US 8273735

US Patent 8,273,735: Process for Preparing Benzazepine Compounds

Title: Process for preparing benzazepine compounds or salts thereof

Current Assignee: Otsuka Pharmaceutical Co Ltd

Inventors: Yasuhiro Torisawa, Kaoru Abe, Yasuaki Muguruma, Shigekazu Fujita, Hidenori Ogawa, Naoto Utsumi, Masahiro Miyake

Filing Date: September 1, 2006

Issue Date: September 25, 2012

Abstract:
The patent describes a process for preparing benzazepine compounds or their salts, particularly 2,3,4,5-tetrahydro-1H-1-benzazepine compounds or their salts. The invention also covers intermediate compounds. The primary goal is to provide an improved industrial process for producing these compounds in high yield and purity, which are useful as intermediates for pharmaceutically active benzazepine compounds with vasopressin antagonistic activity, such as tolvaptan.

Plain-Language Overview of Independent Claims:

Independent Claim 1:
This claim describes a process for creating a benzazepine compound of a specific Formula (1) or a salt of that compound. The process involves reacting a compound of Formula (2) (a specific benzazepine compound) or its salt, with an amide compound of Formula (3) or its salt. This reaction must occur in the presence of a carbonylating agent. In Formula (1), (2), and (3), R1 and R2 are independently a "lower alkyl group" (a straight or branched chain alkyl with 1 to 6 carbon atoms, such as methyl, ethyl, propyl), and X1 and X2 are halogen atoms (fluorine, chlorine, bromine, or iodine).

Independent Claim 7:
This claim details a process for making a benzoic acid compound of Formula (4) or its salt. R1 and R2 are defined as in Claim 1 (lower alkyl groups). The process involves reacting an amide compound of Formula (11) or its salt with an oxalyl halide compound of Formula (19), where X6 and X7 are independently halogen atoms. This is one of four disclosed methods for preparing benzoic acid compounds (4), which are useful intermediates for the pharmaceutically active benzazepine compound.

Independent Claim 8:
This claim outlines a process for producing a benzoic acid compound of Formula (4) or its salt, where R1 and R2 are defined as lower alkyl groups. This process specifically involves oxidizing an amide compound of Formula (12) or its salt, where X3 is a halogen atom.

Independent Claim 9:
This claim describes a process for preparing a benzoic acid compound of Formula (4) or its salt, with R1 and R2 being lower alkyl groups. This method involves hydrolyzing an amide compound of Formula (13) or its salt, where X3 is a halogen atom.

Independent Claim 10:
This claim focuses on a process for synthesizing a benzoic acid compound of Formula (4) or its salt, where R1 and R2 represent lower alkyl groups. The process requires oxidizing an amide compound of Formula (14) or its salt.

Independent Claim 11:
This claim sets forth a process for preparing a 2,3,4,5-tetrahydro-1H-1-benzazepine compound of Formula (10) or a salt thereof. R1, R2, and X1 are defined as in Claim 1. The process involves reducing a benzazepine compound of Formula (1) or its salt in the presence of a hydrogenating agent. Crucially, the hydrogenating agent is used in an amount of 0.1 to 1 mole per 1 mole of the compound (1). The patent highlights that this specific molar ratio helps in achieving high yield and purity by minimizing undesirable dehalogenating reactions. The hydrogenating agent can be lithium aluminum hydride, sodium borohydride, zinc borohydride, or diborane.

Litigation:
US Patent 8,273,735 is currently active and is involved in multiple litigations. Several cases have been filed in the Delaware District Court, including Otsuka Pharm. Co., Ltd. v. Zenara Pharma Private Ltd., 26-0181 (D. Del.), filed February 19, 2026, concerning Jynarque® (tolvaptan tablets). Additionally, there is a US case filed in the Court of Appeals for the Federal Circuit (CAFC), No. 24-2297. In Otsuka Pharmaceutical Co. v. Lupin Ltd., No. 24-2297 (Fed. Cir. May 21, 2026), a Federal Circuit panel affirmed a judgment that Lupin's tolvaptan ANDA process does not infringe Otsuka's U.S. Patent Nos. 8,273,735 and 8,501,730. The court also found the asserted method claims invalid as obvious over Kondo's 1999 paper. The patent claims teach reducing the amount of sodium borohydride hydrogenating agent to 0.25–1 molar equivalents per mole of benzazepine precursor to reduce impurities. Lupin's process was found not to infringe as it uses at least 1.2 molar equivalents. The patent is set to expire on August 14, 2028.