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Ketoprofen intermediate, preparation method and applications thereof

A technology of ketoprofen and asana, which is applied in the field of ketoprofen intermediates and its preparation, can solve the problems of highly toxic reaction reagents, harsh reaction conditions, and high production costs

Inactive Publication Date: 2020-03-03
JIANGSU RUIKE MEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] In order to solve the above-mentioned technical problems, the present invention provides a ketoprofen intermediate, which is used as a raw material to prepare ketoprofen and its general formula compound, which eliminates the high production cost existing in the existing preparation process. , The reaction reagents are highly toxic, there are many reaction by-products, and the reaction conditions are harsh, so it is suitable for industrial production

Method used

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  • Ketoprofen intermediate, preparation method and applications thereof
  • Ketoprofen intermediate, preparation method and applications thereof
  • Ketoprofen intermediate, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0178] Embodiment 1: the preparation of formula II compound

[0179]

[0180] After adding compound of formula I (13.0g, 0.057mol), DMF (68ml) and water (13.6ml) into the reaction flask, stirring and dissolving, the ozone reaction was started, and the reaction solution gradually became shallower and exothermic, and the temperature rose to 40 ℃ or so. After about 1 hour, a sample was taken for testing. After the raw material disappears, turn off the ozone, change to air or nitrogen for 10-20 minutes, add an appropriate amount of ethyl acetate hydrate, stir, stand still, separate layers, then extract with a small amount of ethyl acetate, and wash the organic layer with water. The organic layer was concentrated to dryness under reduced pressure. 14.6 g of the compound of formula II was obtained, with a content of 93.2% and a yield of 91.9%.

Embodiment 2

[0181] Embodiment 2: the preparation of formula III compound

[0182]

[0183] Add formula II compound (10g, 0.038mol), DMF (50ml), K 2 CO 3 (11g, 0.080mol), start to heat up after stirring evenly, when the temperature is 80°C, add a DMF solution of methyl cyanoacetate (6.6g, 0.066mol) dropwise, and after dripping at 80°C for 30 minutes, take a sample to detect the central control, when After the raw materials disappeared, the temperature was lowered to about 10°C, and the pH was adjusted to 1-2 with 1N dilute HCl, extracted with ethyl acetate, the organic layer was washed with an appropriate amount of water, and concentrated to dryness under reduced pressure to obtain 12.1 g of the compound of formula III, with a content of 87.3%. , yield 85%.

Embodiment 3

[0184] Embodiment 3: the preparation of formula IV compound

[0185]

[0186] Add the compound of formula III (10 g, 0.03 mol), Pd / C (50 mg) and methanol (30 ml) into a 100 ml reaction flask, and stir the reaction with hydrogen gas. After reacting at 25°C for 5 hours, sampling and testing were started. When the raw materials disappeared, suction filtration, washing with an appropriate amount of methanol, and concentration of the mother liquor to dryness under reduced pressure gave 8.97 g of the compound of formula IV, with a content of 97.2% and a yield of 96.1%.

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Abstract

The invention relates to the field of medicine synthesis, particular to a ketoprofen intermediate, a preparation method and applications thereof. The preparation method comprises the following steps:carrying out a Diels-Alder reaction on p-nitrohalobenzene or o-nitrohalobenzene or a mixture of p-nitrohalobenzene and o-nitrohalobenzene as a raw material and phenylacetonitrile to form an isoxazolecompound, and sequentially carrying out an oxidation reaction, a substitution reaction, a reduction reaction, deamination, ester group removal and an acidic hydrolysis reaction to prepare ketoprofen,wherein the reaction formula is defined in the specification, X2 or the group defined in the specification is located at the ortho-position or para-position of nitro or amino, R1 is -CONR4R5, -COX1, -COOR2 or -CN, R2, R3, R4, R5 and R6 are the same or different and are H or C1-C6 alkyl, and X1 and X2 are the same or different and are F, Cl, Br or I.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a ketoprofen intermediate and its preparation method and application. Background technique [0002] Ketoprofen, also known as "ketoprofen", was first listed in France in 1973, and then officially entered China in the 1980s. Now it has developed various dosage forms such as oral tablets, patches, and diaphragms. And has been widely used at home and abroad. The drug is a non-steroidal anti-inflammatory analgesic with anti-inflammatory, antipyretic and analgesic effects, and is mainly used for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout wait. Its analgesic effect is superior to similar drugs and lasts for a long time. Its toxic and side effects are small, and the adverse reactions are generally intestinal and stomach discomfort or rash, headache, and tinnitus. [0003] The chemical name of ketoprofen is 3-be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/84C07C51/08C07C253/30C07C255/41C07C255/42C07C255/40C07C201/06C07C205/45
CPCC07C59/84C07C51/08C07C253/30C07C255/41C07C255/42C07C255/40C07C201/06C07C205/45
Inventor 高照波刘声民王长发郭必豹郑辉胡剀梅义将
Owner JIANGSU RUIKE MEDICAL SCI & TECH CO LTD
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