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'via Blog this'

Here’s an improved synthesis of benzazepines

Benzazepines are heterocyclic chemical compounds consisting of a benzene ring fused to an azepinering. Examples include benazepril, fenoldopam, lorcaserin and varenicline

Benzazepines at the US National Library of Medicine Medical Subject Headings (MeSH)

Fenoldopam

Lorcaserin

Benzazepines such as compound 3are intermediates for synthesizing drugs used to treat heart and kidney disorders. Y. Torisawa and co-inventors state that existing methods for preparing the intermediates are inefficient for industrial production because of low yields and purity.

The route they used for preparing 3 is the reaction of chlorotetrahydrobenzazepine 1with bromoaniline derivative 2 in the presence of CO and a Pd–Ph3P catalyst (Figure 1); DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene. The product is isolated, purified by column chromatography, and recovered in 85% yield and 99.1% purity. The patent contains 1H and 13C NMR, IR, and mass spectroscopy data.

The reaction gives small quantities (≈0.01–0.03 wt%) of four byproducts that are formed by the reaction of 3 with 1. These compounds are easily separated from 3, and their 1H NMR data are reported.

The inventors also describe the synthesis of 2 and several structurally related compounds by routes outlined in Figure 2. The preparation of 2 begins with the condensation of toluidine 4 and benzoyl chloride 5 in the presence of NaOH to form amide 6, isolated in 96.6% yield. In the second step, 6 is brominated in HOAc, and 2 is isolated in 97% yield. Although the purities of 2 and 6 are not reported, both have sharp melting points; 1H NMR data are provided.

Compound 6 can also be used to prepare acid 7 by treating it with (COCl)2 in the presence of AlCl3, and then hydrolyzing the product. The crude acid is isolated, treated with aq NaOH, and recovered in 65.8% yield and 99.4% purity after recrystallization from MeOH.

The reaction of 6 and AcCl in the presence of AlCl3 gives compound 8, isolated in 66.8% yield. The purity is not reported, but the compound has a sharp melting point, and 1H NMR data are given. Oxidizing 8 with NaOCl forms 7, which is isolated in 77.2% yield and 99.8% purity after recrystallization from MeOH.

A key feature of the processes described in this patent is the commercial availability of starting materials 1 and 2. The inventors claim that the processes give the desired compounds in higher yields and purities than existing methods. (Otsuka Pharmaceutical [Tokyo]. US Patent 8,273,735, )

Process for preparing benzazepine compounds or salts thereof

www.google.co.in/patents/US8273735

Grant - ‎Filed 1 Sep 2006 - ‎Issued 25 Sep 2012 - ‎Yasuhiro Torisawa - ‎Otsuka Pharmaceutical Co., Ltd.

This invention provides a process for preparing benzazepine compounds of the formula (1): wherein X1 is a halogen atom, R1 and ...

Paper | Regular issue | Vol 53, No. 9, 2000, pp.2009-2018
Published online: 

DOI: 10.3987/COM-00-8982

■ A Synthesis of 2,3,4,5-Tetrahydro-1H-3-benzazepines via Pummerer-Type Cyclization of N-(2-Arylethyl)-N-(2-phenylsulfinylethyl)formamides

Jun Toda, Tsuyoshi Ichikawa, Toshiaki Saitoh, Yoshie Horiguchi, and Takehiro Sano*

*Showa Pharmaceutical University, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

A construction of 2,3,4,5-tetrahydro-1H-3-benzazepine ring system (7) was achieved via Pummerer-type cyclization of N-(2-arylethyl)-N-2- (phenylsulfinylethyl)formamides (6). This route produced the benzazepines (10) and (11) in six steps starting from readily available 2-arylethylamines (2) and 2-chloroethyl phenyl sulfide. 

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