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【结 构 式】 
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【分子编号】21081 【品名】Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde 【CA登记号】1003-29-8 |
【 分 子 式 】C5H5NO 【 分 子 量 】95.10084 【元素组成】C 63.15% H 5.3% N 14.73% O 16.82% |
合成路线1
该中间体在本合成路线中的序号：N1,N1'-Dithiobis(ethane-2,1-diyl)bis(hexane-1,6-diamine) (II) is prepared starting from 6-aminohexylcyste amine (I) by potassium ferricyanide oxidation. The condensation of (II) with pyrrol 2-carboxaldehyde and subsequent reduction with NaHB4 of the resulting Schitf base gives (III), which is crvstallized as tetraoxatate.
| 【1】 Angeli, P.; et al.; Structure-activity relationships among benextramine-related tetraamine disulfides at peripheral alpha-adrenoreceptors. J Med Chem 1985, 28, 11, 1643. |
| 【2】 Brasili, L.; Pyrextramine. Drugs Fut 1986, 11, 1, 32. |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(I)Title compound has been obtained by two synthetic procedures: 1) Pyrrole-2-carbaldehyde (I) was alkylated with 2-nitrobenzyl bromide (II) in the presence of NaH to afford the N-nitrobenzyl pyrrole (III). Then, reductive cyclization over Pd/C produced the pyrrolobenzodiazepine (IV). Subsequent condensation of (IV) with acid chloride (VI), prepared from 3-methoxy-4-nitrobenzoic acid (V) and oxalyl chloride, gave benzamide (VII). The nitro group of (VII) was then reduced by catalytic hydrogenation over Pd/C, and the resulting amine (VIII) was further acylated with biphenyl-2-carbonyl chloride (IX) in the presence of diisopropyl ethylamine (DIEA) to yield diamide (X). Finally, the Mannich reaction with tetramethyl diaminomethane and paraformaldehyde introduced the (dimethylamino)methyl group into the pyrrole nucleus. 2) In a related procedure, 3-methoxy-4-nitrobenzoic acid (V) was esterified with MeOH in the presence of SOCl2. The nitrobenzoic ester (XI) was reduced to aminoester (XII) by hydrogenation over Pd/C, and then acylated with biphenyl-2-carbonyl chloride (IX) and DIEA to produce amide (XIII). Subsequent saponification of the ester function of (XIII), followed by treatment with oxalyl chloride furnished acid chloride (XIV), which was then condensed with the tricyclic intermediate (IV) to yield diamide (X). Finally, the (dimethylamino)methyl group was introduced, as before, by means of a Mannich reaction.
| 【1】 Ashwell, M.A.; et al.; The design, synthesis and physicochemical properties of a novel series of human vasopressin-V2 receptor antagonists. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 061. |
| 【2】 Bagli, J.F.; Ashwell, M.A.; Caggiano, T.J.; et al.; The design, synthesis and physical chemical properties of novel human vasopressin V2-receptor antagonists optimized for parenteral delivery. Bioorg Med Chem Lett 2000, 10, 8, 783. |
| 【3】 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.-W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. JP 2000510154; US 5753648; WO 9749707 . |
| 【4】 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. US 5700796; WO 9749708 . |
| 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) | 21081 | Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde | 1003-29-8 | C5H5NO | 详情 | 详情 |
| (II) | 21082 | 1-(bromomethyl)-2-nitrobenzene；2-Nitrobenzyl bromide;alpha-Bromo-2-nitrotoluene | 3958-60-9 | C7H6BrNO2 | 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) | 21085 | 3-methoxy-4-nitrobenzoic acid；4-Nitro-3-methoxybenzoic acid | 5081-36-7 | C8H7NO5 | 详情 | 详情 |
| (VI) | 21086 | 3-methoxy-4-nitrobenzoyl chloride | C8H6ClNO4 | 详情 | 详情 | |
| (VII) | 21087 | (3-methoxy-4-nitrophenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone | C20H17N3O4 | 详情 | 详情 | |
| (VIII) | 21088 | (4-amino-3-methoxyphenyl)[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone | C20H19N3O2 | 详情 | 详情 | |
| (IX) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 | |
| (X) | 21090 | N-[2-methoxy-4-[5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]phenyl][1,1'-biphenyl]-2-carboxamide | C33H27N3O3 | 详情 | 详情 | |
| (XI) | 21091 | methyl 3-methoxy-4-nitrobenzoate | 5081-37-8 | C9H9NO5 | 详情 | 详情 |
| (XII) | 21092 | methyl 4-amino-3-methoxybenzoate | 41608-64-4 | C9H11NO3 | 详情 | 详情 |
| (XIII) | 21093 | methyl 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-methoxybenzoate | C22H19NO4 | 详情 | 详情 | |
| (XIV) | 21094 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-methoxybenzoyl chloride | C21H16ClNO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)IThe 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.
| 【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5
该中间体在本合成路线中的序号：(I)The intermediate pyrrolobenzodiazepine (IV) was prepared by alkylation of pyrrole-2-carboxaldehyde (I) with 2-nitrobenzyl bromide (II), followed by reductive cyclization of the resulting nitro aldehyde (III).
| 【1】 Reich, M.F.; Delos Santos, E.G.; Albright, J.D.; Dusza, J.P.; Sum, F.-W.; 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 antagonist with selectivity for V2 receptors. J Med Chem 1998, 41, 14, 2442-44. |
| 【2】 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.-W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. JP 2000510154; US 5753648; WO 9749707 . |
| 【3】 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. US 5700796; WO 9749708 . |
| 【4】 Caggiano, T.J.; Bagli, J.F.; Trybulski, E.J.; Molinari, A.J.; Ashwell, M.A. (American Home Products Corp.); 3-Carboxamide derivs. of 5H-pyrrolo[1,2-c][1,4]-benzodiazepines. US 5880122 . |
| 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) | 21081 | Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde | 1003-29-8 | C5H5NO | 详情 | 详情 |
| (II) | 21082 | 1-(bromomethyl)-2-nitrobenzene；2-Nitrobenzyl bromide;alpha-Bromo-2-nitrotoluene | 3958-60-9 | C7H6BrNO2 | 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 |
合成路线6
该中间体在本合成路线中的序号：(X)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 |