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Synthesis method of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid

A technology of diphenylpropionic acid and its synthetic method, which is applied in the preparation of oxygen-containing compounds, chemical instruments and methods, and preparation of carboxylic acid esters. It can solve the problems of increasing hidden dangers in the quality control of intermediates and final products, and avoid genotoxicity Impurities, suitable for industrial production, mild reaction conditions

Inactive Publication Date: 2020-05-05
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The sulfuric acid used in the ring-opening reaction of this method is easily esterified with methanol to generate highly toxic dimethyl sulfate, which increases hidden dangers for the control of impurities in the intermediate and the quality control of the final product.

Method used

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  • Synthesis method of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid
  • Synthesis method of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid
  • Synthesis method of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] step a

[0031] Add 20g of compound II and 23.8g of methyl chloroacetate into N,N-dimethylformamide, stir to dissolve, add 69.9g of potassium phosphate, heat to 70°C for reaction, wait until TLC detects that the reaction of compound II is complete, and cool down to room temperature , adding water to the reaction solution, adding dichloromethane for extraction, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound III as a light yellow oil.

[0032] step b

[0033] Add compound III to methanol, stir to dissolve, add 1.3g trifluoroacetic acid, control the temperature below 45°C, wait for TLC to detect that compound III has reacted completely, cool down to 0-10°C to crystallize, filter to obtain white solid compound IV, and HPLC detection showed that the purity was 99.54%, benzophenone was not detected, and the maximum single impurity was 0.10%. step c

[0034] Add compound IV to 120mL ...

Embodiment 2

[0036] step a

[0037] Add 20g of compound II and 23.8g of methyl chloroacetate into N,N-dimethylformamide, stir to dissolve, add 81.5g of potassium phosphate, heat to 70°C for reaction, wait until TLC detects that the reaction of compound II is complete, and cool down to room temperature , adding water to the reaction solution, adding dichloromethane for extraction, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound III as a light yellow oil.

[0038] step b

[0039] Add compound III to methanol, stir to dissolve, add 1.8g trifluoroacetic acid, control the temperature below 45°C, wait for TLC to detect that compound III has reacted completely, cool down to 0-10°C to crystallize, filter to obtain white solid compound IV, and HPLC detection showed that the purity was 99.46%, benzophenone was not detected, and the maximum single impurity was 0.12%. step c

[0040] Add compound IV to 120mL ...

Embodiment 3

[0042] step a

[0043]Add 20g of compound II and 26.0g of methyl chloroacetate into N,N-dimethylformamide, stir to dissolve, add 69.9g of potassium phosphate, heat to 80°C for reaction, wait until TLC detects that the reaction of compound II is complete, and cool down to room temperature , adding water to the reaction solution, adding dichloromethane for extraction, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound III as a light yellow oil.

[0044] step b

[0045] Add compound III to methanol, stir to dissolve, add 1.8g trifluoroacetic acid, control the temperature below 40°C, wait for TLC to detect that compound III has reacted completely, cool down to 0-10°C to crystallize, filter to obtain white solid compound IV, and HPLC detection showed that the purity was 99.52%, benzophenone was not detected, and the maximum single impurity was 0.14%. step c

[0046] Add compound IV into 120mL...

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Abstract

The invention relates to a synthetic method of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid. The invention relates to a preparation method of an ambrisentan key intermediate 2-hydroxy-3-methoxy-3,3-diphenyl propionic acid. According to the preparation method of 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid, benzophenone and methyl chloroacetate are used as raw materials, and 2-hydroxy-3-methoxy-3, 3-diphenyl propionic acid is obtained after a Darzens reaction, a ring-opening reaction and a hydrolysis reaction. The synthesis method is mild in reaction condition, free of genotoxicity andother high-toxicity substances, low in cost and suitable for industrial production of drugs.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of ambrisentan intermediate 2-hydroxyl-3-methoxyl-3,3-diphenylpropionic acid. Background technique [0002] Ambrisentan is a selective endothelin receptor A (ETAR) antagonist with the chemical name (+)-2S-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3 -Methoxy-3,3-diphenylpropionic acid, which is another drug for the treatment of pulmonary arteries following bosentan and sitaxsentan, is currently synthesized with benzophenone as the starting material, after 2 -Hydroxy-3-methoxy-3,3-diphenylpropionic acid racemate intermediate, which is then resolved to give 2-hydroxy-3-methoxy-3,3-diphenyl Propionic acid monomer, which is then reacted with 4,6-dimethyl-2-methylsulfonylpyrimidine to obtain ambrisentan. [0003] Literature (J.Med.Chem., 1996, vol.39, No.11, p.no.2123-2128.) describes a synthetic 2-hydroxy-3-methoxy-3,3-diphe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C27/02C07C59/64
CPCC07C51/09C07C67/31C07D301/02C07D303/48
Inventor 熊龙牛群单文俊
Owner JIANGSU HANSOH PHARMA CO LTD
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