- Biphasic Bioelectrocatalytic Synthesis of Chiral β-Hydroxy Nitriles
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Two obstacles limit the application of oxidoreductase-based asymmetric synthesis. One is the consumption of high stoichiometric amounts of reduced cofactor. The other is the low solubility of organic substrates, intermediates, and products in the aqueous phase. In order to address these two obstacles to oxidoreductase-based asymmetric synthesis, a biphasic bioelectrocatalytic system was constructed and applied. In this study, the preparation of chiral β-hydroxy nitriles catalyzed by alcohol dehydrogenase (AdhS) and halohydrin dehalogenase (HHDH) was investigated as a model bioelectrosynthesis, since they are high-value intermediates in statin synthesis. Diaphorase (DH) was immobilized by a cobaltocene-modified poly(allylamine) redox polymer on the electrode surface (DH/Cc-PAA bioelectrode) to achieve effective bioelectrocatalytic NADH regeneration. Since AdhS is a NAD-dependent dehydrogenase, the diaphorase-modified biocathode was used to regenerate NADH to support the conversion from ethyl 4-chloroacetoacetate (COBE) to ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE) catalyzed by AdhS. The addition of methyl tert-butyl ether (MTBE) as an organic phase not only increased the uploading of COBE but also prevented the spontaneous hydrolysis of COBE, extended the lifetime of DH/Cc-PAA bioelectrode, and increased the Faradaic efficiency and the concentration of generated (R)-ethyl-4-cyano-3-hydroxybutyrate ((R)-CHCN). After 10 h of reaction, the highest concentration of (R)-CHCN in the biphasic bioelectrocatalytic system was 25.5 mM with 81.2% enantiomeric excess (eep). The conversion ratio of COBE achieved 85%, which was 8.8 times higher than that achieved with the single-phase system. Besides COBE, two other substrates with aromatic ring structures were also used in this biphasic bioelectrocatalytic system to prepare the corresponding chiral β-hydroxy nitriles. The results indicate that the biphasic bioelectrocatalytic system has the potential to produce a variety of β-hydroxy nitriles with different structures.
- Dong, Fangyuan,Chen, Hui,Malapit, Christian A.,Prater, Matthew B.,Li, Min,Yuan, Mengwei,Lim, Koun,Minteer, Shelley D.
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Read Online
- Efficient biosynthesis of ethyl (R)-3-hydroxyglutarate through a one-pot bienzymatic cascade of halohydrin dehalogenase and nitrilase
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An effective one-pot bienzymatic synthesis of ethyl (R)-3-hydroxyglutarate (EHG) from ethyl (S)-4-chloro-3-hydroxybutyrate (ECHB) was achieved by using recombinant Escherichia coli cells expressing separately or co-expressing a mutant halohydrin dehalogenase gene from Agrobacterium radiobacter AD1 and a nitrilase gene from Arabidopsis thaliana. The activity of nitrilase was inhibited by high concentration of ECHB and NaCN. Consequently, the one-pot one-step process was implemented by fed-batch of ECHB and NaCN with high accumulative product concentration (up to 0.9 mol L-1). The biotransformation of ECHB to EHG was successfully achieved at 1.2 mol L-1 substrate concentration by a one-pot two-step process. As such, this one-pot bienzymatic transformation should be useful in synthesizing these important optical pure β-hydroxycarboxylic acids.
- Yao, Peiyuan,Wang, Lei,Yuan, Jing,Cheng, Lihua,Jia, Rongrong,Xie, Meixian,Feng, Jinhui,Wang, Min,Wu, Qiaqing,Zhu, Dunming
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Read Online
- Nitrilases
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition, methods of designing new nitrilases and methods of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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- Nitrilases, nucleic acids encoding them and methods for making and using them
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The invention relates to nitrilases and to nucleic acids encoding the nitrilases. In addition methods of designing new nitrilases and method of use thereof are also provided. The nitrilases have increased activity and stability at increased pH and temperature.
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- Synthesis of ethyl (R)-4-cyano-3-hydroxybutyrate in high concentration using a novel halohydrin dehalogenase HHDH-PL from Parvibaculum lavamentivorans DS-1
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We identified and characterized a novel halohydrin dehalogenase HHDH-PL from Parvibaculum lavamentivorans DS-1. Study of substrate specificity indicated that HHDH-PL possessed a high activity toward ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE). After optimizations of the pH and temperature, whole cell catalysis of HHDH-PL was applied to the synthesis of ethyl (R)-4-cyano-3-hydroxybutyrate (HN) at 200 g L-1 of (S)-CHBE, which gave 95% conversion and 85% yield in 14 h.
- Wan, Nan-Wei,Liu, Zhi-Qiang,Huang, Kai,Shen, Zhen-Yang,Xue, Feng,Zheng, Yu-Guo,Shen, Yin-Chu
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p. 64027 - 64031
(2015/02/19)
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- Multi-enzymatic biosynthesis of chiral β-hydroxy nitriles through co-expression of oxidoreductase and halohydrin dehalogenase
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To establish a system for the efficient one bacterial multi-enzymatic biosynthesis of both (R)- and (S)-β-hydroxy nitriles, we co-expressed alcohol dehydrogenases with opposite stereoselectivities, cofactor regeneration enzymes, and a halohydrin dehalogenase in Escherichia coli. By researching cofactor recycling and various co-expression strategies and by selecting and engineering the halohydrin dehalogenase, we engineered two E. coli strains, which were subsequently used in a cascade of reactions to produce chiral β-hydroxy nitriles with high enantiomeric excess directly from prochiral α-halo ketones. Three valuable pharmaceutical intermediates were prepared by means of this catalytic system, and substrate conversion reached about >99%. More importantly, the system is of low cost because there is no need for expensive cofactors or for expression and purification of the component enzymes. Copyright
- Chen, Shao-Yun,Yang, Chen-Xi,Wu, Jian-Ping,Xu, Gang,Yang, Li-Rong
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p. 3179 - 3190
(2013/12/04)
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- Biocatalytic and Structural Properties of a Highly Engineered Halohydrin Dehalogenase
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Two highly engineered halohydrin dehalogenase variants were characterized in terms of their performance in dehalogenation and epoxide cyanolysis reactions. Both enzyme variants outperformed the wild-type enzyme in the cyanolysis of ethyl (S)-3,4-epoxybutyrate, a conversion yielding ethyl (R)-4-cyano-3-hydroxybutyrate, an important chiral building block for statin synthesis. One of the enzyme variants, HheC2360, displayed catalytic rates for this cyanolysis reaction enhanced up to tenfold. Furthermore, the enantioselectivity of this variant was the opposite of that of the wild-type enzyme, both for dehalogenation and for cyanolysis reactions. The 37-fold mutant HheC2360 showed an increase in thermal stability of 8°C relative to the wild-type enzyme. Crystal structures of this enzyme were elucidated with chloride and ethyl (S)-3,4-epoxybutyrate or with ethyl (R)-4-cyano-3-hydroxybutyrate bound in the active site. The observed increase in temperature stability was explained in terms of a substantial increase in buried surface area relative to the wild-type HheC, together with enhanced interfacial interactions between the subunits that form the tetramer. The structures also revealed that the substrate binding pocket was modified both by substitutions and by backbone movements in loops surrounding the active site. The observed changes in the mutant structures are partly governed by coupled mutations, some of which are necessary to remove steric clashes or to allow backbone movements to occur. The importance of interactions between substitutions suggests that efficient directed evolution strategies should allow for compensating and synergistic mutations during library design.
- Schallmey, Marcus,Floor, Robert J.,Hauer, Bernhard,Breuer, Michael,Jekel, Peter A.,Wijma, Hein J.,Dijkstra, Bauke W.,Janssen, Dick B.
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p. 870 - 881
(2013/07/25)
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- Experimental and computation studies on Candida antarctica lipase B-catalyzed enantioselective alcoholysis of 4-bromomethyl-β-lactone leading to enantiopure 4-bromo-3-hydroxybutanoate
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Both enantiomers of optically pure 4-bromo-3-hydroxybutanoate, which is an important chiral building block in the syntheses of various biologically active compounds including statins, were synthesized from rac-4-bromomethyl-β- lactone through kinetic resolution. Candida antarctica lipase B (CAL-B) enantioselectively catalyzes the ring opening of the β-lactone with ethanol to yield ethyl (R)-4-bromo-3-hydroxybutanoate with high enantioselectivity (E>200). The unreacted (S)-4-bromomethyl-β-lactone was converted to ethyl (S)-4-bromo-3-hydroxybutanoate (>99% ee), which can be further transformed to ethyl (R)-4-cyano-3-hydroxybutanoate, through an acid-catalyzed ring opening in ethanol. Molecular modeling revealed that the stereocenter of the fast-reacting enantiomer, (R)-bromomethyl-β-lactone, is ～2 A from the reacting carbonyl carbon. In addition, the slow-reacting enantiomer, (S)-4-bromomethyl-β-lactone, encounters steric hindrance between the bromo substituent and the side chain of the Leu278 residue, while the fast-reacting enantiomer does not have any steric clash. Copyright
- Lim, Jung Yun,Jeon, Nan Young,Park, A-Reum,Min, Bora,Kim, Bum Tae,Park, Seongsoon,Lee, Hyuk
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p. 1808 - 1816
(2013/07/19)
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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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- Selective reduction of aldehydes and ketones to alcohols with ammonia borane in neat water
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Chemoselective reduction of various carbonyl compounds to alcohols with ammonia borane (AB), a nontoxic, environmentally benign, and easily handled reagent, in neat water was achieved in quantitative conversions and high isolated yields. Interestingly, α- and β-keto esters were selectively reduced to corresponding hydroxyl esters by AB, while diols were obtained when sodium borohydride was used as a reducing agent. The procedure is also compatible with the presence of a variety of base-labile protecting groups, such as tosyl, acetyl, benzoyl, ester groups, and acid-labile protecting groups such as trityl and TBDMS groups, and others, such as the unsaturated double bond, nitro and cyano groups. Finally, a kilo scale reaction of methyl benzoylformate with AB was conducted in water and gave methyl mandelate in 94% yield.
- Shi, Lei,Liu, Yingying,Liu, Qingfeng,Wei, Bin,Zhang, Guisheng
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experimental part
p. 1372 - 1375
(2012/06/04)
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- A green-by-design biocatalytic process for atorvastatin intermediate
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The development of a green-by-design, two-step, three-enzyme process for the synthesis of a key intermediate in the manufacture of atorvastatin, the active ingredient of the cholesterol lowering drug Lipitor, is described. The first step involves the biocatalytic reduction of ethyl-4-chloroacetoacetate using a ketoreductase (KRED) in combination with glucose and a NADP-dependent glucose dehydrogenase (GDH) for cofactor regeneration. The (S) ethyl-4-chloro-3-hydroxybutyrate product is obtained in 96% isolated yield and >99.5% e.e. In the second step, a halohydrin dehalogenase (HHDH) is employed to catalyse the replacement of the chloro substituent with cyano by reaction with HCN at neutral pH and ambient temperature. The natural enzymes were highly selective but exhibited productivities that were insufficient for large scale application. Consequently, in vitro enzyme evolution using gene shuffling technologies was employed to optimise their performance according to predefined criteria and process parameters. In the case of the HHDH reaction, this afforded a 2500-fold improvement in the volumetric productivity per biocatalyst loading. This enabled the economical and environmentally attractive production of the key hydroxynitrile intermediate. The overall process has an E factor (kg waste per kg product) of 5.8 when process water is not included, and 18 if included.
- Ma, Steven K.,Gruber, John,Davis, Chris,Newman, Lisa,Gray, David,Wang, Alica,Grate, John,Huisman, Gjalt W.,Sheldon, Roger A.
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experimental part
p. 81 - 86
(2010/05/18)
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- Asymmetric reduction of substituted α- and β-ketoesters by Bacillus pumilus Phe-C3
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The enantioselective reduction of substituted α- and β-ketoesters using resting cells of Bacillus pumilus Phe-C3 was investigated. Effects of substrate concentration on the catalytic efficiency of the microorganism were studied. Preparative scale productions were carried out under the optimized conditions with 62.4-91.0% yields and 90.2-97.1% ee. The cells retained 80% of initial activity after recycling for six times.
- He, Chunmao,Chang, Dongliang,Zhang, Jie
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p. 1347 - 1351
(2008/12/20)
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- Stereoselective synthesis of (2S,4R)-4-hydroxypipecolic acid
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A new synthetic route to enantiopure (2S,4R)-4-hydroxypipecolic acid from commercial ethyl (3S)-4-chloro-3-hydroxybutanoate is reported. The synthesis is based on the Pd-catalyzed methoxycarbonylation of a 4-alkoxy-substituted δ-valerolactam-derived vinyl triflate followed by the stereocontrolled hydrogenation of the enamine double bond. The final product was obtained after exhaustive hydrolysis in 20 % yield over 10 steps. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Occhiato, Ernesto G.,Scarpi, Dina,Guarna, Antonio
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p. 524 - 531
(2008/09/18)
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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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- A simple and practical approach to enantiomerically pure (S)-3-hydroxy-γ-butyrolactone: Synthesis of (R)-4-cyano-3-hydroxybutyric acid ethyl ester
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The oxidation of α- or β-(1,4) linked disaccharides or oligosaccharides with cumene hydroperoxide in the presence of a base gave (S)-3,4-dihydroxybutyric acid, which was cyclized under acidic conditions to furnish (S)-3-hydroxy-γ-butyrolactone. This was subsequently converted into (R)-cyano-3-hydroxybutyric acid ethyl ester, an intermediate for statin based drugs and other related compounds.
- Kumar, Pradeep,Deshmukh, Anis N.,Upadhyay, Rajesh K.,Gurjar, Mukund K.
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p. 2717 - 2721
(2007/10/03)
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- ENZYMATIC PROCESSES FOR THE PRODUCTION OF 4-SUBSTITUTED 3-HYDROXYBUTYRIC ACID DERIVATIVES AND VICINAL CYANO, HYDROXY SUBSTITUTED CARBOXYLIC ACID ESTERS
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The present invention provides methods and composition for preparing 4-substituted 3-hydroxybutyric acid derivatives by halohydrin dehalogenase-catalyzed conversion of 4-halo-3-hydroxybutyric acid derivatives. The present invention further provides methods and compositions for preparing 4-halo-3-hydroxybutyric acid derivatives by ketoreductase-catalyzed conversion of 4-halo-3ketobutyric acid derivatives. The present invention also provides methods and compositions for preparing vicinal cyano, hydroxyl substituted carboxylic acid esters.
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Page/Page column 54
(2008/06/13)
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- METHOD FOR PRODUCING 4-CYANO-3-HYDROXYBUTYRIC ACID ESTERS
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The invention relates to a method for producing 4-cyano-3-hydroxybutyric acid esters by reaction of hydroxybutyric acid ester substituted in position 4 with a cyanide salt in an organic solvent in the presence of one or several other salts.
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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 12
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- IMPROVED SYNTHETON SYNTHESIS
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The present disclosure relates to an improved synthesis of the commercially important syntheton ECHB starting from the readily available 3-hydroxy-γ-butyrolactone. The reaction employs a single pot procedure without isolation or purification of the intermediates. It has the advantage over procedures previously employed in the art of using reagents and conditions which minimize undesired side reactions and which can be readily employed at commercial scale. The product is produced in high yield and is readily purified to provide an excellent intermediate for further synthesis of commercially important products such as L-carnitine and the pharmaceutically important active substances used in HMG-coA reductase inhibitor products such as Lipitorè.
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- Process for producing optically active 4-halo-3-hydroxybutanoate
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There are provided a polynucleotide sequence coding for an amino acid sequence capable of preferentially producing (S)-4-bromo-3-hydroxy-butanoate by asymmetrically reducing 4-bromo-3-oxobutanoate, A DNA construct having a promoter in operative linkage with the polynucleotide sequence, a recombinant vector containing the polynucleotide sequences a transformant, a recombinant vector and the like.
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- CONTINUOUS PROCESS FOR THE CYANATION OF HYDROGENATED BETA-KETOESTERS
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The present invention relates to a continuous process for the cyanation of hydrogenated β-ketoesters in a cyanation zone maintained under conditions of temperature and pressure effective for cyanation of a hydrogenated R-ketoester. A substrate comprising a hydrogenated β-ketoester is continuously supplyed to the cyanation zone together with a cyanide. The substrate is contacted with the cyanide in the cyanation zone for a period effective for at least partial cyanation of the hydrogenated β-ketoester and a product stream is continuously extracted from the cyanation zone.
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Page/Page column 12-13
(2008/06/13)
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- PROCESSES FOR MAKING (R)-ETHYL 4-CYANO-3-HYDROXYBUTYRIC ACID
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The invention provides novel processes for making ethyl-4-cyano-3-hydroxybutyrate, e.g., (R)-ethyl 4-cyano-3-hydroxybutyric acid, and 4-cyano-3-hydroxybutyric acid. The invention provides protocols for making and 4-cyano-3-hydroxybutyric acid and ethyl-4-cyano-3-hydroxybutyrate by whole cell processes, cell lysate processes, "one pot processes" and "multi-pot" processes using a variety of parameters.
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- Process for preparing(R)-4-cyano-3-hydroxybutyric acid ester
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The present invention relates to a process for preparing (R)-4-cyano-3-hydroxybutyric acid ester derivatives and more particularly, to a process for preparing optically pure (R)-4-cyano-3-hydroxybutyric acid ester derivatives expressed by formula (1) in high yield by performing cyanation and sequential esterification of (S)-3,4-epoxybutyric acid salt as a starting material. In said formula, R represents linear or branched alkyl group with 1?5 carbon atoms or benzyl group.
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- An enzyme library approach to biocatalysis: Development of nitrilases for enantioselective production of carboxylic acid derivatives
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The discovery, from Nature, of a large and diverse set of nitrilases is reported. The utility of this nitrilase library for identifying enzymes that catalyze efficient production of valuable hydroxy carboxylic acid derivatives is demonstrated. Unprecedented enantioselectivity and substrate scope are highlighted for three newly discovered and distinct nitrilases. For example, a wide array of (R)-mandelic acid derivatives and analogues were produced with high rates, yields, and enantiomeric excesses (95-99% ee). We also have found nitrilases that provide direct access to (S)-phenyllactic acid and other aryllactic acid derivatives, again with high yields and enantioselectivities. Finally, different nitrilases have been discovered that catalyze enantiotopic hydrolysis of 3-hydroxyglutaronitrile to afford either enantiomer of 4-cyano-3-hydroxybutyric acid with high enantiomeric excesses (>95% ee). The first enzymes are reported that effect this transformation to furnish the (R)-4-cyano-3-hydroxybutyric acid which is a precursor to the blockbuster drug Lipitor. Copyright
- DeSantis, Grace,Zhu, Zuolin,Greenberg, William A.,Wong, Kelvin,Chaplin, Jenny,Hanson, Sarah R.,Farwell, Bob,Nicholson, Lawrence W.,Rand, Cynthia L.,Weiner, David P.,Robertson, Dan E.,Burk, Mark J.
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p. 9024 - 9025
(2007/10/03)
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- 4-cyano-3-hydroxybutanoyl hydrazines, derivatives and process for the preparation thereof
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Novel 4-cyano-3-hydroxybutanoyl hydrazides (10), particularly R-chiral intermediates are described. The intermediates are useful in preparing (R)-3-hydroxy-4-trimethylaminobutyric acid (L-carnitine) and R-4-amino-3-hydroxybutyric acid (GABOB) and chiral chemical intermediates which are medically useful.
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- Process for producing butyric ester derivatives
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PCT No. PCT/JP98/03686 Sec. 371 Date Sep. 7, 1999 Sec. 102(e) Date Sep. 7, 1999 PCT Filed Aug. 20, 1998 PCT Pub. No. WO99/31050 PCT Pub. Date Jun. 24, 1999This invention has its objects to provide a process for producing a butyric acid ester derivative of the above general formula (2) which is capable of removing various impurity byproducts whose formation cannot be avoided by the prior art technology, particularly the compound of the above general formula (1), with good efficiency. This invention is related to a process for producing a butyric acid ester derivative of the general formula (2) which comprises treating a mixture containing a compound of the following general formula (1) with an addition reagent capable of adding itself to said ethylenic bond to thereby convert said compound of the general formula (1) to an addition product which can be easily separated from said butyric acid ester derivative of the general formula (2) and a process for producing a butyric acid ester derivative of the general formula (2) which comprises reacting a compound of the general formula (3) with a salt of prussic acid by a flow method. HOCH2-CH=CH-COOR(1)
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- Synthetic routes to L-carnitine and L-gamma-amino-betahydroxybutyric acid from (S)-3-hydroxybutyrolactone by functional group priority switching
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(R)-3-Hydroxy-4-trimethylaminobutyric acid (L-carnitine) and (R)-4- amino-3-hydroxybutyric acid (GABOB) are two compounds with a very high level of medical significance. They can be prepared from (R)-3-hydroxy-γ- butyrolactone which is not readily available in significant quantities. The corresponding (S)-lactone is available in large quantities but attempts at inverting the stereochemistry of the hydroxyl group lead to elimination to give the furanone. Here we describe a straightforward route to these two compounds, starting from (S)-3-hydroxy-γ-butyrolactone by adding a highly oxidized carbon at one end whilst removing one carbon from the other, thus switching the functional group priorities. In this method, the lactone is transformed to an (R)-4-cyano-3-hydroxybutyric acid ester which is then converted to an acyl hydrazide by treatment with hydrazine. This stable, crystalline hydrazide has not been described before. It is readily converted to (R)-4-amino-3-hydroxybutyronitrile, a precursor of L-carnitine and GABOB, by Curtius rearrangement under conditions that do not result in deamination.
- Wang, Guijun,Hollingsworth, Rawle I.
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p. 1895 - 1901
(2007/10/03)
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- Method for producing (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester
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Crude (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester, obtained by subjecting an (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester to a cyano-introducing reaction, is purified by distillation carried out in the presence of a solvent having a boiling point within the range of 50° C. to 160° C. at 10 Torr.
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- Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid
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The invention is an improved process for the preparation of a compound of formula I wherein R and R1 are each independently alkyl of from 1 to 3 carbon atoms; and R2 is alkyl of from 1 to 8 carbon atoms. STR1
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- T-butyl (R)-(-)-4-cyano-3-hydroxybutyrate and process for preparing the same
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T-butyl (R)-(-)-4-cyano-3-hydroxybutyrate having an optical purity of 99%ee or higher and a process for producing the same are disclosed, the process comprising cyanogenation of a t-butyl (S)-(-)-4-halogeno-3-hydroxybutyrate obtained by enantioselective hydrogenation of a t-butyl 4-halogenoacetoacetate. Recrystallization of the resulting crude product gives the optically active compound with high optical purity.
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- Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
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An improved process for the preparation of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate is described where a halo hydroxyester or other activated dihydroxyester is converted in two steps to the desired product.
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