A kind of preparation method of etoricoxib intermediate 3-amino-2-chloropropenal

The technology of chloroacrolein and etoricoxib is applied in the field of preparation of etoricoxib intermediates, and can solve the problems of high production risk factor, unfavorable production operation, strong aniline toxicity, etc., and achieves simple post-processing process, low toxicity, Strong nucleophilic effect

Active Publication Date: 2016-03-30
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reagent aniline used in this reaction is highly toxic, and it uses a strong base for high-temperature reaction, and it is acidified with strong hydrochloric acid in the later stage. The production risk factor is high, which is not conducive to production operations, and the reaction steps are long and the yield is low.

Method used

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  • A kind of preparation method of etoricoxib intermediate 3-amino-2-chloropropenal
  • A kind of preparation method of etoricoxib intermediate 3-amino-2-chloropropenal
  • A kind of preparation method of etoricoxib intermediate 3-amino-2-chloropropenal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add 350g of furochloric acid and 700ml of tetrahydrofuran into the reaction bottle, stir to dissolve, cool down to -3°C, slowly add 488g of p-methylaniline, cool down to 0°C and stir for 1h, slowly add 2800ml of cold water, stir at 0~10°C for 2h , suction filtration, and drying to obtain 622.8 g of yellow solid 7, with a yield of 93.6% and a content of 98.12%.

[0032] Add 500g of intermediate 7 and 4000ml of water to the reaction bottle, raise the temperature to 70-80°C, add 120ml of glacial acetic acid, raise the temperature to 100°C, stir for 2h, cool down to 35°C after the reaction, heat and crystallize for 2h, filter with suction, and dry 283.5 g of khaki intermediate 8 was obtained, with a yield of 93.1% and a content of 98.64%.

[0033] Add 200g of intermediate 8 to the reaction flask, add 1800ml of ammonia water (concentration: 25%), heat up to 45°C, react for 5h and spot the plate, the raw materials are basically reacted, add 1000ml of toluene to extract three ...

Embodiment 2

[0035] Add 350g of furochloric acid and 1100ml of tetrahydrofuran into the reaction bottle, stir to dissolve, cool down to 0°C, slowly add 443.9g of p-methylaniline, cool down to 0°C and stir for 1.5h, slowly add 1750ml of cold water, and stir at 0~10°C After 2.5 hours, suction filtration and drying gave 600.2 g of yellow solid 7 with a yield of 90.2% and a content of 97.58%.

[0036] Add 500g of intermediate 7 and 2500ml of water into the reaction bottle, raise the temperature to 70-80°C, add 75ml of formic acid, raise the temperature to 100°C, stir for 2h, cool down to 35°C after the reaction, stir for 2h, filter with suction, and dry to obtain 280.4g The khaki intermediate 8 has a yield of 92.1% and a content of 98.84%.

[0037] Add 200g of intermediate 8 to the reaction bottle, add 1700ml of ammonia water (concentration: 25%), raise the temperature to 45°C, react for 6 hours, spot the plate, the raw materials are basically reacted, add 800ml of toluene to extract three tim...

Embodiment 3

[0039] Add 350g of furochloric acid and 1750ml of tetrahydrofuran into the reaction bottle, stir to dissolve, cool down to -5°C, slowly add 555g of p-methylaniline, cool down to 0°C and stir for 1.5h, slowly add 3500ml of cold water, and stir at 0-10°C After 3 hours, suction filtration and drying gave 608.2 g of yellow solid 7 with a yield of 91.4% and a content of 98.51%.

[0040] Add 500g of intermediate 7 and 5000ml of water into the reaction bottle, raise the temperature to 70-80°C, add 150ml of n-propionic acid, raise the temperature to 100°C, stir for 2h, cool down to 35°C after the reaction, stir for 2h, filter with suction, and dry to obtain 277.4g of khaki intermediate 8, yield 91.1%, content 98.56%.

[0041] Add 200g of intermediate 8 to the reaction bottle, add 2000ml of ammonia water (concentration: 25%), heat up to 45°C, react for 4h, spot the plate, the raw materials are basically reacted, add 1500ml of toluene to extract three times, take the water layer, and co...

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Abstract

The invention discloses a preparation method of an etoricoxib intermediate 3-amino-2-chloroacrolein. The method comprises the following steps: by using mucochloric acid as an initial raw material, reacting the mucochloric acid with p-methylaniline to obtain an intermediate 7; hydrolyzing the intermediate 7 in organic acid to obtain an intermediate 8; and reacting the intermediate 8 in ammonia water to obtain the 3-amino-2-chloroacrolein. The p-methylaniline adopted by the method is solid, and has the advantages of low toxicity, higher nucleophilicity than aniline and high yield. The method simplifies the operation steps, lowers the production cost, and is beneficial to performance of industrialized reaction. The after-treatment process is simpler, and further lowers the complexity of technical operation on the premise of enhancing the impurity removal efficiency.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of an etoricoxib intermediate. Background technique [0002] Etoricoxib, chemical name: 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-dipyridine, molecular formula: C 18 h 15 ClN 2 o 2 S, molecular weight: 358.84, structural formula: [0003] [0004] Etoricoxib is a potent and selective cyclooxygenase-2 inhibitor indicated for the treatment of symptoms and signs of osteoarthritis in the acute and chronic phases and for the treatment of acute gouty arthritis. The original study of etoricoxib was Merck in the United States, and its trade name in the European Union was Arcoxia. It was first launched in Mexico, the United Kingdom, and Brazil in 2002. By 2004, the drug had been approved for marketing in many European countries. Etoricoxib has been approved by the regulatory authorities for clinical use as a non-steroidal anti-inflammatory drug...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C223/02C07C221/00C07D213/61
Inventor 秦春霞王树鹏李德才刘荣旺李保勇吴柯张兆珍董廷华常宝磊柏明士
Owner 山东安信制药有限公司
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