5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole

Base Information

• Chemical Name: 5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole
• CAS No.: 1030377-33-3
• Molecular Formula: C23H23ClN6O2
• Molecular Weight: 450.928
• Mol file: 1030377-33-3.mol

Synonyms:MK-4305

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Chemical Property of 5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole

Chemical Property:

• Melting Point: 153℃
• Boiling Point: 669.803 °C at 760 mmHg
• PKA: 1.47±0.40(Predicted)
• Flash Point: 358.884 °C
• PSA: 80.29000
• Density: 1.419 g/cm³
• LogP: 4.11420
• Storage Temp.: Room Temperature
• Solubility.: Acetonitrile (Slightly), Chloroform (Slightly), DMSO (Slightly, Heated), Methano

Purity/Quality:

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• General Description: 5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole (MK-4305) is a potent dual orexin receptor antagonist developed for the treatment of insomnia. It was optimized from earlier compounds to improve pharmacokinetics and reduce reactive metabolite formation, ultimately demonstrating good potency, brain penetration, and in vivo efficacy. MK-4305 advanced to phase III clinical trials as a promising therapeutic for primary insomnia.

Technology Process of 5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole

There total 73 articles about 5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 95.0%

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (956317-36-5) + 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole (1266975-27-2) + C13H16ClN3O*C18H14O8 (1276666-14-8) → Suvorexant (1030377-33-3)

Guidance literature:

C₁₃H₁₆ClN₃O*C₁₈H₁₄O₈; With sodium hydroxide; In dichloromethane; water; at 20 ℃; for 1h;

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid; With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 10 ℃; for 1h;

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole; With triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 15 ℃; for 1h; optical yield given as %ee;

DOI:10.1021/op1002853

Reference yield: 92.0%

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole (1266975-27-2) + 5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid → Suvorexant (1030377-33-3)

Guidance literature:

5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid; With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 10 ℃; for 1h;

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole; With triethylamine; In dichloromethane; at -10 - -5 ℃; for 1h;

Reference yield: 91.0%

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (956317-36-5) + 5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride (1266664-66-7) → Suvorexant (1030377-33-3)

Guidance literature:

With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20 ℃; for 3h;

DOI:10.1016/j.tetlet.2021.153014

upstream raw materials:

2,5-dichloro-1,3-benzoxazole

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

Refernces

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

10.1021/jm100541c

The research focuses on the development of a dual orexin receptor antagonist for treating insomnia. The study began with compound 4, a diazepane-based orexin receptor antagonist, which had excellent brain penetration and potency but suffered from high clearance and low bioavailability. Efforts to improve its pharmacokinetics led to the identification of compound 10 with a 7-methyl substitution on the diazepane core, which displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy. However, compound 10 formed reactive metabolites in microsomal incubations. A mechanistic hypothesis and an in vitro assay to assess bioactivation led to the 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. Chemicals such as 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid, 2,5-dichloro-1,3-benzoxazole, and various diazepane cores played crucial roles in the synthesis and optimization of these compounds.