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A kind of ezetimibe intermediate and preparation method thereof

A compound and reaction technology, applied in the field of preparation of ezetimibe, can solve problems such as many steps and mutual interference, and achieve the effects of simple reaction process, high purity and high yield

Active Publication Date: 2019-10-22
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Considering that there are many steps in the preparation of the ezetimibe intermediate compound, the reason for the many steps is that the reaction site involves the reaction of hydroxyl and carboxyl groups. In order to avoid the mutual interference between the two when participating in the reaction, the above patent Formed a complex process route

Method used

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  • A kind of ezetimibe intermediate and preparation method thereof
  • A kind of ezetimibe intermediate and preparation method thereof
  • A kind of ezetimibe intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0037]

[0038] Take 21.2g of the compound of formula I dissolved in 110ml of DMF, and replace it with nitrogen, under the protection of nitrogen, lower the temperature to -10~0°C, control the temperature, add 16g of sodium hydrogen in batches, keep it warm for 0.5h, slowly add pivaloyl chloride 30.2 g, control the temperature at -10~0°C, keep it warm for 1h after the dropwise addition, raise the temperature to 20~25°C, put in 15.5g of S-4-phenyl-2-oxazolidinone, after the feeding is completed, keep warm, and the reaction is complete, then use water Extract with methyl tert-butyl ether, stand to separate the layers, wash the organic layer with saturated brine, and distill under reduced pressure to obtain an oily substance. Stir and crystallize with a mixture of ethyl acetate and hexane, wash with hexane by suction filtration, and dry in vacuo to obtain 38.9 g of a white solid with a molar yield of 93.1% and an HPLC purity of 95.8%. It does not need to be refined and can be ...

Embodiment 2

[0041] Take 21.2g of the compound of formula I dissolved in 110ml of DMF, and replace it with nitrogen, under the protection of nitrogen, lower the temperature to -10~0°C, control the temperature, add 16g of lithium hydride in batches, keep it warm for 0.5h, slowly add methyl chloroformate dropwise 30.2g, control the temperature at -10~0°C, keep it warm for 1h after the dropwise addition, raise the temperature to 20~25°C, put in 15.5g of S-4-phenyl-2-oxazolidinone, after feeding, keep warm, the reaction is complete, Extract with water and methyl tert-butyl ether, stand to separate the layers, wash the organic layer with saturated brine, and distill under reduced pressure to obtain an oily substance. Stir and crystallize with a mixture of ethyl acetate and hexane, wash with hexane by suction filtration, and dry in vacuo to obtain 38.8 g of a white solid product with a molar yield of 92.9% and an HPLC purity of 95%. It does not need to be refined and can be directly used in the ...

Embodiment 3

[0043] Take 21.2g of the compound of formula I dissolved in 110ml of DMF, and replace it with nitrogen, under the protection of nitrogen, lower the temperature to -10~0°C, control the temperature, add 16g of lithium hydride in batches, keep it warm for 0.5h, slowly add phenyl chloroformate dropwise 30.2g, control the temperature at -10~0°C, keep it warm for 1h after the dropwise addition, raise the temperature to 20~25°C, put in 15.5g of S-4-phenyl-2-oxazolidinone, after feeding, keep warm, the reaction is complete, Extract with water and methyl tert-butyl ether, stand to separate the layers, wash the organic layer with saturated brine, and distill under reduced pressure to obtain an oily substance. Stir and crystallize with a mixture of ethyl acetate and hexane, filter with suction, wash with hexane, and dry in vacuo to obtain 38.8 g of a white solid with a yield of 92.9% and an HPLC purity of 94%. It does not need to be refined and can be directly used in the next step.

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Abstract

The present invention relates to the technical field of medicine synthesis, particularly to an ezetimibe intermediate compound and a preparation method thereof. The preparation method specifically comprises that under the effect of a strong base, a compound represented by a formula I, P1-Cl and a compound represented by a formula III are subjected to a reaction to prepare a compound represented by a formula II, wherein P1 is C1-C8 alkoxycarbonyl, C1-C8 alkylcarbonyl or benzoyl, preferably P1 is methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or trimethylacetyl.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of ezetimibe. Background technique [0002] The structural formula of the following compounds is as follows: [0003] [0004] It is an intermediate for the preparation of ezetimibe, and the route for preparing ezetimibe can refer to the patent WO2010113175 (disclosure date 2010-10-7, applicant: Matrix laboratories Ltd), as follows: [0005] . [0006] The above-mentioned WO2010113175 also provides the preparation route of the intermediate, as follows: [0007] , [0008] In its embodiment 9, a compound of formula 6 in which R is a phenyl group is prepared, specifically with P 1 The compound of formula 4 which is benzyl is used as the starting material, and reacted with compound 5 under the action of pivaloyl chloride to prepare the compound of formula 6 (R is phenyl). [0009] And WO2007017705 (publication date 2013-3...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/10
Inventor 朱国良李运广杨立军孙礼国陈祥源
Owner ZHEJIANG JIUZHOU PHARM CO LTD