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【结 构 式】

【分子编号】26678

【品名】methyl 4-amino-2-chlorobenzoate

【CA登记号】

【 分 子 式 】C8H8ClNO2

【 分 子 量 】185.60976

【元素组成】C 51.77% H 4.34% Cl 19.1% N 7.55% O 17.24%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VII)

The acylation of 4-amino-2-chlorobenzoic acid methyl ester (VII) with 5-fluoro-2-methylbenzoyl chloride (VI) gives the corresponding amide (VIII), which is hydrolyzed at the ester group yielding the corresponding free acid (IX). The reaction of (IX) with SOCl2 affords the acyl chloride (X), which is finally condensed with the pyrrolobenzodiazepine (II) (obtained by the reductocyclization of 1-(2-nitrobenzyl)pyrrole-2-carbaldehyde (I)) to provide the target compound.

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
(VI) 26677 5-fluoro-2-methylbenzoyl chloride C8H6ClFO 详情 详情
(VII) 26678 methyl 4-amino-2-chlorobenzoate C8H8ClNO2 详情 详情
(VIII) 26679 methyl 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoate C16H13ClFNO3 详情 详情
(IX) 26680 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoic acid C15H11ClFNO3 详情 详情
(X) 26681 2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoyl chloride C15H10Cl2FNO2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

Acid chloride (VI) prepared from 2-biphenylcarboxylic acid (V) and SOCl2 was coupled with methyl 4-amino-2-chlorobenzoate (VII) to yield amide (VIII). After hydrolysis of the ester group of (VIII) with NaOH, the resulting carboxylic acid (IX) was converted to acid chloride (X) using SOCl2. Finally, condensation of (X) with the tricyclic amine (IV) in the presence of DIEA furnished the title compound.

1 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. US 5700796; WO 9749708 .
2 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.-W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. JP 2000510154; US 5753648; WO 9749707 .
3 Caggiano, T.J.; Bagli, J.F.; Trybulski, E.J.; Molinari, A.J.; Ashwell, M.A. (American Home Products Corp.); 3-Carboxamide derivs. of 5H-pyrrolo[1,2-c][1,4]-benzodiazepines. US 5880122 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 21084 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine 22162-53-4 C12H12N2 详情 详情
(V) 18505 [1,1'-biphenyl]-2-carboxylic acid 947-84-2 C13H10O2 详情 详情
(VI) 18506 [1,1'-biphenyl]-2-carbonyl chloride C13H9ClO 详情 详情
(VII) 26678 methyl 4-amino-2-chlorobenzoate C8H8ClNO2 详情 详情
(VIII) 41621 methyl 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoate C21H16ClNO3 详情 详情
(IX) 41622 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoic acid C20H14ClNO3 详情 详情
(X) 41623 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoyl chloride C20H13Cl2NO2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

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