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【结 构 式】 
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【药物名称】CT-5276-00, CT-5276 【化学名称】N-[4-[2-(Diethylamino)ethoxy]-3,5-dimethoxyphenyl]-9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-amine 【CA登记号】209740-42-1 【 分 子 式 】C29H38N4O4 【 分 子 量 】506.65061 |
【开发单位】Celltech (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunomodulators, Src Kinase Inhibitors |
合成路线1
Condensation of anisole (I) with gamma,gamma-dimethylbutyrolactone (II) in the presence of AlCl3 in 1-nitropropane gave 4-(4-methoxyphenyl)-4-methylpentanoic acid (III), which was cyclized to the tetralone (V) using polyphosphoric acid. Subsequent treatment of (V) with refluxing N,N-dimethylformamide dimethyl acetal provided the dimethylamino-methylene compound (VI). This was cyclized with guanidinium carbonate in boiling isopropanol to furnish the benzoquinazoline (VII). Then, diazotization of (VII) in aqueous sulfuric acid generated the quinazolinone (VIII), which was subsequently converted to the chloroquinazoline (IX) using phosphoryl chloride and DMF. Aniline (XIII) was obtained by alkylation of 2,6-dimethoxy-4-nitrophenol (X) with (diethylamino)ethyl chloride (XI) in the presence of Cs2CO3 to give (XII), followed by catalytic transfer hydrogenation of the nitro group of (XII) with ammonium formate and Pd/C. Finally, condensation of chloroquinazoline (IX) with aniline (XIII) in refluxing ethoxyethanol yielded the title compound.
| 【1】 Davis, J.M.; Hutchings, M.C.; Moffat, D.; Batchelor, M.; Parry, D.M.; Johnson, J.; Berg, D.A.; Davis, P.D.; Benzo[h]-5,6-dihydroquinazoline-2-amines as potent. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.234. |
| 【2】 Moffat, D.F.C.; Davis, J.M.; Batchelor, M.J.; Davis, P.D. (Celltech Chiroscience plc); Fused polycyclic 2-aminopyrimidine derivs., their . EP 0946523; US 6057329; WO 9828281 . |
| 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) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (II) | 23768 | 5,5-dimethyldihydro-2(3H)-furanone | C6H10O2 | 详情 | 详情 | |
| (III) | 23769 | 4-(4-methoxyphenyl)-4-methylpentanoic acid | 23203-48-7 | C13H18O3 | 详情 | 详情 |
| (V) | 23770 | 7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (VI) | 23771 | 2-[(E)-(dimethylamino)methylidene]-7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C16H21NO2 | 详情 | 详情 | |
| (VII) | 23772 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-ylamine; 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-amine | C15H17N3O | 详情 | 详情 | |
| (VIII) | 23773 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one | C15H16N2O2 | 详情 | 详情 | |
| (IX) | 23774 | 2-chloro-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-9-yl methyl ether; 2-chloro-9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazoline | C15H15ClN2O | 详情 | 详情 | |
| (X) | 23778 | 2,6-dimethoxy-4-nitrophenol | C8H9NO5 | 详情 | 详情 | |
| (XI) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (XII) | 23779 | N-[2-(2,6-dimethoxy-4-nitrophenoxy)ethyl]-N,N-diethylamine; 2-(2,6-dimethoxy-4-nitrophenoxy)-N,N-diethyl-1-ethanamine | C14H22N2O5 | 详情 | 详情 | |
| (XIII) | 23780 | 4-[2-(diethylamino)ethoxy]-3,5-dimethoxyaniline; N-[2-(4-amino-2,6-dimethoxyphenoxy)ethyl]-N,N-diethylamine | C14H24N2O3 | 详情 | 详情 |