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Method for synthesizing loxoprofen sodium

The technology of a kind of loxoprofen sodium, synthetic method is applied in the synthetic field of loxoprofen sodium, can solve problems such as low product conversion rate, sensitive reaction conditions, complex reaction route, achieves high product conversion rate, simple and convenient operation, The effect of a simple reaction route

Inactive Publication Date: 2016-01-06
上海立科化学科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Existing loxoprofen sodium synthetic method reaction route is comparatively complicated, more sensitive to reaction conditions, regioselectivity is poor, and product transformation rate is lower, therefore, it is necessary to improve existing loxoprofen sodium synthetic method

Method used

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  • Method for synthesizing loxoprofen sodium
  • Method for synthesizing loxoprofen sodium
  • Method for synthesizing loxoprofen sodium

Examples

Experimental program
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preparation example Construction

[0024] See figure 1 , the synthetic method of loxoprofen sodium provided by the invention, comprises the steps:

[0025] Step S1: using dimethyl adipate as a starting material;

[0026] Step S2: adding a certain base to make the dimethyl adipate ring-closed to generate methyl 2-oxocyclopentylcarboxylate intermediate; such as organic base, inorganic base or alkali metal compound;

[0027] Step S3: add a certain amount of organic solvent to stir and dilute the dimethyl adipate after ring closure; the mass ratio of base to dimethyl adipate and organic solvent is preferably 0.5:1:1 to 3:1:10 Between; the selection of organic solvent is comparatively important, neither can be removed during vacuum distillation because of its lower boiling point, nor can it be difficult to recover and separate when its boiling point is higher in post-treatment. Recovery cost; after many experiments, the organic solvent is preferably MeOH (methanol), EtOH (ethanol), EtOH 2 O (diethyl ether), MTBE ...

Embodiment 1

[0032] 1000mL four-necked glass bottle, equipped with internal temperature thermometer, condenser and mechanical stirring, put 130g dimethyl adipate at room temperature, add toluene 450mL under stirring, mix well, add metal sodium 17.2g in batches under stirring, heat up and reduce The methanol produced in the reaction was removed by distillation under pressure. After the reaction of dimethyl adipate was complete, 121 g of 2-(4-bromomethylphenyl) was added, and the temperature was raised until the reaction was complete. After cooling down to room temperature, 300 mL of water was added, and 20 mL of Dilute hydrochloric acid (6MHCl) with a concentration of 6 moles per liter adjusted the system to about PH = 6-7, extracted with toluene, dried and concentrated to dryness to obtain 191g of yellow oil, which is the precursor of loxoprofen sodium, without purification Directly put into the next step of decarboxylation reaction.

Embodiment 2

[0034] 1000mL four-necked glass bottle, equipped with internal temperature thermometer, condenser and mechanical stirring, put 130g dimethyl adipate at room temperature, add toluene 200mL under stirring, mix well, add metal sodium 17.2g in batches under stirring, heat up and reduce Remove the methanol generated in the reaction by distillation under pressure. After the reaction of dimethyl adipate is complete, add 121 g of 2-(4-bromomethylphenyl), heat up and react until the reaction is complete, cool down to room temperature, add 300 mL of water, and add 20 mL of 6M HCl Adjust the system to PH=6-7, extract with toluene, dry and concentrate to dryness to obtain 182 g of yellow oil, which is directly put into the next reaction without purification.

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Abstract

The invention discloses a method for synthesizing loxoprofen sodium. The method comprises the following steps: (a) using dimethyl adipate as an initial raw material; (b) adding a certain amount of alkali to enable the dimethyl adipate to perform ring closing and generate a 2-oxocyclopentyl carboxylate intermediate; (c) adding a certain amount of an organic solvent into the ring-closed dimethyl adipate to perform stirring and diluting; (d) removing methanol generated in ring-closing by adopting reduced pressure distillation, and promoting forward performance of a ring-closing reaction; and (e) adding 2-(4-bromomethyl)phenylpropionic acid after complete ring-closing reaction of the dimethyl adipate, performing complete reaction at a certain temperature, performing decarboxylation and quaternization reactions after extracting and drying to obtain the loxoprofen sodium. According to the method, the generated intermediate does not need post-treatment and separation purification, and directly reacts with the 2-(4-bromomethyl)phenylpropionic acid. The method is simple to operate, has simple, safe, environment-friendly reaction route, has low cost, mild reaction condition, good regioselectivity and relatively high production conversion rate.

Description

technical field [0001] The invention relates to a medicine synthesis method, in particular to a synthesis method of loxoprofen sodium. Background technique [0002] Loxoprofen Sodium (Loxoprofen Sodium) is a new type of non-steroidal aryl propionic acid antipyretic, analgesic and anti-inflammatory drug, which has the advantages of small oral dosage, high efficiency, low toxicity and low side effects. It is widely used clinically for the relief of osteoarthritis, rheumatoid arthritis, various fevers and various pain symptoms. [0003] Loxoprofen Sodium (Loxoprofen Sodium) is a new type of phenylpropionic acid non-steroidal anti-inflammatory drug developed by Sankyo Co., Ltd. of Japan. Clinical trials have shown that it has the best analgesic effect among known aryl propionic acid drugs. , has strong anti-inflammatory, analgesic, antipyretic effects, small oral dose, fast absorption, small gastrointestinal side effects, and curative effect is significantly better than other a...

Claims

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Application Information

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IPC IPC(8): C07C51/41C07C59/82
CPCC07C67/313C07C51/38C07C51/412C07C67/343
Inventor 刘庆曾柴文玉甘建刚张芳江
Owner 上海立科化学科技有限公司
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