- 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; 0019
(2019/02/21)
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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; 0025; 0028; 0032
(2019/09/14)
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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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Paragraph 0013; 0030-0032; 0039-0041; 0050
(2018/06/04)
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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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Page/Page column 5-9
(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 0038; 0039; 0040
(2017/05/27)
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- SYNTHESIS OF (S)-PREGABALIN
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Provided is a process for preparing (S)-Pregabalin
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Page/Page column 20
(2017/06/12)
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- 1,4-DICARBONYL-PIPERIDYL DERIVATIVES
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Compounds of the formula I in which Z, W, Q, R and Y have the meanings indicated in Claim 1, are inhibitors of Tankyrase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.
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Page/Page column 46
(2017/07/01)
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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 0061
(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 18
(2012/07/27)
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- Enantioselective alcoholysis of meso-glutaric anhydrides catalyzed by Cinchona-based sulfonamide catalysts
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The bifunctional Cinchona-based sulfonamide catalysts showed the highest levels of enantioselectivity reported to date in the alcoholytic desymmetrization of meioglutaric anhydrides. Density functional theory (DFT) computational studies provide detailed insight into the observed sense of enantioselectivity. Moreover, detailed experimental studies and single crystal X-ray analysis confirmed that these bifunctional organocatalysts 3 do not form Hbonded self-aggregates in both solution and solid state. The synthetic utility of this methodology was also demonstrated in the synthesis of pharmaceutically important γ-amino acids, such as (S)-pregabalin. Of the many asymmetric syntheses of enantiomerically pure (S)-pregabalin reported to date, our synthesis requires the least number of and the simplest steps.
- Park, Sang Eun,Nam, Eun Hye,Jang, Hyeong Bin,Oh, Joong Suk,Some, Surajit,Lee, Yong Seop,Song, Choong Eui
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supporting information; experimental part
p. 2211 - 2217
(2010/11/19)
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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 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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- PROCESS FOR PREPARING PREGABALIN AND ITS OPPOSITE ENANTIOMER
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The invention relates to the preparation of pregabalin and its opposite enantiomer, or a pharmaceutically-acceptable salt of either thereof, and to the intermediates used for their preparation.
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Page/Page column 8-9
(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 30
(2008/06/13)
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- An efficient synthesis of (S)-3-aminomethyl-5-methylhexanoic acid (Pregabalin) via quinine-mediated desymmetrization of cyclic anhydride
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A highly enantioselective synthesis of (S)-3-aminomethyl-5-methylhexanoic acid 1 (Pregabalin) is reported. The key step of the synthesis is a quinine-mediated ring opening of 3-isobutylglutaric anhydride with cinnamyl alcohol. A Curtius rearrangement and subsequent deprotection provides 1 in high yield and excellent enantiomeric excess.
- Hamersak, Zdenko,Stipetic, Irena,Avdagic, Amir
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p. 1481 - 1485
(2008/02/11)
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