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Preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester

A technology of isopropyl acetate and 4r-cis, applied in the field of biopharmaceuticals, can solve problems such as high cost, cumbersome steps, complicated post-processing, etc., and achieve the effects of safe reaction and short reaction route

Inactive Publication Date: 2015-12-09
CODEXIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method adopts the reaction route of first nitrilation followed by ring opening, which is not effective when applied to the synthesis of statins.
[0015] Patent WO2013068917 discloses the use of aldolase to synthesize the analogue of the target product (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate Method, the method needs to generate (4R)-6-(chloromethyl)-4-hydroxy tetrahydro-2H-pyran-2,4-diol with enzyme catalysis Hydrogen-2H-pyran-2-one, the amount of enzyme is 10% of the substrate, the cost is higher, the post-treatment is complicated, and the product obtained needs to undergo transesterification to obtain (4R-cis)-6-chloromethyl- 2,2-Dimethyl-1,3-dioxane-4-acetic acid isopropyl ester, the steps are cumbersome
[0016] In summary, there is currently no convenient method for synthesizing (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate, The synthesis of its analogs also has the problem of being difficult for industrial application

Method used

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  • Preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester
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  • Preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester

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Experimental program
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Effect test

Embodiment 1

[0036] Add 140ml of pH 6.5 0.1MPBS buffer solution into a 500ml reactor, add 2.55g of DERA enzyme (purchased from Suzhou Hanzyme, brand EW069, the same below) at 25°C, and then add mass 49.1 g of chloroacetaldehyde with a fraction of 24%, 13.7 g of acetaldehyde with a mass fraction of 99.6%, and 100 ml of deionized water are added to provide a reaction environment for DERA, and the addition is controlled within 3 hours, and the pH is controlled during the entire reaction process. Between 6.5 and 6.7, after the dropwise addition, continue to stir the reaction for 1 h until the reaction is complete, then add acetone to the system to remove the aldolase, then filter through diatomaceous earth, extract three times with ethyl acetate, combine the organic phases, dry and spin Evaporate to obtain 14g of light yellow oily liquid, which is compound ⅳ ((4R)-6-(chloromethyl)tetrahydro-2H-pyran-2,4-diol), its GC purity is 77%, single-step The resulting molar yield was 56%.

Embodiment 2

[0038] At a temperature of 25°C, add 2.55 g of DERA enzyme (purchased from Suzhou Hanzyme, brand EW069) and 140 ml of deionized water into the reactor, stir evenly, and add chloroacetaldehyde with a mass fraction of 24% by feeding 75g, 13.7g of acetaldehyde with a mass fraction of 99.6%. The pH is controlled between 6.5 and 6.7 during the entire reaction process. After the dropwise addition is completed, continue to stir the reaction for 1h until the reaction is complete, and then add acetone to the system to remove the aldolase. Filtration with diatomaceous earth, extraction with ethyl acetate three times, combined organic phases, drying, and rotary evaporation gave 15.8 g of light yellow oily liquid iv with a GC purity of 70% and a single-step molar yield of 61.2%.

Embodiment 3

[0040] At a temperature of 25°C, add 2.55g of DERA enzyme and 140ml of deionized water into the reactor, stir evenly, and add 49.1g of chloroacetaldehyde with a mass fraction of 24%, and acetaldehyde with a mass fraction of 99.6% 20g, the pH is controlled between 6.5 and 6.7 during the whole reaction process. After the dropwise addition, continue to stir the reaction for 1h until the reaction is complete, then add acetone to the system to remove the aldolase, and then filter through diatomaceous earth and extract with ethyl acetate. Three times, the combined organic phases were dried and rotary evaporated to obtain 14.5 g of light yellow oily liquid iv with a GC purity of 70% and a single-step molar yield of 58%.

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Abstract

The invention discloses a preparation method of (4R-cis)-6-chloromethyl-2, 2-dimethyl-1, 3-dioxane-4-acetic acid isopropyl ester. The preparation method has the advantages that chloroacetaldehyde and acetaldehyde serve as reaction substrates to complete a condensation reaction under the action of aldolase, an open-loop esterification reaction between an oxidative obtained product and isopropanol is achieved in the presence of a catalyst, and ester exchange between the product and 2, 2-dimethoxy propane is completed to obtain a target product, so that synthetic route is short, highly toxic products are not used in the whole reaction process, and raw materials are low in cost.

Description

technical field [0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for preparing (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-isopropyl acetate . Background technique [0002] (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid isopropyl ester (formula I) is a synthetic hypolipidemic drug rosuvastatin calcium ( Rosuvastatincalcium) key chiral intermediates (WO0049014, WO2010077062, and WO2011132172, etc.). [0003] [0004] At present, the synthetic route report about rosuvastatin calcium side chain (4R-cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-acetate is mainly chemical method. The steps of this type of method are relatively long, and the reaction conditions are relatively harsh. [0005] For example: the route reported by U.S. Patent No. 5,399,722 is as follows: [0006] [0007] This method requires six-step reactions to complete, and two-step reactions require high-pressure hydrogenation, ...

Claims

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Application Information

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IPC IPC(8): C12P7/62
Inventor 陶军华马百超
Owner CODEXIS INC
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