- A One-Step Biocatalytic Process for (S)-4-Chloro-3-hydroxybutyronitrile using Halohydrin Dehalogenase: A Chiral Building Block for Atorvastatin
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(S)-4-Chloro-3-hydroxybutyronitrile [(S)-CHBN] was used as a chiral building block for the preparation of atorvastatin. In this study, (R,S)-epichlorohydrin [(R,S)-ECH] and 1,3-dichloro-2-propanol (1,3-DCP) were investigated to prepare (S)-CHBN by using the halohydrin dehalogenase HheC from Agrobacterium radiobacter AD1. Preparing (S)-CHBN from (R,S)-ECH gave a modest enantiomeric excess (ee), whereas by using 1,3-DCP as the substrate, (S)-CHBN was obtained with 97.3 % ee after pH optimization. However, a low ee value and low yield of (S)-CHBN were obtained if the substrate concentration was increased to 10 g L-1. To obtain a higher ee value and yield, 16 mutants were constructed and screened. The variant W249F with improvements in activity and enantioselectivity was identified and applied at a 1,3-DCP loading of 10 g L-1, which gave (S)-CHBN in 86 % yield with 97.5 % ee in 1 h. This is the first report of a one-step biocatalytic process for the preparation of (S)-CHBN from prochiral 1,3-DCP.
- Wan, Nan-Wei,Liu, Zhi-Qiang,Xue, Feng,Shen, Zhen-Yang,Zheng, Yu-Guo
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- Efficient activation of zinc: Application of the Blaise reaction to an expedient synthesis of a statin intermediate
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Efficient and practical in situ zinc activation was accomplished by treatment with catalytic amount of an organic acid. The protocol was applied successfully to the Blaise reaction of various nitriles. Noteworthy is the excellent Blaise transformation of (S)-4-chloro-3-trimethylsilyloxybutyronitrile (2b) into tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate (1), a key intermediate for the preparation of HMG-CoA reductase inhibitors (statins).
- Shin, Hyunik,Choi, Bo Seung,Lee, Ki Kon,Choi, Hyeong-Wook,Chang, Jay Hyok,Lee, Kyu Woong,Nam, Do Hyun,Kim, No-Soo
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- Method for synthesizing high-content (S)-4-chloro-3-hydroxybutyronitrile
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The invention relates to a method for synthesizing high-content (S)-4-chloro-3-hydroxybutyronitrile. The method comprises the following step: by taking S-type epoxy chloropropane as a reaction substrate and trimethylsilyl cyanide as a cyaniding agent in the presence of water, obtaining the (S)-4-chloro-3-hydroxybutyronitrile. According to the invention, traditional sodium cyanide or hydrogen cyanide is not used as a cyaniding agent, so that potential safety hazards in production are avoided, harsh production conditions are not needed, cyanide-containing wastewater is not generated, the wastewater treatment cost of enterprises is reduced, side reactions are reduced, the yield of target products is increased, and the subsequent purification difficulty is reduced; and the method further optimizes the molar ratio of the catalyst to the reaction substrate to the cyaniding agent to water to the catalyst, the reaction time, the reaction temperature and other conditions so as to further reduce the probability of side reaction, and improve the yield and the purity of the product.
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Paragraph 0029-0030; 0035-0072
(2022/01/08)
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- A Cyanide-free Biocatalytic Process for Synthesis of Complementary Enantiomers of 4-Chloro-3-hydroxybutanenitrile From Allyl Chloride
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A biocatalyst used for selective ring scission of (±)-5-(chloromethyl)-4, 5-dihydroisoxazole to synthesize chiral (R)-4-chloro-3-hydroxybutanenitrile (90 % ee, 39 % isolated yield) and (S)-5-(chloromethyl)-4, 5-dihydroisoxazole (99 % ee, 39 % isolated yield) was developed by site-saturated mutagenesis on aldoxime dehydratase derived from Pseudomonas chlororaphis B23 (OxdA). The positive mutant (OxdA-L318I, E=68) improved the enantiomeric ratio E by 6-fold as compared to the wild type enzyme (OxdA-wild, E=11). The racemic precursor of (±)-5-(chloromethyl)-4, 5-dihydroisoxazole, used in the reaction, can be synthesized from readily available allyl chloride without utilizing highly toxic cyanide. The enantiopure (S)-5-(chloromethyl)-4, 5-dihydroisoxazole remaining in the kinetic resolution can be transformed into corresponding chiral (S)-4-chloro-3-hydroxybutanenitrile without loss of enantiomeric excess by treating it with triethylamine in acetonitrile (99 % ee, 72 % isolated yield) or catalysis of OxdA-wild enzyme (99 % ee, 88 % isolated yield).
- Zheng, Daijun,Asano, Yasuhisa
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p. 4237 - 4242
(2021/08/25)
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- Method for synthesizing butyrolactone derivative
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The invention discloses a method for synthesizing a butyrolactone derivative. The method comprises steps as follows: (1), after being activated by a titanium reagent, an epoxy compound represented asa formula (II) is subjected to an addition reaction by a Grignard reagent, and a compound represented as a formula (III) is obtained; (2), the compound represented as the formula (III) is subjected tocyano hydrolysis under the alkaline condition, and a carboxylic acid derivative represented as a formula (IV) is obtained; (3), the carboxylic acid derivative represented as the formula (IV) is subjected to a dehydration cyclization reaction, and the butyrolactone derivative represented as a formula (I) is obtained. The method has the advantages of being simple in synthesis step, low in production cost and high in functional group selectivity, regioselectivity and yield; the synthetic route is shown in the description.
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Paragraph 0026; 0027; 0028; 0029
(2018/05/16)
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- A new practical synthesis of ethyl (R)-(-)-4-Cyano-3-hydroxybutyrate from (S)-3-chloro-1,2-propanediol
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A practical chemical synthesis of ethyl (R)-(-)-4-Cyano-3- hydroxybutyrate((R)-CNHB) has been accomplished from (S)-3-chloro-1,2- propanediol, which is a main by-product originating from (S,S)-Salen Co(III) catalyzed by hydrolytic kinetic resolution (HKR) of epichlorohydrin. The new synthetic approach demonstrated an efficient utilization of organic by-product for the asymmetric synthesis of the intermediate of atorvastatin.
- Jiang, Chengjun,Hong, Huabin
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p. 520 - 521
(2012/11/06)
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- METHOD FOR THE PREPARATION OF 3-SUBSTITUTED-3’-HYDROXYPROPIONITRILE
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The present invention relates to a method for the preparation of 3-substituted-3’-hydroxypropionitrile, more particularly, to a method for the preparation of 3-substituted-3’-hydroxypropionitrile which comprises performing ring opening of 1-substituted-ethylene oxide using sodium cyanide and citric acid in a range of pH 7.8 ~ 8.3 to provide 3-substituted-3’-hydroxypropionitrile in high optical purity and with high yield.
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Page/Page column 9-10
(2008/06/13)
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- PROCESS FOR PREPARING 4-CHLORO-3-HYDROXYBUTANOIC ACID ESTER
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The present invention relates to a process for preparing 4-chloro-3-hydroxybutanoic acid ester, an intermediate for preparing atorvastatin, in high purity and yield, by comprising the steps of 1) reacting epichlorohydrin of formula (2) with cyanide of formula (3) under the condition of pH ranging from 7 to 8, to form the 4-chloro-3-hydroxybutyronitrile of formula (4) and 2a) dissolving the 4-chloro-3-hydroxybutyronitrile of formula (4) in an alcoholic solvent and reacting it with hydrogen chloride, or 2b) reacting the 4-chloro-3-hydroxybutyronitrile of formula (4) in an alcoholic solvent saturated with hydrogen chloride, to form the 4-chloro-3-hydroxybutyronitrile acid ester of formula (I).
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- An Epoxide Ring-Opening Reaction via Hypervalent Silicate Intermediate: Synthesis of Statine
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The azide- and cyanide-opening reaction of epoxide with TBAF and TMSN 3 in THF or TBAF and TMSCN in MeCN occurred regioselectively to afford β-hydroxy azides and cyanides in good yield. These hypervalent silicates have been shown to be highly effective as nucleophilic azide and cyanide donors under mild conditions. This methodology has been applied to the preparation of statine.
- Konno, Hiroyuki,Toshiro, Emi,Hinoda, Naoyuki
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p. 2161 - 2164
(2007/10/03)
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- Preparation of (R)- and (S)-4-chloro-3-acetoxybutyronitrile using microbial resolution
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A new preparation of optically active 4-chloro-3-acetoxybutyronitrile (AcBN) was developed using the resting cells of bacteria. The resolution was based on enantioselective hydrolysis of the ester function of the substrate. (R)-AcBN was prepared using Pseudomonas sp. DS-K-717, and the resulting (R)-AcBN was obtained with high enantiomeric excess of >98% with a yield of 36% during the microbial resolution step. (S)-AcBN was prepared in the same manner using the resting cells of Pseudomonas sp. DS-K-19 and showed a high enantiomeric excess of >98% with a yield of 32%. The enzyme activity was enhanced and induced by the addition of AcBN, particularly the (R)-ester hydrolysis, which was enhanced 20-fold.
- Idogaki, Hideaki,Kasai, Naoya,Takeuchi, Motoko,Hatada, Miki,Suzuki, Toshio
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p. 369 - 373
(2007/10/03)
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- Production of (S)-4-chloro-3-hydroxybutyronitrile using microbial resolution
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A new production procedure of (S)-4-chloro-3-hydroxybutyronitrile was developed using microbial resolution. The resting cells of Pseudomonas sp. OS-K-29 preferentially converted (R)-4-chloro-3-hydroxybutyronitrile to the corresponding 1,2-diol by the dehalogenating activity so that (S)-4-chloro-3-hydroxybutyronitrile (94.5%ee) was obtained from the racemate in 40% yield at the microbial resolution step.
- Suzuki, Toshio,Idogaki, Hideaki,Kasai, Naoya
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p. 2581 - 2584
(2007/10/03)
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- A novel generation of optically active ethyl 4-chloro-3-hydroxybutyrate as a C4 chiral building unit using microbial dechlorination
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A novel procedure for the generation of optically active ethyl 4-chloro-3-hydroxybutyrate using bacterial cells was developed. Ethyl (S)-4-chloro-3-hydroxybutyrate was prepared by Pseudomonas sp. OS-K-29, which stereoselectively assimilates 2,3-dichloro-1-propanol. The reaction was based on its kinetic dehalogenation for both enantiomers using the resting cells. The obtained 4-chloro-3-hydroxybutyrate and high enantiomeric excess of >98% with a yield of 33% at the microbial resolution step. Moreover, several C4 compounds having the 4-chloro-3-hydroxyl function were also resolved and gave good enantiomeric purities (>95% ee). Ethyl (R)-4-chloro-3-hydroxybutyrate was also obtained with high enantiomeric purity (>98% ee) using the cells of Pseudomonas sp. DS-K-NR818. Copyright (C) Elsevier Science Ltd.
- Suzuki, Toshio,Idogaki, Hideaki,Kasai, Naoya
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p. 3109 - 3112
(2007/10/03)
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- A New Enzymatic Synthesis of (R)-γ-Chloro-β-Hydroxybutyronitrile
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A new enzymatic synthesis of (R)-γ-chloro-β-hydroxybutyronitrile from epichlorohydrin or 1,3-dichloro-2-propanol using halohydrin hydrogen-halide-lyase purified from a recombinant Escherichia coli that carried the enzyme gene of Corynebacterium sp. strain N1074 was described.
- Nakamura, Tetsuji,Nagasawa, Toru,Yu, Fujio,Watanabe, Ichiro,Yamada, Hideaki
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p. 11821 - 11826
(2007/10/02)
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