【结 构 式】 |
【药物名称】RO-1169132/238 【化学名称】4-(3,4-Dichlorobenzyl)-1-methyl-1-[3-methyl-2(R)-[3-(3,4,5-trimethoxyphenyl)ureido]butyl]piperidinium chloride 【CA登记号】270572-42-4 【 分 子 式 】C28H40Cl2IN3O4 【 分 子 量 】680.4591 |
【开发单位】Roche Bioscience (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Chemokine CCR3 Antagonists |
合成路线1
Condensation of 3,4-dichlorobenzyl bromide (I) with triphenylphosphine affords the phosphonium salt (II). The ylide obtained from (II) and butyllithium is then subjected to a Wittig reaction with N-Boc-4-piperidinone (III) to provide the benzylidene piperidine (IV). Catalytic hydrogenation of (IV) over PtO2 gives rise to the corresponding benzylpiperidine (V). After acidic Boc group cleavage in (V), the deprotected piperidine (VI) is coupled with N-Boc-D-valine (VII) in the presence of EDC to furnish amide (VIII). Further N-Boc group cleavage in (VIII) employing trifluoroacetic acid yields amino amide (IX), which is then reduced to diamine (X) by means of borane in THF. Coupling of amine (X) with 3,4,5-trimethoxyphenyl isocyanate (XI) leads to urea (XII). Finally, quaternization of the piperidine N of (XII) with iodomethane provides the title piperidinium salt.
【1】 Kertesz, D.J.; Smith, D.B.; Hirschfeld, D.R. (F. Hoffmann-La Roche AG); Piperidine CCR-3 receptor antagonists. DE 19955793; EP 1131290; GB 2343894; JP 2002530375; US 6342509; WO 0031033 . |
【2】 Wilhelm, R.S.; Smith, D.B.; Talamas, F.X.; Gong, L.; tesz, D.J. (Syntex (USA) LLC); Cyclic amine derivs.-CCR-3 receptor antagonists. US 6339087 . |
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) | 42911 | 4-(bromomethyl)-1,2-dichlorobenzene | 18880-04-1 | C7H5BrCl2 | 详情 | 详情 |
(II) | 58924 | (3,4-dichlorobenzyl)(triphenyl)phosphonium bromide | C25H20BrCl2P | 详情 | 详情 | |
(III) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
(IV) | 58925 | tert-butyl 4-(3,4-dichlorobenzylidene)-1-piperidinecarboxylate | C17H21Cl2NO2 | 详情 | 详情 | |
(V) | 58926 | tert-butyl 4-(3,4-dichlorobenzyl)-1-piperidinecarboxylate | C17H23Cl2NO2 | 详情 | 详情 | |
(VI) | 58927 | 4-(3,4-dichlorobenzyl)piperidine | C12H15Cl2N | 详情 | 详情 | |
(VII) | 48375 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
(VIII) | 58928 | tert-butyl (1R)-1-{[4-(3,4-dichlorobenzyl)-1-piperidinyl]carbonyl}-2-methylpropylcarbamate | C22H32Cl2N2O3 | 详情 | 详情 | |
(IX) | 58929 | (2R)-2-amino-1-[4-(3,4-dichlorobenzyl)-1-piperidinyl]-3-methyl-1-butanone | C17H24Cl2N2O | 详情 | 详情 | |
(X) | 58930 | (2R)-1-[4-(3,4-dichlorobenzyl)-1-piperidinyl]-3-methyl-2-butanamine; (1R)-1-{[4-(3,4-dichlorobenzyl)-1-piperidinyl]methyl}-2-methylpropylamine | C17H26Cl2N2 | 详情 | 详情 | |
(XI) | 58931 | 3,4,5-trimethoxyphenyl isocyanate; 5-isocyanato-1,2,3-trimethoxybenzene | C10H11NO4 | 详情 | 详情 | |
(XII) | 58933 | 7-Octene-1,2-diol | C8H16O2 | 详情 | 详情 |