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【结 构 式】 
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【药物名称】CP-122721 【化学名称】(+)-(2S,3S)-3-[2-Methoxy-5-(trifluoromethoxy)benzylamino]-2-phenylpiperidine 【CA登记号】145742-28-5 【 分 子 式 】C20H23F3N2O2 【 分 子 量 】380.41371 |
【开发单位】Pfizer (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Antidepressants, Asthma Therapy, Mood Disorders, Treatment of, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, RESPIRATORY DRUGS, Tachykinin NK1 Antagonists |
合成路线1
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
In an alternative procedure, the reductive alkylation of 3-amino-2-chloropyridine (IV) with 2-methoxy-5-trifluoromethoxybenzaldehyde (III) in the presence of NaBH(OAc)3 produced the 3-(benzylamino)pyridine (V). The 2-phenyl pyridine derivative (VII) was then prepared by chloride displacement with phenylmagnesium bromide (VI) in the presence of bis(triphenylphosphino)nickel(II) chloride. Catalytic hydrogenation of pyridine (VII) produced the racemic cis-piperidine, which was finally resolved into the enantiomers by using (S)-mandelic acid.
| 【1】 Rosen, T.J.; Godek, D.M.; Ruggeri, S.G.; Wint, L.T. (Pfizer Inc.); Preparation of substd. piperidines. WO 9311110 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 59236 | 2-methoxy-5-(trifluoromethoxy)benzaldehyde | C9H7F3O3 | 详情 | 详情 | |
| (IV) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (V) | 59237 | N-(2-chloro-3-pyridinyl)-N-[2-methoxy-5-(trifluoromethoxy)benzyl]amine; 2-chloro-N-[2-methoxy-5-(trifluoromethoxy)benzyl]-3-pyridinamine | C14H12ClF3N2O2 | 详情 | 详情 | |
| (VI) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (VII) | 59238 | N-[2-methoxy-5-(trifluoromethoxy)benzyl]-2-phenyl-3-pyridinamine; N-[2-methoxy-5-(trifluoromethoxy)benzyl]-N-(2-phenyl-3-pyridinyl)amine | C20H17F3N2O2 | 详情 | 详情 |
合成路线3
The precursor 2-methoxy-5-trifluoromethoxybenzaldehyde (III) was prepared as follows. Alkylation of 4-(trifluoromethoxy)phenol (VIII) by means of iodomethane and K2CO3 or dimethyl carbonate and DMAP furnished 4-(trifluoromethoxy)anisole (IX). Formylation of (IX) to the target aldehyde (III) was achieved by treatment with dichloromethyl methyl ether and TiCl4 or with hexamethylenetetraamine and trifluoroacetic acid.
| 【1】 Lowe, J.A. III; Rosen, T.J. (Pfizer Inc.); Fluoroalkoxybenzylamino derivs. of nitrogen containing heterocycles. EP 0589924; JP 1994506473; WO 9300331 . |
| 【2】 Snyder, W.M.; Godek, D.M.; Stewart, A.M. (Pfizer Inc.); Formylation process for aromatic aldehydes. WO 9424081 . |