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【结 构 式】

【分子编号】37996

【品名】2-chloro-4-fluorobenzoyl chloride

【CA登记号】21900-54-9

【 分 子 式 】C7H3Cl2FO

【 分 子 量 】193.0040232

【元素组成】C 43.56% H 1.57% Cl 36.74% F 9.84% O 8.29%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

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.

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

该中间体在本合成路线中的序号:(V)

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.

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
Extended Information