| 摘要 |
The invention discloses a novel quinazoline derivative LU1501 and a preparing method thereof, wherein the quinazoline derivative has a chemical name of N-[(4-fluorophenyl)methyl]-4-N-{7-methoxy-6-[(2-pyrrolidin-1-yl)hydroxyethyl]quinazoline-4-yl}phen-1,4-diamine. The quinazoline derivative and a pharmaceutically acceptable salt, a solvate and a hydrate thereof have excellent anti-tumor activity in vitro and in vivo to MCF-7, SK-BR-3, A549, HCT 116, U-118 MG; U-87 MG and MDA-MB-468, and have preferable application prospects on preparing anti-tumor drugs. |
| 主权项 |
1. A method for preparing a quinazoline derivative comprising the following steps of:
S1: adding DMF to SOCl2 dropwise slowly under the protection of nitrogen to catalyze, then adding 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate, heating at 60-100° C. for 3-6 h, and reacting to generate a compound (1) which is 4-chloro-7-methoxy quinazolin-6-yl acetate; S2: adding NH3-methanol solution dropwise slowly to the compound (1) while stirring in an ice bath, reacting for over 30 min while stirring when the reaction fluid is under 10° C., filtering, and washing a filter residue with diethyl-ether, thus obtaining a reduced product compound (2) which is 4-chloro-7-methoxy quinazolin-6-ol; S3: dissolving the compound (2), N-(2-hydroxyethyl)pyrrolidine, and PPh3 in tetrahydrofuran under the protection of nitrogen, adding DTAD while stirring in an ice bath, and reacting for over 6 h, thus generating a compound (3) which is 4-chloro-7-methoxy-6-[(2-pyrrolidin-1-yl)hydroxyethyl]quinazoline; S4: dissolving 1-fluoro-4-nitrobenzene, 4-fluorophenyl methylamine and sodium carbonate with DMSO under the protection of argon, and reacting for 4-12 h with stirring at 100-120° C., thus generating a compound (4) which is N-[(4-fluorophenyl)methyl]-4-nitroaniline; S5: adding the compound (4) to Boc2O with dichloromethane as a solvent in an ice bath under the protection of nitrogen, then adding DMAP to catalyze, reacting for 4-12 h with stirring, and performing secondary amine Boc protection, thus generating a compound (5) which is tert-butyl N-[(4-fluorophenyl)methyl]-N-(4-nitrophenyl)carbamate; S6: dissolving the compound (5) in methanol, adding 10% Pd/C to catalyze, pumping in H2, and reacting for 4-12 h with stirring to reduce to a compound (6) which is tert-butyl N-(4-aminophenyl)-N-[(4-fluorophenyl)methyl]carbamate; S7: dissolving the compound (6) and the compound (3) in isopropanol, and reacting for 3-12 h at 80-100° C. under the catalysis of p-toluenesulfonic acid with stirring, thus generating a compound (7) which is tert-butyl N-[(4-fluorophenyl)methyl]-N-4-{7-methoxy-6-[(2-pyrrolidin-1-hydroxyethyl]quinazolin-4-yl}aminophenyl carbamate; and S8: dissolving the compound (7) in a mixed solvent of dichloromethane/trifluoroacetic acid, and stirring at 25-45° C. for 1-6 h to remove Boc, thus generating a quinazoline derivative of compound (8) which is N-[(4-fluorophenyl)methyl]-4-N-{7-methoxy-6-[(2-pyrrolidin-1-yl)hydroxyethyl]quinazolin-4-yl}phen-1,4-diamine. |
