WAY-VNA-932, VNA-932, -Drug Synthesis Database

【结构式】

【药物名称】WAY-VNA-932, VNA-932

【化学名称】10-[2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine
　　　　　　[2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)phenyl](10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-y-)methanone

【CA登记号】220460-92-4

【分子式】C₂₃H₁₉ClN₄O

【分子量】402.88708

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】Antidiuretics, RENAL-UROLOGIC DRUGS, Vasopressin V2 Agonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

2-Chloro-4-fluorobenzoic acid (I) was converted to acid chloride (II) upon treatment with oxalyl chloride and a catalytic amount of DMF. Subsequent coupling of (II) with pyrrolobenzodiazepine (III) yielded the corresponding amide (IV). Then, displacement of the fluorine atom of (IV) by the sodium salt of 3-methylpyrazole (V) produced a mixture of the required compound and its regioisomer (VI), which were separated by column chromatography.

参考文献中间体

【1】 Dusza, J.P.; Ashwell, M.A.; Caggiano, T.J.; et al.; VNA-932: First orally active, nonpeptide, vasopressin V2 receptor selective agonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 203.
【2】 Trybulski, E.J.; Ashwell, M.A.; Molinari, A.J.; Bagli, J.F.; Chan, P.S.; Failli, A.A.; Dusza, J.P.; Albright, J.D.; Caggiano, T.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000062; WO 9906409 .

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)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(II)	37996	2-chloro-4-fluorobenzoyl chloride	21900-54-9	C₇H₃Cl₂FO	详情	详情
(III)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(IV)	37997	(2-chloro-4-fluorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₄ClFN₂O	详情	详情
(V)	37998	3-methyl-1H-pyrazole	1453-58-3	C₄H₆N₂	详情	详情
(VI)	37999	[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)phenyl][5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₂₃H₁₉ClN₄O	详情	详情

合成路线2

Treatment of benzonitrile derivative (I) with 3-methylpyrazole (II) and NaH in DMF or KOtBu in THF yields a mixture of regioisomers from which compound (III) is obtained by recrystallization. Compound (III) is then converted into the corresponding benzamide (IV) by means of K2CO3 and H2O2 in DMSO. Hydrolysis of (IV) with aqueous H2SO4 and NaNO2 affords benzoic acid derivative (V), which is then condensed with benzodiazepine (VI) in the presence of DIEA by means of oxalyl chloride in CH2Cl2 and catalytic DMF. Alternatively (V) can be obtained by direct hydrolysis of (III) with NaOH in EtOH or by following this route: Condensation of methyl ester (VII) with 3-methyl pyrazole (II) by means of KH in DMF provides a mixture of regioisomers from which compound (VIII) is chromatographically separated and finally saponified by treatment with LiOH in THF or NaOH in acetonitrile.

参考文献中间体

【1】 Dusza, J.P.; Ashwell, M.A.; Caggiano, T.J.; et al.; VNA-932: First orally active, nonpeptide, vasopressin V2 receptor selective agonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 203.
【2】 Ashwell, M.A.; et al.; Synthesis and structure-activity relationships (SAR) of pyrrolobenzodiazepines related to the potent selective orally active nonpeptide vasopressin V2-receptor agonist VNA-932. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 202.
【3】 Trybulski, E.J.; Ashwell, M.A.; Molinari, A.J.; Bagli, J.F.; Chan, P.S.; Failli, A.A.; Dusza, J.P.; Albright, J.D.; Caggiano, T.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000062; WO 9906409 .

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)	43492	2-chloro-4-fluorobenzonitrile	60702-69-4	C₇H₃ClFN	详情	详情
(II)	37998	3-methyl-1H-pyrazole	1453-58-3	C₄H₆N₂	详情	详情
(III)	43493	2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzonitrile		C₁₁H₈ClN₃	详情	详情
(IV)	43494	2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzamide		C₁₁H₁₀ClN₃O	详情	详情
(V)	43495	2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoic acid		C₁₁H₉ClN₂O₂	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)	43496	methyl 2-chloro-4-fluorobenzoate	85953-29-3	C₈H₆ClFO₂	详情	详情
(VIII)	43497	methyl 2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoate		C₁₂H₁₁ClN₂O₂	详情	详情

合成路线3

The pyrrolobenzodiazepine (I) is prepared in two steps. The sodium salt of pyrrole-2-carboxaldehyde (II) is prepared in DMF using NaH. Alkylation with 2-nitrobenzyl bromide (III) proceeds in excellent yield. Reduction with hydrogen over Raney nickel effects reduction of the nitro group to the amine which cyclizes in situ to the seven-membered imine that is reduced to the pyrrolobenzodiazepine in excellent yield in one pot.

参考文献中间体

【1】 Caggiano, T.J.; WAY-VNA-932. Drugs Fut 2002, 27, 3, 248.
【2】 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.

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)I	21081	Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde	1003-29-8	C₅H₅NO	详情	详情
(I)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(III)	21082	1-(bromomethyl)-2-nitrobenzene；2-Nitrobenzyl bromide;alpha-Bromo-2-nitrotoluene	3958-60-9	C₇H₆BrNO₂	详情	详情
(IV)	21083	1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde	22162-51-2	C₁₂H₁₀N₂O₃	详情	详情

合成路线4

Acylation of the pyrrolobenzodiazepine (I) with 2-chloro-4-fluorobenzoyl chloride (V) prepared from the acid (VI) and oxalyl chloride and catalytic DMF with Hünig's base in dichloromethane gives the acylated pyrrolobenzodiazepine (VII). Treatment of (VII) with a solution of the sodium salt of 3-methylpyrazole (VIII) in DMF yields a 85:15 mixture of WAY-VNA-932 and its 5-methyl isomer (IX) which can be separated by column chromatography using an ethyl acetate/hexane mixture over silica gel.

参考文献中间体

【1】 Caggiano, T.J.; WAY-VNA-932. Drugs Fut 2002, 27, 3, 248.
【2】 Trybulski, E.J.; Ashwell, M.A.; Molinari, A.J.; Bagli, J.F.; Chan, P.S.; Failli, A.A.; Dusza, J.P.; Albright, J.D.; Caggiano, T.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000062; WO 9906409 .

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)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(V)	37996	2-chloro-4-fluorobenzoyl chloride	21900-54-9	C₇H₃Cl₂FO	详情	详情
(VI)	10801	2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid	2252-51-9	C₇H₄ClFO₂	详情	详情
(VII)	37997	(2-chloro-4-fluorophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₁₉H₁₄ClFN₂O	详情	详情
(VIII)	37998	3-methyl-1H-pyrazole	1453-58-3	C₄H₆N₂	详情	详情
(IX)	52180	[2-chloro-4-(5-methyl-1H-pyrazol-1-yl)phenyl][5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone		C₂₃H₁₉ClN₄O	详情	详情

合成路线5

Alternatively, treatment of 2-chloro-4-fluorobenzonitrile (X) with the potassium salt of 3-methylpyrazole (VIII) in THF produces an excellent yield of a 9:1 mixture of the 2-chloro-4-(3-methylpyrazol-1-yl)benzonitrile (XI) and 2-chloro-4-(5-methylpyrazol-1-yl)benzonitrile (XII) which can be separated by fractional crystallization. Hydrolysis of the nitrile (XI) to the acid, activation as the acid chloride and acylation of the pyrrolobenzodiazepine using Hünig's base in dichloromethane yields WAY-VNA-932 which is isolated by direct crystallization.

参考文献中间体

【1】 Caggiano, T.J.; WAY-VNA-932. Drugs Fut 2002, 27, 3, 248.
【2】 Trybulski, E.J.; Ashwell, M.A.; Molinari, A.J.; Bagli, J.F.; Chan, P.S.; Failli, A.A.; Dusza, J.P.; Albright, J.D.; Caggiano, T.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000062; WO 9906409 .

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)	21084	10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine	22162-53-4	C₁₂H₁₂N₂	详情	详情
(VIII)	37998	3-methyl-1H-pyrazole	1453-58-3	C₄H₆N₂	详情	详情
(X)	43492	2-chloro-4-fluorobenzonitrile	60702-69-4	C₇H₃ClFN	详情	详情
(XI)	43493	2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzonitrile		C₁₁H₈ClN₃	详情	详情
(XII)	52181	2-chloro-4-(5-methyl-1H-pyrazol-1-yl)benzonitrile		C₁₁H₈ClN₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)