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Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole

A technology of diphenyl and impurities, which is applied in the field of medicinal chemistry and can solve problems such as cumbersome routes

Inactive Publication Date: 2014-05-07
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In summary, the route reported in the literature is cumbersome and involves the use of highly toxic drugs. A new route is designed to prepare trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo [2,3:6,7]oxazolo[4,5-c]pyrrole and avoidance of strong drugs is essential

Method used

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  • Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole

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Experimental program
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Embodiment 1

[0013] Implementation example one: the synthesis of compound (II):

[0014] Into a 100 mL three-neck flask, add trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxazepine[4 ,5-c] pyrrole, add 15.0 mL of toluene and 0.74 g of sodium carbonate, stir for 30 min to fully dissolve. Add a blend of 0.76 g of ethyl chloroformate and 5.0 mL of toluene to it, and slowly drop it in with a constant pressure dropping funnel. After the dripping was completed, the temperature of the reaction solution was raised to 110°C and refluxed. The complete reaction of raw materials was monitored by TLC, quenched with 20.0 mL of water, extracted with 20.0 mL of ethyl acetate, and then separated, the organic phase was washed twice with 20.0 mL of water, then twice with 20.0 mL of saturated brine, and washed twice with anhydrous sulfuric acid Sodium drying for 4 h. The filter cake was removed by suction filtration, the filter cake was washed with ethyl acetate, and the filtrate was sp...

Embodiment 2

[0015] Implementation example two: the synthesis of compound (Ⅲ):

[0016] Add 100 mg of compound (II) to a 50 mL three-neck flask, measure 5.0 mL of 40% hydrobromic acid into a constant pressure dropping funnel, and let it drop slowly. After the dripping was completed, the temperature of the reaction solution was raised to 80°C and refluxed. The completion of the raw material reaction was monitored by TLC, and the reaction solution was spin-dried to obtain a red solid. Slurry with 10.0 mL ethyl acetate for 30 min, filter with suction, and wash the filter cake with a small amount of ethyl acetate. Collect the filter cake and send it to blow dry at 40°C. 88.1 mg of white solid was obtained, with a yield of 85.89%. 1 H-NMR (DMSO- d 6 ) δ 3.43 (m, 2H), 3.66 (m, 2H), 3.90 (m, 2H), 7.14~7.36 (m, 7H), 9.69 (brs, 2H). MS ( m / z ): [M+H] + 272.0.

Embodiment 3

[0017] Example 3: Asenapine impurity C, namely compound (IV) trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxazepine[ Synthesis of 4,5-c]pyrrole:

[0018] Add 50 mg of compound (Ⅲ), 5 mL of water and 45 mg of sodium carbonate into a 50 mL three-necked flask, heat up and stir to reflux, and react for 2 h. Monitor the pH at 8.0-11.0, add 10 mL of dichloromethane for extraction. After separation, the organic phase was washed twice with 5.0 mL of water, then twice with 5.0 mL of saturated brine, and dried over anhydrous sodium sulfate for 4 h. The filter cake was removed by suction filtration, and the filter cake was washed with a small amount of dichloromethane. The filtrate was spin-dried to obtain 35.1 g of a white solid, with a yield of 91.12%.

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and provides a preparation method of an asenapine key impurity (IV) trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole. The trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole is prepared from trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole used as the initial raw material. The impurity is a very key impurity for synthesizing asenapine, and is also an important intermediate for controlling the asenapine end product quality standard.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxazo[4,5- c] A new method for the preparation of pyrrole [the key impurity of Asenapine (Ⅳ)]. Background technique [0002] The new atypical antipsychotic drug Asenapine (Chinese name Asenapine), the chemical name is trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2, 3:6,7]oxazolo[4,5-c]pyrrole. It was developed by Organon and later applied for marketing by Schering-Plough. On August 14, 2009, the US FDA approved its marketing request. It is a multi-targeted atypical antipsychotic drug mainly used for the emergency treatment of adults with schizophrenia, mania and bipolar disorder mixed episodes. Its structural formula is as follows Ⅰ: [0003] [0004] trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxazolo[4,5-c]pyrrole [Asenapine impurity (Ⅳ) ] is a very critical impurity in the synth...

Claims

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Application Information

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IPC IPC(8): C07D491/044
CPCC07D491/044
Inventor 魏赛王进敏马苏峰
Owner AVENTIS PHARMA HAINAN
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