WO2014080345A2 - Improved process for the preparation of pregabalin - Google Patents
Improved process for the preparation of pregabalin Download PDFInfo
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- WO2014080345A2 WO2014080345A2 PCT/IB2013/060276 IB2013060276W WO2014080345A2 WO 2014080345 A2 WO2014080345 A2 WO 2014080345A2 IB 2013060276 W IB2013060276 W IB 2013060276W WO 2014080345 A2 WO2014080345 A2 WO 2014080345A2
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- pregabalin
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- reaction mass
- carbamoylmethyl
- reaction medium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Definitions
- the invention relates to process for the preparation of Pregabalin with low ash content and the process is a reverse addition process. More specifically, the invention relates to process for the preparation of Pregabalin which is viable for large scale preparation.
- HOO NH 2 is the international commonly accepted name for (5)-(+)-3-aminomethyl-5-methyl-l- hexanoic acid and has an empirical formula of C 8 H 17 N0 2 .
- Pregabalin is also known as (S)-(+)-3-(2-methylpropyl)-4-aminobutanoic acid or (5)-(+)-3-isobutyl-GABA.
- Pregabalin is a commercially marketed pharmaceutically active substance known to be useful as therapeutic agent for treatment of pain, convulsions, general anxiety related disorders and epileptic seizures.
- Pregabalin and its pharmaceutically acceptable salts are described in WO/92/09560, along with two different synthetic processes for their preparation.
- these routes involve expensive and/or difficult to handle substances such as (4R, 5S)-4-methyl-5- phenyl-2-oxazolidinone, n-butyl lithium, and "azide” intermediates.
- U.S. Patent No. 5,616,793, WO 2006/122258 WO 2006/122255 and WO 2006/121557 disclose a preparation of Pregabalin by means of a Hofmann rearrangement of 3- (carbamoylmethyl)-5-methylhexanoic acid in the presence of bromine and an alkali hydroxide.
- present invention has unexpected benefits i.e., the resulted product from the above mentioned process is crystalline and overcomes all the drawbacks (i.e., ash content, froth formation), which is suitable for human consumption and meeting the international standards of limit on residue on ignition.
- drawbacks i.e., ash content, froth formation
- the primary objective of the present invention is the method to produce Pregabalin.
- a further objective of the present invention is to employ method of preparation of Pregabalin with low ash content.
- a method for the preparation of Pregabalin which comprises of: ⁇ (3fl)-3-(carbamoylmethyl)-5-methylhexanoic acid treated with caustic lye followed by the reaction with Sodium hypochlorite in low temperature and maintain the reaction medium to the temperature range of 40-45 °c;
- the reverse-addition is done by quenching the reaction medium into the aqueous solution of hydrochloric acid.
- the aqueous solution of hydrochloric acid can be prepared by dissolving the con.HCI in process water taken in the separate flask.
- the conventional methods of preparation of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid obtained from (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid via Hofmann Reaction, which is well known to those skilled in the art.
- Hofmann Reaction The conditions under which a Hofmann Reaction can be carried out are well known to those skilled in the art, and any such condition known in the art may be used to obtain (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid from (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid.
- a suitable Hofmann reagent is an alkali metal hypohalite, which can be prepared by combining a base such as sodium hydroxide with a halogen such as bromine. Other alkali metal or alkaline earth metal bases or other halogens can be used.
- the second aspect of the invention provides the pure Pregabalin with ash content less than 0.1 5 wt % by the reverse addition process.
- the third aspect of the invention provides the pure Pregabalin having a purity of greater than 98%, preferably greater than 99%, most preferably greater than 99.9% and it is suitable for use in medicine.
- the ash content which is a measure of the total amount of inorganic impurities can be determined using methods known in the art. For example, ash content in the purified final compound may be determined using gravimetric methods. Typically, the ash content produced by the method disclosed herein is less than about 0.1 5 wt %.
- Table-1 Analytical results of crude and pure Pregabalin formed by alternative workup protocols
- Racemic 3-(carbamoylmethyl)-5-methylhexanoic acid (550.0g, 2.9374moles, 1 .0mol eq) was added to chloroform 7425ml in a 10L four necked RB flask at room temperature to form slurry. The temperature was raised to 52.5 ⁇ 2.5°C followed by addition of D-(+)- phenyl ethylamine (253.0g, 2.0878moles, 0.71 mole eq) over a period of 12.5 ⁇ 2.5 min at 52.5 ⁇ 2.5°C. The reaction mass was turned clear solution and stirred for 55.0 ⁇ 5.0min at same temperature.
- Racemic 3-(carbamoylmethyl)-5-methylhexanoic acid (10. Og, 0.0534moles, 1 .0mol eq) was added to chloroform 135ml in a 500ml_ four necked RB flask at room temperature to form slurry. Then D-(+)-phenyl ethylamine (4.6g, 0.0380moles, and 0.71 mol eq) was added slowly over a period of 12.5 ⁇ 2.5mins during which material goes into solution and turned to slurry reaction mass. The temperature was raised to 52.5 ⁇ 2.5°C and stirred for 55.0 ⁇ 5.0min at same temperature.
- the fl-CMHA salt (350. Og, 1 .1348moles, LOmol eq) was dissolved in 980ml process water at 42.5 ⁇ 2.5°C, and filtered through hyflo supercel to remove the insoluble particles followed by washing the bed with 70ml process water. After cooling the filtrate to 22.5 ⁇ 2.5°C, Con. hydrochloric acid (1 17ml, 1 .1796moles, 1 .039mol eq) was added to adjust the pH to 1 .0-2.0. The solid formed was cooled down to 2.5 ⁇ 2.5°C, filtered and washed with 350ml 1 .0% aqueous hydrochloric acid solution.
- the fl-CMHA salt (60. Og, 0.1945moles, 1 .0 mol eq) was dissolved in 1 68ml process water at 42.5 ⁇ 2.5°C, and filtered through hyflo supercel to remove the insoluble particles followed by washing the bed with 1 2ml process water. After cooling the filtrate to 7.5 ⁇ 2.5°C, con. hydrochloric acid (20ml_, 0.2021 moles, 1 .039mole eq) was added to adjust the pH to 1 .0-2.0. The solid formed was filtered and washed with 60ml 1 .0% aqueous hydrochloric acid solution (pre-chilled).
- the fl-CMHA (185.0g, 0.9880moles, I .OOmole eq) was slurried in 463ml process water and cooled down to 7.5 ⁇ 2.5°C in a 2.0L four-necked RB flask.
- Caustic soda lye 250. Og, 3.0000moles, 3.04mole eq was added to the reaction mass over a period of 45.0 ⁇ 5.0min at 7.5 ⁇ 2.5°C.
- reaction mass was further cooled to 2.5 ⁇ 2.5°C and sodium hypochlorite solution (min 10% assay) (743ml, 0.9978moles, 1 .01 mole eq) was added drop wise over a period of 50.0 ⁇ 10.0min at 2.5 ⁇ 2.5°C and maintained for 17.5 ⁇ 2.5min at same temperature.
- the reaction mass was warmed to room temperature initiating an exotherm which heats up to a maximum of 45°C and cools down thereafter.
- the temperature of the reaction mass was maintained at 42.5 ⁇ 2.5°C for about 55.0+5.0 mins by external heating.
- reaction mass was cooled to 25- 30 °C over a period of 1 7.5 ⁇ 2.5 min and treated with a solution of sodium metabisulfite (1 1 .2g, 0.0589 moles, 0.06mole eq) in 18.5ml process water drop-wise over a period of 17.5 ⁇ 2.5 min at 27.5 ⁇ 2.5°C.
- the reaction mass was added slowly at 27.5 ⁇ 7.5°C to a mixture of 328.0ml con. hydrochloric acid and 185ml process taken in second flask over a period of 40.0+5.0 min to a final pH of 2.9-3.3.
- the clear reaction mass was then neutralized back to 6.0-6.5 by addition of caustic soda lye during which product is thrown out as white solid.
- the fl-CMHA (10. Og, 0.0534moles, LOOmol eq) was slurried in 25ml_ process water and cooled down to 7.5 ⁇ 2.5°C in a 2.0L four-necked RB flask.
- Caustic soda lye (1 3.2g, 0.1 65moles, 3.04mole eq) was added to the reaction mass over a period of 45.0 ⁇ 5.0min at 7.5 ⁇ 2.5°C.
- reaction mass was further cooled to 2.5 ⁇ 2.5°C and sodium hypochlorite solution (min 10% assay) (40.5ml, 0.0544moles, 1 .02mole eq) was added drop wise over a period of 50.0 ⁇ 10.0min at 2.5 ⁇ 2.5°C and maintained for 17.5 ⁇ 2.5min at same temperature.
- the reaction mass was warmed to room temperature initiating an exotherm which heats up to a maximum of 45°C and cools down thereafter.
- the temperature of the reaction mass was maintained at 42.5 ⁇ 2.5°C for about 55.0 ⁇ 5.0 mins by external heating.
- the reaction mass was cooled to 22.5 ⁇ 2.5 °C and pH was adjusted to 6.0-6.5 by slow addition of con.HCI during which product is thrown out as white solid.
- the crude Pregabalin (100.0g, 0.6280moles, LOOmole eq) was dissolved in a mixture of 668ml IPA and 382ml purified water at reflux (77.5 ⁇ 2.5 °C), micron-filtered under hot condition and washed with preheated mixture of 32ml IPA and 18ml purified water.
Abstract
Disclosed is the process suitable for industrial synthesis of Pregabalin from (R)-(-)-3- (carbamoylmethyl)-5-methylhexanoic using sodium hypochlorite with low ash content by means of reverse addition.
Description
IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN
TECHNICAL FIELD:
The invention relates to process for the preparation of Pregabalin with low ash content and the process is a reverse addition process. More specifically, the invention relates to process for the preparation of Pregabalin which is viable for large scale preparation. BACKGROUND OF THE INVENTION:
Pregabalin, a compound of Formula I,
HOO
NH2 is the international commonly accepted name for (5)-(+)-3-aminomethyl-5-methyl-l- hexanoic acid and has an empirical formula of C8H17 N02. Pregabalin is also known as (S)-(+)-3-(2-methylpropyl)-4-aminobutanoic acid or (5)-(+)-3-isobutyl-GABA. Pregabalin is a commercially marketed pharmaceutically active substance known to be useful as therapeutic agent for treatment of pain, convulsions, general anxiety related disorders and epileptic seizures.
Pregabalin and its pharmaceutically acceptable salts are described in WO/92/09560, along with two different synthetic processes for their preparation. However, these routes involve expensive and/or difficult to handle substances such as (4R, 5S)-4-methyl-5- phenyl-2-oxazolidinone, n-butyl lithium, and "azide" intermediates.
U.S. Patent No. 5,616,793, WO 2006/122258 WO 2006/122255 and WO 2006/121557 disclose a preparation of Pregabalin by means of a Hofmann rearrangement of 3-
(carbamoylmethyl)-5-methylhexanoic acid in the presence of bromine and an alkali hydroxide.
However, this synthetic method is not desirable for industrial implementation, since it requires the use of bromine, which is very toxic and corrosive. Moreover, during this process, heavy froth formation occurs in the reactor which is very disadvantageous in terms of material loss.
Hoekstra et al. in Organic Process Research & Development 1997, 1 , 26-38, and WO2009068967 discloses the process which involves the usage of sodium hypochlorite for the Pregabalin preparation.
However, this method is not viable for commercial production since it encounters froth formation when the reaction precedes conventionally which results in the complicating work up procedures and it requires a reaction vessel with large head space thereby restricting the batch size. Also it is relatively difficult to filter this foamy reaction mass. Further the resulting product is with high ash content which is difficult to control to required pharmaceutical limits even upon subjecting to multiple purification procedures. In view of the foregoing, there is a need to provide improved process for preparing Pregabalin which is suitable for industrial implementation and to achieve low ash content meeting the international standards of limit on residue on ignition.
SUMMARY OF THE INVENTION:
Surprisingly, we have now found a reverse addition process which is simpler than the prior art process and can give good yields of the desired Pregabalin with low ash content and easily scalable as compared with conventional processes.
Applicants have surprisingly discovered that present invention has unexpected benefits i.e., the resulted product from the above mentioned process is crystalline and
overcomes all the drawbacks (i.e., ash content, froth formation), which is suitable for human consumption and meeting the international standards of limit on residue on ignition. OBJECTIVE OF THE INVENTION:
The primary objective of the present invention is the method to produce Pregabalin.
A further objective of the present invention is to employ method of preparation of Pregabalin with low ash content.
It is the further objective of the present invention to employ process which is considered to be consistent in terms of yield and purity with controlled limit of ash content. DESCRIPTION OF THE INVENTION:
According to first aspect of the present invention, there is provided a method for the preparation of Pregabalin which comprises of: · (3fl)-3-(carbamoylmethyl)-5-methylhexanoic acid treated with caustic lye followed by the reaction with Sodium hypochlorite in low temperature and maintain the reaction medium to the temperature range of 40-45 °c;
• Treating with solution of sodium metabisulfite
• Adding the resultant reaction medium into the aqueous hydrochloric acid by reverse addition;
• Maintain the reaction medium to the pH range of less than 4;
• Neutralising the resultant reaction medium with caustic acid to get the desired product.
The reverse-addition is done by quenching the reaction medium into the aqueous solution of hydrochloric acid.
The aqueous solution of hydrochloric acid can be prepared by dissolving the con.HCI in process water taken in the separate flask. The conventional methods of preparation of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid obtained from (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid via Hofmann Reaction, which is well known to those skilled in the art. The conditions under which a Hofmann Reaction can be carried out are well known to those skilled in the art, and any such condition known in the art may be used to obtain (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid from (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid. A suitable Hofmann reagent is an alkali metal hypohalite, which can be prepared by combining a base such as sodium hydroxide with a halogen such as bromine. Other alkali metal or alkaline earth metal bases or other halogens can be used.
The second aspect of the invention provides the pure Pregabalin with ash content less than 0.1 5 wt % by the reverse addition process.
The ash content in the product is found to be easily decreased in a subsequent washing step and this method (i.e., "reverse-addition") affords better results than the traditional (i.e., "normal-addition") method.
The third aspect of the invention provides the pure Pregabalin having a purity of greater than 98%, preferably greater than 99%, most preferably greater than 99.9% and it is suitable for use in medicine.
The ash content, which is a measure of the total amount of inorganic impurities can be determined using methods known in the art. For example, ash content in the purified final compound may be determined using gravimetric methods. Typically, the ash content produced by the method disclosed herein is less than about 0.1 5 wt %.
Table-1 : Analytical results of crude and pure Pregabalin formed by alternative workup protocols
Best modes of carrying out the present invention will be described in further detail using various embodiments with reference to the accompanying scheme and examples. Example: 1
Preparation of (3ff)-3-(carbamoylmethyl)-5-methylhexanoic acid phenyl ethylamine salt (fl-CMHA salt) from racemic-3-(carbamoylmethyl)-5-methylhexanoic acid with seeding
Racemic 3-(carbamoylmethyl)-5-methylhexanoic acid (550.0g, 2.9374moles, 1 .0mol eq) was added to chloroform 7425ml in a 10L four necked RB flask at room temperature to form slurry. The temperature was raised to 52.5±2.5°C followed by addition of D-(+)- phenyl ethylamine (253.0g, 2.0878moles, 0.71 mole eq) over a period of 12.5±2.5 min at
52.5±2.5°C. The reaction mass was turned clear solution and stirred for 55.0±5.0min at same temperature. A seed of pure (3fl)-3-(carbamoylmethyl)-5-methylhexanoic acid phenyl ethylamine salt was added to the reaction mass at 51 .0±1 .0 °C. The reaction mass was cooled slowly to 30.5±2.5°C over a period of 3.5±0.5hrs to form thick slurry. Filtration of the reaction mass at room temperature (30.5±2.5°C) followed by washing and drying under vacuum at 57.5±2.5°C afford (S/^-S-icarbamoylmethy -S- methylhexanoic acid phenyl ethylamine salt as white. Yield=367.0g, HPLC purity = 99.8%. Example: 2
Preparation of (3/?)-3-(carbamoylmethyl)-5-methylhexanoic acid phenyl ethylamine salt (fl-CMHA salt) from racemic-3-(carbamoylmethyl)-5-methylhexanoic acid without seeding
Racemic 3-(carbamoylmethyl)-5-methylhexanoic acid (10. Og, 0.0534moles, 1 .0mol eq) was added to chloroform 135ml in a 500ml_ four necked RB flask at room temperature to form slurry. Then D-(+)-phenyl ethylamine (4.6g, 0.0380moles, and 0.71 mol eq) was added slowly over a period of 12.5±2.5mins during which material goes into solution and turned to slurry reaction mass. The temperature was raised to 52.5±2.5°C and stirred for 55.0±5.0min at same temperature. The reaction mass was cooled slowly to 30.5±2.5°C over a period of 3.5±0.5hrs to form thick slurry. Filtration of the reaction mass at room temperature (30.5±2.5°C) followed by washing and drying under vacuum at 57.5±2.5°C afford (3fl)-3-(carbamoylmethyl)-5-methylhexanoic acid phenyl ethylamine salt as white powder. Yield=6.5g.
Example: 3 Preparation of (3/?)-3-(carbamoylmethyl)-5-methylhexanoic acid (fl-CMHA) at ambient temperature
The fl-CMHA salt (350. Og, 1 .1348moles, LOmol eq) was dissolved in 980ml process water at 42.5±2.5°C, and filtered through hyflo supercel to remove the insoluble particles followed by washing the bed with 70ml process water. After cooling the filtrate to 22.5±2.5°C, Con. hydrochloric acid (1 17ml, 1 .1796moles, 1 .039mol eq) was added to adjust the pH to 1 .0-2.0. The solid formed was cooled down to 2.5±2.5°C, filtered and washed with 350ml 1 .0% aqueous hydrochloric acid solution. Drying the filtered material under vacuum at 57.5±2.5°C afford (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid (fl-CMHA) as white powder. Yield=194.0g, HPLC purity=99.65%
Example: 4
Preparation of (3ff)-3-(carbamoylmethyl)-5-methylhexanoic acid (fl-CMHA) at low temperature
The fl-CMHA salt (60. Og, 0.1945moles, 1 .0 mol eq) was dissolved in 1 68ml process water at 42.5±2.5°C, and filtered through hyflo supercel to remove the insoluble particles followed by washing the bed with 1 2ml process water. After cooling the filtrate to 7.5±2.5°C, con. hydrochloric acid (20ml_, 0.2021 moles, 1 .039mole eq) was added to adjust the pH to 1 .0-2.0. The solid formed was filtered and washed with 60ml 1 .0% aqueous hydrochloric acid solution (pre-chilled). Drying the filtered material under vacuum at 57.5±2.5°C afford (3R)-3-(carbamoylmethyl)-5-methylhexanoic acid {R- CMHA) as white powder. Yield=32.0g, HPLC purity=99.29%.
Example: 5 Preparation of (S)-3-aminomethyl-5-methylhexanoic acid (crude pregabalin) by reverse quenching method
The fl-CMHA (185.0g, 0.9880moles, I .OOmole eq) was slurried in 463ml process water and cooled down to 7.5±2.5°C in a 2.0L four-necked RB flask. Caustic soda lye (250. Og, 3.0000moles, 3.04mole eq) was added to the reaction mass over a period of 45.0±5.0min at 7.5±2.5°C. The reaction mass was further cooled to 2.5±2.5°C and sodium hypochlorite solution (min 10% assay) (743ml, 0.9978moles, 1 .01 mole eq) was added drop wise over a period of 50.0±10.0min at 2.5±2.5°C and maintained for 17.5±2.5min at same temperature. The reaction mass was warmed to room temperature initiating an exotherm which heats up to a maximum of 45°C and cools down thereafter. The temperature of the reaction mass was maintained at 42.5±2.5°C for about 55.0+5.0 mins by external heating. Then the reaction mass was cooled to 25- 30 °C over a period of 1 7.5±2.5 min and treated with a solution of sodium metabisulfite (1 1 .2g, 0.0589 moles, 0.06mole eq) in 18.5ml process water drop-wise over a period of 17.5±2.5 min at 27.5±2.5°C. The reaction mass was added slowly at 27.5±7.5°C to a mixture of 328.0ml con. hydrochloric acid and 185ml process taken in second flask over a period of 40.0+5.0 min to a final pH of 2.9-3.3. The clear reaction mass was then neutralized back to 6.0-6.5 by addition of caustic soda lye during which product is thrown out as white solid. The reaction mass was chilled down to 2.5±2.5°C, filtered, washed with pre-chilled water and dried under vacuum at 57.5±2.5°C to afford crude Pregabalin as white solid. Yield=1 1 1 .0g, HPLC purity=92.8%, Residue on lgnition=0.45%.
Example: 6 Preparation of Preparation of (S)-3-aminomethyl-5-methylhexanoic acid (crude Pregabalin) by normal quenching method
The fl-CMHA (10. Og, 0.0534moles, LOOmol eq) was slurried in 25ml_ process water and cooled down to 7.5±2.5°C in a 2.0L four-necked RB flask. Caustic soda lye (1 3.2g, 0.1 65moles, 3.04mole eq) was added to the reaction mass over a period of 45.0±5.0min at 7.5±2.5°C. The reaction mass was further cooled to 2.5±2.5°C and sodium hypochlorite solution (min 10% assay) (40.5ml, 0.0544moles, 1 .02mole eq) was added drop wise over a period of 50.0±10.0min at 2.5±2.5°C and maintained for 17.5±2.5min at same temperature. The reaction mass was warmed to room temperature initiating an exotherm which heats up to a maximum of 45°C and cools down thereafter. The temperature of the reaction mass was maintained at 42.5±2.5°C for about 55.0±5.0 mins by external heating. The reaction mass was cooled to 22.5±2.5 °C and pH was adjusted to 6.0-6.5 by slow addition of con.HCI during which product is thrown out as white solid. The reaction mass was chilled down to 2.5±2.5°C, filtered, washed with pre- chilled water and dried under vacuum at 57.5±2.5°C to afford crude Pregabalin as white solid. Yield=7.0g, HPLC purity=90.34%, Residue on lgnition=8.4%.
Example: 7 Purification of (S)-3-aminomethyl-5-methylhexanoic acid
The crude Pregabalin (100.0g, 0.6280moles, LOOmole eq) was dissolved in a mixture of 668ml IPA and 382ml purified water at reflux (77.5±2.5 °C), micron-filtered under hot condition and washed with preheated mixture of 32ml IPA and 18ml purified water. The reaction mass was cooled down slowly to 2.5±2.5°C at an approximate rate of 10°C/h over a period of 7.0-8.0 h. After maintaining the reaction mass at 2.5±2.5°C for
75.0±15.0 mins, the crystals were filtered, washed with 100ml pre-chilled IPA and dried under vacuum to afford pure Pregabalin as white crystalline solid. Yield=87.0g, HPLC Purity=99.91 %, Chiral purity=99.96%.
Claims
1 . A method for the preparation of Pregabalin which comprises of:
• (3fl)-3-(carbamoylmethyl)-5-methylhexanoic acid treated with caustic lye followed by the reaction with Sodium hypochlorite in low temperature and maintain the reaction medium to the temperature range of 40-45 °c;
• Treating with solution of sodium metabisulfite
• Adding the resultant reaction medium into the aqueous hydrochloric acid by reverse addition;
• Maintain the reaction medium to the pH range of less than 4;
• Neutralising the resultant reaction medium with caustic acid to get the desired product.
2. A process as claimed in claim 1 , wherein the reverse addition is by quenching.
3. A process as claimed in claim 2, wherein the quenching is done by charging the reaction medium into the aqueous solution of hydrochloric acid.
4. A process as claimed in claim 1 , wherein the Pregabalin as produced has ash content of less than 0.15% wt.
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CN109678737A (en) * | 2019-02-18 | 2019-04-26 | 常州制药厂有限公司 | A kind of preparation method of Pregabalin |
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US20090192331A1 (en) * | 2006-07-04 | 2009-07-30 | Annibale Salvi | Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates |
US20100324307A1 (en) * | 2005-09-19 | 2010-12-23 | Vinod Kumar Kansal | Novel asymmetric synthesis of (s)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
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US20060063804A1 (en) * | 2004-09-17 | 2006-03-23 | Li Chen | Thiazolinone 2-substituted quinolines |
US20100324307A1 (en) * | 2005-09-19 | 2010-12-23 | Vinod Kumar Kansal | Novel asymmetric synthesis of (s)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
US20090192331A1 (en) * | 2006-07-04 | 2009-07-30 | Annibale Salvi | Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates |
WO2009087650A2 (en) * | 2007-10-15 | 2009-07-16 | V.B. Medicare Pvt. Ltd. | A novel process for synthesis of pregabalin from substituted cyclopropane intermediate and a process for enzymatic resolution of racemic pregabalin |
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CN109678737A (en) * | 2019-02-18 | 2019-04-26 | 常州制药厂有限公司 | A kind of preparation method of Pregabalin |
CN109678737B (en) * | 2019-02-18 | 2021-12-24 | 常州制药厂有限公司 | Preparation method of pregabalin |
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