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(e)-4-(1-imidazole methyl) the preparation method of methyl cinnamate

A technology of methyl cinnamate and imidazole methyl, which is applied in the field of preparation of ozagrel intermediate, 4-methyl cinnamate, can solve the problems affecting subsequent reactions and achieve high yield and less impurities

Active Publication Date: 2017-11-21
山东致泰医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the conventional process of preparing imidazolium anions may introduce other anions to affect subsequent reactions.
[0004] At present, there is no report on the preparation of imidazolium anions by the reaction of metal sodium and imidazole

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1 (E)-4-(1-imidazole methyl) methyl cinnamate preparation 1

[0025] Add 60 ml of anhydrous tetrahydrofuran and 30 g of imidazole into a 250 ml three-necked flask, stir, heat slightly (about 30°C) to dissolve the material, add 2.0 g of chopped metal sodium, and the metal sodium reacts completely in about 4 hours, then add 60 ml of tetrahydrofuran to dilute the reaction system, keep warm at 15°C-20°C, add dropwise a solution made of 22g methyl 4-bromomethyl cinnamate and 60ml tetrahydrofuran, drop it in about 1.5-2 hours, keep warm at 20°C-25°C for 3 hours, and filter the reaction system to obtain The filtrate, the filtrate was transferred to a 500ml three-neck flask, concentrated under reduced pressure until no distillation occurred, and about 300ml of purified water was added to the residue, stirred to precipitate crystals, filtered to obtain a white solid, and vacuum-dried at 60°C. The molar yield is 85%.

Embodiment 2

[0026] Embodiment 2 (E)-4-(1-imidazole methyl) methyl cinnamate preparation 2

[0027] Add 60 ml of toluene and 20 g of imidazole into a 250 ml three-necked flask, stir, heat to 90°C to make the material dissolve and clear, add 5.0 g of chopped metallic sodium (there will be a lot of bubbles in the reaction), and the reaction of metallic sodium is completed in about 2~3 hours ( There are a small amount of unreacted particles due to the oxide film formed during the cutting process of sodium metal), concentrated under reduced pressure to remove toluene, added 60 ml tetrahydrofuran, stirred, kept warm at 15 ° C ~ 20 ° C and added dropwise 51 g of 4-bromomethyl The solution made of methyl cinnamate and 120ml tetrahydrofuran was dripped in about 1.5~2h, kept warm at 20°C~25°C for 3h, filtered the reaction system to obtain the filtrate, transferred the filtrate into a 500ml three-necked flask, concentrated under reduced pressure until no Distillation stopped, about 300 ml of purifie...

Embodiment 3

[0028] Example 3 Preparation of (E)-4-(1-imidazolylmethyl) methyl cinnamate 3

[0029] Add 60 ml of toluene and 20 g of imidazole into a 500ml three-necked flask, stir, heat to 90°C to make the material dissolve and clear, add 5.0 g of chopped metallic sodium (there will be a lot of bubbles in the reaction), and the reaction of metallic sodium is completed in about 2~3 hours ( There are a small amount of unreacted particles due to the oxide film formed during the cutting process of sodium metal), concentrated under reduced pressure to remove toluene, added 60 ml of acetone, stirred, kept warm at 15°C to 20°C and added dropwise 51g of 4-bromomethyl The acetone solution of methyl cinnamate, about 1.5 ~ 2 hours, keep warm at 20 ℃ ~ 25 ℃ for 3 hours, concentrate under reduced pressure until no distillation stops, add about 300ml of purified water to the residue, stir to precipitate crystals, filter to obtain White solid, vacuum dried at 60°C. The molar yield is 95%.

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Abstract

The invention belongs to the medicine technical field, and in particular, relates to a preparation method of an ozagrel intermediate namely (E)-4-(1-imidazole methyl)methyl cinnamate, wherein the method includes the following steps: (a) preparation of imidazole negative ions, and (b) preparation of (E)-4-(1-imidazole methyl)methyl cinnamate; the method has the advantages of high yield and less impurity.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an ozagrel intermediate, namely (E)-4-(1-imidazolylmethyl)methyl cinnamate. Background technique [0002] Ozagrel is a new anti-platelet aggregation drug with the chemical name (E)-4-(1-imidazolylmethyl)cinnamic acid. Ozagrel blocks the production of thromboxane A from prostaglandin H2 (PGH2) 2 (TXA 2 ), promote platelet-derived PGH 2 Turns to endothelial cells, which synthesize PGI 2 , thus improving the TX A 2 PGI 2 abnormal balance. Ozagrel inhibits platelet aggregation and dilates blood vessels. [0003] There are many kinds of synthetic techniques for ozagrel. The difficulty and focus of the synthesis lies in the synthesis of ozagrel methyl ester, that is, the synthesis of (E)-4-(1-imidazole methyl ester with 4-bromomethyl cinnamate and imidazolium anion. base) reaction of methyl cinnamate, the key of this reaction is to be able t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 王景成牛华英郭庆军赵利军
Owner 山东致泰医药技术有限公司
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