- 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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- Y-shaped potential third-order nonlinear optical material-3-(2-amino-2-oxoethyl)-5-methyl hexanoic acid: An analysis of structural, spectroscopic and docking studies
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The present work reports an analysis of the structure, spectroscopic signatures, nonlinear optical properties and docking studies of synthesized 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid (abbreviated as AOEMHA) with the empirical formula C19H17NO3. The structure in the solid state determined by the single crystal X-ray diffraction technique revealed that AOEMHA is Y-shaped with the methine carbon atom acting as a junction point. The dihedral angles between the three segments forming the Y-shaped structure are 77.7(3)°, 86.2(9)° and 19.9(2)°. In the crystal structure, the O-H?O and N-H?O hydrogen bonded chains result in an infinite two-dimensional architecture parallel to the ac-plane. Intermolecular interactions were further visualized and topologically analyzed (using the quantum theory of atoms in molecules) with the support of the Crystal Explorer and Multiwfn program. The reactivity parameters (the frontier molecular orbital, molecular electrostatic surface potential, atomic charges and Fukui function) and topological studies (localized orbital locator and electron localization function) were also estimated for the investigated compound. For hydrogen and all the other single acyclic bonds, bond dissociation energy calculations have been performed to assess the possible degradation properties by the autoxidation mechanism. The linear refractive index and the third-order nonlinear susceptibility (χ(3)) are calculated as a function of the electric field frequency by using the supermolecule approach (SM) at the DFT/CAM-B3LYP/aug-cc-pVTZ level for analyzing the nonlinear optical properties in a simulated crystalline environment. The χ(3) value for the AOEMHA crystal at ω = 0.086 a.u. is significant when compared to experimental results from other organic crystals which demonstrate the opportunities for the AOEMHA crystal as a nonlinear optical (NLO) material. Molecular docking studies were performed with AKR1C3 inhibitors for the AOEMHA compound. This journal is
- Poojith, Nuthalapati,Potla, Krishna Murthy,Osório, Francisco A. P.,Valverde, Clodoaldo,Vankayalapati, Suneetha,Suchetan,Raja
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p. 18185 - 18198
(2020/11/13)
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- Pregregregabalin intermediate mother liquor and method for recycling wastewater
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The invention provides a preparation method for mechanically applying Pregabalin 3-isobutyl-glutarate monoamide intermediate mother liquid and waste water. The method comprises the following steps: (1) dropwise adding 3-isobutyl glutaric anhydride into stronger ammonia water with the mass fraction of 25-28%, and carrying out insulation reaction; (2) adding reclaimed waste water into the system, and then dropwise adding acid slowly into the system to adjust the pH value to be 2.0-3.0; (3) adding the mother liquid into the system, extracting with an organic solvent for layering, and then carrying out reduced pressure distillation on an organic layer; and (4) cooling to 5-15 DEG C within 2-3 hours, crystallizing, insulating for 1.5-2 hours, carrying out suction filtration, preserving suction filtration mother liquid, and baking filter cakes, thereby obtaining the target product 3-isobutyl-glutarate monoamide. The method provided by the invention has the advantages that the operation is simple, and the ammonolysis yield is effectively improved; before the ammonolysis mother liquid is mechanically applied, the yield is generally 70-85%; and after the ammonolysis mother liquid is mechanically applied, the yield can reach 99.0-102.0%, so that the productivity is effectively enlarged, and the cost of industrial production is lowered.
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Paragraph 0032-0049
(2020/09/23)
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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; 0020; 0021
(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; 0026; 0028; 0033
(2019/09/14)
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- Synthetic method of pregabalin intermediate
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The invention relates to the technical field of pharmaceutical preparation, and especially relates to a synthetic method of a pregabalin intermediate. Aims at the defects of unfavorable operations, environment-unfriendliness, and the like in the prior art
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Paragraph 0023; 0024; 0025; 0028; 0031
(2019/01/07)
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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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- Pregabalin intermediate splitting of the stock solution of racemic recovery method (by machine translation)
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This invention relates to a kind of Pregabalin intermediate split recovery method for the racemization of the stock solution, comprises the following steps : (1) the (R)-phenethylamine split 3 - (Carboxamide methyl) - 5- methyl oneself acid racemate of the mother liquor after concentrated then dissolved in water, adjusted with concentrated hydrochloric acid to pH 1-3, cooling crystallization, to obtain (S) - 3 - (Carboxamide methyl) - 5- methyl oneself acid ; (2) the (S) - 3 - (Carboxamide methyl) - 5- methyl oneself acid added to the xylene, dissolve, heat to 80-150 °C carry out dehydration cyclization, to obtain 3-isobutylglutaric imide ; (3) the 3-isobutylglutaric imide the hydrolysis under alkaline conditions to obtain 3 - (Carboxamide methyl) - 5- methyl oneself acid eliminating the body. The method of the present invention select xylenecyanol as dehydrating cyclization reaction solvent, to obtain a high recovery yield, but reaction time is relatively short, and does not need to use the higher price of the reagent, thus the cost is relatively low, can be suitable for industrial production. (by machine translation)
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Paragraph 0018; 0019; 0020; 0021; 0022; 0023; 0024
(2016/12/01)
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- Method for preparing pregabalin intermediate 3-isobutyl glutaric acid monoamide
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The invention discloses a method for preparing pregabalin intermediate 3-isobutyl glutaric acid monoamide. The method includes steps of adding 3-isobutyl glutaric acid and urea into organic solvents; carrying out heating, heat-insulation reflux, cooling a
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Paragraph 0031-0032
(2017/05/12)
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- NOVEL PROCESS FOR RACEMIZATION OF AN OPTICALLY ACTIVE (S)-3-CARBAMOYLMETHYL-5-METHYL-HEXANOIC ACID TO CORRESPONDING 3-CARBAMOYLMETHYL-5-METHYL-HEXANOIC ACID RACEMATE
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A novel process for racemization of (S)-3-carbamoylmethyl-5-methyl-hexanoic acid to 3-carbamoylmethyl-5-methyl-hexanoic acid racemate has been developed.
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Page/Page column 5
(2013/06/06)
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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 20-21
(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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- 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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experimental part
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 26
(2009/03/07)
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- Prodrugs containing novel bio-cleavable linkers
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The invention provides the compounds of formula (I) or pharmaceutically acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one more of pharmaceutically acceptable carriers, vehicles or diluents. The invention further provides methods of preparation and methods of use of prodrugs including NO-releasing prodrugs, double prodrugs and mutual prodrugs comprising the compounds of formula I.
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Page/Page column 135
(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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