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Preparation method of chiral warfarin and chiral warfarin derivatives

A derivative and chiral technology, applied in the field of preparation of coumarin anticoagulants - chiral warfarin and its derivatives, can solve the problem of weakening effect, increasing blood coagulation effect, and failing to obtain good experimental results, etc. problem, to achieve the effect of low cost and easy operation

Inactive Publication Date: 2013-04-10
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

④ Barbiturates and phenytoin induce liver drug enzymes, and oral contraceptives can weaken the effect of these drugs due to increased blood coagulation
But unfortunately, when the substituent of unsaturated enone is phenyl, that is, when the product structure is warfarin, good experimental results have not been obtained.

Method used

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  • Preparation method of chiral warfarin and chiral warfarin derivatives
  • Preparation method of chiral warfarin and chiral warfarin derivatives
  • Preparation method of chiral warfarin and chiral warfarin derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] 1) Preparation of intermediate substituted benzylidene acetone. Reaction formula:

[0044]

[0045] Steps:

[0046] In a 50ml single-necked round bottom flask, add benzaldehyde (0.02mol) and acetone (0.56mmol). Then add 0.5ml of 10% NaOH aqueous solution, then add 2ml H 2 O. Stir at room temperature for 3h. After the reaction, the pH was adjusted with dilute HCl to make the solution neutral. Separation and purification (distillation under reduced pressure) gave a viscous oily liquid, and after cooling, a pale yellow solid—benzylidene acetone (150-160°C / 3333Pa (7mmHg)) was obtained.

[0047] 2) Preparation of chiral warfarin. Reaction formula:

[0048]

[0049] Steps:

[0050] 10ml reaction test tube, add 4-hydroxycoumarin (0.1mmol), benzylidene acetone (0.12mmol), chiral primary amine catalyst (5mmol%), lithium perchlorate (5mmol%), Acetic acid (1mmol, 10eq), and finally 2ml of 1,4-dioxane was added. Stirring at room temperature for 24h, adding water to ...

Embodiment 2

[0061] 1) the preparation of intermediate product 4-methylbenzylidene acetone, reaction formula:

[0062]

[0063] Steps:

[0064] In a 50ml single-necked round bottom flask, add 4-methylbenzaldehyde (0.02mol) and acetone (0.56mmol). Then add 0.5ml of 10% NaOH aqueous solution, then add 2ml H 2 O. Stir at room temperature for 3h. After the reaction, the pH was adjusted with dilute HCl to make the solution neutral. Separation and purification (distillation under reduced pressure) gave a viscous oily liquid, and after cooling, a pale yellow solid—benzylidene acetone (150-160°C / 3333Pa (7mmHg)) was obtained.

[0065] 2) Preparation of chiral warfarin derivatives, reaction formula:

[0066]

[0067] Steps:

[0068] 10ml reaction test tube, add 4-hydroxycoumarin (0.1621g, 0.1mmol, 1eq), intermediate product 4-methylbenzylideneacetone (0.220g, 0.12mmol, 1.2eq), chiral primary amine catalyst at one time (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), an...

Embodiment 3

[0070] 1) Preparation of intermediate product 2-methoxybenzylideneacetone. Reaction formula:

[0071]

[0072] Steps:

[0073] In a 50ml single-necked round bottom flask, add 2-methoxybenzaldehyde (0.02mol) and acetone (0.56mmol). Then add 0.5ml of 10% NaOH aqueous solution, then add 2ml H 2 O. Stir at room temperature for 3h. After the reaction, the pH was adjusted with dilute HCl to make the solution neutral. Separation and purification (distillation under reduced pressure) of the distillate gives a viscous oily liquid, and after cooling, a pale yellow solid—benzylidene acetone (150-160°C / 3333Pa (7mmHg))

[0074] 2) Preparation of chiral warfarin derivatives, reaction formula:

[0075]

[0076] (3);

[0077] Steps:

[0078] 10ml of reaction test tube, one-time addition of 4-hydroxycoumarin (0.1mmol), intermediate product 2-methoxybenzylidene acetone (0.12mmol), chiral primary amine catalyst (5mmol%), lithium perchlorate ( 5mmol%), acetic acid (1mmol, 10eq), and ...

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Abstract

The invention relates to a preparation method of chiral warfarin and chiral warfarin derivatives. The invention aims to provide a preparation method which is simple to operate, has low cost and is is suitable for industrial production. The preparation method comprises the following steps: 1) performing alcohol-aldehyde reaction in a mixed solvent of ethanol and water, wherein the volume ration ofethanol to water in the mixed solvent is 5:2-3 and the dosing molar ratio of substituted benzaldehyde to acetone is 1:2; the aqueous solution is maintained to be alkaline in the reaction process; after the reaction, the product is separated and purified to obtain light yellow solid which is the intermediate product substituted benzalacetone; and 2) in the reaction solvent, performing 1,4-additionreaction between the substituted benzalacetone and 4-hydroxycoumarin under the joint action of chiral catalyst, acetic acid and auxiliary catalyst, wherein the dosing molar ratio of substituted substituted benzalacetone to 4-hydroxycoumarin is 1:1.5-1.6, and the acetic acid is 1-10 times as much as 4-hydroxycoumarin; adjusting the pH value to 7 after the reaction to obtain the chiral warfarin andderivative products of the chiral warfarin.

Description

technical field [0001] The invention relates to a preparation method of a class of medicines, more specifically to a preparation method of coumarin anticoagulant-chiral warfarin and its derivatives. Background technique [0002] The chemical name of warfarin is warfarin, and its structure is as follows I formula: [0003] [0004] Warfarin is a coumarin oral anticoagulant, which is clinically used for the prevention and treatment of thromboembolic diseases. The incidence of venous thrombosis in major surgical operations, rheumatic heart disease, hip arthrodesis, artificial heart valve replacement, etc. In addition, it can also be used to treat venous thrombosis after surgery or trauma, and can be used as an auxiliary drug for myocardial infarction. It must also be taken routinely after a variety of surgical and interventional operations. [0005] Warfarin is mainly metabolized by the hepatic cytochrome P450 (CYP) enzyme system, and drugs that can inhibit CYP activity c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/56
Inventor 徐利文杨化萌蒋剑雄来国桥
Owner HANGZHOU NORMAL UNIVERSITY
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