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【结 构 式】 
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【分子编号】55576 【品名】phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate 【CA登记号】 |
【 分 子 式 】C22H20O4 【 分 子 量 】348.3984 【元素组成】C 75.84% H 5.79% O 18.37% |
合成路线1
该中间体在本合成路线中的序号：(II)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
该中间体在本合成路线中的序号：(II)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 P/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 morpholine (XII) in DMF provides the morpholinyl 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】 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) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XIII) | 55586 | 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate | C25H37N5O5 | 详情 | 详情 | |
| (XIV) | 55587 | methyl 7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)-6-quinazolinyl ether; 6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)quinazoline | C20H29N5O3 | 详情 | 详情 | |
| (XV) | 55585 | 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate | C10H11NO2 | 详情 | 详情 |