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【结 构 式】

【分子编号】22464

【品名】4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenol

【CA登记号】

【 分 子 式 】C8H5F3N4O

【 分 子 量 】230.1492696

【元素组成】C 41.75% H 2.19% F 24.76% N 24.34% O 6.95%

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:(V)

The acylation of 4-benzyloxyaniline (I) with trifluoroacetyl chloride and triethylamine in dichloromethane gives the corresponding amide (II), which is treated with resin-supported triphenylphosphine and CCl4 to yield the iminochloride (III). The cyclization of (III) with sodium azide in hot acetic acid affords the tetrazole (IV), which is debenzylated with H2 over Pd/C in ethanol/THF, giving the phenol (V). The reaction of (V) with hexamethylenetetramine (HMT) in hot trifluoroacetic acid yields the benzaldehyde (VI), which by methylation with methyl iodide/K2CO3 in acetone affords 2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (VII). Finally, this compound is reductocondensed with (2S,3S)-2-phenylpiperidin-3-amine (VIII) by means of sodium triacetoxyborohydride/acetic acid in dichloromethane. The chiral (2S,3S)-2-phenylpiperidin-3-amine (VIII) has been obtained as follows: The condensation of 2-chloro-3-nitropyridine (IX) with phenylboronic acid (X) by means of palladium tetrakis(triphenylphosphine) and Na2CO3 in dimethoxyethane gives 3-nitro-2-phenylpyridine (XI), which is hydrogenated with H2 over Pd/C in ethanol/HCl, yielding (?-cis-2-phenylpiperidin-3-amine (XII). Finally, this compound is submitted to optical resolution by means of di-p-toluoyl-L-tartaric acid in ethanol/water.

1 Congreve, M.; Chung, K.M.L.; Armour, D.R.; et al.; Tetrazole NK1 receptor antagonists: The identifica. Bioorg Med Chem Lett 1996, 6, 9, 1015.
2 Silvestre, J.S.; Castañer, J.; Sorbera, L.A.; GR-205171. Drugs Fut 1999, 24, 3, 254.
3 Armour, D.R.; Evans, B.; Giblin, G.M.P.; Hann, M.M.; Hubbard, T.; Lewell, X.; Middlemiss, D.; Naylor, A.; Pegg, N.A.; Vinader, M.V.; Watson, S.P. (Glaxo Wellcome plc); 3-(5-Tetrazolyl-benzyl)amino-piperidine derivs. an. EP 0720609; JP 1999106341; US 5703240; US 5843966; WO 9508549 .
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) 22460 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine C13H13NO 详情 详情
(II) 22461 N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroacetamide C15H12F3NO2 详情 详情
(III) 22462 N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroethanimidoyl chloride C15H11ClF3NO 详情 详情
(IV) 22463 1-[4-(benzyloxy)phenyl]-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; benzyl 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl ether C15H11F3N4O 详情 详情
(V) 22464 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenol C8H5F3N4O 详情 详情
(VI) 22465 2-hydroxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde C9H5F3N4O2 详情 详情
(VII) 22466 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde C10H7F3N4O2 详情 详情
(VIII) 22467 (2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine C11H16N2 详情 详情
(IX) 10321 2-Chloro-3-nitropyridine 5470-18-8 C5H3ClN2O2 详情 详情
(IX) 16593 Phenylboronic acid;Benzeneboronic acid;Phenylboron dihydroxide 98-80-6 C6H7BO2 详情 详情
(XI) 22470 3-nitro-2-phenylpyridine C11H8N2O2 详情 详情
Extended Information