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【结 构 式】

【分子编号】67943

【品名】5-chlorobenzo[d]oxazole

【CA登记号】17200-29-2

【 分 子 式 】C7H4ClNO

【 分 子 量 】153.5676

【元素组成】C 54.75% H 2.63% Cl 23.09% N 9.12% O 10.42%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XVII)

Enantioselective synthesis of suvorexant is based on enzymatic transamination and described as follows. Cyclization of 2-amino-4-chlorophenol (XVI) with trimethyl orthoformate HC(OMe)3 in the presence of p-TsOH in THF provides 5-chlorobenzoxazole (XVII), which subsequently reacts with LiHMDS in THF followed by bromination of the resulting anion with NBS to afford 2-bromo-5-chlorobenzoxazole (XVIII). Condensation of crude bromo derivative (XVIII) with ethanolamine (XIX) in acetonitrile gives 2-(5-chloro-2-benzoxazolylamino)ethanol (XX), which is subjected to aza-Michael addition with methyl vinyl ketone (II) in the presence of NaOH in DMF to yield the β-amino ketone (XXI). Activation of crude alcohol (XXI) with MsCl in the presence of Et3N in i-PrOAc provides keto mesylate (XXII), which by transamination and cyclization with i-PrNH2 in the presence of CDX-017 enzyme and pyridoxal phosphate in DMSO, and subsequent acidification with HCl, provides the (R)-azepane derivative (XXIII). Finally, Schotten-Baumann acylation of amine (XXIII) with 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride (XXIV) in the presence of K2CO3 in i-PrOAc/H2O affords suvorexant. Chloride (XXIV) was prepared from 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) by treatment with (COCl)2 in the presence of DMF in i-PrOAc .

1 Mangion, I.K., Sherry, B.D., Yin, J., Fleitz, F.J. Enantioselective synthesis of a dual orexin receptor antagonist. Org Lett 2012, 14(13): 3458-61.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 30324 3-buten-2-one; methyl vinyl ketone 78-94-4 C4H6O 详情 详情
(IX) 67936 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid   C10H9N3O2 详情 详情
(XVI) 67942 2-amino-4-chlorophenol 95-85-2 C6H6ClNO 详情 详情
(XVII) 67943 5-chlorobenzo[d]oxazole 17200-29-2 C7H4ClNO 详情 详情
(XVIII) 67944 2-bromo-5-chlorobenzo[d]oxazole   C7H3BrClNO 详情 详情
(XIX) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol;2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(XX) 67945 2-(5-chloro-2-benzoxazolylamino)ethanol   C9H9ClN2O2 详情 详情
(XXI) 67946 4-((5-chlorobenzo[d]oxazol-2-yl)(2-hydroxyethyl)amino)butan-2-one   C13H15ClN2O3 详情 详情
(XXII) 67947 2-((5-chlorobenzo[d]oxazol-2-yl)(3-oxobutyl)amino)ethyl methanesulfonate   C14H17ClN2O5S 详情 详情
(XXIII) 67948 (R)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole hydrochloride   C13H16ClN3O.HCl 详情 详情
(XXIV) 67949 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride   C10H8ClN3O 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XVII)

Preparation of racemic suvorexant was used as a proof of the direct amination of benzoxazoles using 2,2,6,6-tetramethylpiperidine-Noxoammonium tetrafluoroborate as organic oxidant. In this case, chlorobenzoxazole (XVII) was aminated by racemic diazepane rac-(XIII) using Sc(OTf)3 and TEMPOBF4 to provide racemic suvorexant in 84% yield .

1 Wertz, S., Kodama, S., Studer, A. Amination of benzoxazoles and 1,3,4-oxadiazoles using 2,2,6,6-tetramethylpiperidine-N-oxoammonium tetrafluoroborate as an organic oxidant. Angew Chem Int Ed 2011, 50(48): 11511-5.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(XIII) 67955 (7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone   C16H21N5O 详情 详情
(XVII) 67943 5-chlorobenzo[d]oxazole 17200-29-2 C7H4ClNO 详情 详情
(XXXII) 67956 (4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone   C23H23ClN6O2 详情 详情
Extended Information