5-chlorobenzo[d]oxazole -Drug Synthesis Database

【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 合成路线2

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 .

参考文献中间体

合成目标

【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 .

参考文献中间体

合成目标

【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