- Regio and enantioselective reduction of t-butyl 6-chloro-3,5-dioxohexanoate with baker's yeast
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Whole baker's yeast cells reduce t-butyl 6-chloro-3,5-dioxohexanoate regioselectively to the corresponding C5 hydroxy keto ester. While the (R)-alcohol was favored, the enantioselectivity was poor (41% ee). A variety of process conditions were evaluated in order to improve both the enantioselectivity and yield of this reduction. Including a nonpolar resin in the reaction mixture afforded the (R)-alcohol in 94% ee and 50% isolated yield. The enantioselectivity was further improved to >99% ee by substituting purified YGL157w in place of whole yeast cells. This reductase was identified by screening a collection of yeast enzymes uncovered by genome sequence analysis.
- Wolberg, Michael,Kaluzna, Iwona A.,Mueller, Michael,Stewart, Jon D.
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Read Online
- Method for synthesizing ADA
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The invention relates to a compound synthesized in the medicine field, and particularly relates to a rosuvastatin intermediate. The method for synthesizing ADA comprises the following five steps: 1, reacting S-4-chloro-3-hydroxy butyronitrile with hexamethyl-disilazane to generate an intermediate I; 2, reacting the prepared intermediate I, a reducing agent and methanesulfonic acid with tert-butyl bromoacetate to prepare an intermediate II; 3, preparing an intermediate III from the prepared intermediate II by enzyme selective reduction; 4, reacting the prepared intermediate III with acetone acetal to prepare an intermediate IV; and 5, reacting the prepared intermediate IV and tetrabutylammonium bromide with sodium acetate to prepare the target intermediate ADA. According to the method, operation for preparing ADA is more convenient; and the method has high safety coefficient and low cost, and is very suitable for industrial production.
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Paragraph 0081; 0086; 0087; 0088; 0105
(2018/02/04)
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- NOVEL BORONATE ETHER INTERMEDIATES FOR PREPARATION OF STATIN COMPOUNDS, PREPARATION METHOD THEREOF AND PREPARATION METHOD OF STATIN COMPOUNDS USING SAID BORONATE ETHER INTERMEDIATES
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The present invention relates to a novel boronate ether compound and a manufacturing method thereof. Provided is a novel boronate ether compound denoted by chemical formula 1 or chemical formula 2 as an intermediate to manufacture rosuvastatin calcium or pitavastatin calcium which is one of the statin based compounds to reduce the level of low density lipoprotein (LDL) of patients who have hyperlipidemia and are accordingly cured, and statin compounds with high purity are easily manufactured and separated compared with an existing patented method and are easily provided in a method of mass production.
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Paragraph 0117-0119
(2017/01/02)
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- Stereoselective reduction of δ-hydroxy β-ketoesters to syndiol in achiral micellar system
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A novel, efficient and stereo-selective process for synthesis of statin side chain, a key intermediate for statin type cholesterol lowering drugs such as Lipitor (atorvastatin) and Crestor (rosuvastatin) in achiral micellar media is reported. The key feature of this process is sodium borohydride reduction of δ-hydroxy β-ketoester in achiral micellar system in 92% de, thereby avoiding metal chelation methods which employ triakylborane, titanium (IV) isopropoxide or cerium (III) chloride prior to reduction.
- Roy, Bhairab Nath,Singh, Girij Pal,Lathi, Piyush Suresh,Agrawal, Manoj K,Mitra, Rangan
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p. 1247 - 1251
(2015/11/24)
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- A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE
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The present invention provides a process of preparation of an intermediate useful for the preparation of statins more particularly the present invention relates to an eco-friendly and cost effective process for the preparation of tert -butyl (3R,5S)-6-oxo-3,5-dihydroxy- 3,5-O-isopropylidene-hexanoate [I].
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Page/Page column 35; 36
(2015/01/07)
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- NOVEL PROCESS FOR PREPARING A 5-HYDROXY-3-OXO-HEXANOIC ACID DERIVATIVE
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The present invention is related to a novel process for preparing an optically active 5-hydroxy-3-oxo-hexanoic acid derivative or its tautomer which is useful intermediate for preparing statins such as atorvastatin and rosuvastatin. Blaise reaction of (S)-4-halo-3 -hydroxybutyronitrile with -haloacetate is utilized as a key reaction to provide the product with minimal formation of side products and in good yield.
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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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- Processes for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives
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This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low-temperature reactor.Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acidwhich comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below ?20° C.Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acidwhich comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I),and permitting a lithium amide to act upon the mixture at a temperature not below ?20° C.
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- Asymmetric total synthesis of (-)-callystatin A employing the SAMP/RAMP hydrazone alkylation methodology
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(equation presented) The asymmetric total synthesis of (-)-callystatin A has been achieved. The key steps generating the stereogenic centers rely on the asymmetric α-alkylation of aldehydes or ketones exploiting the SAMP/RAMP hydrazone alkylation methodology, as well as an enzymatic enantioselective reduction of a 3,5-dioxocarboxylate. For the construction of the alkene moieties, highly selective Wittig or Horner-Wadsworth-Emmons reactions were employed.
- Vicario, Jose L.,Job, Andreas,Wolberg, Michael,Mueller, Michael,Enders, Dieter
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p. 1023 - 1026
(2007/10/03)
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- Biocatalytic reduction of β,δ-diketo esters: A highly stereoselective approach to all four stereoisomers of a chlorinated β,δ-dihydroxy hexanoate
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A stereoselective chemoenzymatic synthesis of all four stereoisomers of tert-bulyl 6-chloro-3,5-dihydroxyhexanoate (6a) is presented. The key step of the sequence is a highly regio-and enantioselective single-site reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (1a) by two enantiocomplementary biocatalysts. Alcohol dehydrogenase from Lactobacillus brevis (recLBADH) afforded a 72% yield of enantiopure tert-butyl (5)-6-chloro-5-hydroxy-3-oxohexanoate [(S)-2a]. The enantiomer (R)-2a was prepared with 90-94% ee by Baker's yeast reduction in a biphasic system (50% yield). Both biotransformations were performed on a gram scale. The β-keto group of the enantiomeric δ-hydroxy-β-keto esters 2a thus obtained was reduced by synand anti-selective borohydride reductions. Permutation of the reduction methods yielded all four stereoisomers of the crystalline target compound 6a (≥99.3% ee, dr≥205:1), which is a versatile 1,3-diol building block. recLBADH accepts a variety of β,δ-diketo esters as was determined in a photometric assay. tert-Butyl 3,5-dioxohexanoate (1b) and tert-butyl 3,5-dioxoheptanoate (1c) were reduced on a preparative scale as well to afford the corresponding δ-hydroxy-β-keto esters (R)-2b and (R)-2c with 99.4% ee and 98.1% ee, respectively. Wiley-VCH Verlag GmbH, 2001.
- Wolberg, Michael,Hummel, Werner,Mueller, Michael
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p. 4562 - 4571
(2007/10/03)
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- Highly regio- and enantioselective reduction of 3,5-dioxocarboxylates
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Only the keto group in position C-5 is reduced in the enzymatic reduction of 3,5-dioxocarboxylates by the alcohol dehydrogenase of Lactobacillusbrevis (LBADH; see scheme). The strategy of nature for manipulating β-keto metabolites inspired the development of a chemoenzymatic approach to virtually enantiopure 3,5-dihydroxycarboxylate building blocks. The crucial enzymatic step can be performed on an attractively large scale.
- Wolberg, Michael,Hummel, Werner,Wandrey, Christian,Mueller, Michael
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p. 4306 - 4308
(2007/10/03)
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