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Method for preparing (2s)-6-fluoro-3,4-dihydro-4-oxy-2H-1-benzopyranyl-2-carboxylic acid

A benzopyran and dihydro technology is applied in the field of preparing the key intermediate of oral aldose reductase inhibitor fidarestat, which can solve the problem that the target product of optical configuration cannot be obtained, the difficulty of product separation and purification is increased, and the separation The effect is not obvious, and the process parameters are easier to control, difficult to buy, and the price is low.

Inactive Publication Date: 2010-05-19
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Disadvantages of this method: the final product of synthesis is epicyclic, the resolution effect is not obvious, the target product with a single optical configuration cannot be obtained, and the raw materials are expensive and difficult to purchase
However, because there may be other pathways in the cells that can metabolize the products, the conversion yield may be low, and other metabolites of the cells or autolysates of the cells may enter the conversion reaction system during the conversion process, increasing the difficulty of separation and purification of the products.

Method used

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  • Method for preparing (2s)-6-fluoro-3,4-dihydro-4-oxy-2H-1-benzopyranyl-2-carboxylic acid
  • Method for preparing (2s)-6-fluoro-3,4-dihydro-4-oxy-2H-1-benzopyranyl-2-carboxylic acid
  • Method for preparing (2s)-6-fluoro-3,4-dihydro-4-oxy-2H-1-benzopyranyl-2-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Lipase adopts lipase NOVO 435, product of Danish NOVO company.

[0037] Add 5.0g of compound (±)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid, 150ml of methanol, and add 0.1% sulfuric acid with a weight concentration of 98%. ml, reflux for 4 hours, concentrate under reduced pressure, and recrystallize from methanol to obtain 5.1 g of compound II as a solid;

[0038] Take 1.0 g of the above solid, 0.1 g of lipase, 9.5 ml of acetonitrile, and 0.5 ml of water, and react for 12 hours at 37° C. with a pH value of 7.0. After the reaction is completed, filter out the lipase, and add 15 ml of 2.5% NaHCO by weight to the filtrate. 3 solution, stirred in an ice bath for 3h, filtered;

[0039] The filtrate was adjusted to pH = 1 with 32% hydrochloric acid by weight to obtain solid (2S)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid 0.37 g.

[0040] The above-mentioned solid is detected by high performance liquid phase, detection condition: use chir...

Embodiment 2

[0044] Using lipase RMIM, the product of Japan Nuoyou Enzyme Preparation Co., Ltd.;

[0045] Compound (±)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid 5.0g, ethanol 150ml, pass through dry HCL gas for 30 minutes, reflux reaction 4h, concentrated under reduced pressure, and recrystallized with methanol to obtain 5.4g of solid. Take 1.0g of the above solid, 0.03g of lipase, 9.7ml of acetonitrile, and 0.3ml of water. React for 6h at 30°C with a pH value of 6.0, and filter after the reaction is complete. Remove lipase, add 15ml weight concentration and be 2.5%Na in the filtrate 2 CO 3 Solution, stirred in ice bath for 4h, filtered: the filtrate was adjusted to pH=1 with concentrated hydrochloric acid to obtain solid (2S)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2 - Carboxylic acid 0.20 g. The above-mentioned solid is detected by high performance liquid phase, detection condition: use chiral column AD-H, mobile phase is n-hexane:isopropanol=87%:13%.

[0046] M...

Embodiment 3

[0048] Lipase adopts lipase NOVO 435, product of Danish NOVO company.

[0049] Compound (±)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid 5.0g, n-propanol 150ml, flow into dry HCL gas for 30 minutes, Reflux for 6 hours, concentrate under reduced pressure, and recrystallize with methanol to obtain 5.8 g of solid. Take 1.0 g of the above solid, 0.04 g of lipase, 9.5 ml of acetonitrile, and 0.5 ml of water. Filter to remove lipase, add 15ml 2.5% KHCO to the filtrate 3 Solution, stirred in ice bath for 4h, filtered: the filtrate was adjusted to pH=1 with concentrated hydrochloric acid to obtain solid (2S)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2 - Carboxylic acid 0.28 g. The above-mentioned solid is detected by high performance liquid phase, detection condition: use chiral column AD-H, mobile phase is n-hexane:isopropanol=87%:13%.

[0050] Melting point, mp 174-176°C; Optical rotation: [α] D 20 +56°(c 1.0, MeOH) NMR 1 H-NMR (DMSO-d): δ: 3.1 (d, 2H), 5.2 (t...

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Abstract

Preparation of 2s-6-fluorine-3, 4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid disclosed herewith is carried out by: refluxing compounds in alcoholic solvent in presence of acid catalyst, collecting its products in aqueous solution of lipase and acetonitrile, hydrolyzing, filtering and collecting filtered liquid, depressurizing to concentrate, evaporating to obtain solid, dissolving the solid in aqueous weak-alkali solution, filtering, regulating pH 1-2, collecting precipitated solid, i.e., the final product said above. Resources concerned herewith are abundant and cheap. No toxic reagents,such as sulfur oxychloride, are used. Its process is easy, with moderate conditions and less side reactions, and its parameters are easily controllable.

Description

technical field [0001] The present invention relates to a kind of method for preparing the key intermediate of oral aldose reductase inhibitor fidarestat (fidarestat), more specifically relates to (2s)-6-fluoro-3,4-dihydro-4-oxo The preparation method of generation-2H-1-benzopyran-2-carboxylic acid. Background technique [0002] (2s)-6-fluoro-3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid is an aldose reductase inhibitor fidarestat (fidarestat), chemical Named (2S-cis)-6-fluoro-2,3-dihydro-2',5'-dioxaspiro(4H-1-benzopyran-4,4'-imidazolidine)-2- Key intermediates of amides. There are two methods for chemically synthesizing fidarestat that have been reported so far: Route 1, using 6-fluoro-1-benzopyran as a starting material, reacting with bromine to obtain the brominated product 3-bromo-6-fluoro- 1-benzopyrone, 2,3 elimination reaction in triethylamine, addition reaction with trimethylsilyl cyanide under the catalysis of zinc iodide, acidolysis of cyano group into car...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/06
Inventor 任宇红黄磊魏东芝
Owner EAST CHINA UNIV OF SCI & TECH