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Preparation method of 2-deoxy-2, 2-difluoro-D-red-3, 5-dibenzoate

A technology of dibenzoate and dibenzoyl ester, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of unstable overall yield, lack of α-isomer purity, harsh conditions, etc. Conducive to transformation, reducing production costs and reducing risks

Active Publication Date: 2019-04-19
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, the Chinese patent (authorized announcement number: CN101899072B) discloses a method for preparing gemcitabine intermediates based on sodium borohydride reduction, including 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D- Reduction of ribofuranolide to 2-deoxy-2,2-difluoro-3,5-dibenzoyl-D-ribofuranose in the presence of glacial acetic acid and Lewis acid using sodium borohydride as reducing agent , and the Lewis acid is cerium trichloride, but it has higher requirements for the catalytic reduction system, so that under the mixed system of glacial acetic acid and Lewis acid, combined with sodium borohydride, the borane that may be formed can work, through The control of glacial acetic acid is used to suppress the products of side reactions and avoid the problem of ring opening. The conditions are harsh and not conducive to control; Low and unstable, while the reaction does not have issues specific to the α-isomer purity of the product

Method used

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  • Preparation method of 2-deoxy-2, 2-difluoro-D-red-3, 5-dibenzoate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] At room temperature, 150 mL of THF solvent was added to the reactor, and then 2-deoxy-2,2-difluoro-D-erythro-1-furanulose-3,5-dibenzoyl ester 20 g ( 0.054mol), sodium borohydride 2.2g (0.06mol) and PPO-CBS immobilized catalyst 2.0g, then, under agitation, slowly add methanol 6g dropwise, and control the temperature at 20°C to 30°C during the dropwise addition; After the addition is complete, continue to control the temperature at about 22°C for heat preservation reaction for 3 hours. After the reaction, add hydrochloric acid dropwise to the reaction solution to adjust the pH value of the system to 6.5, stir for 10 minutes, filter, and recover the solid PPO-CBS immobilized catalyst. Apply mechanically, the filtrate is left to stand for 30min, and then the organic phase is collected in layers; the aqueous layer can be extracted twice with 50mL of tetrahydrofuran, and the combined organic phase is washed once with 50mL of saturated aqueous sodium bicarbonate solution, left ...

Embodiment 2

[0024]At room temperature, 112 mL of THF solvent was added to the reactor, and then 20 g of 2-deoxy-2,2-difluoro-D-erythro-1-furanulose-3,5-dibenzoyl ester was added ( 0.054mol), sodium borohydride 2.2g (0.06mol) and PPO-CBS immobilized catalyst 1.8g, then, under stirring conditions, slowly add methanol 6g dropwise, and control the temperature at 20°C to 25°C during the dropwise addition; After the addition is complete, continue to control the temperature at about 22°C for heat preservation reaction for 3.5 hours. After the reaction, add hydrochloric acid dropwise to the reaction solution to adjust the pH value of the system to 6.5, stir for 10 minutes, filter, and recover the solid PPO-CBS immobilized catalyst. Apply mechanically, the filtrate is left to stand for 30min, and then the organic phase is collected in layers; the aqueous layer can be extracted twice with 50mL of tetrahydrofuran, and the combined organic phase is washed once with 50mL of saturated aqueous sodium bic...

Embodiment 3

[0026] At room temperature, 250 mL of THF solvent was added to the reactor, and then 20 g of 2-deoxy-2,2-difluoro-D-erythro-1-furanulose-3,5-dibenzoyl ester was added ( 0.054mol), sodium borohydride 2.4g (0.065mol) and PPO-CBS immobilized catalyst 2.2g, then, under the condition of stirring, slowly add methanol 8g dropwise, and control the temperature at 25°C to 30°C during the dropwise addition; After the addition is complete, continue to control the temperature at about 27°C for heat preservation reaction for 2.5 hours. After the reaction, add hydrochloric acid dropwise to the reaction solution to adjust the pH value of the system to 6.5, stir for 10 minutes, filter, and recover the solid PPO-CBS immobilized catalyst. Apply mechanically, the filtrate is left to stand for 30min, and then the organic phase is collected in layers; the aqueous layer can be extracted twice with 50mL of tetrahydrofuran, and the combined organic phase is washed once with 50mL of saturated aqueous so...

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Abstract

The invention relates to a preparation method of 2-deoxy-2, 2-difluoro-D-red-3, 5-dibenzoate and belongs to the technical field of medicine intermediate synthesis. In order to solve the problems of poor selectivity and safety in the prior art, the invention provides the preparation method of the 2-deoxy-2, 2-difluoro-D-red-3, 5-dibenzoate, which comprises carrying out redox reaction on 2-deoxy-2,2-difluoro-D-red-1-ketofuranose-3, 5- dibenzoate under the combined action of immobilized catalysts of sodium borohydride and PPO-CBS to convert to the product of 2-deoxy-2, 2-difluoro-D-red-3, 5-dibenzoate. The method has the advantage of high chiral selectivity, improves the integral conversion rate, plays a better asymmetric reduction role, and achieves the purpose that the purity of the isomer is more than 95%.

Description

technical field [0001] The invention relates to a preparation method of 2-deoxy-2,2-difluoro-D-erythro-3,5-dibenzoate, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Gemcitabine hydrochloride is a difluoronucleoside antimetabolite anticancer drug that disrupts cell replication, and has a good inhibitory effect on human leukocytes and human tumor xenografts. And the important intermediate of synthesizing gemcitabine at present is 2-deoxy-2,2-difluoro-D-erythro-3,5-dibenzoate, which plays a key role in the process of synthesizing gemcitabine, therefore, Research on the synthesis of this 2-deoxy-2,2-difluoro-D-erythro-3,5-dibenzoate is currently also relatively high. [0003] In the prior art, most of the preparation methods of 2-deoxy-2,2-difluoro-D-erythro-3,5-dibenzoate are based on 2-deoxy-2,2-difluoro-D-erythro -1-furanose-3,5-dibenzoyl ester is used as raw material, and the corresponding intermediate product is o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H1/00
CPCC07B2200/07C07H1/00C07H15/18
Inventor 张锦涛程加铭王福军刘玉坤卢文才汪东海
Owner 江苏八巨药业有限公司
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