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Method for synthesizing lobeline hydrochloride intermediate through enzyme catalysis chiral reduction

A technology for lobeline hydrochloride and intermediates, which is applied in the field of enzyme-catalyzed chiral reduction to synthesize lobeline hydrochloride intermediates, which can solve the problems of low selectivity of chiral reagents, long synthetic process routes, and high prices, and achieve mild conditions , The method is simple, the effect of reducing the cost

Pending Publication Date: 2022-01-28
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The purpose of the present invention is to overcome the problems of existing lobeline hydrochloride synthesis process route, low yield, low selectivity of chiral reagents, high price, etc., and provide a method for synthesizing lobeline hydrochloride intermediates through enzymatic chiral reduction , the method uses enzymes for reduction, the conditions are mild, the method is simple, and the cost is greatly reduced

Method used

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  • Method for synthesizing lobeline hydrochloride intermediate through enzyme catalysis chiral reduction
  • Method for synthesizing lobeline hydrochloride intermediate through enzyme catalysis chiral reduction
  • Method for synthesizing lobeline hydrochloride intermediate through enzyme catalysis chiral reduction

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preparation example Construction

[0040] Above-mentioned two kinds of pyrrolidines are prepared into the preparation method of acid chloride:

[0041] Under the protection of nitrogen, add 100ml of dichloromethane, sodium bicarbonate (25.2g, 0.3mol), triphosgene (29.7g, 0.1mol) to the dry 250ml reaction flask, stir and cool down to 10°C, slowly add pyrrolidine (0.15 mol) in dichloromethane solution. During the dropping process, the temperature is controlled below 10°C. After the dropwise addition, the temperature was slowly raised to 25° C. and kept for 20 hours. Nitrogen pressure filtration, the filtrate was distilled under reduced pressure until there was no liquid, and the concentrated solution was spin-dried and recrystallized with toluene to obtain the target product.

[0042] Substrate 1 lobetanone can be purchased directly, or can be prepared voluntarily according to the following reaction formula:

[0043]

[0044] Baker's yeast (purchased by Japan Oriental Yeast Industry Co., Ltd.), after return...

Embodiment 1

[0049] Synthesis of Intermediate III

[0050]

[0051] Add 100g of toluene, 5g of n-butanol, and 20.0g of substrate I into a 500ml reaction flask. After the addition, control the reaction temperature at -10~-5°C. After the temperature stabilizes, slowly add (2S,4S)- 4-(diphenylphosphino)-2-((diphenylphosphino)methyl)-pyrrole-1-carbonyl chloride 32.3g, then add 40.0g of pretreated immobilized enzyme in the reaction flask, react Start immediately, keep warm at -10~-5°C, and react for about 48 hours. The central control will confirm the completion of the reaction (sampling HPLC or spot plate monitoring). After the reaction is completed, the enzyme is filtered off, and the filtrate is the toluene solution of the intermediate III.

[0052] Synthesis of Product IV

[0053] Add the filtrate from the previous step reaction to the reaction flask, bring the temperature to 0°C, then add 5% hydrochloric acid to the reaction flask to adjust the pH to 1-2, stir for 0.5 hours, then rais...

Embodiment 2

[0058] Other conditions are consistent with Example 1, compound II is replaced by (3S,4R)-3,4-bis(diphenylphosphine)pyrrole-1-carbonyl chloride, and the ratio of product IV to the reaction chiral isomer is 99.5: 0.5, yield 52.5%.

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Abstract

The invention discloses a method for synthesizing a lobeline hydrochloride intermediate through enzyme catalysis chiral reduction. The method comprises the following steps: adding an organic solvent, purified water, a buffer salt, a substrate I and a compound II into a reaction flask, controlling the temperature to be proper, adjusting the pH value to be in a proper range, adding an enzyme, carrying out heat preservation reaction for 12 hours to obtain a corresponding intermediate III, and hydrolyzing the intermediate III to obtain a product IV. The yield and the purity of the method are superior to those of a chiral chemical reagent preparation process. The substrate I is reduced by adopting a green and environment-friendly enzymatic process, so that the problems of low selectivity, use danger, relatively high cost, difficulty in environment-friendly treatment and the like of a chiral chemical reagent preparation process are solved.

Description

technical field [0001] The invention relates to a method for synthesizing a drug intermediate through enzyme-catalyzed chiral reduction, in particular to a method for synthesizing a lobeline hydrochloride intermediate through enzyme-catalyzed chiral reduction. Background technique [0002] Lobeline hydrochloride, English name is Lobeline hydrochloride, chemical name is 2-[6-(2-hydroxy-2-phenylethyl)-1-methyl-2-piperidinyl]-1-acetophenone hydrochloride Salt, the structural formula is as follows. [0003] [0004] Lobeline hydrochloride is a reflex respiratory center stimulant. Because it stimulates the carotid body and aortic arch chemoreceptors, it reflexively excites the medullary respiratory center, and also reflexively excites the vagus nerve center and vasomotor center; it first excites and then blocks the autonomic ganglion. For respiratory depression caused by various reasons. Commonly used in neonatal asphyxia, carbon monoxide, opioid poisoning, etc. [0005] T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/12
CPCC12P17/12
Inventor 吴璇邹泽锦胡振宇
Owner JIANGSU HANSYN PHARMA
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