word “recemic(s)” or “racemic mixture(s)” means the 50:50 mixture of individual R and S enantiomers.

The term ‘solvent’ used herein, refers to the single solvent or mixture of solvents.

In accordance with the objective the present invention provides an improved process for the preparation of R,S-ester of formula (I);

where step (a) comprises reacting compound of formula (II) with isovaleraldehyde (III) to obtain compound of formula (IV) involving a Knoevenagel condensation.

In one embodiment of the present invention the Knoevenagel condensation is carried-out in presence of proline or substituted proline.

In another embodiment of the present invention, wherein the said proline or substituted prolineis selected from D/L-proline, N-carbobenzyloxy proline, N-tert-butoxycarbonyl-proline, N-nitrosoproline, 1-benzyl-pyrrolidine-2-carboxylic acid, 1-(4-methylbenzyl)pyrrolidine-2-carboxylic acid, 1-formylpyrrolidine-2-carboxylic acid, N-propyl-proline, and N-phenylproline; preferably L-Proline .

In another embodiment of the present invention, wherein the said cyanide source is selected from lithium cyanide, sodium cyanide, potassium cyanide, trimethylsilyl cyanide; preferably sodium cyanide.

In another embodiment of the present invention wherein, the cyanide source optionally is used in 1-50% excess.

In another embodiment of the present invention, wherein the said base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium hydride (NaH), potassium tert-butoxide (KtOBu), sodium methoxide (NaOMe), hydrazine hydrate (NH2NH2.H2O), ammonia (NH3), alkali and alkaline earth metal, and C1 to C6 alkoxide; preferably potassium hydroxide.

In another embodiment of the present invention, wherein the said acid catalyst is selected from sulfuric acid, hydrochloric acid, nitric acid, glacial acetic acid, citric acid, boric acid, and ethylene diamine tetra acetic acid; preferably sulfuric acid.

In another embodiment of the present invention, wherein the said alcoholic solvent used in is preferably selected from ethyl alcohol, methyl alcohol, isopropyl alcohol, n-propanol, n-butanol and the like; more preferably methanol, ethanol.

In still another embodiment of the present invention, wherein the one or more steps from (a) to (d) of the instant invention may be performed in in-situ manner.

In accordance with the objectives the present invention provides an improved process for the preparation of compound of formula (I), where R is methyl, ethyl;

where step (a) comprises reacting dimethyl malonate or diethyl malonate of formula (II) with isovaleraldehyde (III) to obtain compound of formula (IV) involving Knoevenagel condensation.

In one embodiment of the present invention, wherein the Knoevenagel condensation is carried-out in presence of proline or substituted proline in an alcoholic solvent.

In another embodiment of the present invention, wherein the said proline or substituted proline used for Knoevenagel condensation is selected from the group consisting of D/L-proline, N-carbobenzyloxy proline, N-tert-butoxycarbonyl-proline, N-nitrosoproline, 1-benzyl-pyrrolidine-2-carboxylic acid, 1-(4-methylbenzyl)pyrrolidine-2-carboxylic acid, 1-formylpyrrolidine-2-carboxylic acid, N-propyl-proline, and N-phenylproline; preferably L-Proline.

In another embodiment of the present invention, where step (b) comprises obtaining of racemic compound of formula (I) directly from compound of formula (IV) by three inherent reaction transformations of; where, firstly compound of formula (IV) is reacting with cyanide source in presence or absence of acid catalyst; which subsequently reacted with base; finally reacted with alcoholic solvent in presence of a acid catalyst.

In another embodiment of the present invention, wherein the said cyanide source is selected from the group consisting of lithium cyanide, sodium cyanide, potassium cyanide, and trimethylsilyl cyanide; preferably sodium cyanide. In another embodiment of the present invention wherein, the cyanide source optionally is used in 1-50% excess.

In another embodiment of the present invention, wherein the said acid catalyst is selected from sulfuric acid, hydrochloric acid, nitric acid, glacial acetic acid, citric acid, boric acid, and ethylene diamine tetra acetic acid; preferably sulfuric acid.

In another embodiment of the present invention, wherein the said base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium hydride (NaH), potassium tert-butoxide (KtOBu), sodium methoxide (NaOMe), hydrazine hydrate (NH2NH2.H2O), ammonia (NH3), alkali and alkaline earth metal, and C1 to C6 alkoxide; preferably potassium hydroxide

In another embodiment of the present invention, wherein the said alcoholic solvent used for preparation of racemic methyl-3-cyano-5-methyl-hexanoate of formula (I) is preferably selected from ethyl alcohol, methyl alcohol, isopropyl alcohol, n-propanol, n-butanol and the like; more preferably methanol, ethanol.

In another embodiment of the present invention, wherein compound of formula (IV)is used as such or purified by distillation or other techniques well understood by those skilled in the art.

In another embodiment of the present invention, wherein the entire process for preparation of R,S-ester is carried out at a temperature 20°C to 80°C.

In another embodiment of the present invention, wherein the overall cycle time for preparation of R,S-ester is 4 to 10 hours.

In accordance with the objective an improved process for the preparation of compound R,S-ester of formula (I) obtained by the process described herein is further used for the preparation of pregabalin.

The following non-limiting examples are given by way of illustration of the present invention and therefore should not be construed as limitation of the invention scope.

EXAMPLES

Example 1:Preparation of dimethyl 2-(3-methylbutylidene) malonate (IV).

The dimethyl malonate (500.0 g, 1.0 eq), isovaleraldehyde (359 g, 1.1 eq), methanol (250mL, 0.5V) and L-proline (21.77g, 0.05eq) were added at 20°C to 30°C and stirred for 4-6 hours. After completion, solvent was removed under vacuum at 40°C to 50°C.The reaction mixture was cooled to room temperature and filtered to remove L-proline to obtain yellow to brown coloured dimethyl 2-(3-methylbutylidene) malonate(737.2g 97.31% yield, HPLC assay98.03 %.).

Example 2: Preparation of diethyl 2-(3-methylbutylidene) malonate (IV)

The diethyl malonate (5.0 Kg, 1.0 eq), isovaleraldehyde (2.95 Kg, 1.1 eq), ethanol (5.0 L, 1.0 V) and L-proline (0.179 Kg, 0.05 eq) were added at 20 °C to 30 °C and stirred for 10-12 hours. After completion, solvent was removed under vacuum at 40°C to 50°C. The reaction mixture was cooled to room temperature and filtered to remove L-proline to obtain yellow to brown coloured diethyl 2-(3-methylbutylidene) malonate (6.84 Kg, 95.98 % yield, GC Purity 92.58 %.).

Example 3: Preparation of racemic methyl -3-cyano-5-methyl-hexanoate (I).

To a solution of methanol (1080ml, 1.5V) and sodium cyanide (167.87 g, 0.95 eq), adimethyl 2-(3-methylbutylidene) malonate (720.0 g, 1.0eq) was added maintaining the temperature at 20°C to 40°C and further stirred 1.0 hour. After completion of reaction, the reaction mixture was cooled to 10°Cto 20°C and concentrated sulfuric acid (193.8 g ,0.55eq) was added, stirred for 1.0hour. To the reaction mixture, a solution of potassium hydroxide (242.1g, 1.2 eq) in methanol (1080mL, 1.5V) was added and heated to 60°C to 70°C for 4-5hours. The reaction mixture was cooled to room temperature and concentrated sulfuric acid (246.7g, 0.7eq), methanol (720 mL, 1.0V) were added and further heated to 60°C to 70°C. The reaction mixture was cooled to room temperature and quenched by adding sodium bicarbonate (90.62 g, 0.30 eq.)and stirred for 10 to 20 minutes. The reaction mixture was filtered, washed with methanol and solvent was removed under vacuum. To the reaction mixture water was added and aqueous layer was extracted with toluene. The organic layer was washed with water and concentrated under vacuum to obtain racemic methyl -3-cyano-5-methyl-hexanoate (576g , 95% yield, GC assay 93.31%), which was purified by high vacuum distillation to obtain pure pale yellow methyl -3-cyano-5-methyl-hexanoate ( 456.3g, 75% yield with GC Assay 96.42%.).
,CLAIMS:We claim:

1. A process for preapration of R,S-ester of formula (I), which comprises the steps of:

a) reacting compound of formula (II) with isovaleraldehyde (III) to obtain compound of formula (IV) in presence of proline or substituted proline in an alcoholic solvent;

wherein R1 and R2 are same or different and selected fromlinear or branched C1 to C4 alkyl;
b) obtaining compound of formula (I) by inherent reaction transformation of compound formula (IV): wherein first compound of formula (IV) reacting with cyanide source in presence or absence of acid catalyst in alcoholic solvent, resulting recemic compound of formula (V) reacting with base in alcoholic solvent, and finally compound of formula (VI) reacting with alcoholic solvent in presence of an acid catalyst.

2. The process as claimed in claim 1 ,wherein said proline or substituted proline is selected from D/L-proline, N-carbobenzyloxy proline, N-tert-butoxycarbonyl-proline, N-nitrosoproline, 1-benzyl-pyrrolidine-2-carboxylic acid, 1-(4-methylbenzyl)pyrrolidine-2-carboxylic acid, 1-formylpyrrolidine-2-carboxylic acid, N-propyl-proline, and N-phenylproline.

3. The process as claimed in claim 1, wherein said cyanide source is selected from lithium cyanide, sodium cyanide, potassium cyanide, and trimethylsilyl cyanide.

4. The process as claimed in claim 1,wherein said base is selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium hydride (NaH), potassium tert-butoxide (KtOBu), sodium methoxide (NaOMe), hydrazine hydrate (NH2NH2.H2O), ammonia (NH3), alkali and alkaline earth metal, and C1 to C6 alkoxide.

5. The process as claimed in claim 1, wherein said acid catalyst is selected from sulfuric acid, hydrochloric acid, nitric acid, glacial acetic acid, citric acid, boric acid, and ethylene diamine tetra acetic acid.

6. The process as claimed in claim 1, wherein said alcoholic solvent selected from ethyl alcohol, methyl alcohol, isopropyl alcohol, n-propanol, and n-butanol.

7. The process as claimed in claim 1 is carried out at temperature 20°C to 80°C for 4 to 10 hours.

8. The process as claimed in claim 1, wherein compound of formula (I) obtained by cited process is used for preparation of Pregabalin.