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【结 构 式】

【分子编号】22467

【品名】(2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine

【CA登记号】

【 分 子 式 】C11H16N2

【 分 子 量 】176.26152

【元素组成】C 74.96% H 9.15% N 15.89%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(II)

The title compound was synthesized starting from the known drug CP-99,994 (I), which was subjected to catalytic hydrogenolysis of the N-(2-methoxybenzyl) group to yield (S,S)-3-amino-2-phenylpiperidine (II). Subsequent reductive alkylation of amine (II) with 2-methoxy-5-trifluoromethoxybenzaldehyde (III) in the presence of either NaBH3CN or NaBH(OAc)3 furnished the title compound.

1 Rosen, T.J.; Coffman, K.J.; McLean, S.; Crawford, R.T.; Bryce, D.K.; Gohda, Y.; Tsuchiya, M.; Nagahisa, A.; Nakane, M.; Lowe, J.A. III; Synthesis and structure-activity relationships of CP-122,721, a second-generation NK-1 receptor antagonist. Bioorg Med Chem Lett 1998, 8, 3, 281.
2 Lowe, J.A. III; Rosen, T.J. (Pfizer Inc.); Fluoroalkoxybenzylamino derivs. of nitrogen containing heterocycles. EP 0589924; JP 1994506473; WO 9300331 .
3 Rosen, T.J. (Pfizer Inc.); Stereoselective preparation of substd. piperidines. WO 9217449 .
4 Snyder, W.M.; Godek, D.M.; Stewart, A.M. (Pfizer Inc.); Formylation process for aromatic aldehydes. WO 9424081 .
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) 59235 N-(2-methoxybenzyl)-N-[(2S,3S)-2-phenylpiperidinyl]amine; (2S,3S)-N-(2-methoxybenzyl)-2-phenyl-3-piperidinamine C19H24N2O 详情 详情
(II) 22467 (2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine C11H16N2 详情 详情
(III) 59236 2-methoxy-5-(trifluoromethoxy)benzaldehyde C9H7F3O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

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3

该中间体在本合成路线中的序号:(VIII)

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
Extended Information