【结 构 式】 |
【药物名称】MLN-518, CT-53518(former code name) 【化学名称】N-(4-Isopropoxyphenyl)-4-[6-methoxy-7-[3-(1-piperidinyl)propoxy]quinazolin-4-yl]piperazine-1-carboxamide 【CA登记号】387867-13-2, 387867-14-3 (sulfate) 【 分 子 式 】C31H42N6O4 【 分 子 量 】562.71819 |
【开发单位】Kyowa Hakko (Originator), Millennium (Originator) 【药理作用】Leukemia Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Antimitotic Drugs, Flt3 (FLK2/STK1) Inhibitors, Inhibitors of Signal Transduction Pathways, KIT (C-KIT) Kinase Inhibitors, PDGFRalpha Inhibitors, PDGFRbeta Inhibitors |
合成路线1
The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over Pd/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with piperidine (XII) in DMF provides the piperidinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.
【1】 Pandey, A.; et al.; Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 2002, 45, 17, 3772. |
【2】 Nomoto, Y.; Scarborough, R.M.; Ichimura, M.; Fujiwara, S.; Ide, S.; Oda, S.; Pandey, A.; Tsukuda, E.; Matsuno, K.; Irie, J. (Kyowa Hakko Kogyo Co., Ltd.; Millennium Pharmaceuticals, Inc.); Quinazoline derivs. as kinase inhibitors. WO 0216351 . |
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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
(II) | 55576 | phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H20O4 | 详情 | 详情 | |
(III) | 55577 | phenylmethyl 5-(methyloxy)-2-nitro-4-[(phenylmethyl)oxy]benzoate | C22H19NO6 | 详情 | 详情 | |
(IV) | 55578 | phenylmethyl 2-amino-5-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H21NO4 | 详情 | 详情 | |
(V) | 31530 | 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone | C16H14N2O3 | 详情 | 详情 | |
(VI) | 51531 | 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole | C15H12ClN3O2 | 详情 | 详情 | |
(VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
(VIII) | 55579 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C25H30N4O4 | 详情 | 详情 | |
(IX) | 55580 | 1,1-dimethylethyl 4-[7-hydroxy-6-(methyloxy)-4-quinazolinyl]-1-piperazinecarboxylate | C18H24N4O4 | 详情 | 详情 | |
(X) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
(XI) | 55582 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C28H36N4O7S | 详情 | 详情 | |
(XII) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
(XIII) | 55583 | 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(1-piperidinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate | C26H39N5O4 | 详情 | 详情 | |
(XIV) | 55584 | 6-(methyloxy)-4-(1-piperazinyl)-7-{[3-(1-piperidinyl)propyl]oxy}quinazoline; methyl 4-(1-piperazinyl)-7-{[3-(1-piperidinyl)propyl]oxy}-6-quinazolinyl ether | C21H31N5O2 | 详情 | 详情 | |
(XV) | 55585 | 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate | C10H11NO2 | 详情 | 详情 |
合成路线2
The condensation of 4-hydroxy-3-methoxybenzoic acid ethyl ester (I) with 3-chloropropyl bromide (II) by means of K2CO3 in refluxing DMF gives the 4(3-chloropropoxy)-3-methoxybenzoic acid ethyl ester (III), which is nitrated by means of HNO3 and AcOH to yield the 2-nitro derivative (IV). The condensation of (IV) with piperidine (V) by means of K2CO3 in hot toluene affords 5-methoxy-2-nitro-4-[3-(1-piperidinyl)propoxy]benzoic acid ethyl ester (VI), which is reduced by means of Pd/C and HCO2K in ethanol/water to provide the 2-amino derivative (VII). The cyclization of (VII) with formamide and ammonium formate at 135 C gives the quinazoline (VIII), which is treated with SOCl2 in refluxing toluene to yield the chloro derivative (IX). Finally this compound is condensed with the piperazinecarboxamide (X) by means of K2CO3 in hot DMF/toluene to afford the target CT-53518.
【1】 Pandey, A.; et al.; Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 2002, 45, 17, 3772. |
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) | 57016 | 3-Methoxy-4-hydroxybenzoic acid ethyl ester; 4-Hydroxy-3-methoxybenzoic acid ethyl ester; Ethyl 4-hydroxy-3-methoxybenzoate; Ethyl vanillate; Ethyl-3-Methoxy-4-Hydroxybenzoate; Vanillic acid ethyl ester | 617-05-0 | C10H12O4 | 详情 | 详情 |
(II) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
(III) | 57017 | ethyl 4-(3-chloropropoxy)-3-methoxybenzoate | C13H17ClO4 | 详情 | 详情 | |
(IV) | 57018 | ethyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate | C13H16ClNO6 | 详情 | 详情 | |
(V) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
(VI) | 57019 | ethyl 5-methoxy-2-nitro-4-[3-(1-piperidinyl)propoxy]benzoate | C18H26N2O6 | 详情 | 详情 | |
(VII) | 57020 | ethyl 2-amino-5-methoxy-4-[3-(1-piperidinyl)propoxy]benzoate | C18H28N2O4 | 详情 | 详情 | |
(VIII) | 57021 | 6-methoxy-7-[3-(1-piperidinyl)propoxy]-4-quinazolinol | C17H23N3O3 | 详情 | 详情 | |
(IX) | 57022 | 4-chloro-6-methoxy-7-[3-(1-piperidinyl)propoxy]quinazoline; 4-chloro-6-methoxy-7-quinazolinyl 3-(1-piperidinyl)propyl ether | C17H22ClN3O2 | 详情 | 详情 | |
(X) | 57023 | N-(4-isopropoxyphenyl)-1-piperazinecarboxamide | C14H21N3O2 | 详情 | 详情 |