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【结 构 式】 
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【分子编号】21084 【品名】10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine 【CA登记号】22162-53-4 |
【 分 子 式 】C12H12N2 【 分 子 量 】184.24076 【元素组成】C 78.23% H 6.56% N 15.2% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(II)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：(IV)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：(IV)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5
该中间体在本合成路线中的序号：(III)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6
该中间体在本合成路线中的序号：(VI)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7
该中间体在本合成路线中的序号：(I)The 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8
该中间体在本合成路线中的序号：(I)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9
该中间体在本合成路线中的序号：(I)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10
该中间体在本合成路线中的序号：(IV)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11
该中间体在本合成路线中的序号：(IV)Acid chloride (VI) prepared from 2-biphenylcarboxylic acid (V) and SOCl2 was coupled with methyl 4-amino-2-chlorobenzoate (VII) to yield amide (VIII). After hydrolysis of the ester group of (VIII) with NaOH, the resulting carboxylic acid (IX) was converted to acid chloride (X) using SOCl2. Finally, condensation of (X) with the tricyclic amine (IV) in the presence of DIEA furnished the title compound.
| 【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】 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】 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 |
|---|---|---|---|---|---|---|
| (IV) | 21084 | 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine | 22162-53-4 | C12H12N2 | 详情 | 详情 |
| (V) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (VI) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 | |
| (VII) | 26678 | methyl 4-amino-2-chlorobenzoate | C8H8ClNO2 | 详情 | 详情 | |
| (VIII) | 41621 | methyl 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoate | C21H16ClNO3 | 详情 | 详情 | |
| (IX) | 41622 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoic acid | C20H14ClNO3 | 详情 | 详情 | |
| (X) | 41623 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-2-chlorobenzoyl chloride | C20H13Cl2NO2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VI)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 |