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Novel oxidation method for preparing alcaftadine

A technology of akapatadine and intermediates, which is applied in the field of compound preparation, can solve the problems of unsuitability for industrial scale-up production, polycarboxylic acid impurities, high toxicity and the like, and achieves the effects of low cost, high yield and few impurities

Active Publication Date: 2015-10-21
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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  • Novel oxidation method for preparing alcaftadine
  • Novel oxidation method for preparing alcaftadine
  • Novel oxidation method for preparing alcaftadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 30.9g (0.1mol) of AT3, 300mL of dichloromethane, and 150mL of tetrahydrofuran into a 1000mL three-neck flask, stir and dissolve at 10-20°C, add 84.8g (0.2mol) of Dess-Martin reagent, and heat up to 20-20°C after the addition is complete. Continue stirring at 30°C for 1-2 hours, monitor by TLC until the reaction is complete, filter with suction, wash the filtrate once with 100 mL of 10% sodium thiosulfate solution, separate the organic layer, then wash with 100 mL of saturated 5% sodium bicarbonate solution, separate The organic layer was taken out, dried by adding anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. Add 50 mL of isopropanol to the obtained oil and stir, cool down to precipitate a solid, filter and dry to obtain 27.5 g of off-white solid, yield 89.6%. HPLC purity: 98.5%.

Embodiment 2

[0028] Add 30.9g (0.1mol) of AT3, 300mL of dichloromethane, and 150mL of tert-butanol into a 1000mL three-neck flask, stir and dissolve at 10-20°C, add 63.6g (0.15mol) of Dess-Martin reagent, and heat up to Continue stirring at 20-30°C for 1-2 hours, monitor by TLC until the reaction is complete, filter with suction, wash the filtrate once with 100 mL of 10% sodium thiosulfate solution, separate the organic layer, and wash with 100 mL of saturated 5% sodium bicarbonate solution , the organic layer was separated, dried by adding anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The obtained oil was added with 50 mL of isopropanol and stirred, the temperature was lowered to precipitate a solid, which was filtered and dried to obtain 26.8 g of an off-white solid with a yield of 87.3%. HPLC purity: 98.6%.

Embodiment 3

[0030] Add 30.9g (0.1mol) of AT3, 200mL dichloromethane, and 200mL acetone into a 1000mL three-neck flask, stir and dissolve at 10-20°C, add 84.8g (0.2mol) of Dess-Martin reagent, and heat up to 20-20°C after adding Continue stirring at 30°C for 1-2 hours, monitor by TLC until the reaction is complete, filter with suction, wash the filtrate once with 100 mL of 10% sodium thiosulfate solution, separate the organic layer, then wash with 100 mL of saturated 5% sodium bicarbonate solution, separate The organic layer was taken out, dried by adding anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The obtained oil was added with 50 mL of isopropanol and stirred, the temperature was lowered to precipitate a solid, and it was filtered and dried to obtain 26.5 g of an off-white solid with a yield of 86.3%. HPLC purity: 98.8%.

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Abstract

The invention relates to a novel oxidation method for preparing a histamine H1 receptor antagonist--alcaftadine. The method comprises the step of using a Dess-Martin periodinane as an oxidation reagent to oxidize an intermediate--6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-imidazo[2,1-b][3]benzazepine-3- methanol so as to obtain the alcaftadine. The novel oxidation method for preparing the alcaftadine is simplified and has the advantages of simple operation, environment-friendly process, cheap and easily-available raw materials and reagents, high yield and more applicability to industrial production.

Description

technical field [0001] The invention relates to a new method for preparing a compound, in particular to a new method for the oxidation reaction of a histamine H1 receptor antagonist—alcaftadine. 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 Applications(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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