186038-82-4Relevant academic research and scientific papers
Preparation method of 1-cyano-3-methylbutyldiethyl malonate
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Paragraph 0060; 0063-0066, (2021/06/12)
The invention provides a preparation method of 1-cyano-3-methylbutyldiethyl malonate (CNDE), and belongs to the technical field of medical technology (organic synthesis). The technical key point is that the preparation method comprises the following steps: (1) carrying out Knoevenagel condensation reaction on isovaleraldehyde, diethyl malonate and a solvent in the presence of catalysts dipropylamine and acetic acid to obtain a CNDE01 product; and (2) adding the CNDE01, sodium cyanide, water and a solvent into a closed kettle, and reacting under the action of carbon dioxide to obtain the CNDE product. The invention aims to provide the preparation method of the 1-cyano-3-methylbutyldiethyl malonate (CNDE), the defects of the existing production process are overcome, and the preparation method has the advantages of low raw material cost, high product purity and yield, few three wastes and the like.
Preparation method of pregabalin
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, (2020/07/12)
The invention discloses a preparation method of pregabalin, and particularly discloses a synthesis method of pregabalin, and relates to a compound shown as a formula I shown in the specification.
Method for synthesizing Pregabalin by taking isovaleraldehyde as raw material
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, (2016/10/08)
The invention discloses a method for synthesizing Pregabalin by taking isovaleraldehyde as a raw material. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and diethyl malonate in a cyclohexane solvent by taking a mixture of di-n-propylamine and acetic acid as a catalyst; carrying out Michael addition on the product obtained in the step one in an alkaline alcohol solvent; carrying out deacidifying reaction on the product obtained in the step two in a solvent prepared from DMSO and water by taking lithium chloride as a catalyst under the condition of heating; carrying out hydrolytic reaction on the product obtained in the step three under alkaline conditions; carrying out catalytic hydrogenation on the product obtained in the step four by taking Raney nickel as a catalyst; and carrying out chiral resolution on the product obtained in the step five by adopting lipase Lipolase 100T. According to the method, isovaleraldehyde, which is cheap and is readily available, serves as a raw material and is subjected to Knoevenagel condensation reaction, Michael addition, decarboxylation, hydrolysis, hydrogenation reaction 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.
Asymmetric cyanation of activated olefins with ethyl cyanoformate catalyzed by a modular titanium catalyst
Wang, Jun,Li, Wei,Liu, Yanling,Chu, Yangyang,Lin, Lili,Liu, Xiaohua,Feng, Xiaoming
supporting information; experimental part, p. 1280 - 1283 (2010/06/15)
"Chemical Equation Presented" Asymmetric cyanation of a class of easily available olefins with a favorable cyanide source ethyl cyanoformate (CNCOOEt) was realized by an interesting modular catalyst. High yields and ee values were obtained for a range of substrates under solvent-free and mild reaction conditions. The products obtained could be easily transformed to the enantioenriched useful intermediates 5,6, and pharmaceutically Important γ-aminobutyric acid 7.
MALONATE ESTERS
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Page/Page column 28-32, (2010/08/05)
The invention provides a compound of formula (I), in an enantiomerically enriched form; wherein R1 and R2 are each independently selected from optionally substituted alkyl, cycloalkyl, aryl-alkyl and aryl, wherein the 3S-enantiomer is present in excess and the enantiomeric excess is at least 10%. There is also provided a method of preparing, in an enantiomerically enriched form, the compound of formula (I). Use of a compound of formula (I) in a method of preparing pregabalin is also discussed.
PROCESS TO PREPARE HIGHLY PURE (S)-PREGABALIN
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Page/Page column 14, (2010/06/17)
A process for the preparation of (S)-pregabalin of formula I containing cyanide ion content less than 5 ppm or free from the cyanide ion,by extracting its cyano diester intermediate of formula III, wherein R11 and R22 are the same or different and are hydrogen, C11-C66 alkyl, aryl, benzyl, substituted benzyl, or C33-C66 cycloalkyl. with an aqueous solution containing a cyanide quenching agent to remove free cyanide ion from the reaction mixture.
An efficient process of racemization of 3-(Carbamoylmethyl)-5- methylhexanoic acid: A pregabalin intermediate
Chavan, Anil B.,Maikap, Golak C.,Gurjar, Mukund K.
scheme or table, p. 812 - 814 (2010/04/22)
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.
Development of a chemoenzymatic manufacturing process for Pregabalin
Martinez, Carlos A.,Hu, Shanghui,Dumond, Yves,Tao, Junhua,Kelleher, Patrick,Tully, Liam
, p. 392 - 398 (2013/01/03)
A new manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac-2-earboxyethyl-3-cyano-5- methylhexanoic acid ethyl ester (1) can be resolved to form 2-carboxyethyl-3- cyano-5-methylhexanoic acid (2). A heat-promoted decarboxylation of 2 efficiently generates (S)-3-cyano-5-rnethylhexanoic acid ethyl ester (3), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of (R)-l. The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40-45% after one recycle of (R)-l), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.
CRYSTALLINE FORMS OF PREGABALIN
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Page/Page column 18-20, (2008/12/05)
The invention relates to crystalline form of Pregabalin and their process of preparation. The invention also relates to a process for preparing 2-carbethoxy-5- methylhex-2-enoic acid ethyl ester, an important intermediate for synthesis of crystalline Pregabalin, having less than about, 1-2% 2-carbethoxy-5-methylhex-3-enoic acid ethyl ester. Moreover, the present invention provides industrially applicable process for recovery of chiral reagent used for resolution of the (±)-Pregabalin; thereby to provide cost effective and economical process for preparation of Pregabalin.
Preparation of pregabalin and related compounds
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Page/Page column 18, (2008/06/13)
Materials and methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.
