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【结 构 式】

【分子编号】26675

【品名】(2-chloro-4-nitrophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone

【CA登记号】

【 分 子 式 】C19H14ClN3O3

【 分 子 量 】367.79128

【元素组成】C 62.05% H 3.84% Cl 9.64% N 11.43% O 13.05%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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:(VIII)

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
Extended Information