- Regioselective ring cleavage of chiral β-trichloromethyl-β- propiolactone with organoaluminum compounds for the synthesis of optically active intermediates
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A novel alkylating ring cleavage reaction of enantiomerically pure β- trichloromethyl-β-propiolactone as a chiral building block with organoaluminum compounds provided ring-opened products with a chiral trichloromethyl carbinol moiety. A product was demonstrated to be used as an effective chiral synthon for the synthesis of chiral bioactive derivatives such as ipsdienol and sodium cilastatin.
- Fujisawa, Tamotsu,Ito, Takatoshi,Nishiura, Shin,Shimizu, Makoto
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Read Online
- (S)-2,2-dimethylcyclopropanecarboxamide preparation method
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The invention relates to the technical field of chemical engineering, and discloses a (S)-2,2-dimethylcyclopropanecarboxamide preparation method, wherein the raw materials comprise, by weight, glycineethyl ester hydrochloride, a chiral catalyst, ethyl diazoacetate, glycine ethyl ester hydrochloride, sodium nitrite, dilute sulfuric acid, 3,5-di-tert-butylsalicylaldehyde, amidation and L-tartaric acid, wherein the chiral catalyst is Schiff base, L-tartaric acid is split with 1,2-cyclohexanediamine to obtain cyclohexanediamine tartrate, the cyclohexanediamine tartrate reacts with 3,5-di-tert-butylsalicylaldehyde to obtain the Schiff base ligand, the yield is 95%, and the content is 99%. The preparation method of the invention has advantages of production safety improving, low preparation cost and the like, and solves the problems of high danger degree of isobutene and other used materials and high preparation cost in the actual operation of the chiral dimethylcyclopropanecarboxamide preparation method in the prior art.
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Paragraph 0023; 0028; 0030; 0035
(2020/01/12)
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- A chiral dimethyl cyclopropanecarboxylic preparation method of the formamide
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The invention discloses a preparation method of chiral dimethyl cyclopropyl carboxamide. The method comprises a step of asymmetric cyclopropyl alkylation and a step of catalytic amidation of cyclopropyl formic ether, wherein in the step of asymmetric cyclopropyl alkylation, a cyclopropyl alkylation reaction is carried out on ethyl diazoacetate and isobutene under the catalysis of a chiral ligand complex of a cuprous salt so as to obtain (S)-dimethyl cyclopropyl formate; and in the step of catalytic amidation of cyclopropyl formic ether, an ammonolysis reaction is carried out on the (S)-dimethyl cyclopropyl formate by one step so as to directly obtain (S)-2,2-dimethyl cyclopropyl carboxamide, and refining the carboxamide with an alcohol so as to obtain the chiral dimethyl cyclopropyl carboxamide with chemical purity being greater than 99.5% and an e.e. value being greater than 99.5%. Thus, the method used for synthesizing the (S)-2,2-dimethyl cyclopropyl carboxamide is environment-friendly, simple, rapid and efficient.
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Paragraph 0058; 0059; 0060; 0061; 0073; 0076; 0081; 0085
(2018/11/03)
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- Kinetic resolution of (R,S)-2,2-dimethylcyclopropanecarboxamide by Delftia tsuruhatensis ZJB-05174: Role of organic cosolvent in reaction medium
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Both enantioselectivity and catalytic activity were greatly enhanced in Delftia tsuruhatensis ZJB-05174 catalyzed kinetic resolution of 2,2-dimethlycyclopropanecarboxamide in the presence of ethanol and acetonitrile. The enantiomeric ratio (E) rose from 27 to 140 and 90 by addition of 5% acetonitrile and ethanol, respectively. In the scaled-up biotransformation, the reaction time was shortened to 1.33 h with an ees of 99% and 12.4 g of optically pure product (43.5% total yield) was afforded. These results indicated that addition of cosolvent was a simple and practical tool to improve amidase properties and would be extensively applied in amidase-catalyzed bioprocess.
- Zheng, Ren-Chao,Wang, Yuan-Shan,Zheng, Yu-Guo,Shen, Yin-Chu
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- Industrial production of S-2,2-dimethylcyclopropanecarboxamide with a novel recombinant R-amidase from Delftia tsuruhatensis
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R-Stereoselective amidase, a key enzyme responsible for the formation of chiral center of cilastatin, has been cloned from Delftia tsuruhatensis and expressed in Escherichia coli under T7 promoter. This recombinant amidase exhibits strict R-selectivity towards 2,2-dimethylcyclopropanecarboxamide (DMCPCA). The amidase activity of the engineered E. coli strain reached 2963 U/L in a 5-L bioreactor, which was 8.27 times higher than that of D. tsuruhatensis, and was further increased to 5255 U/L in a 100-L bioreactor. Using cell-free extract prepared from 1 kg (wet cell weight) of recombinant E. coli cells as catalyst, 60 kg of R,S-DMCPCA was resolved into S-DMCPCA (28.6 kg) and R-2,2-dimethylcyclopropanecarboxylic acid (R-DMCPCS 31.7 kg) in 18 h, and the enantiomeric excess (ee) value of S-DMCPCA reached 99.32%. During the purification process, 24.6 kg of S-DMCPCA was eluted from adsorption resin HZ801 with 80% (v/v) acetone, and then 20.5 kg of pure S-DMCPCA was obtained after concentration and crystallization, corresponding to a total yield of 34.2% from R,S-DMCPCA. Therefore, the industrial production process of S-DMCPCA was successfully established using recombinant R-amidase from D. tsuruhatensis.
- Yang, Zhong-Yi,Ni, Ye,Lu, Zhong-Yuan,Liao, Xiang-Ru,Zheng, Yu-Guo,Sun, Zhi-Hao
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experimental part
p. 182 - 187
(2011/08/06)
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- Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
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Provided is a novel preparation method of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid represented by the following formula (1), a key intermediate of cilastatin used as a supplement to imipenem. The novel preparation method of the invention produces a pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid, a key intermediate of cilastatin, by selective hydrolysis of E isomers.
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Page/Page column 6
(2008/12/05)
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- PROCESS FOR PREPARING OPTICALLY ACTIVE CYCLOPROPANE CARBOXAMIDE AND DERIVATIVES THEREOF
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The present invention relates to a process for preparing optically active cyclopropane carboxamide in a specific structure using an enzyme.
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Page/Page column 12
(2008/06/13)
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE AMIDE
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The present invention relates to a new process for preparing a medical intermediate compound of formula (I). According to the present invention, an intermediate compound for cilastatin can be simply prepared with a high yield of 99.0% or more and a high optical purity of 99.5% without undergoing any dangerous processes.
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- Inhibition of the Mammalian β-Lactamase Renal Dipeptidase (Dehydropeptidase-I) by (Z)-2-(Acylamino)-3-substituted-propenoic Acids
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The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract.A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo.Many of the compounds were prepared in one step from an α-keto acid and a primary amide.The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl.With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 μM and a range of pharmacokinetic properties.By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer.The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.
- Graham, Donald W.,Ashton, Wallace T.,Barash, Louis,Brown, Jeannette E.,Brown, Ronald D.,et al.
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p. 1074 - 1090
(2007/10/02)
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