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Method for synthesizing loxoprofen sodium

A technique for loxoprofen sodium and a synthetic method, which is applied in the field of pharmaceutical and chemical engineering, and can solve problems such as harsh synthetic conditions, difficult catalyst recycling, and complex raw materials

Active Publication Date: 2011-11-09
ZHEJIANG APELOA JIAYUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the noble metal catalysts used are difficult to synthesize, the price is relatively expensive, and there are certain difficulties in the recycling of the catalysts.
High temperature and high pressure make the synthesis conditions harsh, which limits the popularization and application
[0012] "Synthesis of Ketoprofen by Iodine Rearrangement Method" ("Chinese Journal of Medicinal Chemistry", 1998, 12 (2), 302-304) by Hu Yeli etc. discloses taking aryl acetone and triethyl orthoformate as raw materials , Under the promotion of iodine, 1,2-aryl rearrangement is carried out, and the rearrangement product is hydrolyzed to obtain 2-aryl propionic acid. This method requires complex raw materials, triethyl orthoformate is expensive, and the reaction time is long. The yield Low, the product purity is not high, not suitable for industrial production
[0013] CN1294115A discloses taking 2-chloropropionyl chloride as starting raw material, with toluene in anhydrous AlCl 3 Under the catalysis, 2-chloro-1-(4-methylphenyl)-1-propanone is obtained, and then the carbonyl is protected with neopentyl glycol, and the 1,2-aryl is regenerated under the catalysis of zinc oxide and cuprous oxide. row, followed by hydrolysis and acidification to obtain 2-aryl propionic acid, the process route is simple and easy to implement, but the raw material 2-chloropropionyl chloride is expensive, thus hindering the large-scale production of the 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
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1 Preparation of 1-(4-methylphenyl)-1-ethanol (compound I)

[0105]6.7g (0.05mol) of 4-methylacetophenone, 30ml of methanol, stir evenly, cool down in an ice-water bath, add 2.28g (0.06mol) of sodium borohydride, react at 30°C for 3 hours, add 20ml of water, stir evenly, water The layer was extracted with dichloromethane, and the layers were separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain 6.56 g of 1-(4-methylphenyl)-1-ethanol (Compound I), with a yield of 96.4%, detected by HPLC The content is more than 99%.

Embodiment 2

[0106] The preparation of embodiment 2 (1-(4-methylphenyl)-1-ethanol) sulfonate (compound II)

[0107] 6.8g (0.05mol) of compound I, 9.1g (0.09mol) of triethylamine, 30ml of dichloromethane, stirred, and cooled in an ice-water bath. 10.3 g (0.09 mol) of methanesulfonyl chloride was slowly added dropwise at below 15°C. After the dropwise addition was continued and stirred for 3 hours, the heating was stopped, and the layers were separated. The organic phase was washed with saturated sodium bicarbonate until pH = 7, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 9.81 g of compound II. The yield is 91.7%, and the content detected by HPLC is 95%.

Embodiment 3

[0108] Example 3 Preparation of 1-(4-methylphenyl)-1-chloroethane (compound II')

[0109] 61g (0.448mol) of compound I, 200ml of carbon tetrachloride, and 80g (0.67mol) of thionyl chloride were added dropwise at room temperature. After dropping, the mixture was heated to reflux for 3 hours. Cool down to room temperature, add an appropriate amount of water to wash the organic phase, and then wash the organic phase with saturated sodium bicarbonate until the pH of the aqueous layer = 7, and add anhydrous sodium sulfate to dry. Filtration, carbon tetrachloride was distilled off under reduced pressure to obtain 65 g of compound II', the yield was 93.5%, and the content detected by HPLC was 97%.

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Abstract

The invention discloses a synthetic method for loxoprofen sodium, which is prepared by taking methyl acetophenone as an initial raw material through reduction, acylation or halogen substituent, cyanation, hydrolysis, bromination, condensation, decarboxylation and salifying. The method has the advantages of easily obtained raw material, unique technology, simple and stable operation, and high productive rate in each step of reaction; and all solvents used in the synthesis process can be recycled, so the production cost is reduced greatly. Tests show that the obtained product has reliable quality and stable performance, and can be further used for making preparation of non-steroidal anti-inflammatory drugs such as the loxoprofen sodium.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a method for synthesizing loxoprofen sodium. Background technique [0002] Loxoprofen sodium (Loxwprofen sodium), structural formula (VIII) [0003] [0004] The chemical name is 2-[4-(2-oxocyclopentane-1-methyl)phenyl]propionate sodium dihydrate, which belongs to 2-arylpropionic acid non-steroidal anti-inflammatory drugs, of which 2- Arylpropionic acid is an extremely important intermediate of non-steroidal anti-inflammatory drug iprofen, and there are many illegal reports on its synthesis. The specific synthesis methods are as follows: [0005] "Introduction of α-(acyl)methylthiomethyl group into thearomatic ring by Friedel-Crafts reaction" ("Tetrahedron Lett." 1980, 21, 2547) by Y.Tamura et al. disclosed that 2-chloro-2-methylthiopropionic acid Esters are used as alkylating reagents to prepare 2-arylpropionic acid through electrophilic substitution reaction. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C59/86C07C51/377
Inventor 张兴贤胡克斌倪建昆周敦峰陈文龙杨平陈志峰
Owner ZHEJIANG APELOA JIAYUAN PHARMA
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