FIELD OF THE INVENTION:

The present invention relates to improved, safe and industrially applicable process for preparing impurities of (3S)-3-(aminomethyl)-5-methylhexanoic acid.

BACKGROUND OF THE INVENTION:

m •

Pregabalin of formula-1 is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. Pregabalin is marketed by pfizer under the trade name lyrica. Pregabalin has been developed for use in the treatment of epilepsy, Pain, anxiety and Physiological conditions associated with Psychomotor stimulants, inflammation, gastrointestinal damages, alcoholism, insomnia, convulsions, attention deficit hypersensitivity disorder (ADHD) and various psychiatric disorders, including depression, mania, bipolar disorder.
Pregabalin first synthesis has been disclosed in US 5563175 and EP 641330.

US 5,616,793 discloses methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid starting from isovaleraldehyde with an alkyl cyanoacetate mainly ethyl cyanoacetate to form a 2-cyano-5-methylhex-2-enoic acid alkyl ester further reacting it with diethyl malonate, in the presence of a base such as di-n-propylamine in an inert solvent such as hexane, heptane, toluene and then adding a hydrochloric acid solution to form 3-isobutylglutaric acid. The anhydride is formed by reacting the 3-isobutylglutaric acid with acetic anhydride or acetyl chloride with a Hofmann reagent to obtain (S)-(+)-3-aminomethyl 5-methylhexanoic acid

(vm). '

The present invention provides-preparation of 3-carbamoyl-5-methylhexanoic acid and 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid which are non-pharmacopoeial impurities for Pregabalin.
SUMMARY OF THE INVENTION:

The present invention relates to improved, eco-friendly process for the preparation for the 3-carbamoyl-5-methylhexanoic acid of formula-2 and 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid of formula-3
One embodiment of the present invention provides process for preparing 3-carbamoyl-5-methylhexanoic acid of formula-2 comprises;

(a) reacting 2-isobutylsuccinic acid with aq. Ammonia solution

(b) basifying 3-Isobutylpyrrolidine-2,5-dione in presence of base

(c) isolating 3-carbamoyl-5-methylhexanoic acid

(d) purifying 3-carbamoyl-5-methylhexanoic acid in presence of solvent or mixture of solvents

One another embodiment of the present invention provides process for preparing process for preparing 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid of formula-3 comprises;

(a) reacting 2-isobutylsuccinic acid with acetic anhydride

(b) basifying 3-Isobutylpyrrolidine-2,5-dione in presence of base, solvent

(c) isolating 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid

(d) purifying 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid in presence of solvent or mixture of solvents

BRIEF DESCRIPTION OF DRAWINGS:

1. 'H NMR(CDCh) spectrum of 3-carbamoyl-5-methylhexanoic acid

2. IR spectrum of 3-carbamoyl-5-methylhexanoic acid

3. Mass spectrum of 3-carbamoyl-5-methylhexanoic acid
4. HPLC of 3-carbamoyl-5-methylhexanoic acid

5. ’H NMR(CDCb) spectrum of 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid

6. IR spectrum of 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid

* *

7. HPLC of 2-(2-amino-2-oxoethy))-4-methylpentanoic acid

OBJECT OF THE INVENTION:

(1) The main object of the present invention is that the process establishes new impurity of pregabalin.

(2) The another object of the present invention is that the process is suitable for identification of unknown impurity (non-pharmacopeia) of pregabalin.

(3) One another object of the present invention is that the process gives good yield with good purity.

DETAIL DESCRIPTION OF THE INVENTION:

The present invention relates to robust, safe and industrially feasible process for the preparation of 3-carbamoyl-5-methylhexanoic acid of formula-2 and 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid of formula-3
One aspect of the present invention provides process for preparing 3-carbamoyl-5-methylhexanoic acid of formula-2 comprises;
(a) reacting 2-isobutylsuccinic acid with aq. Ammonia solution

(b) basifying 3-Isobutylpyrrolidine-2,5-dione in presence of base

(c) isolating 3-carbamoyl-5-methylhexanoic acid
(d) purifying 3-carbamoyl-5-methylhexanoic acid in presence of solvent or mixture of solvents

The aq. Ammonia solution used in step (a) is 10-20%.

The temperature for step (a) is about 30-150°C.

The base for step (b) is selected from the group consisting inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; and organic bases like diisopropylethylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide (LDA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazole and the like; organosilicoii bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); n-butyl lithium or mixtures thereof.

The solvent used for purification in step (c) is selected from the group consisting of acetone, Cyclohexane, Hexane, Dichloromethane, Toluene, methyl tert butyl ether or mixture thereof. .

The process for preparation of 3-carbamoyl-5-methylhexanoic acid of formula-2 given in the below reaction scheme-1
The 3-carbamoyl-5-methylhexanoic acid impurity is characterized by lH NMR(CDCb) 0.82-0.88 (6H,d,C(6,7)H); 1.06-1.13(1H,m,C(5)H); 1.36-1.43(lH,m,C(4)H);. 1.45-

1.53(lH,m,C(4)H); 2.15-2.21(lH,dd,C(2)H); 2.37-2.43(1 H,m,C(3)H); 2.57-

2.64(1 H,m,C(2)H); 6.78(1 H,s,NH2); 7.38(1 H,s,NH2). lH NMRspectrum is depicted in Fig.l.

The 3-carbamoyl-5-methylhexanoic acid impurity is characterized by IR having peak at 3418.58 for NH2(CONH2); 2973.87 for OH(COOH); 1713.25 for CO(COOH); 1650.89 for CO(CONH2). IR spectrum is depicted in Fig. 2.

The 3-carbamoyl-5-methylhexanoic acid impurity is characterized by Mass having peak at 174.41 (M+H)+. Mass spectrum is depicted in Fig.3

The 3-carbamoyl-5-methylhexanoic acid impurity is characterized by HPLC having peak at 99.09%. HPLC spectrum is depicted in Fig.4

The 3-carbamoyl-5-methylhexanoic acid impurity is having melting range about 168.5°C to 180.1°C.

One aspect of the present invention provides process for preparing 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid of formula-3 comprises;
.. (a) reacting 2-isobutylsuccinic acid with acetic anhydride

(b) basifying 3-Isobutylpyrrolidine-2,5-dione in presence of base, solvent

(c) isolating 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid * *

(d) purifying 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid in presence of solvent or mixture of solvents

The temperature for step (a) is about 30-150°C.

The base for step (b) is selected from the group consisting inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; and organic bases like diisopropylethylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide (LDA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazole and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); n-butyl lithium or mixtures thereof.

The solvent used for step (b) is selected from the group consisting of acetone, Cyclohexane, Hexane, Dichloromethane, Toluene, methyl tert butyl ether or mixture thereof.

For isolation step (c) dilute mineral acid is used with pH 1.0-3.0. The mineral acid is selected from the group consisting of hydro halide acids, sulphuric acid, nitric acid, phosphoric acid and like.

The solvent used for purification in step (c) is selected from the group consisting of acetone, Cyclohexane, Hexane, Dichloromethane, Toluene, methyl tert butyl ether or mixture thereof.
The process for preparation of 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid of formula-3 given in the below reaction scheme-2
The 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid impurity is characterized by 'H NMR(CDCh) 0.83-0.87 (6H,dd,C(63 7)H); 1.14-1.21 (lH,m,C(5)H); 1.38-1.45 (lH,m, C(4)H); 1.51-1.58 (lH,m,C(4)H); 2.11-2.16 (lH,dd,C(2)H); 2.30-2.36 (lH,dd,C(2)H); 2.62-2.68 (1 H3mJC(3)H); 6.78 (IH^NTh); 7.32 (1H,sjNH2). 'H NMR spectrum is depicted in Fig-5.

The 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid impurity is characterized by IR having peak at 3433.27 for NH2(CONH2); 2960.25 for OH(COOH); 1707.63 for CO(COOH); 1651.05 for CO(CONH2). IR spectrum is depicted in Fig. 6.

The 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid impurity is characterized by HPLC having peak at 92.60%. HPLC spectrum is depicted in Fig.7

The 2-(2-amino-2-oxoethyl)-4-methylpentanoic acid impurity is having melting range about

• 125.7°C to 128.8°C.
The following examples explain various other embodiments without limiting the scope of the present invention.

Example-1: Preparation of 3-lsobutylpyrroIidine-2,5-dione

To a solid of Diacid, aq. Ammonia solution was slowly added at 0-10 °C with continuous stirring for 1.0 hr. After completion of addition the reaction mixture was slowly distilled out with the rotary evaporator under temperature control. After distillation, crude mass was refluxed at the 120°C to 130°C until the completion of reaction (checked by TLC analysis). Reaction mixture slowly cool to room temperature, solid formed in the reaction mixture and sodium bicarbonate solution was added into the reaction mixture and stir for 1.0 hr at RT °C. RM was filtered and washed with water hexane to obtain the desired compound as a white solid. Yield: 49.0%.

Example-2: Preparation of 3-carbamoyl-5-methylhexanoic acid

To 3-lsobutylpyrrolidine-2,5-dione, aqueous sodium hydroxide solution was slowly added at room temperature. After completion of addition, the reaction mixture was heated at the 60-70°C for 3-4 hrs. On completion of the reaction (checked by TLC analysis), reaction mixture cool to room temperature and acidified with dilute HC1 solution (pH 1.0 - 3.0). RM was stirred for 1 to 2 hrs at 0-5 °C. Solid separated, filtered and washed with water to obtain the desired compound as a white solid. Yield: 48.27 %.

Example-3: Purification of 3-carbamoyl-5-methylhexanoic acid

To dry 3-carbamoyl-5-methylhexanoic acid, Acetone added and heated the mass at 40-45 °C. Afterwards slowly cool to RT and then stirred for 1-2 hrs at 0-5 °C. Solid separated out, filtered the solid and washed with Acetone. Solid was again purified with the MTBE and Acetone mixture to get 3-carbamoyl-5-methylhexanoic acid. Yield: 5.7 %.

Melting point: 168.5-180.1 °C.

HPLC Purity: 99.09%

Example-4: Preparation of 2-(2-amino-2-oxocthyl)-4-methyIpentanoic acid

To a solid of Diacid, Acetic anhydride was slowly added at RT with continuous stirring for 1.0 hr. After completion of addition the reaction mixture was refluxed at the 90-110°C until the completion of reaction (checked by TLC analysis). Distilled the mass. Reaction mass was diluted with MTBE. Slowly added the aqueous ammonia solution and stirred for lhr. Separated the layers. Aqueous layer was acidified with dilute HC1 solution (pH 1.0 - 3.0). Reaction mixture was stirred at 15-20 °C. Filtered the solid and washed with water. Solid was
treated with a mixture of MTBE and hexane to obtain the desired compound as a white solid. ' Yield: 53.33 %.

Melting point: 125.7-128.8 °C.

HPLC Purity: 92.60%