Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate

A technology of tert-butyl hydroxyhexanoate and tert-butyl carbonylhexanoate, which is applied in the field of preparation of (3R,5S)-6-chloro-3,5-dihydroxyhexanoate tert-butyl, can solve the problem of large enzyme consumption , Low substrate concentration, low product yield and other problems, to achieve the effect of increasing substrate concentration, increasing substrate concentration, and reducing the amount of enzyme

Inactive Publication Date: 2015-06-24
ENZYMEWORKS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it needs to use more expensive triethanolamine buffer solution and titrate with 4 N sodium hydroxide solution at the same time, the substrate concentration is low (13 g / L), and the enzyme dosage is large (KRED 3.3%, GDH 3.3%, coenzyme 0.67%), Low product yield (66.7%)

Method used

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  • Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate
  • Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate
  • Preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate

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Experimental program
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Effect test

Embodiment 1

[0030] Substrate (S)-150 g of 6-chloro-5-hydroxy-3-oxoylhexanoic acid tert-butyl ester and 252 g of glucose were added to a 2 L reactor filled with 0.3 L of 50 mM pH 6.5 phosphate buffer solution, Add 3.75 g of KRED (purchased from Suzhou Hanzyme, brand EW005), 1.25 g of GDH (purchased from Suzhou Hanzyme, brand EW002), 0.75 g of mercaptoethanol, and 0.3 g of NADP, and control with 30% sodium carbonate solution at 30°C PH6.2, stirred for 24 hours, HPLC / MS detected that the reaction was complete, added an equal volume of ethyl acetate to filter, took the organic phase, extracted the aqueous phase twice with an equal volume of ethyl acetate, and combined the organic phases to obtain the product (3R, 5S )-6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester 145 g of light yellow liquid, de value 99.9%, purity 99.0%.

Embodiment 2

[0032] Substrate (S)-150 g of 6-chloro-5-hydroxy-3-oxoylhexanoic acid tert-butyl ester and 252 g of glucose were added to a 2 L reactor filled with 0.3 L of 50 mM pH 6.5 phosphate buffer solution, Add 3.75 g of KRED (purchased from Suzhou Hanzyme, brand EW005), 1.25 g of GDH (purchased from Suzhou Hanzyme, brand EW002), 0.75 g of mercaptoethanol, and 0.3 g of NADP, and control with 20% sodium carbonate solution at 30 °C PH6.3, stirred for 24 hours, HPLC / MS detected that the reaction was complete, added an equal volume of ethyl acetate to filter, took the organic phase, extracted the aqueous phase twice with an equal volume of ethyl acetate, combined the organic phases and rotary evaporated to obtain the product (3R, 5S )-6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester 145 g of light yellow liquid, de value 99.9%, purity 99.0%.

Embodiment 3

[0034] Substrate (S)-150 g of 6-chloro-5-hydroxy-3-oxoylhexanoic acid tert-butyl ester and 252 g of glucose were added to a 2 L reactor filled with 0.3 L of 50 mM pH 6.5 phosphate buffer solution, Add 3.75 g of KRED (purchased from Suzhou Hanzyme, brand EW005), 1.25 g of GDH (purchased from Suzhou Hanzyme, brand EW002), 0.75 g of mercaptoethanol, and 0.3 g of NADP, and control with 10% sodium carbonate solution at 30°C PH6.2, stirred for 24 hours, HPLC / MS detected that the reaction was complete, added an equal volume of ethyl acetate to filter, took the organic phase, extracted the aqueous phase twice with an equal volume of ethyl acetate, and combined the organic phases to obtain the product (3R, 5S )-6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester 145 g of light yellow liquid, de value 99.9%, purity 99.0%.

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Abstract

The invention relates to a preparation method of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate. The preparation method is characterized in that tert-butyl (S)-6-chloro-5-hydroxy-3-carbonylhexanoate is taken as a substrate and the substrate is subjected to reduction reaction in the presence of a biocatalyst, a coenzyme and coenzyme regeneration systems to generate tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate; the biocatalyst is ketoreductase; the coenzyme is NADP (nicotinamide adenine dinucleotide phosphate); the coenzyme regeneration systems are glucose and glucose dehydrogenase; the reduction reaction is carried out in a phosphate buffer solution at 25-30 DEG C in the presence of an enzyme protection reagent; the pH value of a reaction system is controlled to be 6.0-8.0 by adding a sodium carbonate solution. The preparation method has the effects of substantially increasing the concentration of the substrate and reducing the usage amount of the enzyme, so that the product has good production environment friendliness and the commercial value of industrialization is prominent.

Description

technical field [0001] The invention belongs to the technical fields of biopharmaceutical and biochemical industry, and specifically relates to a preparation method of (3R,5S)-6-chloro-3,5-dihydroxyhexanoic acid tert-butyl ester. Background technique [0002] Tert-butyl chloro-3,5-dihydroxyhexanoate is a chemical raw material and a key chiral intermediate for the synthesis of the best-selling drug Rosuvastatin. Its structure is as follows figure 1 shown. [0003] The common synthetic method of tert-butyl chloro-3,5-dihydroxyhexanoate is as figure 2 As shown, the key step lies in the synthesis of the 3-position chiral hydroxyl center, and the direct reduction of the carbonyl-containing precursor (S)-6-chloro-5-hydroxy-3-carbonylhexanoic acid tert-butyl ester to the chiral alcohol is undoubtedly It is an ideal method, and the methods of this reaction mainly include chemical method and biological method. Chemical methods such as Angew. Chem. Int. Ed. 2000, 39:4306-4307 repo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/62
CPCC12P7/62
Inventor 刘斌梁晓亮乐庸堂
Owner ENZYMEWORKS
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