Synthetic methods of loxoprofen sodium and intermediate thereof

A technology of loxoprofen sodium and its synthesis method, which is applied in the field of medicine and chemical industry, and can solve the problems of affecting the quality of the final product, causing great environmental pollution, and having no industrial application value, etc.

Inactive Publication Date: 2015-06-17
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield recorded in the Blanc chloromethylation reaction in this document is 90%, which is far higher than the yield of other documents. However, at first, this process needs to use more expensive titanium tetrachloride as the chlorination reagent, and waste The liquid is difficult to handle, the environmental pollution is relatively large, and the production cost is high; secondly, the calculation of its yield is wrong, the product obtained is 92g, and the actual yield is not 90% but should be 81%; more importantly, the reaction operation Complicated, it is necessary to strictly control the rate of addition and the reaction temperature of each raw material, and it is found after repeated tests that the GC purity of the 2-(4-chloromethylphenyl) ethyl propionate obtained is lower, therefore, the The actual yield of the step is not high, and seriously affects the quality of the final product, and qualified loxoprofen sodium cannot be obtained, which has no industrial application value

Method used

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  • Synthetic methods of loxoprofen sodium and intermediate thereof
  • Synthetic methods of loxoprofen sodium and intermediate thereof
  • Synthetic methods of loxoprofen sodium and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Embodiment 1 Preparation of Propiophenone (Compound I)

[0100] Add benzene (86ml) and ferric chloride (9.4g, 58.0mmol) successively in a 100ml three-necked flask, cool down in an ice bath, add propionyl chloride (8.9g, 96.0mmol) dropwise, and after feeding is complete, the oil bath is heated to 50 ~60°C, react for 10 hours. After the reaction was completed, the reaction solution was added into crushed ice, and then the pH of the solution was adjusted to 2-3. The above mixed solution was extracted 2-3 times with ethyl acetate, the organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12.3 g of propiophenone with a yield of 96%.

Embodiment 2

[0101] Embodiment 2 Preparation of Propiophenone (Compound I)

[0102] Add benzene (86ml) and aluminum trichloride (7.7g, 58.0mmol) successively in a 100ml three-necked flask, drop the temperature in an ice bath, add propionyl chloride (8.9g, 96.0mmol) dropwise, after feeding is complete, the oil bath is heated to 50 ~60°C, react for 10 hours. After the reaction was completed, the reaction solution was added into crushed ice, and then the pH of the solution was adjusted to 2-3. The above mixed solution was extracted 2-3 times with ethyl acetate, the organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.9 g of propiophenone, with a yield of 93%.

Embodiment 3

[0103] Embodiment 3 Preparation of Propiophenone (Compound I)

[0104] Add benzene (86ml) and tin tetrachloride (15.1g, 58.0mmol) successively in a 100ml three-necked flask, cool down in an ice bath, add propionyl chloride (8.9g, 96.0mmol) dropwise, and after feeding is complete, the oil bath is heated to 50 ~60°C, react for 10 hours. After the reaction was completed, the reaction solution was added into crushed ice, and then the pH of the solution was adjusted to 2-3. The above mixed solution was extracted 2-3 times with ethyl acetate, the organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11.5 g of propiophenone with a yield of 90%.

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PUM

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Abstract

The invention discloses synthetic methods of loxoprofen sodium and an intermediate thereof; with benzene as a starting material, the key intermediate of loxoprofen sodium is obtained through acylation, halogenation, ketalation, rearrangement and Blanc chloromethylation, then the key intermediate is subjected to condensation, decarboxylation and salt forming reaction to obtain loxoprofen sodium. The methods have the advantages of easily obtained raw materials, simple operation, stable process and high yield; 2-(4-chloromethyl phenyl)propionic acid or propionate is prepared by adopting a method of direct carrying out chloromethylation on a substituted benzene ring, the operation is simple, the yield is high, the use of a chloromethyl ether reagent or stannic chloride and other Lewis acids is avoided, the environmental protection property is high, and relatively good industrial application value is achieved.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a method for synthesizing loxoprofen sodium and its intermediate 2-(4-chloromethylphenyl)methyl propionate. Background technique [0002] Loxoprofen Sodium (Loxoprofen Sodium), molecular formula: C 15 h 17 o 3 Na·2H 2 O, molecular weight: 304.32, chemical name: sodium 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionate dihydrate. Structural formula (Ⅸ): [0003] [0004] Loxoprofen Sodium (Loxoprofen Sodium) is the first propionic acid precursor non-steroidal anti-inflammatory drug (NSAIDs), which was developed by Japan Sankyo Co., Ltd. and was launched in Japan in July 1986. The registered trade name is Le Song. Loxoprofen sodium is a new type of NSAIDs. The drug is a prodrug and has no activity itself. After oral administration, it needs to be metabolized by the liver and converted into trans-OH body before it can exert its therapeutic effect. It has a wid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/65C07C67/343C07C69/612C07C67/08C07D319/06C07D317/12C07C59/86C07C51/41C07C51/38
CPCC07C45/455C07C45/63C07C51/00C07C51/09C07C51/38C07C51/412C07C67/08C07C67/343C07C2601/08C07D317/12C07D319/06
Inventor 张兴贤沈杭州祝方猛吴兴庄程翰李晓黎
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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