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Preparation method for ambrisentan intermediate compound

An ambesentan and compound technology, which is applied in the field of preparation of ambesentan intermediates, can solve the problems of low yield of final products, cannot be produced on a large scale, complex synthesis steps, etc., and achieves simple preparation method, low cost, and reaction yield. high rate effect

Inactive Publication Date: 2014-04-30
上海皓骏医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this method, the synthesis steps are complicated, and there are many side reactions, and it is not easy to split, so the yield of the final product is low, and it cannot be produced on a large scale.

Method used

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  • Preparation method for ambrisentan intermediate compound
  • Preparation method for ambrisentan intermediate compound
  • Preparation method for ambrisentan intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of compound 10, wherein R is methyl:

[0034]

[0035] Dissolve the mixture of 10g benzophenone and 7.1g ethyl chloroacetate in 100ml tetrahydrofuran, add 5.9g sodium methylate and stir for 90 minutes at -4°C, continue stirring for 30 minutes at -10°C--5°C, and then add to 25-35°C, extracted with water and ethyl acetate, washed the organic layer with saline solution, then dried over anhydrous sodium sulfate, and distilled under reduced pressure at 60°C to obtain 13g of the product (compound 10), with a yield of 93%.

Embodiment 2

[0037] Preparation of compound 10, wherein R is methyl:

[0038]

[0039] Dissolve the mixture of 100g benzophenone and 71g ethyl chloroacetate in 1000ml tetrahydrofuran, add 59g sodium methylate and stir for 90 minutes at -4°C, continue stirring for 30 minutes at -10°C--5°C, then add to 25°C -35°C, extracted with water and ethyl acetate, washed the organic layer with saline solution, then dried over anhydrous sodium sulfate, and distilled under reduced pressure at 60°C to obtain 129.8g of the product (compound 10), with a yield of 93%.

Embodiment 3

[0041] Preparation of compound 1, wherein R is methyl:

[0042]

[0043] Dissolve 10g of compound 10 in 20ml of methanol, then add 3.9g of sulfonic acid, stir at 25-35°C for two hours, then add 25g of tris(ethylenediamine) cobalt salt, stir at 55-60°C for 45 minutes, then cool Continue to stir for 1 hour to 25-35 ℃, have solid to separate out, filter, wash with methyl tert-butyl ether, filter, dry, obtain product 4.86g (compound 1), yield is 43%.

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Abstract

The invention discloses a preparation method for an ambrisentan intermediate compound. The preparation method comprises the following step: adding a resolving agent into a compound 10 under an acidic condition to carry out a chiral ring-opening reaction to obtain the ambrisentan intermediate compound. According to the preparation method, used raw materials are easy to obtain and the activity and the selectivity almost have no losses after a plurality of times of reactions; the raw materials can be used for a plurality of times; reaction conditions are moderate and steps are simple; the raw materials do not need to react under an ultralow temperature condition and a flammable and combustible reagent is not used, so that the ambrisentan intermediate compound is suitable for large-scale industrial production and the safety is high; the reaction yield is high and the cost is low. The preparation method is used for synthesizing ambrisentan and has a wide application prospect.

Description

technical field [0001] The invention relates to a preparation method of an ambesentan intermediate. Background technique [0002] The chemical name of the novel highly selective endothelin receptor antagonist drug ambrisentan is (S)-2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3, 3-Diphenylpropionic acid, whose structural formula is shown in formula I, is used in the treatment of congestive or chronic heart failure and intrapulmonary arterial hypertension, and has obtained priority approval from the US FDA. Phase III clinical results show that the compound of formula I has a stronger and more effective effect than the current best-selling endothelin receptor antagonist drug. [0003] [0004] Patent WO201070658 discloses a preparation method of ambrisentan, the synthesis route of which is as follows: [0005] [0006] In this method, the synthesis steps are complicated, and there are many side reactions, and it is not easy to split, so the yield of the final product i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/734C07C67/31C07D303/48C07D301/02
CPCC07C67/31C07C69/734C07D301/02C07D303/48
Inventor 周利利马军庄小东
Owner 上海皓骏医药科技有限公司
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