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【结 构 式】

【分子编号】67937

【品名】2H-1,2,3-triazole

【CA登记号】 

【 分 子 式 】C2H3N3

【 分 子 量 】69.06604

【元素组成】C 34.78% H 4.38% N 60.84%

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:(XI)

The synthesis of suvorexant by the medicinal route starts with conjugate addition of monoprotected diamine (I) to methyl vinyl ketone (II) in Et2O, followed by in situ trapping with benzyl chloroformate in the presence of Et3N to yield the fully protected diaminoketone (III), from which the Boc-protecting group is cleaved by means of HCl in EtOAc to provide primary amine (IV). Intramolecular reductive cyclization of amino ketone (IV) in the presence of NaBH(OAc)3 and AcOH in CH2Cl2 affords benzyl 5-methyl-1,4-diazepane-1-carboxylate (V), which is then N-protected with di-tert-butyl dicarbonate in the presence of Et3N in CH2Cl2 to give the diprotected diazepine derivative (VI). Resolution of racemic diazepine (VI) by means of chiral HPLC provides the desired (R)-enantiomer (VII), which is then N-deprotected with HCl in EtOAc to afford benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate (VIII). Coupling of cyclic amine (VIII) or its hydrochloride with 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) [prepared by condensation of 2-iodo-5-methylbenzoic acid (X) with 1,2,3-triazole (XI) in the presence of Cs2CO3, CuI and t-DAMCH in DMF at 120 °C] using EDC, HOAt and NMM in DMF produces the corresponding amide (XII). N-Deprotection of N-Cbz-amine (XII) by means of H2 over Pd(OH)2/C in EtOAc/MeOH or EtOAc generates the 7(R)-methyldiazepane derivative (XIII), which is finally condensed with 2,5-dichloro-1,3-benzoxazole (XIV) [prepared by the chlorination of 5-chloro-2-mercaptobenzoxazole (XV) with POCl3 and PCl5 in CH2Cl2] in the presence of Et3N in DMF at 75 °C .

1 Bergman, J.M., Breslin, M.J., Coleman, P.J., Cox, C.D., Mercer, S.P.,Roecker, A.J. (Merck & Co., Inc.) Substituted diazepan compounds as orexin receptor antagonists. CN 101880276, EP 2089382, EP 2392572, JP 201051121, JP 2011068665, JP 2011079848, US 2008132490, US 7951797, US 2011195957, WO 2008069997.
2 Cox, C.D., Breslin, M.J., Whitman, D.B. et al. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010, 53(14): 5320-32.
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
(III) 67930 benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(3-oxobutyl)carbamate   C19H28N2O5 详情 详情
(IV) 67931 benzyl (2-aminoethyl)(3-oxobutyl)carbamate   C14H20N2O3 详情 详情
(V) 67932 benzyl 5-methyl-1,4-diazepane-1-carboxylate   C14H20N2O2 详情 详情
(VI) 67933 1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate   C19H28N2O4 详情 详情
(VII) 67934 (R)-1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate   C19H28N2O4 详情 详情
(VIII) 67935 benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate   C14H20N2O2 详情 详情
(IX) 67936 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid   C10H9N3O2 详情 详情
(X) 34151 2-iodo-5-methylbenzoic acid 52548-14-8 C8H7IO2 详情 详情
(XI) 67937 2H-1,2,3-triazole   C2H3N3 详情 详情
(XII) 67938 (R)-benzyl 5-methyl-4-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepane-1-carboxylate   C24H27N5O3 详情 详情
(XIII) 67939 (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone   C16H21N5O 详情 详情
(XIV) 67940 2,5-dichloro-1,3-benzoxazole;2,5-Dichlorobenzoxazole 3621-81-6 C7H3Cl2NO 详情 详情
(XV) 67941 5-chloro-2-mercaptobenzoxazole 22876-19-3 C7H4ClNOS 详情 详情
Extended Information