Acinetobacter zjph1806 and its application in the preparation of miconazole chiral intermediates

A technology of bacillus and wet bacteria, which is applied in the field of preparation of miconazole chiral intermediates, can solve the problems of environmental pollution and low yield, and achieve the effect of high optical purity

Active Publication Date: 2021-05-11
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The preparation of (R)-2-chloro-1-(2,4-chlorophenyl)ethanol by chemical method requires the use of complexes of chiral oxazoboridine and heavy metal ruthenium as a catalyst, which will pollute the environment and reduce the yield. not tall

Method used

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  • Acinetobacter zjph1806 and its application in the preparation of miconazole chiral intermediates
  • Acinetobacter zjph1806 and its application in the preparation of miconazole chiral intermediates
  • Acinetobacter zjph1806 and its application in the preparation of miconazole chiral intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1, screening and identification of Acinetobacter ZJPH1806 strain

[0037] 1. Strain screening

[0038] 1) Enrichment culture and primary screening: Add 1g of fresh soil samples collected near the Jianfeng Mountain Orchard in Wucheng District, Jinhua City, Zhejiang Province, into a 250mL shake flask filled with 50mL enrichment medium, culture at 30°C and 200rpm for 5 days , transfer 1 mL of the culture solution to a fresh enrichment medium, continue the enrichment culture for 5 days, and repeat the enrichment twice. The enrichment medium consists of: (NH 4 ) 2 SO 4 2g / L, KH 2 PO 4 2g / L, NaCl1g / L, MgSO 4 ·7H 2 O 0.5g / L, 2,2',4'-trichloroacetophenone (2g / L) is the only carbon source, the solvent is water, pH 6.5.

[0039] 2) Plate culture: Dilute the enriched culture solution with normal saline for 10 4 -10 6 After doubling, it was spread on a plate containing screening medium, cultured at 30°C for 2 days, and a single colony strain was obtained after...

Embodiment 2

[0060] Embodiment 2 optimizes medium composition

[0061] 1. Optimize the types of carbon sources, nitrogen sources and inorganic salts in the fermentation medium

[0062] Fermentation medium composition: carbon source 15g / L, nitrogen source nitrogen content 1.8g / L, inorganic salt 1mM, solvent is water, pH 6.5.

[0063] Acinetobacter ZJPH1806 was inoculated into fermentation media composed of different carbon sources, nitrogen sources and inorganic salts. The culture conditions were as follows: initial pH value 6.5, shake flask filling volume 100mL / 250mL Erlenmeyer flask, culture temperature 30°C, shaker The rotating speed is 200rpm, the inoculum volume is 10%, and the incubation time is 24h. The enzyme activity and ee value are determined by the method in Example 1.

[0064] By examining the single factor experiments (shown in Table 1-Table 3 and Table 5) of different types of carbon sources, nitrogen sources and inorganic salts, the best carbon sources, nitrogen sources and...

Embodiment 3

[0087] Embodiment 3: the acquisition of wet fungus cells

[0088] (1) Incline culture: Acinetobacter ZJPH1806 was inoculated into the slant medium, cultured in a constant temperature incubator at 30°C for 1-2 days to obtain slant strains, and stored in a refrigerator at 4°C. The final concentration of the slant medium consists of: glucose 15g / L, peptone 7.5g / L, yeast extract 6g / L, (NH 4 ) 2 SO 4 3g / L, KH 2 PO 4 1.5g / L, NaCl 0.75g / L, MgSO 4 ·7H 2 O 0.75g / L, agar powder 20g / L, solvent is water, pH 6.5.

[0089] (2) Seed culture: Inoculate the slant bacteria into the seed medium, cultivate at 30°C and 200rpm for 12 hours, and obtain the seed liquid; the composition of the seed medium is: glucose 15g / L, peptone 20g / L, yeast extract 10g / L, (NH 4 ) 2 SO 4 2g / L, KH 2 PO 4 2g / L, NaCl1g / L, MgSO 4 ·7H 2 O 0.5g / L, solvent is water, pH 6.5.

[0090] (3) Fermentation culture: transfer the seed liquid to the fermentation medium with an inoculum size of 10% (v / v), culture a...

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Abstract

The invention discloses an Acinetobacter ZJPH1806 and its application in the preparation of a chiral intermediate of miconazole. (R)-2-chloro-1 is prepared by asymmetric reduction of 2,2',4'-trichloroacetophenone ‑(2,4‑chlorophenyl)ethanol, the product obtained is of high optical purity. In the pH 7.6 phosphate buffer system, with glycerol as the auxiliary substrate, 2g / L substrate was added to react for 26h, the yield of R-type product was 83.2%, and the e.e. value was >99.9%.

Description

[0001] (1) Technical field [0002] The invention relates to the preparation of a chiral intermediate of miconazole, in particular to a method for asymmetrically synthesizing the chiral intermediate of miconazole by utilizing a new bacterial strain-Acinetobacter ZJPH1806 biocatalysis. [0003] (2) Background technology [0004] 2-Chloro-1-(2,4-dichlorophenyl)ethanol (molecular weight: 225.48, CAS number: 11446-57-0) is a key chiral intermediate for the preparation of miconazole. Among them, the R-configuration compound, that is, the formula (I-a) is the key chiral intermediate for the preparation of miconazole mentioned in the present invention. The chemical name of formula (Ⅲ) is 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole, also It is called diclobendazole. [0005] [0006] Formula (I) is 2,2',4'-trichloroacetophenone, formula (II) is 2-chloro-1-(2,4-chlorophenyl)ethanol, and formula (III) is miconazole. [0007] [0008] Formula (I-a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N1/20C12P7/22C12R1/01
CPCC12N1/20C12P7/22C12N1/205C12R2001/01
Inventor 王普缪彦斐刘月旺
Owner ZHEJIANG UNIV OF TECH
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