- 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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- Method for preparing 3-isobutylglutaric acid
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The invention discloses a method for preparing 3-isobutylglutaric acid. The method includes the following steps: carrying out a Knoevenagel condensation reaction on isovaleraldehyde and diethyl malonate with hexahydropyridine acetate as a catalyst in a cyclohexane solvent; carrying out a heating decarboxylation reaction on a product obtained by the first step in a solution composed of sodium chloride, DMSO and water; carrying out a Michael addition and decarboxylation reaction on a product obtained by the second step and diethyl malonate in an alcohol solvent of an alkali; and carrying out a hydrolysis reaction on a product obtained by the third step under an acidic condition to obtain the 3-isobutylglutaric acid product. The method of the invention uses the cheap and easily available isovaleraldehyde and diethyl malonate as raw materials, overcomes the defect of large steric hindrance of carbon-carbon a double bond in 5-methyl-2-cyano-2-hexenoate in the prior art, shortens the reaction time, and increases the reaction conversion rate of the isovaleraldehyde, thereby ensuring the overall yield of the 3-isobutylglutaric acid product.
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Page/Page column 6-9
(2019/10/04)
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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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Page/Page column 14; 17; 18
(2019/10/29)
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- Pregabalin intermittent synthesis method
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The invention discloses a pregabalin intermittent synthesis method. The method comprises the following step of (1) preparation of 2-cyano-5-methyl-2-hexenyl ethyl ester (A), wherein 94.6 g (1.1mol) ofisovaleraldehyde, 113 g (1.0 mol) of ethyl cyanoacetate, 127 ml of n-hexane and 1.00 g (0.01mol) of di-n-propylamine are put into a 1000 ml reaction bottle in sequence, heating is conducted, reflux reaction is carried out, a water separator is used for water separation, the reaction is carried out until no moisture is separated out, and cooling is conducted. Compared with the prior art, the pregabalin intermittent synthesis method has the following advantages that when methyl tertiary butyl ether is used as a solvent, layering is hard, impurities cannot be removed, the solvent cannot be recycled, the raw material cost is improved, and the amide is low, so that the methyl tertiary butyl ether is not suitable for being used as the solvent; ethyl acetate can be used, however, the intersolubility of the ethyl acetate and water is large, thus a small amount of amide crude product is dissolved in the water, the amide yield is low, meanwhile, the ethyl acetate recovery is low, and by using methylbenzene, the defects of the ethyl acetate are avoided, so that the methylbenzene is selected as an ammoniation solvent. There are no corresponding HPLC standards of the quality situation of amide, however, the quality of the amide obtained by adopting a technology is qualified in later detection.
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Paragraph 0014; 0018
(2019/02/21)
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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 0009; 0010
(2019/10/02)
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- Preparation method and application of high-purity dimethyl 3-isobutylglutarate
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The invention provides a preparation method and application of high-purity dimethyl 3-isobutylglutarate. Specifically, the invention provides the method for preparing dimethyl 3-isobutylglutarate shown as a formula 2, and the method comprises the step of enabling 3-isobutylglutaric acid to react in methanol in the presence of potassium permanganate and concentrated sulfuric acid, so as to obtain the high-purity dimethyl 3-isobutylglutarate. The method is simple, easy to control, high in product conversion rate, mild in reaction condition, convenient for industrial production and low in cost, the product is easy to purify, and the purity is up to 99% or above.
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Paragraph 0124; 0127; 0133; 0135; 0171-0172
(2019/12/02)
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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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Paragraph 0019; 0021; 0024; 0028; 0030
(2019/09/14)
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- Method for preparing Pregabalin intermediate
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The invention provides a method for preparing a Pregabalin intermediate. The method comprises the steps: subjecting cyanoacetamide and isovaleraldehyde to an acylation reaction in the presence of a catalyst, i.e., n-propylamine so as to obtain 3-isobutylglutaric acid, wherein a temperature for the acylation reaction is controlled to 35 DEG C to 40 DEG C; and adding a dehydrant, i.e., acetic anhydride into the obtained 3-isobutylglutaric acid, so as to carry out dehydrated cyclization, thereby obtaining the Pregabalin intermediate, i.e., 3-isobutyl glutaric anhydride, wherein the mole ratio ofthe cyanoacetamide to the isovaleraldehyde to the n-propylamine to the acetic anhydride is 1: (0.4 to 0.6): (0.02 to 0.03): (0.4 to 0.6). According to the method, through controlling the reaction temperature and a material proportioning ratio, side reactions participating in the reaction are less, and then, the obtained product is less in impurity. The Pregabalin intermediate, i.e., 3-isobutyl glutaric anhydride with higher yield and purity is obtained, the yield is greatly increased, and the one-time yield of the product is 80.6%.
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Paragraph 0027-0030; 0036-0039; 0045-0048; 0054-0057
(2019/01/06)
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- Preparation method for 3-carbamoymethyl-5-methylhexanoic acid
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The invention relates to a preparation method for 3-carbamoymethyl-5-methylhexanoic acid, and the product can be used as a pregabalin intermediate. The preparation method comprises the steps that a condensation compound is generated by catalytic condensation using isovaleraldehyde and cyanoacetamide as raw materials under mild conditions; the condensation compound is hydrolyzed to generate 3-Isobutylglutaric acid under acidic conditions; 3-isobutylglutaric anhydride is generated through an anhydride reaction; the final product 3-carbamoymethyl-5-methylhexanoic acid is generated through an amidation reaction. The preparation method for 3-carbamoymethyl-5-methylhexanoic acid effectively improves the condensation reaction efficiency through catalytic condensation of a base catalyst, and is high in production yield, less in by-products, mild in reaction conditions, and is beneficial to treatment of three wastes, and provides an environment-friendly technological route for industrialized mass production. The preparation method is an operation-safety, high-yield, low-cost and environment-friendly route.
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Paragraph 0035; 0036; 0037
(2017/05/27)
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- Method for synthesis of pregabalin from methyl cyanoacetate and isovaleraldehyde as raw materials
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The invention discloses a method for synthesis of pregabalin from methyl cyanoacetate and isovaleraldehyde as raw materials. The method comprises that isovaleraldehyde and methyl cyanoacetate undergo a Knoevenagel condensation reaction in an ethanol solvent in the presence of piperidine as a catalyst, the product and diethyl malonate undergo a Michael addition reaction in a n-hexane solvent in the presence of di-n-propylamine as a catalyst, the product undergoes an acid hydrolysis/decarboxylation reaction under conditions of heating and strong acid catalysis, the product and urea undergo an aminolysis reaction, the product undergoes a Hoffman degradation reaction and the product undergoes a chiral resolution reaction in the presence of (S)-(+)-mandelic acid as a resolving agent. Pregabalin is prepared from cheap and easily available isovaleraldehyde and methyl cyanoacetate as raw materials through Knoevenagel condensation, Michael addition, acid hydrolysis/decarboxylation, aminolysis, Hoffman degradation and chiral resolution. The method has a simple reaction route and a high yield in each reaction and guarantees a pregabalin overall yield and purity.
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Paragraph 0011; 0012; 0054
(2016/10/10)
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- Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate
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The invention discloses a method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as an intermediate. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and methyl cyanoacetate in an ethanol solvent by taking piperidine as a catalyst; carrying out Michael addition on the condensation product and diethyl malonate in a n-hexane solvent by taking di-n-propylamine as a catalyst; carrying out hydrolyzing decarboxylation on the addition product under the catalysis of strong acid and under the condition of heating; dehydrating the hydrolyzing decarboxylation product in a THF solvent under the catalysis of phosphorus pentoxide and under the condition of heating; enabling the dehydrated hydrolyzing decarboxylation product to subject to ammonolysis reaction with urea; carrying out Hoffman degradation on the ammonolysis reaction product; and finally, carrying out chiral resolution on the Hoffman degradation product by taking (S)-(+)-mandelic acid as a resolving agent. According to the method, isovaleraldehyde and methyl cyanoacetate, which are cheap and are readily available, serve as raw materials and are subjected to Knoevenagel condensation, Michael addition, acid hydrolyzing decarboxylation and dehydrating, so as to obtain the intermediate gamma-isobutylglutaric anhydride; and the gamma-isobutylglutaric anhydride is subjected to ammonolysis, Hoffman degradation and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.
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Paragraph 0060
(2016/10/09)
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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 17-18
(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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Page/Page column 15
(2011/07/09)
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- 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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experimental part
p. 266 - 275
(2011/02/22)
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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 25; 26
(2009/03/07)
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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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- 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 19
(2010/01/30)
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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 29
(2008/06/13)
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- Processes for the synthesis of 3-isobutylglutaric acid
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Provided are processes for the synthesis of 3-isobutylglutaric acid, an intermediate in the synthesis of (S)-Pregabalin.
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Page/Page column 13
(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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- Mono- and Di-μ-hydrido-bridged carbodications in acyclic systems
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μ-Hydrido-bridging in carbocations (C-H-C)+ involves a two-electron three-center bond. Such structures have previously been observed only when the two carbons are part of a medium ring (monocyclic, bicyclic, or tricyclic frameworks). Using appropriately constructed carbodications, acyclic systems are now shown to form such structures, including a novel example containing two μ-hydrido-bridged units.
- Sun, Fang,Sorensen
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