- Rhodium-Catalyzed ortho-Cyanation of 2-Aryl-1,2,3-triazole: An Alternative Approach to Suvorexant
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A rhodium-catalyzed ortho-cyanation protocol for 2-aryl-1,2,3-triazole has been developed by using N-cyano-N-phenyl-p-toluensulfonamide (NCTS) as an environmentally friendly cyanide source. This simple cyanation reaction provides a new protocol for the diversification of benzonitriles in moderate to good yields and tolerates useful functional groups. In addition, the method was used to synthesize 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, which is the key intermediate of suvorexant.
- Zhang, Hailong,Jing, Li,Zheng, Yang,Sang, Rui,Zhao, Yi,Wang, Qiantao,Wu, Yong
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Read Online
- A facile electrochemical synthesis of suvorexant
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A facile, scalable electrochemical method to prepare Suvorexant has been developed. Two different electrochemical routes explored. The route with the high yield and less step taken forward.
- Ghoshal, Tanay,Patel, Tarun M.,Kotturi, Sharadsrikar
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- Preparation method and application of suvorexant intermediate
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The invention provides a preparation method and application of a suvorexant intermediate, and relates to the technical field of chemical synthesis. The preparation method of the suvorexant intermediate comprises the following step: (e) reacting a compound as shown in a formula IV under the action of a Grubbs catalyst to obtain a compound as shown in a formula V. The Grubbs catalyst (Grubbs second-generation catalyst) is creatively used for construction of the suvorexant intermediate seven-membered nitrogen-containing chiral heterocycle, an inflammable and highly toxic compound methyl vinyl ketone is not needed, inflammable and explosive toxic gas is not needed, reaction is not needed under the conditions of strong acid, strong alkali and high temperature, generation of a large amount of acid liquor and alkali liquor and high-temperature operation can be avoided, the method is mild in reaction condition, environment-friendly, high in safety coefficient and easy to industrialize.
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Paragraph 0183-0185
(2021/03/31)
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- Racemization method of suvorexant intermediate
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The invention relates to a racemization method of a suvorexant intermediate. Specifically, the invention provides a racemization method of an (S)-5-chloro-2-(5-methyl-[1,4]diazacyclohept-1-yl)-benzoxazole compound as shown in a formula I. The racemization method comprises the following steps: (1) carrying out a chlorination reaction on the compound as shown in the formula I and a chlorination reagent to form a compound as shown in a formula II; (2) under the action of an alkali, carrying out an elimination reaction on the compound shown in the formula II to form a compound shown in a formula III; and (3) under the action of a reducing agent, carrying out a reduction reaction on the compound shown in the formula III to generate the racemization compound shown in the formula IV. According tothe racemization method, (S)-5-chloro-2-(5-methyl-[1,4]diazacyclohept-1-yl)-benzoxazole can be racemized and chirally split to generate (R)-5-chloro-2-(5-methyl-[1,4]diazacyclohept-1-yl)-benzoxazole, which can be used for prepare suvorexant, and the reutilization of (S)-5-chloro-2-(5-methyl-[1,4]diazacyclohept-1-yl)-benzoxazole generated during the suvorexant production process can be realized.
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- SUVOREXANT INTERMEDIATE AND PREPARATION METHOD THEREOF
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The present invention relates to a synthesis process of suvorexant, novel compounds represented by formulas II, III, IV or V, or salts thereof for preparing suvorexant, and a method for preparing the intermediates. The preparation method uses a chiral starting material to synthesize chiral compounds represented by formulas II, III, IV or V, the compounds obtained being used for synthesizing the suvorexant. The preparation method has the advantages of simple operation, low cost, mild reaction conditions, simple post-treatment, easy to purify, high yield, high ee value for the product, and easy to industrialize. In the reaction route shown, R represents benzyl, allyl or 1-phenethyl, or optionally substituted benzyl at the 2 position to 6 position, such as 4-methoxybenzyl, 4-nitrobenzyl, 2-methylbenzyl, 4-chlorobenzyl or 3-fluorobenzyl.
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Paragraph 0087-0091
(2019/02/19)
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- Rhodium-Catalyzed Direct C-H Bond Cyanation in Ionic Liquids
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A Cp?Rh(III)/IL-based direct C-H bond cyanation system was developed for the first time. The system is a mild, efficient, and recyclable method for the synthesis of aryl nitriles. Many different directing groups can be used in this cyanation, and the reaction tolerates a variety of functional groups.
- Lv, Songyang,Li, Yaling,Yao, Tian,Yu, Xinling,Zhang, Chen,Hai, Li,Wu, Yong
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supporting information
p. 4994 - 4997
(2018/08/24)
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- Suvorexant preparation method
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The present invention relates to a suvorexant preparation method, which is performed according to the following route. The method of the present invention has characteristics of convenience, safety, high yield, high product purity and good economic effect, and is suitable for industrial production. The route is defined in the specification.
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Paragraph 0018; 0019; 0020; 0021; 0022; 0023; 0024-0045
(2017/08/30)
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- Method for preparing N-heterocyclic compound
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The invention provides a method for preparing an N-heterocyclic compound and belongs to the technical field of pharmacy. The method for preparing the N-heterocyclic compound comprises the steps of carrying out condensation reaction on an N-heterocyclic intermediate compound and 2-ethoxy-5-chlorobenzoxazole under an acid condition, and carrying out aftertreatment to prepare the compound (1). The method is simple and convenient, and can be applied to industrial production.
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- Preparation method of raw drug suvorexant
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The invention discloses a preparation method of raw drug suvorexant. The preparation method comprises the following step of generating S1 condensation acylation reaction by virtue of an intermediate I and an intermediate II in the presence of a condensing agent so as to generate an intermediate III, wherein the condensing agent is selected from one or combination of more than two of ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole and tri(2,6-dimethoxyphenyl)bismuth. By adopting the proper condensing agent or condensing agent combination in the S1 condensation acylation reaction in the preparation method, and the yield in the prior art can be achieved at a reaction temperature of about 25 DEG C, and the condensing agent and intermediate products are simply separated, so that the energy saving and the consumption reduction in the large-scale industrial production are promoted.
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Paragraph 0051; 0052; 0053; 0055-0058
(2017/11/16)
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- Method for preparing Suvorexantintermediate and analogue thereof
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The invention discloses a method for preparing a Suvorexantintermediate as shown in a formula 8A and an analogue thereof, or pharmaceutically acceptable salts and solvates thereof, wherein R is hydrogen or an alkyl group of C1 to C6. The method comprises the following steps of removing an amino protection group of a compound as shown in a formula 3 to obtain a compound as shown in a formula 4A; d, adopting the compound as shown in the formula 4A for preparing to obtain a compound as shown in a formula 5A; e, adopting the formula 5A for preparing to obtain a compound as shown in a formula 6A; f, reacting the compound as shown in the formula 6A and a compound as shown in a formula 10A for preparing to obtain a compound as shown in a formula 7A; g, adopting the compound as shown in the formula 7A for preparing to obtain the compound as shown in the formula 8A. According to the method provided by the invention, the compound 8 is synthesized through a brand new process route, and is then adopted as an intermediate for preparing Suvorexant, so that the problems of the usage of toxic substances, high cost, long route and low yield in an existing method for preparing the Suvorexant are effectively solved, and the method is suitable for industrial application.
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Paragraph 0303; 0304; 0305
(2017/07/22)
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- NOVEL ROUTES OF SYNTHESIS FOR THE PREPARATION OF SUVOREXANT
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The present invention relates to a process for the preparation of a compound of formula (A), Further, the present invention relates to the respective compound (A) as such and to its use in the preparation of antifungal agent.
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- Process for the preparation of an intermediate for an orexin receptor antagonist
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The present invention is directed to processes for preparing an intermediate for a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved.
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Page/Page column 14; 15; 16
(2017/02/02)
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- PROCESS FOR THE PREPARATION OF SUVOREXANT AND INTERMEDIATES USEFUL IN THE SYNTHESIS OF SUVOREXANT
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A novel processes for the preparation of suvorexant (formula I), its related compounds and its intermediates that are simple, economical and commercially viable. (I)
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- Preparation method of chiral high piperazine ring compound
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The present invention relates to a preparation method of a chiral high piperazine ring compound shown in (R)-I, and the method includes reduction of a compound shown in a formula Int to obtain the compound shown in the formula (R)-I. The invention also relates to a novel intermediate compound shown in the formula Int. The chiral high piperazine ring compound shown in (R)-I is an important intermediate in the synthesis of a medicament Suvorexant for the treatment of sleep disorders. The preparation method introduces a chiral center from the starting material, does not employ reagent or reaction affecting the chiral center in the whole reaction process, and avoids the chiral resolution or chiral catalyst method, which has high cost but low yield; no reaction of chiral participation exists in the process, so as to ensure the purity of the chiral product; and the method uses only the conventional methods and equipment, has the advantages of simple operation, mild condition, short route and high yield, and is applicable to industrialized production.
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Paragraph 0173; 0175
(2016/10/08)
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- Used for preparing suvorexant compound and method for preparing same
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The invention relates to three novel compound formulas I, II and III for preparing suvorexant, stereoisomers or salt thereof and a preparation method of the formulas I, II and III. The invention also relates to a method for preparing the suvorexant. The preparation method disclosed by the invention can be used for synthesizing to obtain the chiral compounds I, II and III through a chiral initiator and use the chiral compounds I, II and III for the synthesis of the suvorexant and has the advantages of easiness for operation, moderation in reaction condition, easiness for post processing, easiness for purification, high yield, high ee value and easiness for industrialization.
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Paragraph 0121-0124
(2016/10/17)
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- PROCESS FOR THE RESOLUTION OF (R,S)-DIAZEPANE AND DIAZEPANONE DERIVATIVES
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The present invention relates to a process for the preparation of an acid salt (T) of a compound of formula (A) (A) as well as to the acid salt (T) and the compound (A) as such,wherein R1 is selected from the group consisting of H, PG1 and RA, with RA being or and wherein PG1 is a suitable protecting group, and wherein n is 0 or 1, wherein the acid salt (T) is the salt of one stereoisomer of a chiral acid, preferably wherein the chiral acid salt is a tartaric acid derivative salt, preferably wherein the tartaric acid derivative salt is selected from the group consisting of 2,3-ditoluoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid salt, 2,3-dianisoyl tartaric acid salt, 2,3-dibenzoyl tartaric acid mono(dimethylamide) salt and a mixture of two or more thereof. Further the present invention relates to use of (T) and/or (A) for the preparation of suvorexant.
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- Facile synthesis of suvorexant, an orexin receptor antagonist, via a chiral diazepane intermediate
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A facile synthesis of suvorexant, an orexin receptor antagonist, is described. The key intermediate 6 was prepared from R-3-aminobutyric acid through protection, condensation, deprotection, cyclization, and hydrogenation steps. The title product was obtained with a total yield of 31% (>99% ee) after eight linear steps using commercially available raw materials.
- Chen, Yin,Zhou, Yan,Li, Jun-Hong,Sun, Jia-Quan,Zhang, Gui-Sen
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p. 103 - 107
(2015/01/30)
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- Laboratory and practical synthesis of Suvorexant, a selective dual orexin receptor antagonist
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The development of a laboratory and practical synthesis of Suvorexant 1, using intramolecular Mitsunobu cyclization reaction of intermediate 5 as the key reaction, has been reported. Compound 5 was obtained from known chiral ester 2 in three steps, and the key cyclization proceeded smoothly to provide the core seven-membered ring compound 6, which was transformed into 1 by an additional four-step sequence. The procedure described here needs no chiral-HPLC separation, no classical resolution, and no unique enzyme reactions, and offers an alternative practical synthesis of 1.
- Minehira, Daisuke,Takahara, Satoyuki,Adachi, Isao,Toyooka, Naoki
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p. 5778 - 5780
(2014/12/11)
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- PROCESS FOR THE PREPARATION OF AN OREXIN RECEPTOR ANTAGONIST
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The present invention is directed to processes for preparing a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is further directed to crystalline forms of this diazepane compound and pharmaceutical compositions thereof.
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- Enantioselective synthesis of a dual orexin receptor antagonist
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A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.
- Mangion, Ian K.,Sherry, Benjamin D.,Yin, Jingjun,Fleitz, Fred J.
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p. 3458 - 3461
(2012/08/08)
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- The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder
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A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane (R)-11. Finally, coupling of (R)-11 with acid 5 furnished the desired drug candidate 1.
- Baxter, Carl A.,Cleator, Ed,Brands, Karel M. J.,Edwards, John S.,Reamer, Robert A.,Sheen, Faye J.,Stewart, Gavin W.,Strotman, Neil A.,Wallace, Debra J.
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p. 367 - 375
(2012/05/19)
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- Discovery of the dual orexin receptor antagonist [(7 R)-4-(5-chloro-1,3- benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2 H -1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia
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Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
- Cox, Christopher D.,Breslin, Michael J.,Whitman, David B.,Schreier, John D.,McGaughey, Georgia B.,Bogusky, Michael J.,Roecker, Anthony J.,Mercer, Swati P.,Bednar, Rodney A.,Lemaire, Wei,Bruno, Joseph G.,Reiss, Duane R.,Harrell, C. Meacham,Murphy, Kathy L.,Garson, Susan L.,Doran, Scott M.,Prueksaritanont, Thomayant,Anderson, Wayne B.,Tang, Cuyue,Roller, Shane,Cabalu, Tamara D.,Cui, Donghui,Hartman, George D.,Young, Steven D.,Koblan, Ken S.,Winrow, Christopher J.,Renger, John J.,Coleman, Paul J.
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experimental part
p. 5320 - 5332
(2010/10/20)
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- Substituted diazepan orexin receptor antagonists
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The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
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Page/Page column 16-17
(2008/12/05)
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