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Synthesis method of non-steroidal anti-inflammatory drug, polmacoxib key intermediate

A non-steroidal anti-inflammatory drug, pomacoxib technology, applied in the field of synthesis of key intermediates of non-steroidal anti-inflammatory drug pomacoxib, can solve the problem of difficult treatment of waste water and waste residue, and achieve less environmental pollution and easy The effect of low processing and equipment requirements

Active Publication Date: 2017-07-25
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The main shortcoming of this method is: (1) used raw material trimethylsilyl cyanide and bromoisobutyryl cyanide, easy hydrolysis produces highly toxic cyanide salt or prussic acid, very high requirements are proposed to production equipment and operation process; (2) The by-product contains sodium cyanide, a highly toxic substance, and the waste water and waste residue are difficult to handle

Method used

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  • Synthesis method of non-steroidal anti-inflammatory drug, polmacoxib key intermediate
  • Synthesis method of non-steroidal anti-inflammatory drug, polmacoxib key intermediate

Examples

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Embodiment 1

[0028] Step 1: Synthesis of 2-bromo-2-methyl-propionic acid-(4-nitro)phenol ester (compound 1)

[0029] Dissolve 30.1g of 4-nitrophenol in 300mL of dichloromethane, add 24.1g of triethylamine dropwise at 0-10°C, and then add 50.2g of bromoisobutyryl bromide dropwise. After the dropwise addition, stir at room temperature for 0.5 hour, then add water to quench the reaction, separate the organic phase, wash the organic phase with 0.5M dilute acid and 5% sodium carbonate solution successively, dry over anhydrous sodium sulfate, filter, concentrate, obtain compound 1 after beating with petroleum ether, and the yield 95.6%.

[0030] Step 2: Synthesis of 2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)furanone (compound A);

[0031] Dissolve 26.5g of compound 1 and 10.4g of compound 2 in tetrahydrofuran, cool down to -20°C, slowly add sodium hexamethyldisilazide (2M, 57.2mL) dropwise, after the dropwise addition, stir for half an hour, add water to quench The reaction...

Embodiment 2

[0033] Step 1: Synthesis of 2-bromo-2-methyl-propionic acid-(2-nitro)phenol ester (compound 1)

[0034] Dissolve 30.1g of 2-nitrophenol in 300mL of dichloromethane, add 30.8g of diisopropylethylamine dropwise at 0-10°C, then add 50.2g of bromoisobutyryl bromide dropwise, after the dropwise addition , stirred at room temperature for 0.5 hours, then added water to quench the reaction, separated the organic phase, and washed the organic phase with 0.5M dilute hydrochloric acid and 5% sodium carbonate solution successively, dried over anhydrous sodium sulfate, filtered, concentrated, and obtained the compound after beating with n-heptane 1. The yield is 91.8%.

[0035] Step 2: Synthesis of 2,2-dimethyl-4-(3-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)furanone (compound A);

[0036] Dissolve 26.5g of compound 1 and 10.4g of compound 2 in tetrahydrofuran, cool down to -20°C, slowly add sodium hexamethyldisilazide (2M, 57.2mL) dropwise, after the dropwise addition, stir for half an ...

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Abstract

The invention provides a synthesis method of non-steroidal anti-inflammatory drug, polmacoxib key intermediate. The synthesis method includes following steps: S1, dissolving nitrophenol in an organic solvent A, dropwise adding organic alkali A at 0-10 DEG C, dropwise adding bromoisobutyryl bromide, allowing reaction for 0.2-2h at room temperature after dropwise adding is finished, adding water for quenching reaction, separating out an organic phase, enabling the organic phase to go through an aftertreatment step, and pulping to obtain a compound 1; S2, dissolving the compound 1 and a compound 2 in tetrahydrofuran, cooling to -20 DEG C, dropwise adding organic alkali B for reaction, adding water for quenching reaction, adding an organic solvent B for extraction, combining the organic phase, using 0.5M sodium hydroxide solution to wash, drying, concentrating, and pulping to obtain the polmacoxib key intermediate. Nitrophenol bromoisobutyrate used in the method has the advantages of simplicity in synthesis, high yield, low cost, low requirements on equipment, freeness of generating an extremely toxic material, cyanide, little pollution and convenience in storage.

Description

technical field [0001] The invention relates to a method for synthesizing a key intermediate of non-steroidal anti-inflammatory drug pomacoxib (polmacoxib), which belongs to the field of chemical and pharmaceutical intermediate production. Background technique [0002] Pomacoxib (Polmacoxib) is a cyclooxygenase inhibitor, which belongs to non-steroidal anti-inflammatory drugs. It was approved by the Korean Ministry of Food and Drug Safety (MFDS) in 2015 for the treatment of osteoarthritis. It is reported in the literature that Polmacoxib is obtained through a series of transformations from Compound A, and the synthesis of Compound A is the key to the synthesis of Polmacoxib. According to literature reports, the synthesis of compound A mainly adopts the following method (WO2015080435A1), and the specific process route is as follows: [0003] [0004] The main shortcoming of this method is: (1) used raw material trimethylsilyl cyanide and bromoisobutyryl cyanide, easy hydr...

Claims

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Application Information

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IPC IPC(8): C07D307/58
CPCC07D307/58
Inventor 徐红岩李响
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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