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【结 构 式】 
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【分子编号】37998 【品名】3-methyl-1H-pyrazole 【CA登记号】1453-58-3 |
【 分 子 式 】C4H6N2 【 分 子 量 】82.10512 【元素组成】C 58.52% H 7.37% N 34.12% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(II)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.
| 【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
该中间体在本合成路线中的序号：(VIII)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 |
合成路线4
该中间体在本合成路线中的序号：(VIII)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.
| 【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5
该中间体在本合成路线中的序号：(VIII)Condensation between 1,2-phenylenediamine (I) and 2-chloronicotinic acid (II) in refluxing cyclohexanol generated the tricyclic system (III). Reduction of keto group of (III) with borane-dimethyl sulfide complex afforded 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (IV). Acid chloride (VI), prepared from 4-fluoro-2-(trifluoromethyl)benzoic acid (V), was then condensed with tricyclic amine (IV) to produce amide (VII). Finally, displamecement of the 4-fluoro group of (VII) by the sodium salt of 3-methylpyrazole (VIII) in hot DMF yielded a 5:1 mixture of the title 3-methylpyrazole derivative and its 5-methyl regioisomer (IX), which were separated by column chromatography.
| 【1】 Failli, A.A.; Steffan, R.J.; Sumsky, J.S.; et al.; Pyridobenzodiazepines: Synthesis and structure-activity relationship of a novel class of orally active vasopressin V2 receptor agonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 201. |
| 【2】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 38946 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one | C12H9N3O | 详情 | 详情 | |
| (IV) | 38947 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine | C12H11N3 | 详情 | 详情 | |
| (V) | 38951 | 4-fluoro-2-(trifluoromethyl)benzoic acid | 141179-72-8 | C8H4F4O2 | 详情 | 详情 |
| (VI) | 38948 | 4-fluoro-2-(trifluoromethyl)benzoyl chloride | C8H3ClF4O | 详情 | 详情 | |
| (VII) | 38949 | 5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl[4-fluoro-2-(trifluoromethyl)phenyl]methanone | C20H13F4N3O | 详情 | 详情 | |
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (IX) | 38950 | 5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl[4-(5-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)phenyl]methanone | C24H18F3N5O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)In a modified procedure, 4-fluoro-2-(trifluoromethyl)benzoic acid (V) was converted to acid chloride (VI) and then esterified with methanol to give methyl ester (X). Condensation of (X) with 3-methylpyrazole (VIII) produced a mixture of regioisomeric pyrazoles (XI) and (XII) from which the major 3-methyl isomer (XI) could be isolated by either flash chromatography or by recrystallization from EtOAc-hexane. Basic hydrolysis of the methyl ester of (XI) gave acid (XIII), which was finally coupled with tricyclic amine (IV) via activation as the mixed anhydride with 2,4,6-trichlorobenzoic acid.
| 【1】 Failli, A.A.; Steffan, R.J.; Sumsky, J.S.; et al.; Pyridobenzodiazepines: Synthesis and structure-activity relationship of a novel class of orally active vasopressin V2 receptor agonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 201. |
| 【2】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 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) | 38947 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine | C12H11N3 | 详情 | 详情 | |
| (V) | 38951 | 4-fluoro-2-(trifluoromethyl)benzoic acid | 141179-72-8 | C8H4F4O2 | 详情 | 详情 |
| (VI) | 38948 | 4-fluoro-2-(trifluoromethyl)benzoyl chloride | C8H3ClF4O | 详情 | 详情 | |
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (X) | 38952 | methyl 4-fluoro-2-(trifluoromethyl)benzoate | C9H6F4O2 | 详情 | 详情 | |
| (XI) | 38953 | methyl 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoate | C13H11F3N2O2 | 详情 | 详情 | |
| (XII) | 38954 | methyl 4-(5-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoate | C13H11F3N2O2 | 详情 | 详情 | |
| (XIII) | 38955 | 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoic acid | C12H9F3N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)An additional improvement in the ratio of regioisomeric pyrazoles was achieved by displacement of 4-fluoro-2-(trifluoromethyl)benzonitrile (XIV) with 3-methylpyrazole (VIII) in the presence of potassium tert-butoxide to afford a 9:1 mixture of the desired 3-methylpyrazole derivative (XV) and its 5-methyl isomer. Direct recrystallization from EtOH provided pure (XV) that was then hydrolyzed to the carboxylic acid (XIII) by means of NaOH in H2O-EtOH.
| 【1】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (XIII) | 38955 | 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoic acid | C12H9F3N2O2 | 详情 | 详情 | |
| (XIV) | 38956 | 4-fluoro-2-(trifluoromethyl)benzonitrile | C8H3F4N | 详情 | 详情 | |
| (XV) | 38957 | 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzonitrile | C12H8F3N3 | 详情 | 详情 |