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【结 构 式】 
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【分子编号】18505 【品名】[1,1'-biphenyl]-2-carboxylic acid 【CA登记号】947-84-2 |
【 分 子 式 】C13H10O2 【 分 子 量 】198.2212 【元素组成】C 78.77% H 5.08% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Alkylation of benzodiazepinone (I) with 3-(chloromethyl)- pyridine (II) in the presence of NaH gave the 1-substituted benzodiazepinone (III). Reduction of the amide group of (III) with borane in THF afforded benzodiazepine (IV). Subsequent condensation with 4-nitrobenzoyl chloride (V) gave nitrobenzamide (VI), which was reduced to amine (VII) by hydrogenation in the presence of Pd/C. This compound was coupled with acid chloride (IX) (prepared by treatment of 2-phenylbenzoic acid (VIII) with oxalyl chloride) to yield the title compound.
| 【1】 Matsuhisa, A.; Koshio, H.; Sakamoto, K.; Taniguchi, N.; Yatsu, T.; Tanaka, A.; Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: Synthesis and pharmacological properties of 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl)benzanilide derivatives. Chem Pharm Bull 1998, 46, 10, 1566. |
| 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) | 18498 | 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C9H10N2O | 详情 | 详情 | |
| (II) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (III) | 18500 | 1-(3-pyridinylmethyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C15H15N3O | 详情 | 详情 | |
| (IV) | 18501 | 1-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine | C15H17N3 | 详情 | 详情 | |
| (V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (VI) | 18503 | (4-nitrophenyl)[5-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]methanone | C22H20N4O3 | 详情 | 详情 | |
| (VII) | 18504 | (4-aminophenyl)[5-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]methanone | C22H22N4O | 详情 | 详情 | |
| (VIII) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (IX) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 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 2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (I) with 4-nitrobenzoyl chloride (II) by means of TEA in CH2Cl2 gives 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (III), which is hydrogenated with H2 over Raney-Ni in MeOH, yielding the corresponding amine derivative (IV). Acylation of (IV) with biphenyl-2-carboxylic acid (V) by means of oxalyl chloride in CH2Cl2 affords the expected amide (VI) which is brominated with either Br2 or CuBr2, providing the alpha-bromo ketone (VII). This ketone (VII) is cyclized with acetamidine hydrochloride (VIII) by means of K2CO3 in MeCN, furnishing a mixture of conivaptan and oxazolo[4,5-d][1]benzodiazepine compound. Finally, conivaptan is separated by column chromatography over silica gel and is treated with 4N HCl to provide the desired hydrochloride.
| 【1】 Castañer, R.M.; Norman, P.; Rabasseda, X.; Leeson, P.A.; Castañer, J.; Conivaptan Hydrochloride. Drugs Fut 2000, 25, 11, 1121. |
| 【2】 Tanaka, A.; Koshio, H.; Taniguchi, N.; Matsuhisa, A.; Sakamoto, K.; Yamazaki, A.; Yatsu, T. (Yamanouchi Pharmaceutical Co., Ltd.); Fused benzazepine deriv. and pharmaceutical compsn. containing the same. EP 0709386; JP 1995505056; US 5723606; WO 9503305 . |
| 【3】 Koshio, H.; Taniguchi, N.; Tanaka, A.; Yatsu, T.; Matsuhisa, A.; Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: Synthesis and pharmacological properties of 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanilide derivatives and 4'-(5,6-dihydro-4H-thiazolo[5,4-d][1]benzoaze. Chem Pharm Bull 2000, 48, 1, 21. |
| 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) | 41810 | 1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C10H11NO | 详情 | 详情 | |
| (II) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 41811 | 1-(4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H14N2O4 | 详情 | 详情 | |
| (IV) | 41812 | 1-(4-aminobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H16N2O2 | 详情 | 详情 | |
| (V) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (VI) | 41813 | N-[4-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide | C30H24N2O3 | 详情 | 详情 | |
| (VII) | 41814 | N-[4-[(4-bromo-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide | C30H23BrN2O3 | 详情 | 详情 | |
| (VIII) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The bromination of 1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (IX) with Br2 in CHCl3 gives the alpha-bromo ketone (X), which is cyclized with acetamidine hydrochloride (VIII) by means of K2CO3, yielding the expected imidazo-benzazepine (XI). This compound is detosylated with hot H2SO4 to provide 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (XII). Acylation of (XII) with 4-nitroben-zoic acid (XIII) by means of pyridine in either hot MeCN or DMF affords the 6-(4-nitro-benzoyl) derivative (XIV), which is reduced with H2 and Raney-Ni in MeOH to the corres-ponding 6-(4-aminobenzoyl) compound (XV). Finally, this compound is condensed with biphenyl-2-carbonyl chloride (XVI) [ obtained by treatment of biphenyl-2-carboxylic acid (V) with oxalyl chloride in CH2Cl2/DMF] by means of pyridine in acetonitrile and treated with 4N HCl.
| 【1】 Castañer, R.M.; Norman, P.; Rabasseda, X.; Leeson, P.A.; Castañer, J.; Conivaptan Hydrochloride. Drugs Fut 2000, 25, 11, 1121. |
| 【2】 Yamazaki, A.; Tanaka, A.; Tsunoda, T. (Yamanouchi Pharmaceutical Co., Ltd.); Novel preparation method of condensed benzazepine derivs.. JP 1996198879 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (VIII) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 | |
| (IX) | 14763 | 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H17NO3S | 详情 | 详情 | |
| (X) | 41815 | 4-bromo-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H16BrNO3S | 详情 | 详情 | |
| (XI) | 41816 | 2-methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine | C19H19N3O2S | 详情 | 详情 | |
| (XII) | 41817 | 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine | 318237-73-9 | C12H13N3 | 详情 | 详情 |
| (XIII) | 18119 | 4-nitrobenzoic acid; p-nitrobenzoic acid | 62-23-7 | C7H5NO4 | 详情 | 详情 |
| (XIV) | 41818 | [2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl](4-nitrophenyl)methanone | C19H16N4O3 | 详情 | 详情 | |
| (XV) | 41819 | (4-aminophenyl)[2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl]methanone | C19H18N4O | 详情 | 详情 | |
| (XVI) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Alternatively, treatment of biphenyl-2-carboxylic acid (V) with SOCl2 and DMF in CH2Cl2 provides the acyl chloride (XVI), which is condensed with 4-aminobenzoic acid (XVII) by means of N,N-dimethylaniline in acetone to give the corresponding 4-(2-phenylbenzamido)benzoic acid (XVIII). Treatment of (XVIII) with SOCl2 and DMF in dry THF affords the acyl chloride (XIX), which is finally condensed with the inmidazobenzazepine (XII) by means of pyridine in MeCN and treated with 4N HCl.
| 【1】 Castañer, R.M.; Norman, P.; Rabasseda, X.; Leeson, P.A.; Castañer, J.; Conivaptan Hydrochloride. Drugs Fut 2000, 25, 11, 1121. |
| 【2】 Yamazaki, A.; Tanaka, A.; Tsunoda, T. (Yamanouchi Pharmaceutical Co., Ltd.); Novel preparation method of condensed benzazepine derivs.. JP 1996198879 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (XII) | 41817 | 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine | 318237-73-9 | C12H13N3 | 详情 | 详情 |
| (XVI) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 | |
| (XVII) | 20004 | p-aminobenzoic acid; 4-aminobenzoic acid | 150-13-0 | C7H7NO2 | 详情 | 详情 |
| (XVIII) | 41820 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoic acid | C20H15NO3 | 详情 | 详情 | |
| (XIX) | 36810 | 4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoyl chloride | C20H14ClNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Nitration of 2-biphenylcarboxylic acid (I) with fuming nitric acid produced a mixture of two regioisomeric dinitro derivatives. Subsequent refluxing of this mixture in dimethylacetamide provided, after crystallization, the required benzocoumarin (II). Catalytic hydrogenation of the nitro group of (II) over Pd/C yielded amine (III). Then, heating of amine (III) with acetone in a sealed tube in the presence of iodine furnished the coumarinoquinoline (IV). The reaction of (IV) with 3-fluorobenzylmagnesium bromide (V) gave the intermediate cyclic hemiacetal (VI), which was finally dehydrated with p-toluenesulfonic acid in CH2Cl2 to afford the title benzylidene compound.
| 【1】 Tegley, C.M.; Zhi, L.; Marschke, K.B.; Gottardis, M.M.; Yang, Q.; Jones, T.K.; 5-Benzylidene 1,2-dihydrochromeno[3,4-f]quinolines, a novel class of nonsteroidal human progesterone receptor agonists. J Med Chem 1998, 41, 22, 4354. |
| 【2】 Jones, T.K.; Goldman, M.E.; Pooley, C.L.F.; Winn, D.T.; Edwards, J.E.; West, S.J.; Tegley, C.M.; Zhi, L.; Hamann, L.G.; Farmer, L.J.; Davis, R.J. (Ligand Pharmaceuticals, Inc.); Steroid receptor modulator cpds. and methods. EP 0800519; JP 1998510840; US 5688808; US 5688810; US 5693646; US 5693647; US 5696127; US 5696130; US 5696133; WO 9619458 . |
| 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) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (II) | 26590 | 8-nitro-6H-benzo[c]chromen-6-one | C13H7NO4 | 详情 | 详情 | |
| (III) | 26591 | 8-amino-6H-benzo[c]chromen-6-one | C13H9NO2 | 详情 | 详情 | |
| (IV) | 26592 | 2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C19H17NO2 | 详情 | 详情 | |
| (V) | 26593 | bromo(3-fluorobenzyl)magnesium | C7H6BrFMg | 详情 | 详情 | |
| (VI) | 26594 | 5-(3-fluorobenzyl)-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C26H24FNO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)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 |