S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and preparation method thereof

A technology of diphenylpropionic acid and diphenylpropionate, which is applied in the field of drug synthesis, can solve problems such as low yield, high product cost, and long construction period, and achieve cost reduction, short synthesis cycle, simple and feasible operation Effect

Active Publication Date: 2016-07-27
GRAND LIFE SCI (LIAONING) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to make S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid meet the quality standards and ensure that ambrisentan meets the pharmaceutical quality standards, the raw material 2-hydroxy-3-methoxy- 3,3-diphenylpropionic acid is recrystallized and purified until it meets the requirements, resulting in long construction period and low yield; at the same time, 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid is used In the separation, sodium methoxide also needs to be added as an acid-binding agent in the reaction to neutralize the hydrochloric acid in L-proline methyl ester hydrochloride, which increases the production cost
[0009] Chinese patent CN1129571C has reported that 1-(4-chlorophenyl) ethylamine is used as a resolving agent to resolve 2-hydroxyl-3-methoxyl-3,3-diphenylpropionic acid and 2-hydroxyl-3- Methyl-3,3-diphenylpropionic acid does not require an acid-binding agent in the resolution process, but 1-(4-chlorophenyl)ethylamine is expensive and the product cost is too high

Method used

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  • S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and preparation method thereof
  • S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and preparation method thereof
  • S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] (1) Sodium 2-hydroxy-3-methoxy-3,3-diphenylpropionate

[0063] Dissolve 230g of diphenyl-2,3-epoxypropionate in 600mL of methanol, stir and dissolve at room temperature, add 5.7g of p-toluenesulfonic acid, stir at 20-25°C for 0.5h, heat to reflux, and then drop into 10% sodium hydroxide 800mL, reflux and stir for 1.5h after the dropwise addition, add 90ml of water after concentrating methanol, place in ice bath and stir for 0.5h, then filter, wash the solid with cold water, and blow dry at 60°C.

[0064] The resulting solid was mixed with 60 ml of ethanol and 30 ml of petroleum ether and stirred for 1 h, filtered, and dried under vacuum at room temperature to obtain about 160 g of a white solid. The HPLC test result of 2-hydroxy-3-methoxy-3,3-diphenylpropionate sodium is shown in Table 1 and figure 1 .

[0065] (2) S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

[0066] Add 100g of synthesized sodium 2-hydroxy-3-methoxy-3,3-diphenylpropionate into methyl tert-butyl...

Embodiment 2

[0074] (1) Potassium 2-hydroxy-3-methoxy-3,3-diphenylpropionate

[0075] Dissolve 210g of diphenyl-2,3-epoxypropionate in 600mL of methanol, stir and dissolve at room temperature, add 15mL of 10% sulfuric acid, stir at 20-25°C for 1h, heat to reflux, and then drop in 10% hydrogen Potassium oxide solution 1100ml, reflux and stir for 1.5h after the dropwise addition, add 400ml of water after concentrating methanol, put in ice bath and stir for 0.5h, then filter, wash the solid with cold water, and blow dry at 60°C.

[0076] The resulting solid was stirred with 130 ml of ethyl acetate for 1 h, filtered, and dried under vacuum at room temperature to obtain about 143 g of a white solid. The HPLC test result of 2-hydroxy-3-methoxy-3,3-diphenylpropionate potassium is shown in Table 4 and Figure 4 .

[0077] (2) S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

[0078] Add 105g of synthesized potassium 2-hydroxy-3-methoxy-3,3-diphenylpropionate into methyl tert-butyl ether (MTB, 2...

Embodiment 3

[0086] (1) Lithium 2-hydroxy-3-methoxy-3,3-diphenylpropionate

[0087] Dissolve 230g of diphenyl-2,3-epoxypropionate in 600mL of methanol, stir and dissolve at room temperature, add 5.5g of benzenesulfonic acid, stir at 20-25°C for 0.5h, heat to reflux, and then drop into 10 %Lithium hydroxide 500mL, reflux and stir for 1.5h after the dropwise addition, add 600ml of water after concentrating the methanol, stir in an ice bath for 0.5h, filter, wash the solid with cold water, and blow dry at 60°C.

[0088] The resulting solid was mixed with 150 ml of dichloromethane and 50 ml of n-hexane and stirred for 1 h, filtered, and dried under vacuum at room temperature to obtain about 156 g of a white solid. The HPLC test result of 2-hydroxy-3-methoxy-3,3-diphenylpropionate lithium is shown in Table 7 and Figure 7 .

[0089] (2) S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

[0090] Add 95g of synthesized lithium 2-hydroxy-3-methoxy-3,3-diphenylpropionate into methyl tert-butyl et...

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Abstract

The invention provides S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid and a preparation method thereof. The preparation method comprises 1, dissolving 2, 3-epoxy-3, 3-dibenzylpropionate in methanol, carrying out acid-catalyzed ring-opening, alkali metal hydroxide hydrolysis and reaction solution condensation, adding water into the condensed solution, filtering the solution after solids are separated, and carrying out solvent washing and purification to obtain refined 2-hydroxy-3-methoxy-3, 3-dibenzylpropionate, and 2, carrying out a reaction process on the refined 2-hydroxy-3-methoxy-3, 3-dibenzylpropionate and methyl L-prolinate, carrying out splitting to obtain methyl S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid-L-prolinate, adding an acid into the methyl S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid-L-prolinate so that the methyl S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid-L-prolinate is free and carrying out extraction, drying, condensation and recrystallization to obtain S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid. The preparation method has simple processes, can produce high purity S-2-hydroxy-3-methoxy-3, 3-dibenzylpropionic acid, can guarantee ambrisentan reaching the standard, can shorten a synthesis period, is free of an acid binding agent in a splitting stage and reduces a cost.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid and a preparation method thereof, in particular to a high-purity S-2-hydroxy-3- Methoxy-3,3-diphenylpropionic acid and a method for its preparation with reduced production costs. Background technique [0002] S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid is an important intermediate in the synthesis of ambrisentan (the reaction process is as follows). [0003] [0004] Ambrisentan is an endothelin receptor antagonist developed by Myogen Corporation of the United States. Its trade name is Letairis, and it is used orally for the treatment of pulmonary arterial hypertension. Pulmonary hypertension is a disease with a high fatality rate, which can lead to the gradual decline of cardiopulmonary function, and there is still a lack of effective treatment drugs. Endothelin-1 (ET-1) plays a very important role in vasoconstriction. When...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/64C07C51/02
Inventor 张良孙亮张春红郞洁邸伟庆孙东薛雁王宏英薛百忠
Owner GRAND LIFE SCI (LIAONING) CO LTD
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