- Efficient and promising asymmetric preparation of enantiopure tolvaptan via transfer hydrogenation with robust catalysts
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Enantiopure tolvaptan, the first and only oral vasopressin antagonist for hyponatremia has been prepared by using an asymmetric transfer hydrogenation as a key step with HCOOH-Et3N or HCOONa-H2O as the hydrogen donor in open air. Good chemical yields with up to 99% enantioselectivity were obtained with a 1000:1 of S/C in an HCOONa-H2O system. The air and water stable catalysts provide a very promising prospect for industrial application.
- Yin, Lu,Zheng, Yourou,Jia, Xian,Li, Xingshu,Chan, Albert S.C.
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- Aminocarbonylation route to tolvaptan
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Pd-catalyzed aminocarbonylation between aryl bromide and NH-benzazepinone was effectively carried out to furnish the key intermediate for tolvaptan (up to 85%) in one step.
- Torisawa, Yasuhiro,Furuta, Takuya,Nishi, Takao,Aki, Shinji,Minamikawa, Jun-ichi
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Read Online
- INTERMEDIATES AND METHODS FOR THE PREPARATION OF TOLVAPTAN AND ITS DERIVATIVES
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The present invention relates to new intermediates for the synthesis of tolvaptan and its derivatives, as well as a method for its preparation involving said intermediates.
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- Novel benzoazepine compound, composition and applications of novel benzoazepine compound and composition
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The invention relates to a novel benzoazepine compound, which comprises a pharmaceutically acceptable salt thereof. The invention also provides a pharmaceutical composition containing the compound and the pharmaceutically acceptable salt thereof. The pres
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Paragraph 0135-0141
(2021/05/29)
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- Preparation method of high-purity tolvaptan
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The invention provides a preparation method of high-purity tolvaptan. Specifically, the quality of an intermediate N-(4-(7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-benzo[b]aza-1-ylcarbonyl)-3-methylphenyl)-2-methylbenzamide is controlled through crystallization and purification, so that the high-purity intermediate is obtained, and the high-purity tolvaptan is obtained by controlling the process conditions of reducing the intermediate to obtain the tolvaptan and subsequently purifying the tolvaptan. The method is low in cost, simple in preparation process and mild in reaction condition, the purity of the prepared tolvaptan reaches 99.9% or above, the yield reaches 80% or above, and industrial production is facilitated.
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- IMPROVED METHODS OF PRODUCING SYNTHETIC INTERMEDIATES OF TOLVAPTAN
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PROBLEM TO BE SOLVED: To provide improved methods of producing 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. SOLUTION: The present invention provides methods of producing 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which are synthetic intermediates of tolvaptan, by condensing an amino group and a carboxyl group in the presence of magnesium hydroxide. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0029; 0030
(2018/04/07)
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- Method for preparing high-purity tolvaptan intermediate
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The invention provides a method for preparing a high-purity tolvaptan intermediate, and concretely provides a method for purifying a tolvaptan intermediate N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepine-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide (formula II). A crude product containing the compound of formula II is recrystallized by an organic solvent composed of ester, haloalkaneand ether to preferably obtain the compound of formula II, having a purity of above 99.00%.
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Paragraph 0044; 0045; 0054; 0055; 0056
(2018/10/02)
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- Preparation method of tolvaptan
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The invention discloses a preparation method of tolvaptan. According to the preparation method, 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one and 4-nitro-2-methyl bromobenzene are taken as the primary raw materials; high purity tolvaptan is obtained after steps of carbonyl inserting reactions, reduction reactions, and acylation reactions, and the yield is high. The preparation method has the advantages that no bromine or tin dichloride is used; the preparation method does not generate a large amount of industrial waste water, and the environment is protected. At the same time, the generation of impurities namely a compound V and a compound VIII is avoided, and the purification becomes easier. No explosive, flammable, and toxic solvent such as chloroform, ether, and the like, is used, the requirements on the protection of workers are lowered, and the safe production is guaranteed. Moreover, the route design is novel, the raw materials are easily available, the operation of the technology is simple and feasible, and a simple and feasible method is provided for the massive industrial production of tolvaptan.
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Paragraph 0017; 0018
(2017/07/22)
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- Preparation method of high-efficiency low-toxicity pitressin antagonist
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The invention provides a preparation method of a high-efficiency low-toxicity pitressin antagonist. Specifically, the invention provides a compound having the formula A shown in the description, and a method for preparing tolvaptan through the compound having the formula A. All groups in the formula are defined in the description. The method has advantages of environmental protection, available raw materials, and high overall yield, and is suitable for industrial preparation of tolvaptan.
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- Preparation method for cardiovascular disease treatment drug
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The invention provides a preparation method for a cardiovascular disease treatment drug. Specifically, the invention provides a compound represented by a formula (IV) shown in the description and a method for preparing Tolvaptan from the compound represented by the formula (IV). The method provided by the invention has the advantages of being environment-friendly, being easy in raw material obtaining and high in total yield, and the like, thereby being applicable to the industrialized preparation of Tolvaptan.
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Paragraph 0170; 0224; 0225
(2016/10/08)
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- Characterization of the stress degradation products of tolvaptan by UPLC-Q-TOF-MS/MS
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Tolvaptan (TVT) is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia. TVT was subjected to forced degradation under hydrolysis, oxidation, dry heat and photolysis conditions, in accordance with the ICH guideline Q1A (R2). The degradation products (DPs) formed have been characterized through UPLC-PDA and UPLC-Q-TOF-MS/MS studies. The chromatographic separation was achieved on an Acquity UPLC HSS T3 column (100 × 2.1 mm, 1.7 μm) with a mobile phase containing a gradient mixture of solvents A (0.1% formic acid) and B (acetonitrile) at a flow rate of 0.3 ml min-1 at 30 °C. The detection wavelength was set at 266 nm. The drug degraded under acid hydrolysis, base hydrolysis and oxidative conditions to form a total of 7 DPs. When methanol was used as the co-solvent during stress degradation, four additional DPs were formed which were absent when acetonitrile was used as the co-solvent. Comparison of the fragmentation pattern of the DPs with that of the drug helped in the elucidation of the structures of all the degradation products. The degradation pathway of the drug was established, which was duly justified by the mechanistic explanation. The developed UPLC method was validated as per ICH guidelines.
- Patel, Prinesh N.,Rajesh Kumar,Gananadhamu,Srinivas
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p. 21142 - 21152
(2015/03/30)
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- PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES
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The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
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Paragraph 0064; 0065
(2013/07/31)
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- BENZAZEPINE COMPOUND
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An object of the present invention is to provide a novel benzazepine compound or a salt thereof, which has excellent vasopressin antagonistic activity. The benzazepine compound or a salt thereof of the present invention is represented by Formula (1): wher
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Page/Page column 7
(2012/09/21)
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- PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES
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The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
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Page/Page column 9
(2012/04/23)
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- PROCESS FOR PREPARING BENZAZEPINE COMPOUNDS OR SALTS THEREOF
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This invention provides a process for preparing benzazepine compounds of the formula (1): wherein X1is a halogen atom, R1and R2are a lower alkyl group, or salts thereof as well as intermediate benzoic acid compounds in high yield and high purity on industrial scale, which are useful as an intermediate for preparing a pharmaceutically active 2,3,4,5-tetrahydro-1H-1-benzazepine compound having vasopressin antagonistic activity.
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Page/Page column 32-33
(2008/06/13)
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- 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist
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We previously reported a series of benzazepine derivatives as orally active nonpeptide arginine vasopressin (AVP) V2 receptor antagonists. After the lead structure OPC-31260 was structurally evaluated and optimized, the introduction of the 7-Cl moiety on the benzazepine and 2-CH3 on the aminobenzoyl moiety enhanced its oral activity. The new AVP-V2 selective antagonist OPC-41061 was determined to be a potent and orally active agent. Copyright (C) 1999 Elsevier Science Ltd.
- Kondo, Kazumi,Ogawa, Hidenori,Yamashita, Hiroshi,Miyamoto, Hisashi,Tanaka, Michinori,Nakaya, Kenji,Kitano, Kazuyoshi,Yamamura, Yoshitaka,Nakamura, Shigeki,Onogawa, Toshiyuki,Mori, Toyoki,Tominaga, Michiaki
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p. 1743 - 1754
(2007/10/03)
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