Synthesis method of carprofen

A technology for compounds and mixtures, applied in the field of producing carprofen and its derivatives, can solve problems such as unrealistic industrial production of carprofen, and achieve the effects of easy and cheap acquisition

Inactive Publication Date: 2016-12-07
凯默斯股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] This method is impractical for the industrial production of carprofen because the starting material, 7-chloro-3-bromocarbazole, itself requires a multi-step synthesis

Method used

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  • Synthesis method of carprofen
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  • Synthesis method of carprofen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: 1-(cyclohex-1-en-1-yl)pyrrolidine

[0083] Into a 10 L reactor equipped with a condenser and Dean-stark head was charged cyclohexanone (1449 g), pyrrolidine (1 kg), macroporous sulfonic acid resin (50 g) and toluene (1.5 L). The reaction mixture was heated to reflux and monitored by GC. After 7 h at reflux, GC showed the reaction was complete. The toluene was then removed by evaporation and the residue was vacuum distilled to afford 1-(cyclohex-1-en-1-yl)pyrrolidine, 1673 g (78.6%), 1 HNMR (CDCl 3 ): δ4.26(s, 1H), 2.97(s, 4H), 2.16(s, 2H), 2.07(s, 2H), 1.80(s, 4H), 1.66(m, 2H), 1.53(m, 2H).

Embodiment 2

[0084] Example 2: 2-(2-oxocyclohexyl) methyl propionate

[0085] To a 1 L round bottom flask containing 1-(cyclohex-1-en-1-yl)pyrrolidine (50 g) and methanol (500 mL) was added ethyl 2-bromopropionate (60 g). The reaction mixture was heated to reflux with stirring for 29 hours. Water (60 mL) was then added to the reaction mixture. Reflux was continued for an additional hour. The mixture was then cooled to room temperature before being diluted with water (500 mL). The resulting mixture was extracted with methyl tert-butyl ether (MTBE) (2 x 300 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated. The crude product was vacuum distilled to give the pure product, 7 g (11.5%). 1 HNMR (CDCl 3 ): δ3.66(d, 3H), 2.71-2.59(mm, 2H), 2.32(m, 2H), 2.03(m, 2H), 1.86(m, 1H), 1.62(m, 2H), 1.32( m, 1H), 1.12-1.05 (dd, 3H). MS(ESI)m / z 185.2[M+1] + .

Embodiment 3

[0086] Example 3: Methyl 2(3-formyl-2-oxocyclohexyl)propionate

[0087] A 250 ml round bottom flask was charged with sodium hydride (2.2 g, 60% in mineral oil) under nitrogen, then THF (50 mL) was added dropwise while stirring at room temperature. Then methyl 2-(2-oxocyclohexyl)propionate (5 g) in THF (10 mL), methyl formate (1.6 g), and Anhydrous methanol (0.1 mL) solution. After the addition, the reaction mixture was stirred at room temperature for an additional 5 hours, then treated with water (100 mL). The resulting mixture was extracted twice with methyl tert-butyl ether (MTBE) (2 x 50 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was then purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 1 g (17%) of pure product. 1 HNMR (CDCl 3 ): δ8.26(dd, 1H), 3.65(d, 3H), 3.10(m, 1H), 2.90-2.75(mm, 1H), 2.26(m, 2H), 1.86(m, 2H), 1.72( m, 1H), 1.47 (m, 2H), 1.18-...

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Abstract

The invention discloses a method and intermediate for synthesizing carprofen and derivatives thereof from cyclohexanone.

Description

field of invention [0001] The present invention relates to a process for the production of carprofen and its derivatives. Background of the invention [0002] Carprofen belongs to the propionate class of nonsteroidal anti-inflammatory drugs (NSAIDs) that includes ibuprofen, naproxen, and ketoprofen. Carprofen reduces inflammation by inhibiting COX-2 and other biological targets of inflammation. Carprofen has been approved by the FDA for use as a veterinary drug for the relief of pain and inflammation associated with osteoarthritis and for the control of postoperative pain associated with soft tissue and orthopedic surgery in dogs. Carprofen is available under the trade names Rimadyl, Novox and Veprofen in dosages of 25 mg, 75 mg and 100 mg carprofen per tablet or caplet. [0003] Carprofen is a white, crystalline compound. Carprofen is almost insoluble in water at 25°C, but easily soluble in ethanol. Carprofen is the nonproprietary name for a substituted carbazole, 6-chl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/88
CPCC07D209/88
Inventor 易林苏西平皮特·沃斯
Owner 凯默斯股份有限公司
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