Lixivaptan, WAY-VPA-985, VPA-985, -Drug Synthesis Database

【结构式】

【药物名称】Lixivaptan, WAY-VPA-985, VPA-985

【化学名称】N-[3-Chloro-4-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide

【CA登记号】168079-32-1

【分子式】C₂₇H₂₁ClFN₃O₂

【分子量】473.93872

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Diuretics, Heart Failure Therapy, RENAL-UROLOGIC DRUGS, Vasopressin V2 Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【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

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

【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3

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

【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

Drug NewChemical Entity Original Patent(1)