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【结 构 式】

【分子编号】67951

【品名】tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)(3-oxobutyl)amino)ethyl)carbamate

【CA登记号】 

【 分 子 式 】C18H24ClN3O4

【 分 子 量 】381.859

【元素组成】C 56.62% H 6.33% Cl 9.28% N 11.00% O 16.76%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXVI)

Process route to suvorexant starts with treatment of dichlorobenzoxazole (XIV) with N-Boc-ethylenediamine (I) in the presence of Et3N to provide 82% yield of 2-aminobenzoxazole (XXV), which by reaction with methyl vinyl ketone (II) in the presence of DBU in acetonitrile provides intermediate (XXVI) in a high yield. Clean deprotection of (XXVI) is achieved with methanesulfonic acid in THF to give 94% of aminoketone in the form of salt (XXVII). Reductive cyclization of this salt by means of Na(OAc)3BH in the presence of NaOAc in CH2Cl2 provides 98% yield of racemic diazepane (XXVIII). An extensive screening of classical resolution methods for racemate (XXVIII) led to optimal conditions based on resolution with dibenzoyl-L-tartaric acid in THF/CH2Cl2, giving 39% yield (74% ee). Recrystallization of this salt in a 4:1 mixture of i-PrAc/MeOH then provided a 70% yield (96% ee). Treatment of the tartrate salt with NaOH provided the free base (XXIX), which is finally condensed with acid chloride (XXIV) in the presence of Et3N, giving a 95% yield of suvorexant .

1 Baxter, C.A., Cleator, E., Brands, K.M.J. et al. The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder. Org Proc Res Dev 2011, 15(2): 367-75.
2 Wallace, D.J. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. 244th ACS Natl Meet Exp (Aug 19-23, Philadelphia) 2012, Abst ORGN-271.
3 Baxter, C.A. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. Balticum Organicum Syntheticum Intl Conf Org Synth (July 1-4, Tallinn) 2012, p 16.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13241 N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate;tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate 57260-73-8 C7H16N2O2 详情 详情
(II) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(XIV) 67940 2,5-dichloro-1,3-benzoxazole;2,5-Dichlorobenzoxazole 3621-81-6 C7H3Cl2NO 详情 详情
(XXIV) 67949 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride   C10H8ClN3O 详情 详情
(XXV) 67950 tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)amino)ethyl)carbamate   C14H18ClN3O3 详情 详情
(XXVI) 67951 tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)(3-oxobutyl)amino)ethyl)carbamate   C18H24ClN3O4 详情 详情
(XXVII) 67952 4-((2-aminoethyl)(5-chlorobenzo[d]oxazol-2-yl)amino)butan-2-one dimethanesulfonate   C13H16ClN3O3.2CH4O3S 详情 详情
(XXVIII) 67953 5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole   C13H16ClN3O 详情 详情
(XXIX) 67954 (R)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole   C13H16ClN3O 详情 详情
Extended Information