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A kind of preparation method of compound

A technology for compound and chemical separation, applied in the direction of organic chemistry, etc., can solve the problems of difficult control of reaction conditions, unfavorable industrial production, long synthesis route, etc., and achieves the effect of omitting the asymmetric hydrogenation reaction step, low price, and improving yield.

Inactive Publication Date: 2017-05-17
四川凯科医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] It can be seen from the above synthesis route that the synthesis process includes an asymmetric hydrogenation reaction. Due to the complex asymmetric hydrogenation reaction, the target product in the hydrogenation addition product is lower, and the reaction conditions are not easy to control, resulting in higher actual synthesis costs. In addition, The synthetic route itself is long, which is not conducive to industrial production

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  • A kind of preparation method of compound
  • A kind of preparation method of compound
  • A kind of preparation method of compound

Examples

Experimental program
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Effect test

Embodiment 1

[0021] 1,1-Dimethylethyl N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]-carbamate preparation method

[0022] Take 10 g of compound 3 and 11 g of D-tartaric acid and add it into 100 ml of methanol, heat to reflux, then cool to room temperature and stir for 4 hours, and filter to obtain the D-tartrate salt of compound 3. Add the D-tartrate of compound 3 into 50ml of water, stir to dissolve, then add sodium hydroxide to adjust the pH to 9, then add 5g of di-tert-butyl dicarbonate for reaction, add ethyl acetate to extract after the reaction, concentrate to dryness to obtain white solid. Add 20ml of acetonitrile, 10ml of glacial acetic acid, 0.04ml of ruthenium trichloride and 10ml of aqueous solution to the white solid, then add 1.7g of sodium bromate, the reaction is complete at 3°C, then add 100ml of water, filter the precipitated solid, and water the solid Washing gave 5.4 g of compound 1 as a white solid with an optical purity of 99.8% e.e.

Embodiment 2

[0024] 1,1-Dimethylethyl N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]-carbamate preparation method

[0025] Take 10 g of compound 3 and 11 g of D-tartaric acid and add it into 150 ml of ethanol, heat to reflux, then cool to room temperature and stir for 4 hours, and filter to obtain the D-tartrate salt of compound 3. Add the D-tartrate of compound 3 into 50ml of water, stir to dissolve, then add sodium hydroxide to adjust the pH to 8, then add 3g of di-tert-butyl dicarbonate, after the reaction is complete, add ethyl acetate for extraction, and concentrate to dryness to obtain a white solid . Add 20ml of acetonitrile, 10ml of glacial acetic acid, 0.04ml of ruthenium trichloride and 10ml of aqueous solution to the white solid, then add 1.7g of sodium bromate, the reaction is complete at 0-5°C, then add 100ml of water, filter the precipitated solid, The solid was washed with water to obtain 6 g of white solid compound 1 with an optical purity of 99.0% e.e. ...

Embodiment 3

[0027] 1,1-Dimethylethyl N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]-carbamate preparation method

[0028] Take 10g of compound 3 and 11g of D-tartaric acid and add it to a mixed solution of 80ml of methanol and 40ml of ethanol, heat to reflux, then cool to room temperature and stir for 4 hours, and filter to obtain the D-tartrate of compound 3. Add the D-tartrate of compound 3 into 50ml of water, stir to dissolve, then add sodium hydroxide to adjust the pH to 8-9, then add 5g of di-tert-butyl dicarbonate, after the reaction is complete, add ethyl acetate to extract, and concentrate to dryness to obtain white solid. Add 20ml of acetonitrile, 10ml of glacial acetic acid, 0.04ml of ruthenium trichloride and 10ml of aqueous solution to the white solid, then add 1.7g of sodium bromate, the reaction is complete at 0-5°C, then add 100ml of water, filter the precipitated solid, The solid was washed with water to obtain 6 g of white solid compound 1 with an opti...

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Abstract

The invention discloses a preparation method of a compound. The preparation method comprises the steps: carrying out chemical resolution on a compound 3 namely 5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-ol, to obtain a salt formed from the compound 3 and a resolving agent; carrying out chemical combination of the salt formed from the compound 3 and the resolving agent with di-tert-butyl dicarbonate in an alkali liquid to obtain a compound 4; and oxidizing hydroxyl of the compound 4 to obtain a compound N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]-carbamic acid 1,1-dimethylethyl ester represented by the formula I. According to the preparation method, by selecting the low-price raw materials, the synthetic route is shortened, asymmetric hydrogenation reaction steps are omitted, and thus the production cost is greatly reduced, and the yield is significantly improved.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a compound N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3 - Base] - the preparation method of 1,1-dimethylethyl carbamate. Background technique [0002] Omarigliptin (aulogliptin) is an ultra-long-acting DPP-4 inhibitor, which can produce sustained DPP-4 inhibitory effect once a week orally. Hypoglycemic reaction, no edema and other advantages. [0003] In the synthesis process of alogliptin, the key intermediate N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl ]-1,1-dimethylethyl carbamate (compound 1 for short in the present invention) is the core key of the process; the chemical structural formula of compound 1 is as shown in formula 1: [0004] [0005] The current synthetic technique of compound 1 is mainly the following synthetic route: [0006] [0007] It can be seen from the above synthesis ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/14
CPCC07D309/14
Inventor 曹鹏钟庆林陈正伟
Owner 四川凯科医药科技有限公司
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