- 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 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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- 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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- 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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- 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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- Preparation method of 1-BOC-3-hydroxymethyl pyrrolidine
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The invention discloses a preparation method of 1-Boc-3-hydroxymethyl pyrrolidine. The preparation method uses epichlorohydrin as a raw material, 3-hydroxymethyl pyrrolidine is obtained through reduction and cyclization reaction, then the 1-Boc-3-hydroxymethyl pyrrolidine is prepared through Boc protection reaction, then 1-BOC-3-methyl formate pyrrolidine is prepared through carboxylation reaction and esterification reaction, and finally the 1-BOC-3-methyl formate pyrrolidine and lithium aluminum hydride are catalyzed by a catalyst to prepare the 1-BOC-3-hydroxymethyl pyrrolidine. The preparation method is high in product synthesis rate, high in product purity and low in production cost, and the raw materials are cheap and easy to obtain.
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Paragraph 0021-0023
(2017/05/10)
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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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- 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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- 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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- LiOH-catalyzed simple ring opening of epoxides under solvent-free conditions
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LiOH has been found to be a very simple and selective catalyst for the rapid and mild synthesis of β-hydroxy sulfides and β-hydroxyl nitriles by ring opening of epoxides with aromatic, aliphatic, and heterocyclic thiols and trimethylsilyl cyanide at room temperature under solvent free conditions. All the reactions proceeded satisfactorily in short times and afforded the corresponding products in good to excellent yields with high regioselectivity and chemoselectivity under mild reaction conditions. Copyright Taylor & Francis Group, LLC.
- Azizi, Najmedin,Khajeh-Amiri, Alireza,Ghafuri, Hossein,Bolourtchian, Mohammad
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experimental part
p. 1550 - 1557
(2010/09/06)
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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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- PROCESS FOR L-CARNITINE AND ACETYL L-CARNITINE HYDROCHLORIDE
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Provided is a process for preparing L-carnitine or acetyl L-carnitine hydrochloride. Specifically, the process comprises sequentially synthesizing racemic 4-chloro-3-hydroxybutyronitrile and racemic 4-chloro-3-hydroxy butyric acid alkyl ester under specific reaction conditions, using racemic epichlorohydrin as a starting material, preparing (R)-4-chloro-3-hydroxy butyric acid alkyl ester from stereoselective hydrolysis of the racemic 4-chloro-3-hydroxy butyric acid alkyl ester using an enzyme, and preparing L-carnitine or acetyl L-carnitine hydrochloride from the (R)-4-chloro-3-hydroxy butyric acid alkyl ester, according to the known method.
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Page/Page column 8
(2010/11/29)
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- Nitrilase-catalysed desymmetrisation of 3-hydroxyglutaronitrile: Preparation of a statin side-chain intermediate
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An efficient, scaleable synthesis of ethyl (R)-4-cyano-3-hydroxybutyrate, a potential intermediate in the synthesis of Atorvastatin (Lipitor), has been developed. The three-stage process starts with reaction of low-cost epichlorohydrin with cyanide to give 3-hydroxyglutaronitrile (3-HGN). The second stage utilises a nitrilase-catalysed desymmetrisation of 3-HGN. The nitrilase reaction has been optimized to work at 3 M (330 g/L) substrate concentration, pH 7.5,27 °C. Under these conditions, with an enzyme loading of 6 wt %, 100% conversion and 99% ee product is obtained in 16 h. This material is then esterified to give the target compound, ethyl (R)-4-cyano-3-hydroxybutyrate. The cost-effectiveness of the process is determined by three factors: use of a low-cost starting material, the introduction of the chiral centre by desymmetrisation as opposed to kinetic resolution, and the use of Pfenex Expression Technology to allow a lower-cost supply of biocatalyst.
- Bergeron, Sophie,Chaplin, David A.,Edwards, John H.,Ellis, Brian S. W.,Hill, Catherine L.,Holt-Tiffin, Karen,Knight, Jonathan R.,Mahoney, Thomas,Osborne, Andrew P.,Ruecroft, Graham
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p. 661 - 665
(2012/12/22)
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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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- 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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- 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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p. 2629 - 2632
(2007/10/03)
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- Micellar media for the efficient ring opening of epoxides with CN-, N3-, NO3-, NO2-, SCN-, Cl- and Br- catalyzed with Ce(OTf)4
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Micellar media are introduced for the efficient ring opening of epoxides with sodium salts of nucleophiles such as CN, N3-, NO3-, NO2, SCN, Br and Cl-, catalyzed with Ce(OTf)4. This method is an efficient procedure for the synthesis of different β-substituted alcohols under mild reaction conditions. The reaction with SCN- is an easy procedure for the high yielding preparation of epoxy sulfides.
- Iranpoor, Nasser,Firouzabadi, Habib,Shekarize, Marzieh
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p. 724 - 727
(2007/10/03)
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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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- Ring opening of epoxides with sodium cyanide catalyzed with Ce(OTf)4
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Efficient and regioselective conversion of epoxides to β-hydroxy nitriles with sodium cyanide in the presence of catalytic amounts of Ce(OTf)4 is described under solvent free conditions.
- Iranpoor,Shekarriz
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p. 2249 - 2254
(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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- 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 new method for the preparation of β-hydroxy nitriles; Transformation of 3-bromo-2-isoxazolines to β-hydroxy nitriles by treatment of alkanethiolates
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3-Bromo-2-isoxazolines are transformed to β-hydroxy nitriles in good yields by treatment with alkanethiolates under a very mild condition.
- Min Hyo Seo,Youn Young Lee,Yang Mo Goo
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p. 1433 - 1439
(2007/10/02)
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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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- Ring Opening of Epoxides with Acetone Cyanohydrin Catalyzed by Lanthanoid(III) Alkoxides
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Ring opening of epoxide and aziridine with acetone cyanohydrin is promoted by a catalytic amount of lanthanoid(III) alkoxide to provide β-hydroxy nitrile and β-amino nitrile, respectively.
- Ohno, Hiroshi,Mori, Atsunori,Inoue, Shohei
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p. 975 - 978
(2007/10/02)
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- Regiospecific opening of 1,2-epoxides with acetone cyanohydrin under mildly basic conditions
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Acetone cyanohydrin with stoichiometric triethylamine opens epoxides regiospecifically to give β-hydroxy nitriles. As expected, addition of cyanide occurs at the least substituted carbon.
- Mitchell,Koenig
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p. 3281 - 3284
(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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- Process for the production of hydroxynitriles from epoxides and ketone cyanohydrins
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Aliphatic, cycloaliphatic and aromatic epoxides are reacted with ketone cyanohydrins of the formula STR1 wherein R1 and R2 are aliphatic groups of 1 to 4 carbon atoms at 20° to 150° C. to produce hydroxynitriles. The reaction optionally can be carried out in an inert organic solvent.
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