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Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one

A synthesis method and azepine technology, applied in the field of organic synthesis, can solve the problems of difficult post-processing purification, unsuitable for scale-up production, and difficult to obtain raw materials, and achieve the effects of convenient product purification, low cost, and avoidance of isomeric by-products.

Active Publication Date: 2015-04-01
ASTATECH CHENGDU BIOPHARM CORP
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Problems solved by technology

[0007] The technical problem to be solved by the present invention is that the existing synthetic method has low yield, high cost, difficulty in post-processing and purification, difficult to obtain raw materials, and is not suitable for scale-up production

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  • Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one
  • Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one
  • Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one

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preparation example Construction

[0023] The synthesis method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one includes the following steps:

[0024] A. The reaction of o-chloroaniline or p-chloroaniline and succinic anhydride: dissolve o-chloroaniline or p-chloroaniline and succinic anhydride in an organic solvent, and then heating and refluxing for 4-8 hours. After the reaction, the organic solvent is removed and Add cold 1N hydrochloric acid to the residue and stir for 10-15 minutes; filter the solid to obtain 4-(2 or 4-chloroanilino)-4-oxobutanoic acid;

[0025] B. Intramolecular Friedel-Crafts reaction: dissolve the above 4-(2 or 4-chloroanilino)-4-oxobutyric acid in dichloroethane, and add anhydrous AlCl 3 , Then react at 55-70 degrees for 4-6 hours; then cool the above reaction solution to room temperature, control the temperature not to exceed 35 degrees, add 3N-6N hydrochloric acid; then separate the liquid to retain the organic phase, and then use dichloroethane for the water phase Extrac...

Embodiment 17

[0031] Example 17-Synthesis of chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one:

[0032] (1) Dissolve 127g of 4-chloroaniline and 100g of succinic anhydride in 600ml of dichloroethane, heat and reflux for 6 hours. After the reaction, the dichloroethane was evaporated under reduced pressure, and 300 mL of cold 1N hydrochloric acid was added to the residue, and stirred for 10 minutes; filtered to obtain 212 g of white solid 4-(4-chloroanilino)-4-oxobutanoic acid, The yield was 93.4%. H 1 NMR(300MHz,DMSO-d6):δ2.61(m,4H),7.39~7.45(d,J=7.2Hz,2H),7.55~7.48(d,J=7.2Hz,2H),10.05(br, 1H), 11.98 (br, 1H).

[0033] (2) 200g 4-(4-chloroanilino)-4-oxobutyric acid is dissolved in 1.2L dichloroethane, and 150g anhydrous AlCl is added 3 . The mixture was heated at 60 degrees to react for 4 hours. The reaction solution was cooled to room temperature, the temperature was controlled not to exceed 35 degrees, and 1L of 3N hydrochloric acid was added in batches under stirring. After separat...

Embodiment 29

[0035] Example 29-Synthesis of chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one

[0036] (1) Dissolve 64 g of 4-chloroaniline and 50 g of succinic anhydride in 300 mL of dichloroethane, and then heat and reflux for 6 hours. After the reaction, the dichloroethane was distilled off under reduced pressure, 150 mL of cold 1N hydrochloric acid was added to the residue, and stirred for 10 minutes; 108 g of white solid 4-(2-chloroanilino)-4-oxobutanoic acid was obtained by filtration. The yield was 93.7%. H 1 NMR (300MHz, DMSO-d6): δ 2.60 (m, 4H), 7.39-7.59 (m, 4H), 10.04 (br, 1H), 12.35 (br, 1H).

[0037] (2) 100g 4-(2-chloroanilino)-4-oxobutyric acid is dissolved in 600mL dichloroethane, and 75g anhydrous AlCl is added 3 . The mixture was heated and reacted at 60 degrees for 4 hours. The reaction solution was cooled to room temperature, the temperature was controlled not to exceed 35 degrees, and 500 mL of 3N hydrochloric acid was added in batches with stirring. Liquid separa...

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Abstract

The invention belongs to the organic synthesis field and specifically relates to a synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one. The synthetic method is used for solving the technical problems that the existing synthetic method is low in yield, high in cost, difficult in aftertreatment purification, difficult in raw material getting and not applicable to enlarged production. The technical scheme for solving the technical problem is to provide the synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one, and the synthetic method comprises the steps of reacting o- or para-chloroaniline with succinic anhydride, carrying out intramolecular Friedel-Craft ring closing reaction of the reaction product, and then carrying out Huangminglong reduction reaction to obtain the 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one. The invention provides a new method which is short in steps, high in total yield and free of use of expensive noble metal catalyst.

Description

Technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one. Background technique [0002] According to literature reports, azepine-2-one as the core fragment of sodium ion channel blocker drugs has been widely used in new drug development. In particular, 7 or 9 chloro-dihydrobenzo[b]azepine-2-one can be used as a functional group that continues to participate in the reaction to achieve various modifications of drug molecules, and it is widely used in new drug development. However, the current synthesis methods of such compounds are mostly achieved by the rearrangement of naphthone and azido or hydroxylamine into oxime. The use of azido is extremely explosive, and the rearrangement method often produces isomers. The separation is difficult and the cost is high. Another method is to construct the ortho-allyl aromatic acrylamide structure first, and...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/16
CPCC07D223/16
Inventor 魏庚辉李仟宁兆伦郭鹏谢国斌
Owner ASTATECH CHENGDU BIOPHARM CORP
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