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Enzymatic synthesis method of (R)-3-chloro-1-phenyl-propan-1-ol

A technology of chlorophenylpropanol and synthetic method, applied in the field of biopharmaceuticals, to achieve good industrialization potential, excellent stereoselectivity, and environmental friendliness

Active Publication Date: 2021-06-18
宿迁阿尔法科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method uses recombinant carbonyl reductase to catalyze an asymmetric reduction reaction to prepare R-configuration chiral alcohols

Method used

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  • Enzymatic synthesis method of (R)-3-chloro-1-phenyl-propan-1-ol

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Embodiment 1

[0027] Step 1: Preparation of Ketocarbonyl Reductase Genetic Engineering Bacteria

[0028] The ketocarbonyl reductase is derived from a wild yeast strain (Candida ATCC2001), and its nucleotide sequence is shown in SEQ ID No.3.

[0029] After the nucleotide sequence of ketone carbonyl reductase from wild yeast was amplified by error-prone PCR, it was loaded into the expression plasmid pRSFDuet-1, the double restriction sites were HindⅢ and BamHI, and the primers were:

[0030] F: CGCGGATCCATGGCTGCTCTACATAAGAACA and

[0031] R: CCCAAGCTTTTACACAAATGGCTTAAATGGCC,

[0032] The recombinant expression plasmid ( figure 1 ) into E.coli BL21 (DE3) competent, pick positive transformants and sequence their nucleotide sequence as shown in SEQ ID No.1 (optimized carbonyl reductase DNA sequence) to obtain ketone carbonyl reductase Expression engineering bacteria: TM-01.

[0033] Step 2: Preparation of recombinant ketone carbonyl reductase

[0034] The obtained carbonyl reductase enginee...

Embodiment 2

[0035] Embodiment 2: the preparation of (R)-3-chlorophenylpropanol

[0036] In the 250ml Erlenmeyer flask, add 60ml PB damping fluid (0.2mM, pH6.5), dissolve successively the recombinant ketone carbonyl reductase that 800mg embodiment 1 obtains, 200mg isopropanol dehydrogenase enzyme powder (commercial enzyme, product number WT2302, purchasing company: Alpha Technology), 10mg NADP+ / NADPH. 1g of the substrate 3-chloropropiophenone was dissolved in 40ml of isopropanol, added to the reactor, stirred at 200rpm, and reacted at 25°C for 16h to obtain (R)-3-chloropropiophenone. The reaction result was detected by HPLC, the conversion rate was 90%, the purity was 99.68%, and the ee value was 99.9%.

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Abstract

The invention discloses an enzyme catalytic synthesis method of (R)-3-chloro-1-phenyl-propan-1-ol. According to the method, 3-chloropropiophenone is used as a substrate, optimized carbonyl reductase is used as a catalyst, and the (R)-3-chloro-1-phenyl-propan-1-ol is prepared through biological catalysis. The method for preparing the R-configuration intermediate through the enzyme method is easy and convenient to operate, environmentally friendly, low in cost, few in by-product and high in ee value of the product, and efficient synthesis of the atomoxetine chiral intermediate is achieved.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and relates to an enzyme-catalyzed synthesis method of (R)-3-chlorophenylpropanol. Background technique [0002] (R)-3-Chlorophenylpropanol is an important chiral intermediate that can be used to prepare atomoxetine hydrochloride and dapoxetine hydrochloride. Mention a kind of preparation method of (R)-3-chloropropiophenone in CN101012147A, this method uses 3-chloropropiophenone and NaBH 4 or KBH 4 Reaction, produce (R)-3-chlorophenylpropanol, wherein the left-handed body of chiral amino acid derivative comprises L-tryptophan derivative, L-isoleucine derivative etc., the cost of amino acid derivative is higher, this method In actual production application, there are certain limitations. [0003] CN104496830A provides a new synthetic route of dapoxetine hydrochloride (the route is as follows), in this route, another synthetic method of (R)-3-chlorophenylpropanol is mentioned, the met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/22C12N9/04C12N15/53C12N15/70C12N1/21C12R1/19
CPCC12P7/22C12N9/0006C12N15/70C12Y101/01184
Inventor 石利平陈本顺何伟徐春涛叶金星程瑞华孙伟振尹斌唐旻奕徐秋斌武涛
Owner 宿迁阿尔法科技有限公司
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