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A new oxidation method for synthesizing alcatadine

A technology of alcaftadine and oxidant, applied in the field of drug preparation, can solve the problems of unsuitability for industrial scale-up production, polycarboxylic acid impurities, high toxicity, etc., and achieve the effects of low cost, high yield, and less impurities

Active Publication Date: 2018-01-12
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because silver nitrate, selenium dioxide, and ammonium cerium nitrate are more expensive and more toxic, and experiments have found that when these oxidants oxidize alcoholic hydroxyl groups, they will be excessively oxidized to carboxyl groups, resulting in more carboxylic acid impurities
These methods are not suitable for industrial scale-up production

Method used

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  • A new oxidation method for synthesizing alcatadine
  • A new oxidation method for synthesizing alcatadine
  • A new oxidation method for synthesizing alcatadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 0.9g (0.1mol) of AT333 (0.1mol), 0.16g (1mmol) of TEMPO, and 300mL of dichloromethane into a 500mL three-neck flask, stir to dissolve, add potassium bromide solution (1.19g of potassium bromide (10mmol) dissolved in 6mL of purified water), Stir and cool down to -10~-5°C, add 53mL (0.15mol) of 10% sodium hypochlorite solution dropwise, after dropping, keep stirring at -10~-5°C for 30min, raise the temperature to 10~20°C, stir for 30min, monitor by TLC until the reaction is complete , standing for stratification, separating the organic layer, washing the organic layer twice with 100mL sodium bicarbonate solution, separating the organic layer, adding anhydrous sodium sulfate for drying, suction filtration, and concentrating the filtrate under reduced pressure. The obtained oil was added with 50 mL of isopropanol and stirred to precipitate a solid, which was filtered and dried to obtain 26.5 g of an off-white solid with a yield of 86.3%. HPLC purity: 98.7%.

Embodiment 2

[0029] Add 0.9g (0.1mol) of AT333 (0.1mol), 0.16g (1mmol) of TEMPO, and 300mL of dichloromethane into a 500mL three-necked flask, stir to dissolve, add sodium bromide solution (1.03g of sodium bromide (10mmol) dissolved in 15mL of purified water), Stir and cool down to -10~-5°C, add 106mL (0.15mol) of 5% sodium hypochlorite solution dropwise, after dropping, keep stirring at 20~30°C for 30min, raise the temperature to 10~20°C, stir for 30min, monitor by TLC until the reaction is complete, statically Separate the layers, separate the organic layer, wash the organic layer twice with 100 mL of sodium bicarbonate solution, separate the organic layer, add anhydrous sodium sulfate to dry, filter with suction, and concentrate the filtrate under reduced pressure. The obtained oil was added with 50 mL of isopropanol and stirred to precipitate a solid, which was filtered and dried to obtain 24.6 g of an off-white solid with a yield of 80.1%. HPLC purity: 98.9%.

Embodiment 3

[0031] Add 0.9g (0.1mol) of AT333 (0.1mol), 0.16g (1mmol) of TEMPO, and 300mL of dichloromethane into a 500mL three-neck flask, stir to dissolve, add potassium iodide solution (1.66g of potassium iodide (10mmol) dissolved in 15mL of purified water), stir and cool down to - 10~-5℃, add 71mL (0.2mol) of 10% sodium hypochlorite solution dropwise, after dropping, keep stirring at -10~-5℃ for 30min, raise the temperature to 10~20℃, stir for another 30min, monitor by TLC until the reaction is complete, let stand Separate the layers, separate the organic layer, wash the organic layer twice with 100 mL of sodium bicarbonate solution, separate the organic layer, add anhydrous sodium sulfate to dry, filter with suction, and concentrate the filtrate under reduced pressure. The obtained oil was added with 50 mL of isopropanol and stirred to precipitate a solid, which was filtered and dried to obtain 26.2 g of an off-white solid with a yield of 85.3%. HPLC purity: 99.0%.

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Abstract

The invention relates to a novel oxidation method for synthesis of a histamine H1 receptor antagonist--alcaftadine. According to the method, sodium hypochlorite / TEMPO is used as oxidation reagents for oxidation of an intermediate, i.e., 6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo[2,1-b][3]benzazepine-3-methanol, so alcaftadine is prepared. The method provided by the invention has the advantages of simplified operation, environment-friendly process, usage of cheap and easily-available raw materials and reagents, high yield and applicability to industrial production.

Description

technical field [0001] The invention relates to a new method for preparing medicine, in particular to a new method for the oxidation reaction of alcaftadine, a histamine H1 receptor antagonist. Background technique [0002] Alcaftadine, trade name: Lastacaft, is a novel histamine H1 receptor antagonist developed by Vistakon Pharmaceuticals. In 2010, it was approved by the FDA for the treatment of itching caused by allergic conjunctivitis, and it was launched in 2010. Lastacaft is now approved for use in pediatric patients over 2 years of age. Alcaftadine is another drug used to treat ocular itching associated with allergic conjunctivitis following Bepreve developed by ISTA Pharmaceuticals. It has a good clinical application prospect. [0003] The oxidation method reported in the patent WO1992022551 about alcaftadine is to convert 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3 ] Benzazepine-3-methanol obtains alcatadine with manganese dioxide oxidation,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 朱毅宁东波潘季红杨波陈国华
Owner WUHAN WUYAO SCI & TECH
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