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Method for preparing 8-chloro-10, 11-dihydro-4-aza-5H-dibenzo[a, d]-5-cycloheptanone

A technology of cycloheptanone and dihydro, which is applied to the preparation of 8-chloro-10, can solve the problems of cumbersome processing and difficult preparation of raw materials, shorten the process flow, make the operation process simple and easy, and avoid the by-products of ortho-cyclization Effect

Inactive Publication Date: 2005-07-20
上海康鸣高科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the raw materials used in this process are difficult to prepare, and the post-processing process is cumbersome.

Method used

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  • Method for preparing 8-chloro-10, 11-dihydro-4-aza-5H-dibenzo[a, d]-5-cycloheptanone
  • Method for preparing 8-chloro-10, 11-dihydro-4-aza-5H-dibenzo[a, d]-5-cycloheptanone
  • Method for preparing 8-chloro-10, 11-dihydro-4-aza-5H-dibenzo[a, d]-5-cycloheptanone

Examples

Experimental program
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Embodiment 1

[0031] The compound 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridinecarboxamide (40g, 0.125mol) was dissolved in 150ml of CH 2 Cl 2 Add dropwise to PCl at 5°C 5 (95%, 52g, 0.25mol) of CH 2 Cl 2 (150ml) solution, stirred until the raw materials reacted completely, and 67g of anhydrous AlCl 3 (0.5mol) was added to the solution and stirred for 5h. Then poured into ice water, heated to reflux for 1h, and cooled to room temperature. The aqueous layer was slowly neutralized to pH = 12 with 40% NaOH solution, and the 2 Cl 2 Extraction; the organic layer was back-extracted with HCl solution and then neutralized to pH=12 with 40% NaOH solution, and then washed with CH 2 Cl 2 extraction. The organic layer was washed with alkali, water, anhydrous MgSO 4 After drying, the oil obtained by spinning off the solvent was recrystallized from isopropyl ether to obtain 16 g of the target compound of formula (1) in the form of white crystals, with a yield of 51.6%. The follo...

Embodiment 2

[0035] Compound 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridinecarboxamide (40g, 0.125mol) was dissolved in 150ml of C 2 h 4 Cl 2 Add dropwise to PCl at 30°C 5 (95%, 26g, 0.125mol) of C 2 h 4 Cl 2 (150ml) solution, stirred until the raw materials were completely reacted, and 20g of anhydrous FeCl 3 (0.125mol) was added to the solution and stirred for 6h. Then poured into ice water, heated to reflux for 1h, and cooled to room temperature. The aqueous layer was slowly neutralized to pH=12 with 40% NaOH solution, and the 2 h 4 Cl 2 Extraction; the organic layer was back-extracted with HCl solution and then neutralized to pH=12 with 40% NaOH solution. 2 h 4 Cl 2 extraction. The organic layer was washed with alkali, water, anhydrous MgSO 4 After drying, the oil obtained by spinning off the solvent was recrystallized from isopropyl ether to obtain 12 g of the target compound of formula (1) in the form of white crystals, with a yield of 38.7%. The followin...

Embodiment 3

[0039] Compound 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridinecarboxamide (40g, 0.125mol) was dissolved in 200ml of C 6 h 5 Cl, add dropwise to POCl at 0°C 3 (155g, 0.625mol) of C 6 h 5 Cl (200ml) solution, stirred until the raw materials reacted completely, and 170g anhydrous ZnCl 2 (1.25mol) was added to the solution and stirred for 6h. Then poured into ice water, heated to reflux for 1h, and cooled to room temperature. The aqueous layer was slowly neutralized to pH=12 with 40% NaOH solution, and the 6 h 5 Cl extraction; the organic layer was back-extracted with HCl solution and then neutralized to pH=12 with 40% NaOH solution. 6 h 5 Cl extraction. The organic layer was washed with alkali, water, anhydrous MgSO 4 After drying, the oil obtained by spinning off the solvent was recrystallized from isopropyl ether to obtain 14 g of the target compound of formula (1) in the form of white crystals, with a yield of 45.2%. The following data were obtained af...

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Abstract

The present invention relates to the new preparation process of 8-chloro-10, 11-dihydro-4-aza-5H-diphenyl[a, d]-5-cycloheptanone as the important intermediate of 2G non-calmative antihistamine loratadine. The preparation process includes successively the chemical reaction of the compound in expression (2) and phosphorus-containing reagent in solvent, the direct catalytic Friedel-Crafts reaction, and final hydrolysis to obtain target product in the same reactor. The synthesis process of the present invention has less reaction steps and simple operation, high product purity, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to an important intermediate of the second generation non-sedating antihistamine loratadine, namely 8-chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]-5- New preparation method of cycloheptanone. Background technique [0002] 8-Chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]-5-cycloheptanone is an important intermediate of the second-generation non-sedating antihistamine Loratadine, Its structural formula is as follows: [0003] [0004] U.S. Patent (US4731447) has reported the following synthetic method: [0005] [0006] The process is: hydrolyze 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridinecarboxamide under vigorous stirring in 40% sulfuric acid aqueous solution For 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid, the resulting compound and HCl gas generate hydrochloride, and SOCl 2 After generating the acid chloride, then with AlCl 3 The Friedel-Crafts reaction occurs to generate the target compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/06
Inventor 吴范宏辛水波
Owner 上海康鸣高科技有限公司
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