- Synthesis and characterization of impurities of an anticonvulsant drug, Pregabalin
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During the process development of Pregabalin 1, a known anticonvulsant drug, six potential impurities were identified in the final crude material ranging from 0.01 to 0.15% by LCMS. All six impurities were subsequently synthesized and characterized by IR, MS and NMR spectral data. Four of the six related substances are known as 4-isobutylpyrrolidin-2-one 6, 3-isobutylglutaric acid 2, (R)-(-)-3-carbamoylmethyl-5-methylhexanoic acid 5 and (R)-(-)-3-aminomethyl-5-methylhexanoic acid 8, whilst (S)-3-aminomethyl-5- methylhexanoic acid isobutyl ester 9 and (S)-3-aminomethyl-5-methylhexanoic acid isopropyl ester 10 are new compounds reported for the first time in our process. The present work describes the formation, synthesis and characterization of these impurities. ARKAT USA, Inc.
- Sripathi, Somaiah,Somesetti, Narender Rao,Veeramalla, Raju,Challa, Nageswar Rao,Peddi, Srinivasa Rao,Karnati, Venugopal Reddy
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- METHOD FOR PREPARING PREGABALIN INTERMEDIATE (R)-3-(CARBAMOYLMETHYL)-5-METHYLHEXANOIC ACID
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A method for preparing pregabalin chiral intermediate (R)-3-(carbamoylmethyl)-5-methylhexanoic acid by a biological enzyme method. In particular, the method comprises: reacting compound (I) 3-isobutylglutaric acid, as a raw material, with a nitrogen-conta
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Paragraph 0039; 0041; 0043; 0045; 0047
(2021/04/23)
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- Method for preparing pregabalin intermediate
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The invention discloses a method for preparing a pregabalin intermediate, namely, R-3-isobutyl glutaric acid monoamide. The method comprises the following steps: (1) adding 3-isobutyl glutaric acid monoamide into a system of chloroform and an alcohol solv
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Paragraph 0023-0042
(2021/03/06)
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- Development of a new synthesis approach for S-pregabalin by optimizing the preparation stages
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In the present study, we aimed to optimize the synthesis stages of S-pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid), a well-known anticonvulsant drug. We used appropriate solvents and compounds to reach a straightforward and applicable method. The advantages of this research were avoiding use of expensive and environment pollutant reagents and solvents, and also using a recoverable reagent. Discarding prevention of the intermediates and reagents besides attaining a higher yield of the obtained product were the additional achievements. All structures were characterized by FT-IR, 1H NMR, and the purity of S-pregabalin was evaluated using the HPLC assay.
- Mansoori, Arsalan,Zahednezhad, Fahimeh,Bavili Tabrizi, Ahad,Shahbazi Mojarrad, Javid
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN
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The present invention relates to an improved process for the preparation of 3-isobutyl glutaric acid compound of formula-1 which is used as the key intermediate in the preparation of Pregabalin compound of formula-A. The present invention also relates to an improved process for the preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid compound of formula-A.
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- Method for synthesizing pregabalin midbody
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The invention discloses a method for synthesizing a pregabalin midbody, and belongs to the technical field of medicine preparation. According to the method for synthesizing the pregabalin midbody, ammonium chloride, ammonium bicarbonate, ammonium carbonate, ammonium oxalate, ammonium formate, ammonium bromide, ammonium iodide, ammonium hydroxide, formamide, acetamide, hydrazine hydrate and other solid or liquid substances are used as an ammonia source, under the action of alkaline, (S)-3-(ethoxy-formyl methyl)-5-methyl caproic acid is subjected to a room temperature reaction, and pregabalin midbody (R)-3-(carbamyl methyl)-5-methyl caproic acid is generated. The method for synthesizing the pregabalin midbody is simple to operate, the pregabalin midbody can be obtained with high yield underordinary-pressure room temperature, the reaction condition is mild, economic and environmentally friendly, and the method for synthesizing the pregabalin midbody is suitable for industrial production.
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Paragraph 0022-0041
(2019/11/20)
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- Preparation method of pregabalin intermediate (R)-3-carbamoyl methyl-5-methylhexanoic acid
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The invention relates to a preparation method of key intermediate (R)-3-carbamoyl methyl-5-methylhexanoic acid of pregabalin treating epilepsy, neuropathic pain and anxiety. The method uses cyanoacetamide and isovaleraldehyde as starting materials to prepare 3-isobutylglutaric acid, 3-isobutylglutaric acid is esterified, enzymatically reacted and aminolyzed to produce the pregabalin intermediate (R)-3-carbamoyl methyl-5-methylhexanoic acid. The invention has the advantages of low cost, simple reaction, environmental friendliness and high yield, and is suitable for industrial production.
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Paragraph 0015; 0016
(2019/10/02)
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- Method for synthesizing optically pure (R)-3-carbamoymethyl-5-methylhexanoic acid
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The invention relates to the technical field of fine chemical engineering production and in particular discloses a method for synthesizing optically pure (R)-3-carbamoymethyl-5-methylhexanoic acid. The method comprises the following steps: 1, synthesizing 2-cyano-5-methyl-2-ene ethyl hexanoate; 2, synthesizing 3-isobutyl-2-cyano-4-ethoxycarbonyl-ethyl glutarate; 3, synthesizing 3-isobutylglutaricanhydride; 4, synthesizing (+/-)-3-carbamoymethyl-5-methylhexanoic acid; and 5, synthesizing the (R)-3-carbamoymethyl-5-methylhexanoic acid. According to the method disclosed by the invention, the defects in the prior art are overcome, and the provided synthetic method is low in raw material cost, high in reaction speed, simple and feasible, is suitable for large-scale industrial production and has very high economic benefits.
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- Asymmetrical synthesis method of lyrica
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The invention discloses an asymmetrical synthesis method of lyrica, wherein the synthesis steps comprise: carrying out a cyclic anhydridization reaction by using 3-isobutylglutaric acid as a raw material, carrying out an asymmetric ring-opening reaction with (R)-(+)-1-phenylethylamine, and sequentially carrying out a hydrogenation reaction and Huffman rearrangement to obtain lyrica. Compared to the synthesis method in the prior art, the synthesis method of the present invention has advantages of inexpensive and easily-available raw materials and less reaction steps, has the total yield of up to 60%, the purity of the product lyrica of more than 99% and the ee value of more than 99%, and has good application prospect in industrial scale up production.
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- PROCESS FOR PREPARATION OF PREGABALIN
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Aspects of the present invention relate to improved process for preparation of (R)(?)-3-(carbamoylmethyl)-5-methylhexanoic acid (R-CMHA) of the formula (II) or its pharmaceutically acceptable salts in the presence of a lewis acid, process for preparation of pregabalin using R-CMHA of the formula (II) or its pharmaceutically acceptable salts prepared according to the present invention and process for preparation of pregabalin with low amount of undesired impurity.
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Paragraph 0096-0098
(2014/09/03)
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- IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN
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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.
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Page/Page column 7
(2014/06/11)
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- CAL-B catalyzed desymmetrization of 3-alkylglutarate: "olefin effect" and asymmetric synthesis of pregabalin
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CAL-B catalyzed desymmetrization of prochiral 3-alkylglutaric acid diesters was performed to prepare optically active 3-alkylglutaric acid monoesters bearing various alkyl substituents, including methyl, ethyl, propyl and allyl groups. Allyl esters showed
- Jung, Jae-Hoon,Yoon, Doo-Ha,Kang, Philjun,Lee, Won Koo,Eum, Heesung,Ha, Hyun-Joon
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p. 3635 - 3641
(2013/06/26)
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- PROCESS FOR THE PREPARATION OF R-(-)-3- (CARBAMOYLMETHYL)-5-METHYLHEXANOIC ACID AND THE INTERMEDIATES
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The invention provides a process for resolution of R (±) - 3- (carbamoylmethyl)-5-methylhexanoic acid I to form enantiomerically pure form of compound of formula (I), the said process comprises resolution of racemic mixture of compound of formula (II) with cinchona class of alkaloids or amines. The invention also provides for a process for preparing (S)-3-(aminomethyl)-5- methylhexanoic acid from R (-)-3-(carbamoylmethyl)-5-methylhexanoic acid I.
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Page/Page column 24-25
(2012/07/27)
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- PROCESS FOR PREPARING PREGABALIN AND ITS INTERMEDIATE
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Processes for preparing pregabalin and its intermediate such as 3-(carbamoylmethyl)-5-methylhexanoic acid are provided. The process for preparing pregabalin mainly comprises reacting 3-(carbamoylmethyl)-5-methylhexanoic acid with (+)-phenyl ethyl amine, followed by reacting with bromine in the presence of base to obtain pregabalin.
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- INTERMEDIATES IN THE ENANTIOSELECTIVE SYNTHESIS OF 3-(AMINOMETHYL)-5-METHYL-HEXANOIC ACID
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(S)-(+)-3-(aminomethyl)-5-methyl-hexanoic acid or (S)-pregabalin is an anticonvulsive drug. In addition to its use as an anticonvulsive agent, pregabalin has also been indicated as a medicament in the treatment of anxiety, neuropathic pain and pain in patients with fibromyalgia. Provided herein are thioester intermediates in the synthesis of and processes for the synthesis of 3-(aminomethyl)-5-methyl-hexanoic acid in the (R) or (S) configuration.
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Page/Page column 27
(2010/08/09)
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- STEREOSELECTIVE ENZYMATIC SYNTHESIS OF (S) OR (R)-ISO-BUTYL-GLUTARIC ESTER
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The present invention relates to a stereoselective enzymatic synthesis of (S) or (R)-iso-butyl-glutaric ester, an intermediate of S-Pregabalin.
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Page/Page column 16-17
(2010/01/30)
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- An efficient process of racemization of 3-(Carbamoylmethyl)-5- methylhexanoic acid: A pregabalin intermediate
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A simple and cost-effective process for racemization of undesired (S)-3-(carbamoylmethyl)-5-methylhexanoic acid (9), produced during the resolution step, is described. The literature procedure is fraught with many difficulties including number of steps and hazardous reagents. We have developed a one pot process for the above-mentioned racemization of S-enantiomer. The basic objective is to convert S-enantiomer into the symmetrical glutarimide derivative followed by hydrolysis with an alkali. The transformation of 9 into glutarimide derivative (10) has been achieved with piperidine in refluxing toluene.
- Chavan, Anil B.,Maikap, Golak C.,Gurjar, Mukund K.
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scheme or table
p. 812 - 814
(2010/04/22)
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- AN IMPROVED PROCESS FOR PREPARATION OF (S)-PREGABALIN AND INTERMEDIATES THEREOF
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The present invention relates to an improved process for the preparation of (S)- Pregabalin of formula (I) and its intermediates thereof. Particularly, the present invention relates to the process for the preparation (S)-Pregabalin having chiral purity not less than 99.0% by area percentage of HPLC. Further, the present invention relates to the process for the preparation of (S)-Pregabalin having low level of impurities, determined by area percentage of HPLC.
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Page/Page column 27
(2009/03/07)
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- PROCESS FOR THE PREPARATION OF (R)-(-)-3-(CARBAMOYLMETHYL)-5-METHYLHEXANOIC ACID AND OF PREGABALIN AND SYNTHESIS INTERMEDIATES
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This invention relates to the preparation of (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid, in particular, the resolution of the acid racemate by means of salification with optically active amines and subsequent acidification to give the (R) enantiomer of the acid; this invention also concerns the salt intermediates formed with said amines and the conversion of said (R)-(-)-3-(carbamoylmethyl)-5- methylhexanoic acid into biologically active molecules such as pregabalin.
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Page/Page column 12
(2008/06/13)
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- CHIRAL 3-CARBAMOYLMETHYL-5-METHYL HEXANOIC ACIDS, KEY INTERMEDIATES FOR THE NEW SYNTHESIS OF (S)-PREGABALIN
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The invention encompasses the synthesis of (S)-(+)-3-(aminomethyl)-5- methylhexanoic acid, (S)-Pregabalin, via the intermediate, (3R)-5-methyl-3-(2-oxo-2{[(lR)- l-phenylethyl]amino} ethyl)hexanoic acid.
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Page/Page column 28-29
(2008/06/13)
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- Processes for the preparation of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof
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Provided are processes for the synthesis of R-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid and salts thereof, intermediates in the synthesis of S-pregabalin.
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Page/Page column 11
(2008/06/13)
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- Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid
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The present invention provides a method of making (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid which comprises condensing isovaleraldehyde with an alkyl cyanoacetate to form a 2-cyano-5-methylhex-2-enoic acid alkyl ester; reacting the 2-cyano-5-methylhex-2-enoic acid alkyl ester with a dialkyl malonate to form 3-isobutylglutaric acid; forming the anhydride of 3-isobutylglutaric acid; reacting the anhydride with ammonia to form (±)-3-(carbamoylmethyl)-5-methylhexanoic acid; reacting (±)-3-(carbamoylmethyl)-5-methylhexanoic acid with (R)-(+)-α-phenylethylamine to obtain the (R)-(+)-α-phenylethylamine salt of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; combining the salt with an acid to obtain (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid; and reacting the (R)-(-)-3-carbamoylmethyl)-5-methylhexanoic acid with a Hofmann reagent to obtain (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid.
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