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Preparation method of reference substance for synthesizing etoricoxib

A technology of etoricoxib and reference substance, applied in the field of drug synthesis, can solve the problems of high labor cost, difficult preparation method, etc., and achieve the effects of simple synthesis method and easy-to-obtain reaction raw materials

Active Publication Date: 2015-10-07
广东暨大基因药物工程研究中心有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This preparation method is very difficult, because when preparing compound C, the content of compound D generated is very low, no more than 4%, and it takes a lot of labor to enrich the amount enough to synthesize compound A

Method used

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  • Preparation method of reference substance for synthesizing etoricoxib
  • Preparation method of reference substance for synthesizing etoricoxib
  • Preparation method of reference substance for synthesizing etoricoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Mix 1.44g (4.0mmol) etoricoxib, 0.60g (4.0mmol) methyl 6-methylnicotinate, 0.22g (4.0mmol) sodium methoxide and 6ml dichloromethane, and react at room temperature for 10h. After the reaction was monitored by TLC, 15ml of water and 15ml of dichloromethane were added, separated, the aqueous phase was extracted with dichloromethane (15ml×2), combined with dichloromethane, washed twice with saturated brine, separated, and the organic phase was used Dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography to obtain 1.10 g of white solid, namely Compound A, with a yield of 57.9%, m.p.187-189°C. EIMS m / z(%):478.0(M + ,100).

[0021] 1 H NMR (500MHz, CDCl 3 ): δ2.588(s,3H),2.658(s,3H),4.739(s,2H),7.126(d,J=8.5Hz,1H),7.316(d,J=8.5Hz,1H),7.390 (d, J=8.5Hz, 2H), 7.498(s, 1H), 7.762(d, J=2.5Hz, 1H), 7.858(d, J=8Hz, 2H), 8.161(m, 1H), 8.491( d,J=2.0Hz,1H),8.732(d,J=2.5Hz,1H),9.023(d,J=2.0Hz,1H). 13 C NMR (125MHz, CDCl 3...

Embodiment 2

[0023] Mix 1.44g (4.0mmol) etoricoxib, 0.73g (4.8mmol) methyl 6-methylnicotinate, 0.19g (4.8mmol) sodium hydride (60% content) and 12ml tetrahydrofuran, heat to reflux for 4h . After the reaction was detected by TLC, slowly add 15ml of water and 15ml of dichloromethane, separate the layers, extract the aqueous phase with dichloromethane (15ml×2), combine the dichloromethane, wash twice with saturated saline, separate the layers, and organic phase After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography to obtain 1.01 g of white solid, namely compound A, with a yield of 52.9%.

Embodiment 3

[0025] Mix 2.88g (8.0mmol) etoricoxib, 1.81g (12.0mmol) methyl 6-methylnicotinate, 1.35g (12.0mmol) potassium tert-butoxide and 25ml tetrahydrofuran, and heat to reflux for 4h. After the reaction was detected by TLC, slowly add 30ml of water and 35ml of dichloromethane, separate the liquids, extract the aqueous phase with dichloromethane (35ml×2), combine the dichloromethane, wash twice with saturated saline, separate the liquids, and organic phase After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography to obtain 2.32 g of white solid, ie Compound A, with a yield of 60.7%.

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Abstract

The invention belongs to the technical field of organic synthesis, and discloses a new compound disclosed as Formula A, which is an impurity generated in the etoricoxib preparation process. The invention discloses a generation source and preparation method of the reference substance, and is convenient for providing the reference substance in the etoricoxib synthesis process and identifying the impurity, thereby avoiding or reducing the generation of the impurity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of a reference substance used in the preparation process of the non-steroidal anti-inflammatory drug etoricoxib. Background technique [0002] The trade name of Etoxib is Ankangxin, which was first successfully developed by Merck and launched in Mexico in 2002. The molecular formula is: C 18 h 15 ClN 2 o 2 S, chemical name: 5-chloro-6-methyl-3-[4-(methylsulfonyl)phenyl]-2,3-bipyridine. The structural formula is: [0003] [0004] Etoricoxib is a highly selective cyclooxygenase-2 (COX-2) inhibitor, which has been proven to be used in the treatment of rheumatoid arthritis, psoriatic arthritis, Ankylosing spondylitis, chronic low back pain, acute pain, osteoarthritis, gout and other diseases. [0005] Patents such as US5861419 and EP6040319 report that the synthesis method of etoricoxib is: using p-thiamphenicol phenylacetic acid and 6-methyl nicotinic acid ...

Claims

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Application Information

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IPC IPC(8): C07D213/61C07D213/50
CPCC07D213/50C07D213/61
Inventor 张庆华陈波徐广宇高清姣
Owner 广东暨大基因药物工程研究中心有限公司
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