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【结 构 式】 
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【分子编号】22466 【品名】2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde 【CA登记号】 |
【 分 子 式 】C10H7F3N4O2 【 分 子 量 】272.1865496 【元素组成】C 44.13% H 2.59% F 20.94% N 20.58% O 11.76% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |
合成路线2
该中间体在本合成路线中的序号：(VIIc)The reduction of 2-iodo-4-nitroanisole (I) with Fe and HOAc/HCl in methanol gives 4-amino-2-iodoanisole (II), which is acylated with trifluoroacetic anhydride and triethylamine to give the corresponding amide (III). The reaction of (III) with PPh3 and CCl4 affords the iminochloride (IV), which is cyclized with sodium azide in acetic acid, giving 1-(3-iodo-4-methoxyphenyl)-5-(trifluoromethyl)tetrazole (V). The reaction of (V) with 13C- or 14C-labeled zinc cyanide and palladium tetrakis triphenylphosphine in DMF yields the labeled benzonitrile (VI), which is treated with Raney-Ni and NaH2PO2 in pyridine/HOAc/water to afford the benzaldehyde (VII). Finally, this compound is reductocondensed with 2(S)-phenylpiperidin-3(S)-amine (VIII) by means of NaH(OAc)3 in dichloromethane.
| 【1】 Sutherland, D.R.; Cable, K.M.; Wells, G.N.; Synthesis of carbon-14 labelled NK-1 receptor antagonists GR203040 and GR205171. J Label Compd Radiopharm 2000, 43, 1, 29. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIc) | 22466 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C10H7F3N4O2 | 详情 | 详情 | |
| (VIa) | 44429 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzonitrile | C10H6F3N5O | 详情 | 详情 | |
| (VIb) | 44430 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzonitrile | C10H6F3N5O | 详情 | 详情 | |
| (VIIa) | 44431 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C10H7F3N4O2 | 详情 | 详情 | |
| (VIIb) | 44432 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C10H7F3N4O2 | 详情 | 详情 | |
| (VIc) | 44433 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzonitrile | C10H6F3N5O | 详情 | 详情 | |
| (I) | 44424 | 2-iodo-1-methoxy-4-nitrobenzene; 2-iodo-4-nitrophenyl methyl ether | C7H6INO3 | 详情 | 详情 | |
| (II) | 44425 | 3-iodo-4-methoxyaniline; 3-iodo-4-methoxyphenylamine | C7H8INO | 详情 | 详情 | |
| (III) | 44426 | 2,2,2-trifluoro-N-(3-iodo-4-methoxyphenyl)acetamide | C9H7F3INO2 | 详情 | 详情 | |
| (IV) | 44427 | 2,2,2-trifluoro-N-(3-iodo-4-methoxyphenyl)ethanimidoyl chloride | C9H6ClF3INO | 详情 | 详情 | |
| (V) | 44428 | 1-(3-iodo-4-methoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; 2-iodo-4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl methyl ether | C9H6F3IN4O | 详情 | 详情 | |
| (VIII) | 22467 | (2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine | C11H16N2 | 详情 | 详情 |