methyl 4-amino-2-chlorobenzoate -Drug Synthesis Database

【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 合成路线2 合成路线3

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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 .

参考文献中间体

合成目标

【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