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Synthesis method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

A technology of benzopyran and synthesis method, which is applied in the direction of organic chemistry, can solve the problem of low resolution and other problems, and achieve the effect of less reaction steps and high synthesis efficiency

Inactive Publication Date: 2012-04-11
SHANGHAI RECORD PHARM CO LTD +1
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0007] It is not difficult to see that in order to obtain optically pure compound 1 or 2, it is necessary to use a high-purity chiral resolution reagent (more expensive), and the resolution The efficiency of is usually low, and it needs to use harsher conditions to hydrolyze the resulting amide

Method used

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  • Synthesis method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid

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Embodiment Construction

[0024] Below in conjunction with specific embodiment further illustrate how the present invention is realized:

[0025] Such as figure 2 Shown in the reaction formula of the present invention, step A:

[0026] In a 100 ml single-necked bottle, add (L)-malic acid 13.4 g and methanesulfonyl chloride 40 ml, heat up to 45 o C was reacted for about 4 hours, and then the excess methanesulfonyl chloride was removed under reduced pressure to obtain 19.3 g of product 3, and the yield was quantitative.

[0027] Step B:

[0028] 5.6 g of p-fluorophenol and 11.6 g of the product 3 of the previous step were mixed and dissolved in 250 ml of 1,2-dichloroethane, 9.9 g of aluminum trichloride was added, and the temperature was raised to reflux overnight. After cooling in an ice-water bath, 10 % hydrochloric acid to quench the reaction, separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous ...

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Abstract

The invention relates to a synthesis method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and in particular relates to a synthesis method of an intermediate of 2-hydroxyl-2-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)acetonitrile (nebivolol hydrochloride). The method comprises the following steps: using optically pure (R) or (S)-malic acid and the corresponding acyl chloride or anhydride containing R1 groups to react to obtain a compound 3; using the compound 3 and a p-substituted phenol compound to perform a Friedel-Crafts reaction in the presence of an lewis acid to obtain a compound 5; using the compound 5 to perform an intramolecular SN2 substitution reaction under the action of a base and obtain a cyclized product 6; and hydrogenizing the carbonyl groups of the compound 6 in the presence of palladium-charcoal and performing benzyl reduction to obtain the target product 1. The method has the advantages of cheap and available starting material, fewer reaction steps, high synthesis efficiency and the like; and the defects of the prior art can be better overcome.

Description

technical field [0001] The present invention relates to a synthetic method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, involving 2-hydroxyl-2-(6- The synthetic method of the intermediate of fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)acetonitrile (nebivolol hydrochloride). Background technique [0002] Nebivolol hydrochloride is a potent and selective third-generation β-receptor blocker, which can increase the level of nitric oxide and has a vasodilation effect. It is mainly used for the treatment of essential hypertension and can effectively Control hypertension and preserve left ventricular function. It has the advantages of remarkable curative effect, convenient taking, little side effect and the like. Nebivolol hydrochloride was developed by Johnson & Johnson Company, and the Italian Menarim Company was approved for marketing; it was first listed in Germany in May 1997, and it was successively listed in more than 30 countries such as the United ...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/66
Inventor 张芳江甘建刚
Owner SHANGHAI RECORD PHARM CO LTD
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