2-chloro-4-fluorobenzonitrile -Drug Synthesis Database

【结构式】

【分子编号】43492

【品名】2-chloro-4-fluorobenzonitrile

【CA登记号】60702-69-4

【分子式】C₇H₃ClFN

【分子量】155.5586632

【元素组成】C 54.05% H 1.94% Cl 22.79% F 12.21% N 9%

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：(I)

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

合成目标

【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2

该中间体在本合成路线中的序号：(X)

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

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(VIII)

Alkylation of the dianion of azetidinonecarboxylic acid (I) with 2-ethoxybenzyl bromide (II) in cold THF affords (III). Oxidative cleavage of the carboxyl group of (III) using lead tetraacetate and HOAc provides the acetate ester (IV), which is desilylated to (V) with tetrabutylammonium fluoride in THF. Azetidinone (V) is coupled with benzhydryl 4-hydroxybenzoate (VI) to yield ether (VII). Curtius rearrangement of carboxylic acid (VIII) provides isocyanate (IX). Coupling between isocyanate (IX) and azetidine (VII) gives rise to urea (X). The benzhydryl ester group of (X) is finally cleaved by treatment with trifluoroacetic acid in the presence of anisole.

参考文献中间体

合成目标

【1】 Nakajima, M.; Kii, M.; Uenaka, M. (Shionogi & Co. Ltd.); Monocyclic beta-lactam cpds. and chymase inhibitors containing the same. EP 1099690; WO 0005204 .

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)	28418	(2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid		C₁₀H₁₉NO₃Si	详情	详情
(II)	56414	2-(bromomethyl)phenyl ethyl ether; 1-(bromomethyl)-2-ethoxybenzene		C₉H₁₁BrO	详情	详情
(III)	56415	(2R,3S)-1-[tert-butyl(dimethyl)silyl]-3-(2-ethoxybenzyl)-4-oxo-2-azetidinecarboxylic acid		C₁₉H₂₉NO₄Si	详情	详情
(IV)	56416	(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-(2-ethoxybenzyl)-4-oxoazetidinyl acetate		C₂₀H₃₁NO₄Si	详情	详情
(V)	56417	(2S,3S)-3-(2-ethoxybenzyl)-4-oxoazetidinyl acetate		C₁₄H₁₇NO₄	详情	详情
(VI)	56418	benzhydryl 4-hydroxybenzoate		C₂₀H₁₆O₃	详情	详情
(VII)	56419	benzhydryl 4-{[(2S,3S)-3-(2-ethoxybenzyl)-4-oxoazetidinyl]oxy}benzoate		C₃₂H₂₉NO₅	详情	详情
(VIII)	43492	2-chloro-4-fluorobenzonitrile	60702-69-4	C₇H₃ClFN	详情	详情
(IX)	56420	1-[isocyanato(4-methylphenyl)methyl]-4-methylbenzene; bis(4-methylphenyl)methyl isocyanate		C₁₆H₁₅NO	详情	详情
(X)	56421	benzhydryl 4-{[(2S,3S)-1-({[bis(4-methylphenyl)methyl]amino}carbonyl)-3-(2-ethoxybenzyl)-4-oxoazetidinyl]oxy}benzoate		C₄₈H₄₄N₂O₆	详情	详情

Extended Information