Method for preparing (R)-3-quinuclidinol

A technology of quinine alcohol and quinine ketone, which is applied in the field of preparation of -3-quinine alcohol, and can solve the problems of long-term cumbersome post-treatment process, low yield and efficiency, etc.

Inactive Publication Date: 2014-08-13
ESTEVE HUAYI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Low yield and efficiency since biotransformation methods are usually performed in highly dilute solutions and require long and tedious work-up processes

Method used

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  • Method for preparing (R)-3-quinuclidinol
  • Method for preparing (R)-3-quinuclidinol
  • Method for preparing (R)-3-quinuclidinol

Examples

Experimental program
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Effect test

Embodiment 1

[0063] Add 3-quininone hydrochloride (3.23g, 20mmol), potassium hydroxide (1.40g, 25mmol), water (300mL) into a 500mL separatory funnel, then add 50mL of dichloromethane, shake well and let stand to separate layers , release the dichloromethane layer of the lower floor, and extract the dichloromethane solution to obtain 3-quininone; repeat the extraction step of the above dichloromethane twice, and combine the organic layers, and then use the dichloromethane solution obtained with anhydrous After drying over magnesium sulfate, filtering, and concentrating under reduced pressure, the solvent was removed to obtain a white solid (2.00 g, 16 mmol), which was 3-quininone, which was sealed and protected from light until use.

Embodiment 2

[0065] Add (1R,2R)-cyclohexanediamine (0.571g, 5mmol) and dichloromethane (125mL) into a 150mL round bottom flask, cool to 0°C in an ice-salt bath, then slowly add N dropwise to the reaction system, N-Dimethylsulfonyl chloride (0.718g, 5mmol), after the dropwise addition, the system was slowly warmed up to room temperature, stirred overnight, and then the resulting mixture was distilled under reduced pressure to obtain a viscous liquid, which was purified by a silica gel column (The eluent is dichloromethane / isopropanol (v:v=6:1)) to obtain a white solid (536mg, 2.42mmol), which is the chiral ligand represented by formula (II-2).

Embodiment 3

[0067] Add (1R,2R)-cyclohexanediamine (2.28g, 20mmol) and dichloromethane (125mL) into a 150mL round-bottomed flask, cool to 0°C in an ice-salt bath, and then slowly dropwise add Toluenesulfonyl chloride (1.14g, 6mmol) in dichloromethane (30mL) solution, after the dropwise addition, the system was slowly warmed up to room temperature, stirred overnight, and then the resulting mixed solution was distilled under reduced pressure to obtain a viscous liquid, Purify it with a silica gel column (eluent is dichloromethane / methanol (v:v=10:1)) to obtain a light red solid (680 mg, 2.53 mmol), which is a chiral compound represented by formula (II-3). Ligand.

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Abstract

The invention provides a method for preparing (R)-3-quinuclidinol. According to the preparation method, an alcohol reacts with 3-quinuclidone under the action of an alkali and a chiral sulfonamide-ruthenium complex, thus preparing the (R)-3-quinuclidinol. The chiral sulfonamide-ruthenium complex serves as a catalyst, and 3-quinuclidone is subjected to asymmetric transfer hydrogenation synthesis to obtain the (R)-3-quinuclidinol. Compared with the prior art, the method provided by the invention is simple,quixk and efficient in preparation process and has extremely high conversion rate, and the product (R)-3-quinuclidinol with high enantio-selectivity and high yield can be obtained and has excellent industrial application prospect.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical intermediates, in particular to a preparation method of (R)-3-quinine alcohol. Background technique [0002] The chemical name of (R)-3-quinine alcohol is R-(-)-1-chloroheterobicyclo[2.2.2]octan-3-ol, which is an intermediate of many anticholinergic drugs, such as Solifenacin And revatropate (Revatropate), which have a good effect on the treatment of urinary incontinence and chronic obstructive pulmonary disease, respectively. At the same time, (R)-3-quinine alcohol is also an important chiral precursor, which is widely used in various asymmetric reactions. [0003] At present, there are two types of preparation methods for (R)-3-quinine alcohol, chemical method and biological method. [0004] Chemical methods are mainly divided into asymmetric catalytic hydrogenation reduction method and asymmetric resolution method. In the asymmetric catalytic hydrogenation reduction method, 3-quinine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02C07B53/00
CPCC07D453/02
Inventor 商永严唐丹郑国荣金积松王昭赵立强吕萍
Owner ESTEVE HUAYI PHARMA
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