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【结 构 式】 
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【药物名称】 【化学名称】2-(4-Chlorophenoxy)-1-[4-(4-fluorobenzyl)-2(R)-methylpiperazin-1-yl]ethanone 【CA登记号】217646-35-0, 217645-39-1 ((S)-isomer), 217645-38-0 (undefined isomer) 【 分 子 式 】C20H22ClFN2O2 【 分 子 量 】376.86194 |
【开发单位】Berlex (Originator) 【药理作用】Antiarthritic Drugs, Immunologic Neuromuscular Disorders, Treatment of, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Chemokine CCR1 Antagonists |
合成路线1
Alkylation of (R)-2-methylpiperazine (I) with 4-fluorobenzyl bromide (II) provides 1-(4-fluorobenzyl)-3-methylpiperazine (III). Subsequent acylation of piperazine (III) with (4-chlorophenoxy)acetyl chloride (IV) furnishes the title amide.
| 【1】 Monahan, S.D.; Xu, W.; Morissey, M.M.; Bauman, J.G.; Ng, H.P.; Hesselgesser, J.E.; Liang, M.; Zheng, W.; Islam, I.; May, K.B.; Ghannam, A.F.; Buckman, B.O.; Horuk, R.; Wei, G.P. (Schering AG); Piperazine derivs. and their use as anti-inflammatory agents. US 6207665; WO 9856771 . |
合成路线2
In an alternative procedure, N-Boc-D-alanine (I) is activated as the mixed anhydride (II) by treatment with isobutyl chloroformate. Coupling of anhydride (II) with N-(4-fluorobenzyl)glycine methyl ester (III) produces dipeptide (IV). Further cleavage of the N-Boc protecting group of (IV) under acidic conditions proceeds with concomitant cyclization to the diketopiperazine (V). This is then reduced by means of LiAlH4 to piperazine (VI). Finally, acylation of piperazine (VI) with (4-chlorophenoxy)acetyl chloride (VII) provides the title compound.
| 【1】 Islam, I.; May, K.; Bauman, J.; et al.; Synthesis and SAR of CCR1-specific non-peptide antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 334. |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 61036 | ®-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride | C13H23NO6 | 详情 | 详情 | |
| (III) | 61037 | methyl 2-[(4-fluorobenzyl)amino]acetate | C10H12FNO2 | 详情 | 详情 | |
| (IV) | 61038 | methyl 2-[{(2R)-2-[(tert-butoxycarbonyl)amino]propanoyl}(4-fluorobenzyl)amino]acetate | C18H25FN2O5 | 详情 | 详情 | |
| (V) | 61039 | (3R)-1-(4-fluorobenzyl)-3-methyl-2,5-piperazinedione | C12H13FN2O2 | 详情 | 详情 | |
| (VI) | 61035 | (3R)-1-(4-fluorobenzyl)-3-methylpiperazine | C12H17FN2 | 详情 | 详情 | |
| (VII) | 24258 | 2-(4-chlorophenoxy)acetyl chloride | 4122-68-3 | C8H6Cl2O2 | 详情 | 详情 |
合成路线3
In a further method, 1-(4-fluorobenzyl)-3-methylpiperazine (I) is acylated by chloroacetyl chloride to provide the chloroacetamide (II). Subsequent chloride displacement with 4-chlorophenol (III) leads to the target chlorophenoxy acetamide.
| 【1】 Monahan, S.D.; Xu, W.; Morissey, M.M.; Bauman, J.G.; Ng, H.P.; Hesselgesser, J.E.; Liang, M.; Zheng, W.; Islam, I.; May, K.B.; Ghannam, A.F.; Buckman, B.O.; Horuk, R.; Wei, G.P. (Schering AG); Piperazine derivs. and their use as anti-inflammatory agents. US 6207665; WO 9856771 . |