- 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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- Preparation method for synthesizing L-carnitine by using R-(-)-epichlorohydrin as starting material
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The invention discloses a preparation method for synthesizing L-carnitine by using R-(-)-epichlorohydrin as a starting material, and belongs to the field of medicinal chemistry. The method comprises the steps: using R-(-)-epoxychlorohydrin and hydrocyanic acid as starting materials, performing a reaction for synthesis of R-4-chloro-3-hydroxybutyronitrile under the action of a basic catalyst, thensynthesizing L-carnitine hydrochloride through two routes, purifying the L-carnitine hydrochloride prepared through the two routes further through resin so as to remove chloride ions, and preparing the final product L-carnitine. The two process routes are simple, the reaction conditions are mild, the operation is simple and feasible, and industrial production is convenient; the whole process is green and environmentally friendly, the reaction yield is high, three waste is little, no sodium cyanide is used, and no solid waste sodium salt is generated; and the hydrolysis by-product ammonium chloride has good quality, and can be sold as a by-product, and great economic benefits and market competitiveness are achieved.
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Paragraph 0041-0049
(2019/11/12)
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- Synthesis method of L-carnitine intermediate L-(-)-chlorination 3-cyano-2-hydroxypropyltrimethylamine
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The invention discloses a synthesis method of L-carnitine intermediate L-(-)-chlorination 3-cyano-2-hydroxypropyltrimethylamine. The synthesis method is characterized in that: (R)-epichlorohydrin serves as a starting material; the (R)-epichlorohydrin is firstly subjected to a ring-opening reaction by gaseous hydrogen cyanide; L-(-)-4-chlorine-3-hydroxybutyronitrile is obtained; then the L-(-)-4-chlorine-3-hydroxybutyronitrile is aminated by trimethylamine; and the L-(-)-chlorination 3-cyano-2-propyltrimethylamine is obtained. After the ring-opening reaction is completed, a small amount of hydrogen cyanide dissolved in a material needs to be replaced with nitrogen, and an end point is that a benzidine-cupric acetate test paper does not change to blue. According to the synthesis method, thegaseous hydrogen cyanide is firstly used to open a ring, and then the trimethylamine is used to perform amination, therefore the L-carnitine intermediate L-(-)-chlorination 3-cyano-2-hydroxypropyltrimethylamine with high yield and high content can be obtained; and by adopting the gaseous hydrogen cyanide to open the ring, only the nitrogen is needed to replace the gaseous hydrogen cyanide after the ring-opening reaction, the subsequent recovery of the trimethylamine is not affected, and the post-treatment process is greatly simplified.
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Paragraph 0034; 0035
(2018/09/21)
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- 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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p. 2446 - 2450
(2015/08/24)
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- Practical and efficient utilisation of (R)-3-chloro-1,2-propanediol in synthesis of L-carnitine
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As a by-product originating from Salen Co(III) catalysed hydrolytic kinetic resolution (HKR) of (±)-epichlorohydrin in the manufacturing procedure of L-Carnitine, (R)-3-chloro-1,2-propanediol was utilised as a starting chiral material to prepare via key nitrile intermediates and by a final hydrolysis L-Carnitine. The new synthetic approach demonstrated an efficient utilisation of the by-product.
- Yang, Yunxu,Wang, Weili,Wumaier, Aikeremu,Sheng, Ruilong,Zhang, Xuetao,Zhang, Tianyi
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experimental part
p. 371 - 372
(2011/10/09)
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- Asymmetric synthesis of l-carnitine from (R)-3-chloro-1,2-propanediol
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A practical chemical synthesis of l-carnitine (1) has been accomplished from (R)-3-chloro-1,2-propanediol ((R)-4), which is a main by-product originated from (R,R)-Salen Co(III) catalyzed hydrolytic kinetic resolution (HKR) of (±)-epichlorohydrin. (R)-4 was utilized as a chiral starting material to prepare the key intermediate cyclic sulfite ((R)-5). The new synthetic approach demonstrated an efficient utilization of organic by-product for the asymmetric synthesis of bioactive compounds.
- Li, Xu Qin,Yang, Yun Xu,Wang, Wei Li,Hu, Bin,Xue, Hui Min,Zhang, Tian Yi,Zhang, Xue Tao
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body text
p. 765 - 767
(2012/01/03)
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- PROCESS FOR PRODUCTION OF BETAINE
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According to the present invention, by using 4-halogeno-3-hydroxybutanamide as a substrate in quaternary amination reaction with trialkylamine which is an important step in betaine (such as carnitine) preparation processes, it becomes possible to reduce the production of crotonic acid derivatives (the major by-product) greatly compared to conventional processes. Consequently, it becomes possible to prepare a betaine, such as carnitine, at a high yield. The present invention also relates to a process for preparing a betaine represented by formula (1) below, comprising a step of quaternary aminating an amide represented by formula (2) below: wherein A1, A2 and A3 individually represent a C1-C20 hydrocarbon group which may have a substituent(s); and X1 is a halogen atom.
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Page/Page column 19-20
(2009/09/26)
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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 10
(2008/06/13)
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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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- 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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- Short and Practical Syntheses of (R)-(-)-Carnitine and (R)-(-)-γ-Amino-β-hydroxybutyric Acid (GABOB)
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Short and practical syntheses of (R)-(-)-carnitine and (R)-(-)-γ-amino-β-hydroxybutyric acid have been developed, both commencing with the catalytic asymmetric dihydroxylation of allyl bromide.
- Kolb, Hartmuth C.,Bennani, Youssef L.,Sharpless, K. Barry
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p. 133 - 141
(2007/10/02)
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- Process for preparing 3-pyrrolidinol
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A process for preparing 3-pyrrolidinol having the formula (II): STR1 or a salt thereof, which comprises reducing 4-chloro-3-hydroxybutyronitrile having the formula (I): STR2 to convert said 4-chloro-3-hydroxybutyronitrile (I) into said 3-pyrrolidinol (II). According to the present invention, 3-pyrrolidinol, particularly optically active 3-pyrrolidinol can be prepared economically and efficiently.
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