|
【结 构 式】 
|
【分子编号】26676 【品名】(4-amino-2-chlorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone 【CA登记号】 |
【 分 子 式 】C19H16ClN3O 【 分 子 量 】337.80836 【元素组成】C 67.56% H 4.77% Cl 10.49% N 12.44% O 4.74% |
合成路线1
该中间体在本合成路线中的序号：(V)The reductocyclization of 1-(2-nitrobenzyl)pyrrole-2-carbaldehyde (I) gives the pyrrolobenzodiazepine (II), which is acylated with 2-chloro-4-nitrobenzoyl chloride (III) giving the expected 10-benzoyl derivative (IV). The reduction of the nitro group of (IV) with H2 over Pd/C or with SnCl2 yields the corresponding 4-amino derivative (V), which is finally acylated with 5-fluoro-2-methylbenzoyl chloride.
| 【1】 Albright, J.D.; Delos Santos, E.G.; Reich, M.F.; et al.; 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): An orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem 1998, 41, 14, 2442. |
| 【2】 Albright, J.D.; Reich, M.F.; Sum, F.-W.; Delos Santos, E.G. (American Cyanamid Co.); Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. CA 2128956; EP 0636625; JP 1995157486; US 5516774 . |
| 【3】 Albright, J.D.; Sum, F.-W.; Delos Santos, E.G.; Reich, M.F. (American Cyanamid Co.); Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5736540 . |
| 【4】 Reich, M.F.; Delos Santos, E.G.; Sum, F.-W.; Albright, J.D. (American Cyanamid Co.); Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5733905 . |
| 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) | 21083 | 1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde | 22162-51-2 | C12H10N2O3 | 详情 | 详情 |
| (II) | 21084 | 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine | 22162-53-4 | C12H12N2 | 详情 | 详情 |
| (III) | 26674 | 2-chloro-4-nitrobenzoyl chloride | 7073-36-1 | C7H3Cl2NO3 | 详情 | 详情 |
| (IV) | 26675 | (2-chloro-4-nitrophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone | C19H14ClN3O3 | 详情 | 详情 | |
| (V) | 26676 | (4-amino-2-chlorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone | C19H16ClN3O | 详情 | 详情 | |
| (VI) | 26677 | 5-fluoro-2-methylbenzoyl chloride | C8H6ClFO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Acylation of methyl 4-amino-2-chlorobenzoate (I) with 5-fluoro-2-methylbenzoyl chloride (II) in the presence of Et3N gives amide (III), which is then hydrolyzed at the ester group using NaOH in boiling H2O/EtOH to yield 2-chloro-4-(5-fluoro-2-methylbenzamido)benzoic acid (IV). Finally, after chlorination of acid (IV) with SOCl2 at reflux, the resulting acid chloride (V) is condensed with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (VI) by means of DIEA in CH2Cl2 .
In a related method, acylation of benzodiazepine (VI) with 2-chloro-4-nitrobenzoyl chloride (VII) by means of Et3N in CH2Cl2 provides the nitrobenzamide (VIII), which is reduced to the corresponding 4-amino derivative (IX) using either H2 or hydrazine in the presence of Pd/C in EtOH or by means of SnCl2. Finally, amine (IX) is acylated with 5-fluoro-2-methylbenzoyl chloride (II) using Et3N in CH2Cl2 .
The tricyclic intermediate (VI) is prepared by alkylation of pyrrole-2-carbaldehyde (X) with 2-nitrobenzyl bromide (XI) by means of NaH in DMF to afford 1-(2-nitrobenzyl)pyrrole-2-carbaldehyde (XII), which undergoes reductocyclization to the pyrrolobenzodiazepine (VI) upon catalytic hydrogenation over Pd/C in EtOH/EtOAc .
| 【1】 Albright, J.D., Reich, M.F., Delos Santos, E.G. et al. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo [2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-hlorophenyl] benzamide (VPA-985): An orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem 1998, 41(14): 2442-4. |
| 【2】 Albright, J.D., Reich, M.F., Sum, F.-W., Delos Santos, E.G. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. CA 2128956, EP 0636625, JP 1995157486, US 5516774. |
| 【3】 Sum, F.-W., Albright, J.D., Delos Santos, E.G., Reich, M.F. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5733905. |
| 【4】 Reich, M.F., Sum, F.-W., Delos Santos, E.G., Albright, J.D. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5736540. |
| 【5】 Reich, M.F., Sum, F.-W., Albright, J.D., Delos Santos, E.G. (Wyeth, LLC). Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US 5624923. |
| 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) | 26678 | methyl 4-amino-2-chlorobenzoate | C8H8ClNO2 | 详情 | 详情 | |
| (II) | 26677 | 5-fluoro-2-methylbenzoyl chloride | C8H6ClFO | 详情 | 详情 | |
| (III) | 26679 | methyl 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoate | C16H13ClFNO3 | 详情 | 详情 | |
| (IV) | 26680 | 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoic acid | C15H11ClFNO3 | 详情 | 详情 | |
| (V) | 26681 | 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoyl chloride | C15H10Cl2FNO2 | 详情 | 详情 | |
| (VI) | 21084 | 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine | 22162-53-4 | C12H12N2 | 详情 | 详情 |
| (VII) | 26674 | 2-chloro-4-nitrobenzoyl chloride | 7073-36-1 | C7H3Cl2NO3 | 详情 | 详情 |
| (VIII) | 26675 | (2-chloro-4-nitrophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone | C19H14ClN3O3 | 详情 | 详情 | |
| (IX) | 26676 | (4-amino-2-chlorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone | C19H16ClN3O | 详情 | 详情 | |
| (X) | 21081 | Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde | 1003-29-8 | C5H5NO | 详情 | 详情 |
| (XI) | 21082 | 1-(bromomethyl)-2-nitrobenzene；2-Nitrobenzyl bromide;alpha-Bromo-2-nitrotoluene | 3958-60-9 | C7H6BrNO2 | 详情 | 详情 |
| (XII) | 21083 | 1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde | 22162-51-2 | C12H10N2O3 | 详情 | 详情 |