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【结 构 式】 
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【分子编号】26677 【品名】5-fluoro-2-methylbenzoyl chloride 【CA登记号】 |
【 分 子 式 】C8H6ClFO 【 分 子 量 】172.5861432 【元素组成】C 55.68% H 3.5% Cl 20.54% F 11.01% O 9.27% |
合成路线1
该中间体在本合成路线中的序号：(VI)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.
| 【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
该中间体在本合成路线中的序号：(VI)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.
| 【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
该中间体在本合成路线中的序号：(VII)Alkylation of pyrrole-2-carboxaldehyde (II) with 2-nitrobenzyl chloride (I) in the presence of NaH afforded the N-benzyl pyrrole (III). Subsequent reductive ring closure of (III) by hydrogenation over Pd/C produced the pyrrolobenzodiazepine (IV). Acid-catalyzed esterification of 6-aminonicotinic acid (V) with either methanol or ethanol provided the corresponding esters (VIa) or (VIb). Further coupling of (VIa) or (VIb) with two equivalents of 5-fluoro-2-methylbenzoyl chloride (VII) gave rise to imide (VIII). Simultaneous hydrolysis of ester function and one benzoyl group of (VIIIa-b) with NaOH furnished acid (IX), which was then converted to the corresponding acid chloride (X) employing either thionyl chloride or oxalyl chloride. Finally, coupling of acid chloride (X) with amine (IV) in the presence of Et3N yielded the target amide.
| 【1】 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. US 5700796; WO 9749708 . |
| 【2】 Burgoyne, D.L.; Shen, Y.; Langlands, J.M.; Rogers, C.; Chau, J.H.-L.; Piers, E.; Salari, H. (InflaZyme Pharmaceuticals Ltd.); 6,7-Oxygenated steroids and uses related thereto. US 6046185; WO 9802450 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 12114 | methyl 6-aminonicotinate | C7H8N2O2 | 详情 | 详情 | |
| (VIb) | 33794 | ethyl 6-aminonicotinate | C8H10N2O2 | 详情 | 详情 | |
| (VIIIa) | 33795 | methyl 6-[bis(5-fluoro-2-methylbenzoyl)amino]nicotinate | C23H18F2N2O4 | 详情 | 详情 | |
| (VIIIb) | 33814 | ethyl 6-[bis(5-fluoro-2-methylbenzoyl)amino]nicotinate | C24H20F2N2O4 | 详情 | 详情 | |
| (I) | 33792 | 1-(chloromethyl)-2-nitrobenzene | 612-23-7 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 21081 | Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde | 1003-29-8 | C5H5NO | 详情 | 详情 |
| (III) | 21083 | 1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde | 22162-51-2 | C12H10N2O3 | 详情 | 详情 |
| (IV) | 21084 | 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine | 22162-53-4 | C12H12N2 | 详情 | 详情 |
| (V) | 33793 | 6-aminonicotinic acid | 3167-49-5 | C6H6N2O2 | 详情 | 详情 |
| (VII) | 26677 | 5-fluoro-2-methylbenzoyl chloride | C8H6ClFO | 详情 | 详情 | |
| (IX) | 33796 | 6-[(5-fluoro-2-methylbenzoyl)amino]nicotinic acid | C14H11FN2O3 | 详情 | 详情 | |
| (X) | 33797 | 6-[(5-fluoro-2-methylbenzoyl)amino]nicotinoyl chloride | C14H10ClFN2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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 .
| 【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 |