Preparation method of chiral warfarin and chiral warfarin derivatives

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

Inactive Publication Date: 2011-08-31
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 product substituted benzylidene acetone. Reaction formula:

[0044]

[0045] Steps:

[0046] A 50ml single neck round bottom flask was charged with benzaldehyde (0.02mol) and acetone (0.56mmol). Then add 0.5ml of 10% NaOH aqueous solution, then add 2ml of 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 (vacuum distillation) to obtain a viscous oily liquid, after cooling to obtain a pale yellow solid-benzylidene acetone (150 ~ 160 ℃ / 3333Pa (7mmHg)).

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

[0048]

[0049] Steps:

[0050] 10ml reaction test tube, add 4-hydroxycoumarin (0.1m mol), benzylidene acetone (0.12m mol), chiral primary amine catalyst (5m mol%), lithium perchlorate (5mmol%), Acetic acid (1mmol, 10eq), and finally add 2ml of 1,4-dioxane. Stir at room temperature for 24 hours, and quench by adding water after th...

Embodiment 2

[0061] 1) Preparation of intermediate product 4-methylbenzylideneacetone, reaction formula:

[0062]

[0063] Steps:

[0064] A 50ml single neck round bottom flask was charged with 4-methylbenzaldehyde (0.02mol) and acetone (0.56mmol). Then add 0.5ml of 10% NaOH aqueous solution, then add 2ml of 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 (vacuum distillation) to obtain a viscous oily liquid, after cooling to obtain a pale yellow solid-benzylidene acetone (150-160°C / 3333Pa(7mmHg)).

[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 in one go (5mmol%), lithium perchlorate (5mmol%), acetic acid (1mmol, 10eq), and finally add 2ml of 1,4-dioxane. ...

Embodiment 3

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

[0071]

[0072] Steps:

[0073] A 50ml single neck round bottom flask was charged with 2-methoxybenzaldehyde (0.02mol) and acetone (0.56mmol). Then add 0.5ml of 10% NaOH aqueous solution, then add 2ml of H 2 O. Stir at room temperature for 3h. After the reaction, the pH was adjusted with dilute HCl to make the solution neutral. Separate and purify the fractions (distilled under reduced pressure) to obtain a viscous oily liquid. After cooling, obtain a light yellow solid-benzylidene acetone (150-160℃ / 3333Pa(7mmHg))

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

[0075]

[0076] (3);

[0077] Steps:

[0078] 10ml reaction test tube, add 4-hydroxycoumarin (0.1mmol), intermediate product 2-methoxybenzylideneacetone (0.12mmol), chiral primary amine catalyst (5mmol%), lithium perchlorate ( 5mmol%), acetic acid (1mmol, 10eq), and finally add 2ml of 1,4-dioxane. S...

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PUM

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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 method for preparing a class of drugs, more specifically, a method for preparing a coumarin anticoagulant, chiral warfarin and its derivatives. Background technique [0002] The chemical name of warfarin is warfarin, and its structure is as follows: Formula I: [0003] [0004] Warfarin is a coumarin-based oral anticoagulant. It is clinically used to prevent and treat thromboembolic diseases. It can prevent the formation and development of thrombosis, such as the treatment of thromboembolic phlebitis, and reduce the incidence and mortality of pulmonary embolism. The incidence of venous thrombosis in major surgical operations, rheumatic heart disease, hip arthrodesis, artificial heart valve replacement surgery, 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 be taken routinely after various surgical and interventional o...

Claims

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Application Information

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Patent Type & Authority Applications(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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