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【结 构 式】 
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【分子编号】19564 【品名】ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate 【CA登记号】 |
【 分 子 式 】C19H15BrClFN2O4 【 分 子 量 】469.6942832 【元素组成】C 48.59% H 3.22% Br 17.01% Cl 7.55% F 4.04% N 5.96% O 13.63% |
合成路线1
该中间体在本合成路线中的序号：(VII)1) The cyclization of 2-(benzyloxycarbonylamino)-4-chlorobenzoic acid (I) by means of PBr3 in refluxing ethyl ether gives 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (II), which is condensed with 4-bromo-2-fluorobenzylamine (III) in refluxing THF yielding 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chloro-benzamide (IV). The cyclization of (IV) with carbonyldiimidazole (CDI) in refluxing dioxane affords 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (V), which is alkylated with ethyl bromoacetate (VI) by means of NaH in DMF to give ethyl 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol.
| 【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 . |
| 【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26. |
| 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) | 19558 | 2-[[(benzyloxy)carbonyl]amino]-4-chlorobenzoic acid | C15H12ClNO4 | 详情 | 详情 | |
| (II) | 19559 | 4-Chloroisatoic anhydride; 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione | C8H4ClNO3 | 详情 | 详情 | |
| (III) | 19560 | (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine | 112734-22-2 | C7H7BrFN | 详情 | 详情 |
| (IV) | 19561 | 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide | C14H11BrClFN2O | 详情 | 详情 | |
| (V) | 19562 | 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione | C15H9BrClFN2O2 | 详情 | 详情 | |
| (VI) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VII) | 19564 | ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate | C19H15BrClFN2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)2) The condensation of 4-chloro-2-nitrobenzoic acid (VIII) with benzylamine (III) by means of CDI in THF gives the corresponding amide (IX), which is reduced with Fe in acetic acid to the 2-aminobenzamide (IV). The cyclization of (IV) with carbonyldiimidazole (CDI) in refluxing dioxane affords 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (V), which is alkylated with ethyl bromoacetate (VI) by means of NaH in DMF to give ethyl 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol.
| 【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 . |
| 【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 19560 | (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine | 112734-22-2 | C7H7BrFN | 详情 | 详情 |
| (IV) | 19561 | 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide | C14H11BrClFN2O | 详情 | 详情 | |
| (V) | 19562 | 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione | C15H9BrClFN2O2 | 详情 | 详情 | |
| (VI) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VII) | 19564 | ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate | C19H15BrClFN2O4 | 详情 | 详情 | |
| (VIII) | 19565 | 4-chloro-2-nitrobenzoic acid | 6280-88-2 | C7H4ClNO4 | 详情 | 详情 |
| (IX) | 19566 | N-(4-bromo-2-fluorobenzyl)-4-chloro-2-nitrobenzamide | C14H9BrClFN2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)3) The alkylation of 2-amino-4-chlorobenzamide (X) with ethyl bromoacetate (VI) by means of K2CO3 in hot DMF gives ethyl 2-(2-carbamoyl-4-chlorophenylamino)acetate (XI), which is cyclized with CDI at 150 C yielding ethyl 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (XII). Finally, this compound is alkylated with 4-bromo-2-fluorobenzyl chloride (XIII) by means of NaH in DMF to afford quinazoline (VII) already obtained.
| 【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 . |
| 【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VII) | 19564 | ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate | C19H15BrClFN2O4 | 详情 | 详情 | |
| (X) | 19567 | 2-amino-4-chlorobenzamide | C7H7ClN2O | 详情 | 详情 | |
| (XI) | 19568 | ethyl 2-[2-(aminocarbonyl)-5-chloroanilino]acetate | C11H13ClN2O3 | 详情 | 详情 | |
| (XII) | 19569 | ethyl 2-[7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate | C12H11ClN2O4 | 详情 | 详情 | |
| (XIII) | 19570 | 4-bromo-1-(chloromethyl)-2-fluorobenzene | C7H5BrClF | 详情 | 详情 |