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Preparation method of loxoprofen sodium ring opened impurity

A technology for loxoprofen sodium and impurities, which is applied in the field of raw material drug preparation, can solve the problems of inability to obtain a compound of formula V and the like, and achieves the effects of good yield, simple process and high purity

Active Publication Date: 2017-11-17
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After searching, there is no literature report on the preparation of this impurity, and the compound of formula V cannot be obtained through conventional acid-base, oxidation, and high-temperature destruction. It is necessary to open up a new route for the directional synthesis of this compound

Method used

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  • Preparation method of loxoprofen sodium ring opened impurity
  • Preparation method of loxoprofen sodium ring opened impurity
  • Preparation method of loxoprofen sodium ring opened impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Step (1): Add p-chloromethylisophenylpropionic acid (80g, 0.40mol), hexamethylenetetramine (112.1g, 0.80mol) and 240ml of chloroform into a 500ml three-neck flask, stir and heat up to reflux (63~65°C), stirred and reacted for 6 hours, sampled and plated for complete reaction, cooled to room temperature, added 60g of 36% concentrated hydrochloric acid, stirred and heated to reflux for 2 hours, cooled to room temperature, separated to obtain an organic layer, and the organic layer was washed with saturated carbonic acid Wash with 200 ml of sodium aqueous solution, separate the layers to obtain an organic layer, and concentrate to dryness under reduced pressure to obtain 66.2 g of 2-(4-formylphenyl)propionic acid, a light yellow solid, yield 92.3%, HPLC purity 94.6%. 1 H-NMR (400 MHz, CDCl3)d11.31(1H, s), 9.99(1H, d), 7.86 (2H, d), 7.50(2H,d), 3.84(1H,q), 1.56(3H, d).

[0033] Step (2): Add 4-formyl-phenylpropionic acid (25g, 0.14mol), 1-(4-morpholine)cyclopentene (43g, 0...

Embodiment 2

[0036] Step (1): Into a 500ml three-necked flask, add p-bromomethylisophenylpropionic acid (96.84g, 0.40mol), hexamethylenetetramine (112.1g, 0.80mol), and 240ml of chloroform, stir and heat up to Reflux (63~65°C), stir and react for 6 hours, take samples and spot the reaction completely, cool down to room temperature, add 60g of 36% concentrated hydrochloric acid, stir and heat up to reflux for 2 hours, cool down to room temperature, and separate to obtain an organic layer, which is saturated with Wash with 200ml of sodium carbonate aqueous solution, separate the layers to obtain an organic layer, and concentrate to dryness under reduced pressure to obtain 67.56g of 2-(4-formylphenyl)propionic acid, a light yellow solid, yield 94.2%, HPLC purity 94.6%.

[0037] Step (2): Add 4-formyl-phenylpropionic acid (25g, 0.14mol), 1-(4-morpholine)cyclopentene (43g, 0.28mol) and 150ml toluene into a 500ml three-necked flask, and stir Raise the temperature to reflux (115°C), stir and reac...

Embodiment 3

[0040] Step (1): Add p-chloromethylisophenylpropionic acid (80g, 0.40mol), hexamethylenetetramine (56.05g, 0.40mol) and 240ml of chloroform into a 500ml three-neck flask, stir and heat up to reflux (63~65°C), stirred and reacted for 6 hours, sampled and plated for complete reaction, cooled to room temperature, added 60g of 36% concentrated hydrochloric acid, stirred and heated to reflux for 2 hours, cooled to room temperature, separated to obtain an organic layer, and the organic layer was washed with saturated carbonic acid Wash with 200 ml of sodium aqueous solution, separate the layers to obtain an organic layer, and concentrate to dryness under reduced pressure to obtain 61.4 g of 2-(4-formylphenyl)propionic acid as a pale yellow solid with a yield of 85.6%. HPLC purity was 94.0%.

[0041]Step (2): Add 4-formyl-phenylpropionic acid (25g, 0.14mol), 1-(4-morpholine)cyclopentene (43g, 0.28mol), and 150ml of dichloromethane into a 500ml three-necked flask , stirred and heated...

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Abstract

The invention relates to a preparation method of a loxoprofen sodium ring opened impurity, and belongs to the technical field of bulk drug preparation. The preparation method comprises the following steps: step one, carrying out substitution reactions between a compound represented by a formula I and hexamethylene tetramine in an organic solvent A, hydrolyzing the reaction product by inorganic acids to obtain a compound represented by a formula II; carrying out condensation reactions between the compound represented by the formula II and a compound represented by a formula III in an organic solvent B to obtain a compound represented by a formula IV; carrying out oxidation and ring opening reactions of the compound represented by the formula IV under the effect of an oxidant and inorganic alkalis to obtain the loxoprofen sodium ring opened impurity represented by a formula V. The invention provides a preparation method of the loxoprofen sodium ring opened impurity.

Description

technical field [0001] The invention relates to a method for preparing ring-opening impurities of loxoprofen sodium, which belongs to the technical field of preparation of raw materials. Background technique [0002] Loxoprofen Sodium (Loxoprofen Sodium), its structural formula is as follows: [0003] [0004] The chemical name is 2-[4-(2-oxocyclopentane-1-methyl)phenyl]propionate sodium dihydrate, which belongs to diarylpropionic acid non-steroidal anti-inflammatory drugs, manufactured by Sankyo Co., Ltd. It was first developed by the company, and it was launched in Japan in 1986. Now it is the No. 1 selling variety of non-steroidal anti-inflammatory drugs in Japan. [0005] The quality standards of loxoprofen sodium in various national pharmacopoeias do not specify known impurities, and the Japanese Pharmacopoeia uses thin-layer chromatography (TLC) technology to control related substances. Improving the quality of clinical medication and reducing side effects are the...

Claims

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Application Information

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IPC IPC(8): C07C51/16C07C51/285C07C59/84
CPCC07C51/16C07C51/285C07C51/373C07C59/84C07C59/86C07C59/92
Inventor 刘彦彬蔡亚辉吴艳华毕可兴李大军
Owner 迪嘉药业集团股份有限公司
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