Preparation method of imrecoxib

A compound and solvent technology, applied in the field of medicinal chemistry, can solve the problems of cumbersome preparation process and purification method, which is not conducive to ensuring product quality, and cannot further reduce the price, and achieves the effect of low cost, low equipment requirements and mild conditions

Active Publication Date: 2019-10-29
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] But synthetic route 3 also involves the disadvantages brought by the intermediate α-bromo (chloro) p-methylsulfonyl acetophenone
In addition, the amide reactive functional group of N-n-propyl p-methylphenylacetamide is low in reactivity, and there is an O-substituted side reaction, and α-bromo (chloro) p-methylsulfonyl acetophenone is easily absorbed by excessive sodium alkoxide and by-products. Destroyed by the sodium hydroxide produced, it is not conducive to ensuring product quality and is not conducive to industrial production
[0017] It can be seen from the above that despite the good efficacy of Erecoxib, its existing preparation process and purification methods are so cumbersome that it is impossible to further reduce its price and include it in the scope of medical insurance catalogues. It is of great significance to establish an industrial preparation method of Erecoxib with simple operation, short and stable process, high purity and high yield

Method used

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  • Preparation method of imrecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Preparation of N-n-propyl-N-p-methylsulfonylbenzoylmethyl-4-methylphenylacetamide (Ⅳ)

[0048] In a 1000 ml four-neck flask connected with a stirring, thermometer, and distillation system, add 350 g of toluene, 127.5 g (0.5 mole) mol) methyl 4-methylphenylacetate (Ⅲ1), stirred and reacted at 85 to 90° C. for 5 hours, while distilling out the by-product methanol. The liquid phase detection reaction was complete, the solvent was recovered by distillation under reduced pressure, 400 g of n-hexane was added to the residue, recrystallized, filtered, and dried to obtain 190.6 g of white solid N-n-propyl-N-p-methylsulfonylbenzoylmethyl Base-4-methylphenylacetamide (Ⅳ), the yield is 98.5%, and the liquid phase purity is 99.7%.

Embodiment 2

[0049] Example 2: Preparation of N-n-propyl-N-p-methylsulfonylbenzoylmethyl-4-methylphenylacetamide (Ⅳ)

[0050] Add 300 grams of N,N-dimethylformamide and 127.5 grams (0.5 moles) of ɑ-n-propylamino-4-methylsulfonyl acetophenone to a 1000-milliliter four-necked flask connected with a stirring, thermometer, and distillation system (II), 90.8 g (0.51 moles) of ethyl 4-methylphenylacetate (III2), stirred and reacted at 95 to 100° C. for 4 hours, while distilling out by-product ethanol. The liquid phase detection reaction was complete, the solvent was recovered by distillation under reduced pressure, 400 g of n-hexane was added to the residue, recrystallized, filtered, and dried to obtain 190.2 g of white solid N-n-propyl-N-p-methylsulfonylbenzoylmethyl Base-4-methylphenylacetamide (Ⅳ), the yield is 98.3%, and the liquid phase purity is 99.8%.

Embodiment 3

[0051] Example 3: Preparation of N-n-propyl-N-p-methylsulfonylbenzoylmethyl-4-methylphenylacetamide (Ⅳ)

[0052] Add 60 grams of N,N-dimethylformamide and 25.5 grams (0.1 moles) of α-n-propylamino-4-methylsulfonyl acetophenone to a 500-milliliter four-necked flask connected with a stirring, thermometer, and distillation system (II), 21.6 g (0.1 mol) of tert-butyl 4-methylphenylacetate (III3), stirred and reacted at 95 to 100° C. for 4 hours, while distilling off by-product tert-butyl alcohol. The liquid phase detection reaction was complete, the solvent was recovered by distillation under reduced pressure, 80 g of n-hexane was added to the residue, recrystallized, filtered, and dried to obtain 37.5 g of white solid N-n-propyl-N-p-methylsulfonylbenzoylmethyl Base-4-methylphenylacetamide (Ⅳ), the yield is 96.9%, and the liquid phase purity is 99.8%.

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Abstract

The invention provides a preparation method of imrecoxib. The preparation method of the imrecoxib comprises the steps that alpha-n-propylamino-4-methyl sulfonate acetophenone (II) and 4-methyl phenylacetate (III) are used as main raw materials, amidation is carried out to obtain N-n-propyl-N-P-methanesulfonyl benzoyl methyl-4-methyl-phenylacetamide (IV), and then the imrecoxib (I) is obtained through an intramolecular cyclization reaction under the action of alkali and ester. The preparation method of the imrecoxib is short in synthetic route and simple and convenient in operation, is easy topurify, has low requirements on equipment, is easy to realize, has less waste water generation quantity, is environmentally friendly, and is suitable for large-scale industrial production; and meanwhile, the reaction selectivity is good, by-products are less, and the product yield and purity are high.

Description

technical field [0001] The invention relates to a preparation method of Erecoxib, which belongs to the technical field of medicinal chemistry. Background technique [0002] Irecoxib (Ⅰ), the English name is Imrecoxib, the trade name is "Hengyang", the chemical name is N-n-propyl-3-p-methylphenyl-4-p-methylsulfonylphenyl-2,5 -Dihydro-1H-2-pyrrolidone, a highly selective cyclooxygenase-2 (COX-2) inhibitor developed by Jiangsu Hengrui Pharmaceutical Company, is a Class 1.1 non-steroidal anti-inflammatory analgesic drug in China (NSAIDs), mainly by inhibiting COX-2, thereby inhibiting the production of inflammatory prostaglandins, its anti-inflammatory and analgesic effects are good, and its mechanism of action is less likely to inhibit COX-1, so it rarely affects physiological protection functions, and has few side effects. It has few adverse reactions and was approved by the CFDA in 2011. It is used to relieve the pain symptoms of osteoarthritis and is suitable for men and wo...

Claims

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Application Information

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IPC IPC(8): C07D207/38
CPCC07D207/38
Inventor 戚聿新刘月盛钱余锋鞠立柱
Owner XINFA PHARMA
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