GILLA GOVERDHAN (IN)
CRASTA SANTOSH (IN)
GUGALE SHIVAJI (IN)
LANDGE RAVINDRA (IN)
| EP2916832B1 | 2019-01-16 |
| CLAIM: 1) An improved process for the preparation of Pregabalin of formula (I), which comprises the steps: a) reacting compound of formula (II) and compound of formula (III) in presence of a cyanide source in water, optionally in presence of phase transfer catalyst to obtain compound of formula (IV); (II) (III) (IV) where Ri is a linear or branched C1-C4 alkyl; b) reacting compound of formula (IV) with Nitrilase enzyme having 60-200% loading and optionally isolating compound of formula (V) or salt thereof; where R2 is a cationic counter ion selected from the group consisting of hydrogen, alkali metal, alkaline earth metal, ammonium, alkyl ammonium, and organic amine; c) esterifying a compound of formula (V)or salt thereof using alcohol(R30H) or alkyl halide (RsX)in presence or absence of acid or base catalyst and solvent or a mixture of solvents thereof to obtain racemic compound of formula (Vl)which is significantly free from impurities; where R3 is selected from the group consisting of a linear or branched Ci-C4alkyl, Ce- Cioaryl, and alkylaryl. d) - separating racemic compound of formula (VI) to (S)-isomer of formula (VII) and (R)-isomer of formula (VIII) or salt thereof by enantio selective hydrolysis in2-10 volume of buffer solution or solvent(s) or a mixture thereof; where, enantio selective hydrolysis is performed using an enzyme selected from the group consisting of: Candida Antarctica lipase A, Candida Antarctica lipase Bl, Candida Antarctica lipase BY2, Novozym 435, Lipase 3.101, Lipase 3.102, Lipase 3.104, Lipase 3.105, Lipase 3.106, Lipase 3.107, Lipase 3.108, Lipase 3.109, Lipase 3.111, Lipase 3.115, Lipase 3.113, Lipase 3.117, Lipase 3.136, e) Optionally obtaining improved yield of racemic compound of formula (VI) by esterification using alcohol (R3OH) or alkyl halide (R3X) in presence or absence of acid or base catalyst and solvent(s) and racemization in presence of base, solvent; f) converting compound of formula (VII) to Pregabalin formula (I) by hydrolyzing ester using a base followed by hydrogenation in presence of solvent(s)with 5-30% catalyst loading. 2) The process as claimed in claim 1, wherein the cyanide source in step (a) is selected from the group consisting of lithium cyanide, sodium cyanide, potassium cyanide, and trimethyls ilyl cyanide. 3) The process as claimed in claim 1, wherein the phase transfer catalyst in step (a) is selected from ammonium salts such as acetylcholine chloride, Aliquat 336, Benzalkonium chloride, Cetyltrimethylammonium chloride, Decyltrimethylammonium bromide, Hexadecyltrimethylammonium bromide, Tetrabutylammonium acetate, Tetrabutylammonium bromide, Tetrabutylammonium iodide, Tetrabutylammonium difluorotriphenylstannate , or selected from Heterocyclic ammonium Salts such as N-(Allyloxycarbonyloxy)succinimide, 1-Butyl- 2,3-dimethylimidazolium chloride, Hexadecylpyridinium bromide, Methyl viologen dichloride hydrate and the like or selected from Phosphonium Salts such as Bis[tetrakis(hydroxymethyl)phosphonium] sulfate solution, Tetrabutylphosphonium bromide, Tetrabutylphosphoniummethane sulfonate. 4) The process as claimed in claim 1, wherein the step (a) is carried out at a temperature 10°C to 120°C; and steps (b) and (c) are carried out at ambient temperature to reflux temperature. 5) The process as claimed in claim 1, wherein loading of Nitrilase enzyme is 60-80%. 6) The process as claimed in claim 1, wherein the step (b), step (c), step (d)are carried out at pH from 1.0 to 8.5. 7) The process as claimed in claim 1, wherein the solvent in steps (c), step (d), step (e),and step (f) is selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n-butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, cyclohexanol, toluene, monochlorobenzene, dichlorobenzene, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethyl amine, dimethyl sulfoxide, sulfolane, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methyl tert-butyl ether, cyclohexane. 8) The process as claimed in claim 1, wherein alcohol (R3OH) in step (c) and step (e) is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n- butyl alcohol, cyclopentanol, and cyclohexanol. 9) The process as claimed in claim 1, wherein alkyl halide (R3X) in step (c) and step (e)is selected from methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl bromide, isopropyl chloride and isopropyl bromide. 10) The process as claimed in claim 1, wherein an acid catalyst in step (c) and step (e) is selected from hydrochloric acid, sulfuric acid, thionyl chloride, trimethylsilyl chloride, methane sulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid, trifluoromethanesulfonic acid, Lewis acid or acidic sulfonated resins. 11) The process as claimed in claim 1, wherein an base catalyst in step (c) and step (e) is from group consisting of mono, di and tri alkyl amine such as triethyl amine, N,N- diisopropylethylamine, 1,8 diazabicyclo[5.4.0]undec-7-ene,l,5- diazabicyclo[4.3.0]non-5-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, pyridine, morpholine, N-methyl morpholine inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, alkali or alkaline earth metal Ci-C6alkoxide. 12) The process as claimed in claim 1, wherein an impurities of step (c) are succinimide and amide ester impurities. 13) The process as claimed in claim 1, wherein racemic compound of formula (VI) in step (c)is significantly free from succinimide impurity and amide ester where the content of impurity is less than 0.1% by GC. 14) The process as claimed in claim 1, wherein enantioselective hydrolysis in step (d) is carried out using an enzyme Novozym 435; and volume of buffer solution is 5.0V. 15) The process according to claim 1, wherein the base in step (f) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, and C1-C5 quaternary ammonium hydroxide; and with 0.75 equivalents to 2.5 equivalents; more preferably 1.5 equivalent. 16) The process as claimed in claim 1, wherein the hydrogenation catalyst in step (f)is selected from the group consisting of Nickel, Palladium, Ruthenium, Rhodium, with or without support and any chemical forms and grades with 10%w/w loading; and hydrogenation is carried out at a temperature 25C to 65°Cwith a hydrogen pressure 7 to 15 kg/cm2. 17) The process as claimed in claim 1, wherein hydrogenation product of step (f) optionally comprises charcoalization and isolated Pregabalin by pH maintenance and crystallization processes with the desired chemical purity more than 99.95% and chiral purity more than 99.9%. 18) The process as claimed in claiml7, wherein pH is maintained in range of 7.0 to 7.5using inorganic or organic acid such as hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, formic acid, trifluoro acetic acid; and crystallization is performed in presence of water, methanol ethanol, n-propanol, isopropanol. |
FIELD OF INVENTION
The invention relates to a commercially viable greener process for manufacturing Pregabalin in high yield with high purity.
BACKGROUND
Pregabalin, chemically known as 3-(S) -(aminomethyl) -5 -methyl hexanoic acid having structure of formula (I) is known to treat several central nervous system disorders that include epilepsy, neuropathic pain, anxiety and social phobia.
(S) -Pregabalin has been found to activate GAD ( L-glutomic acid decarboxylase) in a dose dependent manner and promote production of GABA (gamma-aminobutyric acid), one of the major inhibitory neurotransmitters of brain. The discovery of antiseizure activity was first disclosed in US Patent No. 5, 563, 175. Pregabalin has been prepared in various ways; the most common approach involves synthesis of racemic Pregabalin, typically a 50:50 mixture of R and S isomer and subsequent resolution through diastereomeric salt formation. This approach is disclosed in patent publications such as WO2009122215, W02009087674, W02009044409, W02008138874, WO2009125427 and W02009001372.The major difficulty associated with this approach involves the loss of R-isomer along with desired S- isomer which cannot be effectively recycled leading to overall increase in cost. W02009087674 patent publication involved chemical resolution using chloroform which is not a preferred solvent for preparation of drug substances on commercial scale.
The PCT publication no WO9638405described the synthesis of S-Pregabalin (Schemel). The synthesis involves Knoevenagel condensation followed by Micheal addition and acidic hydrolysis to provide diacid. The diacid was converted to mono amide which was resolved by (R)-phenylethylamine. The prepared R-mono acid amide further converted into (S)- Pregabalin by Hoffmann degradation. The drawback of this process is low overall yield (12%) and obtained after 8 steps. Scheme 1:
The PCT publication no. W02008062460 and patent no. US6,046,353 described condensation of diethyl malonate with isovaleraldehyde followed by cyanation. The product is selectively hydrolyzed and decarboxylated to cyano ester which on hydrolysis gave cyano acid. The cyano acid was hydrogenated to racemic Pregabalin and resolved by (S)-(+) Mandelic acid (Scheme 2). The drawback of this process is use of expensive reagents, low overall yield (15.5%) and obtained after 6 steps. Scheme2: The Patent no.US8,304,252 described the preparation of Pregabalin by enzymatic route (Scheme 3). The process involved condensation of isovaleraldehyde with ethyl cyanoacetate followed by cyanation to provide racemic dicyano compound. The Nitrilase enzyme was used to obtain (S)-cyano acid and the unwanted dinitrile was racemized in presence of DBU in toluene. The hydrogenation of (S)-cyano acid salt gave (S)-Prgabalin in low overall yield (7.7%) obtained after 4 steps. The major drawback of this process is low yield and use of corrosive regents which makes the process economically and environmentally unviable.
Scheme 3 :
Thus, to -overcome the drawbacks of above-mentioned prior art -processes, there is a need to develop an improved process for the preparation of desired (S)-Pregabalin of formula (I) in greater yield with high chemical and chiral purity which is readily applicable on industrial scale. Thus, above drawbacks and need, motivated present inventor to develop an improved and simple process for the preparation of “substantially pure”(S)-Pregabalin of formula (I) from undesired isomer with greater yield, higher chemical and chiral purity. The recycling and reuse of undesired isomer formed in reaction makes process industrially more suitable by using genetically modified Nitrilase enzyme and lipases enzyme in a cost effective and eco- friendly manner.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of Pregabalin of formula (I), which comprises the steps: a) reacting compound of formula (II) and compound of formula (III) in presence of a cyanide source in water, optionally in presence of phase transfer catalyst to obtain compound of formula (IV);
(II) (I") (iv) where Ri is a linear or branched C 1 -C 4 alkyl; b) reacting compound of formula (IV) with minimum loading of Nitrilase enzyme to obtain compound of formula (V) or salts thereof, which is optionally isolated; where R 2 is a cationic counter ion selected from the group consisting of hydrogen, alkali metal, alkaline earth metal, ammonium, alkyl ammonium and organic amine; c) esterifying a compound of formula (V) or salt thereof to obtain a racemic compound of formula (VI) free from impurities; where R 3 is selected from the group consisting of a linear or branched Ci-C 4 alkyl, Ce- C 10 aryl and alkylaryl; d) separating racemic compound of formula (VI) to (S)-isomer of formula (VII) and(R)- isomer of formula (VIII) or salt thereof by enantioselective hydrolysis in minimum volume of buffer solution or solvent or a mixture thereof; e) optionally converting a compound of formula (VIII) to racemic compound of formula (VI) by esterification followed by racemization; f) converting compound of formula (VII) to Pregabalin of formula (I)by hydrolyzing ester group with base followed by hydrogenation with minimum loading of hydrogenation catalyst in solvent.
In one embodiment, the present invention provides a process for the preparation of a compound of formula (I) with reduced cycle time (four steps), 22% overall yield and reduced impurity formation.
In another embodiment, the present invention provides a process for the preparation of a compound of formula (I) using of environmentally benign solvent such as water and low-cost phase transfer catalyst to facilitate greener approach and reduce load on effluent waste.
The above process is illustrated in the following general synthetic scheme: wherein
Riis linear or branched C 1 -C 4 alkyl;
R2 is cationic counter ion selected from the group consisting of hydrogen, alkali metal, alkaline earth metal, ammonium, alkyl ammonium and organic amine;
R3IS selected from the group consisting of a linear or branched Ci-C4alkyl, C 6 -C 10 aryl, and alkyl aryl.
DETAILED DESCRIPTION OF THE INVENTION
The present invention now will be described more fully hereinafter. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly indicates otherwise. The term "substantially pure”(S) enantiomer indicates the presence of (S)and(R) enantiomer in the preferred ratio of 85:15 to 100:0; more preferably in the ratio 95:5 to 100:0; most preferably in the ratio 99:1 to 100:0.
In an embodiment of the present invention, where the present invention provides an improved process for the preparation of a compound of formula (I) via enantioselective enzymatic approach with high chemical and chiral purity.
In an embodiment of the present invention, where the said cyanide source in step (a) is preferably selected from lithium cyanide, sodium cyanide, potassium cyanide, trimethylsilyl cyanide and the like; more preferably sodium cyanide or potassium cyanide.
In an another embodiment of the present invention, where the said phase transfer catalyst in step (a) is selected from ammonium salts such as acetylcholine chloride; Aliquat 336;Benzalkonium chloride (BZK); Cetyltrimethylammonium chloride (CTAC); Decyltrimethylammonium bromide; Hexadecyltrimethylammonium bromide (CTAB); Tetrabutylammonium acetate (TBAC); Tetrabutylammonium bromide (TBAB);Tetra butyl ammonium Iodide (TBAI); Tetrabutylammonium diflu oro triphenyl stannate; or selected from heterocyclic ammonium salts such as N-(allyloxycarbonyloxy)succinimide; 1 -butyl -2,3- dimethylimidazolium chloride; Hexadecylpyridinium bromide; Methyl viologen dichloride hydrate and the like or selected from phosphonium salts such as Bis[tetrakis(hydroxymethyl)phosphonium] sulfate solution; Tetrabutylphosphonium bromide; Tetrabutylphosphoniummethane sulfonate and the like, preferably Tetrabutylammonium bromide.
In another embodiment of the present invention, where water used for the process in any reaction is process water, mineral water, demineralized water and the like.
In another embodiment of the present invention, where the said reaction of step (a) is carried out at 10°C to 120 °C preferably 60°C to 120°C.
In another embodiment of present invention, where of the step (a) involve the formation of by-product which was removed by simple distillation technique to reduce the cost on incineration.
In another embodiment of the present invention, where the said Nitrilase enzyme in step (b) is a genetically modified Nitrilase enzyme such as Nit 9N _ 56_2.
In another embodiment of the present invention, where loading of Nitrilase enzyme in step
(b) is from 50% to 300%;more preferably 65% to 125%.
In an another embodiment of the present invention, where step (b) compound of formula (V) or salts thereof is obtained by maintaining initial pH of reaction mixture between 7.5+1.0; preferably 7.5 +0.5 using base preferably selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxides, ammonia, methyl ammonium chloride, triethyl amine and the like; more preferably sodium bicarbonate and further maintaining later pH of organic solution between 1.0 to 2.0 using an acid selected from acetic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like; more preferably concentrated hydrochloric acid or sulfuric acid.
In another embodiment of the present invention, where the compound of formula (V) or salts thereof is optionally isolated and used as such for subsequent steps without purification.
In another embodiment of the present invention, where the said esterification reaction in step
(c) is performed in presence of alcohol (R 3 OH) or alkyl halide (R 3 X) in presence or absence of acid or base catalyst and solvents. In an another embodiment of the present invention, where the said alcohol (R 3 0H)is preferably selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, 77 -propyl alcohol, 77-butyl alcohol, benzyl alcohol, cyclopentanol, cyclohexanol and the like; more preferably methyl alcohol or ethyl alcohol.
In another embodiment of the present invention, where the said alkyl halide (R3X) is selected from the group consisting of methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, 77- propyl bromide, isopropyl chloride and isopropyl bromide.
In an another embodiment of the present invention, where the said acid catalyst for esterification in step (c) and step (e) is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, thionyl chloride, trimethylsilyl chloride, methanesulfonic acid, paratoluene sulfonic acid, benzene sulfonic acid, trifluoromethanesulfonic acid, Lewis acids or strongly acidic sulfonated resins and the like; more preferably hydrochloric acid or sulfuric acid.
In an another embodiment of the present invention, where the base catalyst for esterification in step (c) and racemization in step (e) is selected from organic or inorganic bases, alkoxides and added either in solid or solution state to minimize the formation of impurities such as succinimide and amide ester impurities.
In an another embodiment of the present invention, where the organic base in step (c) and step (e) is selected from group consisting of mono, di and tri alkyl amine such as triethyl amine, N,N-diisopropylethylamine, 1,8 diazabicyclo[5.4.0]undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, 1,5- diazabicyclo[4.3.0]non-5-ene, imidazole, 4- dimethylaminopyridine, morpholine, N-methyl morpholine; inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide; preferably sodium bicarbonate and alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide and the like; more preferably sodium bicarbonate in step (c) and sodium methoxide in step (e).
In an embodiment of the present invention, where the solvent in step (c)and step (e)is selected from the group consisting of water, ethyl alcohol, methyl alcohol, isopropyl alcohol, 77-butyl alcohol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methyl tert -butyl ether, cyclohexane, toluene, o-xylene and the like.
In an embodiment of the present invention, where the said reaction of step (b) and step (c) is carried out preferably at ambient temperature to reflux temperature.
In an embodiment of present invention, where the step (a) and step (c) compounds may be purified by using thin film evaporator which reduces the time and degradation of compound as compared to traditional high vacuum distillation technique.
In another embodiment of the present invention, where racemic compound of formula (VI)of step (c)free from impurities is isolated by quenching with base, filtration and distillation of solvent to afford residue. The residue on dilution in water, extraction with hydrocarbon solvent(s)or ester solvent(s)and removal of solvent(s).
In another embodiment of the present invention, where racemic compound of formula (VI) of step (c) is free from succinimide impurity(less than 0.1%) and amide ester impurity(less than 0.1% by GC).
In an embodiment of the present invention, where filtration, distillation or concentration in the specification is carried out by known techniques well known in prior art.
In an embodiment of the present invention, where the specification involves the hydrocarbon solvent(s) is selected from Cycloheptane, Cyclohexane, Cyclopentane, Heptane, Hexane, Toluene, Xylene, Pentane and the like; more preferably toluene and the ester solvent(s) is selected from ethyl acetate, isopropyl acetate and the like.
In an embodiment of the present invention, where esterification step (c) is carried out at pH 7.0 ± 1.0; more preferably in the range of 6.8 to 7.2.
In another embodiment of the present invention, where the said enantioselective hydrolysis in step (d) is performed by using enzyme.
In another embodiment of the present invention, where the step (d) enzyme are selected from group of esterase’s, Lipolases, Lipases and the like.
In another embodiment of the present invention, where the step (d) esterase’s, Lipolases, Lipases enzymes are selected from the group consisting of Candida Antarctica lipase A, Candida Antarctica lipase Bl, Candida Antarctica lipase BY2, Novozym 435, Rhizomucor meihei, Thermomyces lanhginosa, Pseudomonas cepecia, Resinase HT, Lipex 100L, Bascillus subtillis, Lipase 3.101, Lipase 3.102, Lipase 3.104, Lipase 3.105, Lipase 3.106, Lipase 3.107, Lipase 3.108, Lipase 3.109, Lipase 3.111, Lipase 3.115, Lipase 3.113, Lipase 3.117, Lipase 3.136, AYS Amino, AS Amano, PS AmanoSD, AK Amano preferably Candida Antarctica Bl or Candida Antarctica BY2 or Novozym 435 have been commercially obtained from vendors Evocatal (Germany), Amano (USA),Chiralvision ( Netherland ) and Novozym 435 (Novozymes); more preferably Novozym 435.
In another embodiment of the present invention, where the enantioselective hydrolysis enzyme in step (d) is loaded in the range of > 0.1% to < 5% w/w compared to the substrate; more preferably the range is 1.0% to 2.0%w/w compared to the substrate.
In an embodiment of the present invention, where the buffer in step (d) is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, calcium hydroxide, magnesium hydroxide, magnesium oxide; more preferably sodium bicarbonate.
In an embodiment of the present invention, where the volume of buffer solution in step (d) is used from the range of 2 to 10 volume; more preferably 5.0 volume.
In an embodiment of the present invention, where the said solvent in step (d) is selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, tert -butyl alcohol, isobutyl alcohol, acetone, methyl isobutyl ketone, acetonitrile, methyl tert-butyl ether, tetrahydrofuran, 2 -methyl tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, dioxane, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methyl tert-butyl ether, cyclohexane, toluene, o-xylene and the like; more preferably solvent is water, toluene, 1 ,4- dioxane, dimethyl sulfoxide.
In an embodiment of the present invention, where the preferred enzymes in step (d), may be recovered and reused for several times till almost full enzyme activity is retained; while during recycling of enzyme if the activity is less then additional amount of fresh enzyme can be added and the additional amount can be in the range of 0.5% to 2.0 % w/w with respect to initial enzyme loading. In an another embodiment of the present invention, where the preparation of compound of formula (VII) and compound of formula (VIII) in step (d)is obtained in pH 7.5+ 1.0 and preferably in 7.7+ 0.7 using a suitable reagent selected from the group consisting of acetic acid, citric acid, boric acid, ethylenediamine acetic acid, hydrochloric acid, sulfuric acid, triethyl amine, diisopropylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, calcium hydroxide, magnesium hydroxide, magnesium oxide or its suitable combination thereof. The selection of the amount of this suitable reagent can be chosen in a manner so that final pH after completion of reaction does not exceed 8.5.
In an embodiment of present invention, where esterification in step (e) is performed in presence of solvent (s)in combination of alcohol and hydrocarbon solvents.
In an another embodiment of the present invention, where the base for hydrolysis in step (f) is selected from alkali or alkaline earth metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C 1 -C 5 quaternary ammonium hydroxide and the like; more preferably potassium hydroxide.
In an embodiment of the present invention, where in base in step (f) is used from 0.75 equivalents to 2.5 equivalents; more preferably 1.5 equivalent.
In an embodiment of the present invention, wherein the said solvent in step (f) is preferably selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n-butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, cyclohexanol, toluene, monochlorobenzene, dichlorobenzene, tetra hydro furan, dioxane, dimethylformamide or a combination thereof; preferably methyl alcohol.
In an embodiment of the present invention, wherein the said hydrogenation catalyst in step (f) is preferably selected from the group consisting of nickel, palladium, ruthenium, rhodium with or without support and their different chemical forms and grades optionally fresh or recovered or mixture of fresh and recovered catalyst, more preferably nickel.
In an embodiment of the present invention, wherein the loading of hydrogenation catalyst in step (f) is preferably from 5-30% w/w loading and more preferablyl0%w/w. In an embodiment of the present invention, where the step (f) preferably carried out at a temperature range between 10°C to 100°C; the more preferably between 25 °C to 65°C.
In an embodiment of the present invention, where hydrogenation in step (f) is preferably carried out with the hydrogen pressure in the range of 0.5 to 25 kg/cm2 or equivalent unit; more preferred pressure is 7 to 15 kg/cm 2 .
In an embodiment of the present invention, where hydrogenation step (f) for isolation of compound (I) optionally required charcoalization step.
In an embodiment of the present invention, where the hydrogenation in step (f) of (S)- Pregabalin of formula (I) is isolated at pH of 6.9 to 7.8; more preferably at pH 7.0 to 7.5; and the pH is maintained using inorganic or organic acid such as hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, formic acid, trifluoroacetic acid and the like; preferred acid is hydrochloric acid or acetic acid.
In an embodiment of the present invention, where step (f) compound of formula (I) is purified by crystallization from water, C 1 -C 5 alcohol or a mixture thereof to obtain chemical purity 99.95% and chiral purity more than 99.9%.
In still another embodiment of the present invention for the preparation of Pregabalin of formula (I) further comprises recovery of Pregabalin of formula (I) from the mother liquor preferably concentration followed by filtration. After filtration solid is subjected to purification from water, C 1 -C 5 alcohol or a mixture thereof.
In yet another embodiment of the present invention for the preparation (S)-Pregabalin of formula (I) each compound may be used as such or purified by known purification technique and used for subsequent steps.
EXAMPLES
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway. Example 1: Preparation of 2-isobutyl succinonitrile
To the reaction mixture containing methyl cyanoacetate(500g, l.Oeq.) and isovaleraldehyde (273 g, l.Oeq.) and TBAB (10 g),a solution of sodium cyanide (250g, l.Oeq) in water (950ml, 1.9V) was added slowly at 10 to 50°C. The reaction mixture was heated to 70 to 80°Cand maintained for 2-3 hours (hrs). After completion of reaction, the solvents were removed and further maintained to 90 to 100°Cfor 5 hrs. The reaction mixture was cooled to room temperature and extracted with toluene (1000ml). The solvent was removed under reduced pressure to obtain crude compound and crude compound on high vacuum distillation orthin film evaporation provide compound of 2-isobutyl succinonitrile with GC purity 98% and 79% yield.
Example 2: Preparation of 3-cyano-5-methyl-hexanoic acid.
To the compound 2-isobutyl succinonitrile (350g, l.Oeq), water (4550ml, 13V) was charged at room temperature. The pH of reaction mixture was maintained using sodium bicarbonate solution and heated to 30 to 40°C. To this reaction mixture Nitrilase enzyme (30.24 g) was added and stirred for 20 to 24 hrs. After completion of reaction, the reaction mixture was filtered, cooled to 0 to 5°C and further acidified with concentrated sulfuric acid. The precipitated compound was filtered to obtain racemic 3-cyano-5-methyl-hexanoic acid compound (378 g).
Example 3: Preparation of methyl 3-cyano-5-methyl-hexanoate.
To a racemic 3-cyano-5-methyl-hexanoic acid compound (400g, l.Oeq), methanol (1500ml, 5.0 V) and concentrated sulfuric acid (60 mL, 0.2 V) was added at room temperature. The reaction mixture was heated to reflux temperature and maintained for 1 hr. After completion of reaction, reaction mixture was cooled to room temperature and neutralized with sodium bicarbonate. The reaction mass was concentrated under vacuum and water (1500ml) was added and stirred for 15 minutes. The aqueous layer was extracted with toluene (600ml) and organic layer concentrated under reduced pressure to obtain residue. The residual mass is subjected to high vacuum distillation to obtain racemic compound methyl 3 -cyano-5 -methyl - hexanoate compound (294.1 g) with GC purity 99.83% and 78.90% yield and succinimide impurity 0.01%
Example 4: Preparation of (S)-methyl 3-cyano-5-methyl-hexanoate.
To a racemic methyl 3 -cyano-5 -methyl -hexanoate compound (600 g, l.Oeq) a solution of sodium bicarbonate (3000 ml, 5 V) and Novozym 435 was added. The pH of reaction mixture was maintained between 7.5 to 8.1 and further stirred for 3 hrs at room temperature. The after completion, reaction mixture was filtered, washed with 600 ml toluene and aqueous layer was extracted with toluene (1200ml). The solvent was removed under reduced pressure and to the residue, methanol (120ml) was added. The reaction solution was stirred, and methanol was removed under vacuum to obtain (S)-methyl 3-cyano-5-methyl-hexanoate compound (256.8g) with chiral purity by GC is 99.39%;unwanted R-isomer is 0.61 % and GC chemical purity 99.40 %with 42.8% yield.
Example 5: Preparation of (S)-Pregabalin (I).
To a (S)-methyl 3-cyano-5-methyl-hexanoate compound (90g, l.Oeq) methanol (225ml, 2.5V) was added at room temperature. The reaction mixture was cooled to 5 to 10°C and a solution of potassium hydroxide (52.5 g) was added slowly. The reaction mixture was stirred, warm to room temperature and maintained fori -2 hrs. The reaction mixture on hydrogenated in presence of Raney Nickel (9 g), methanol (25 ml, 2.5V) for 6 to 8 hrs. After completion the reaction mixture was filtered treated with activated carbon and neutralized. The solvent was removed up to minimum stirrable volume to obtain crude (S)-Pregabalin (71.9 g) which on further purification in presence of water, IPA provides pure (S)-Pregabalin with chiral purity by HPLC 99.91% and yield 80%.
Example 6: Preparation of racemic methyl 3-cyano-5-methyl-hexanoate from(R)-3- cyano-5- methyl-hexanoic acid.
To a compound(R)-3-cyano-5 -methyl-hexanoic acid (298) toluene (894 ml, 1.0V), methanol(298 ml, IV) was added. The solution was stirred and concentrated sulfuric acid (23.8 g, 8 %) was added slowly at 25 to 45°C for 10 minutes. The reaction mixture was heated at 60 to 70°C and maintained for lh. The reaction mixture was quenched with sodium bicarbonate and filtered. The solvent was removed to minimum stirrable volume. To this solution sodium methoxide (0.1 eq.) was added and the reaction mixture was refluxedforl h. The reaction mass was cooled to 0 to 5 °C and pH of reaction mass was adjusted to neutral pH using 10 % hydrochloric acid. The organic layer was concentrated to obtain crude compound and crude compound further purified by using high vacuum distillation to get pure racemic methyl 3-cyano-5-methyl-hexanoate (252.8 g) with GC Purity 99.76% and 77 % yield.