【结 构 式】 |
【分子编号】14763 【品名】1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one 【CA登记号】 |
【 分 子 式 】C17H17NO3S 【 分 子 量 】315.39292 【元素组成】C 64.74% H 5.43% N 4.44% O 15.22% S 10.17% |
合成路线1
该中间体在本合成路线中的序号:(I)A new synthesis of OPC-31260 has been published: The reductocondensation of 1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-one (I) with methylamine and NaBH4 gives N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N-methylamine (II), which is methylated with formaldehyde and sodium cyanoborohydride to yield N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (III). The hydrolysis of (III) with polyphosphoric acid affords N-(2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (IV), which is acylated with 4-nitrobenzoyl chloride to the expected benzoyl derivative (VI). The reduction of the nitro group of (VI) with H2 over Pd/C affords the corresponding 4-aminobenzoyl derivative (VII), which is finally acylated with 2-methylbenzoyl chloride by means of triethylamine in dichloromethane.
【1】 Ogawa, H.; Yamashita, H.; Kondo, K.; et al.; Orally active, nonpeptide vasopressin V2 receptor antagonists: A novel series of 1-[4-(benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and related compounds. J Med Chem 1996, 39, 18, 3574. |
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) | 14763 | 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H17NO3S | 详情 | 详情 | |
(II) | 14764 | N-methyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N-methyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine | C18H22N2O2S | 详情 | 详情 | |
(III) | 14765 | N,N-dimethyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine | C19H24N2O2S | 详情 | 详情 | |
(IV) | 14762 | N,N-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-(2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)amine | C12H18N2 | 详情 | 详情 | |
(V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
(VI) | 14768 | [5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl](4-nitrophenyl)methanone | C19H21N3O3 | 详情 | 详情 | |
(VII) | 14769 | (4-aminophenyl)[5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]methanone | C19H23N3O | 详情 | 详情 | |
(VIII) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IX)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3
该中间体在本合成路线中的序号:(I)Horner-Emmons condensation of benzazepinone (I) with triethyl phosphonoacetate gave unsaturated ester (II). Subsequent reductive treatment of (II) with Mg in MeOH produced the saturated ester (III) with concomitant cleavage of the tosyl group. 2-Chloro-4-(1-pyrrolidinyl)benzoyl chloride (V) (prepared by reaction of the corresponding carboxylic acid (IV) with SOCl2) was then condensed with benzazepine (III) to produce benzamide (VI). Hydrolysis of the methyl ester function of (VI) yielded the racemic carboxylic acid (VII), which was resolved by means of esterification with (R)-2-heptanol, followed by chromatographic separation of the diastereomeric mixture. After saponification of the required diastereoisomeric ester (VIII), the resulting (R)-carboxylic acid was finally coupled with isopropylamine using diethylcyanophosphate as the condensing reagent.
【1】 Kondo, K.; et al.; Characterization of orally active nonpeptide vasopressin V2 receptor agonist. Synthesis and biological evaluation of both the (5R)- and (5S)-enantioisomers of 2-[1-(2-chloro-4-pyrrolidin-1yl-benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]-N-isopropylace. J Med Chem 2002, 45, 17, 3805. |
【2】 Ogawa, H.; Kondo, K.; Shinohara, T.; Kan, K.; Tanada, Y.; Kurimura, M.; Morita, S.; Uchida, M.; Mori, T.; Tominaga, M.; Yabuuchi, Y. (Otsuka Pharmaceutical Co., Ltd.); Benzazepine derivs. with vasopressin agonistic activity. EP 0877736; JP 1998081668; US 6096736; WO 9722591 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 | |
42235 | Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC | 2942-58-7 | C5H10NO3P | 详情 | 详情 | |
(I) | 14763 | 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H17NO3S | 详情 | 详情 | |
(II) | 27544 | ethyl 2-[1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]acetate | C21H23NO4S | 详情 | 详情 | |
(III) | 27545 | methyl 2-(2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)acetate | C13H17NO2 | 详情 | 详情 | |
(IV) | 27546 | 2-chloro-4-(1-pyrrolidinyl)benzoic acid | C11H12ClNO2 | 详情 | 详情 | |
(V) | 27547 | 2-chloro-4-(1-pyrrolidinyl)benzoyl chloride | C11H11Cl2NO | 详情 | 详情 | |
(VI) | 27548 | methyl 2-[1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetate | C24H27ClN2O3 | 详情 | 详情 | |
(VII) | 27549 | 2-[1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetic acid | C23H25ClN2O3 | 详情 | 详情 | |
(VIII) | 27550 | (1R)-1-methylhexyl 2-[(5R)-1-[2-chloro-4-(1-pyrrolidinyl)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]acetate | C30H39ClN2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(V)
【1】 Tsunoda T, Tanaka A, et al.2004.Anew synthetic route to YM087, an argirune asopressin antagonist.Heterocycles, 63: 1113---1122 |
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) | 14763 | 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H17NO3S | 详情 | 详情 | |
(I) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
(II) | 66212 | methyl 2-(4-methylphenylsulfonamido)benzoate | C15H15NO4S | 详情 | 详情 | |
(III) | 66213 | methyl 2-(N-(3-cyanopropyl)-4-methylphenylsulfonamido)benzoate | C19H20N2O4S | 详情 | 详情 | |
(IV) | 66214 | 4-ethynyl-1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one | C19H17N2O3S | 详情 | 详情 | |
(VI) | 41815 | 4-bromo-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H16BrNO3S | 详情 | 详情 | |
(VII) | 41816 | 2-methyl-6-[(4-methylphenyl)sulfonyl]-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine | C19H19N3O2S | 详情 | 详情 | |
(VIII) | 41817 | 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine | 318237-73-9 | C12H13N3 | 详情 | 详情 |
(IX) | 41818 | [2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl](4-nitrophenyl)methanone | C19H16N4O3 | 详情 | 详情 | |
(X) | 41819 | (4-aminophenyl)[2-methyl-4,5-dihydroimidazo[4,5-d][1]benzazepin-6(1H)-yl]methanone | C19H18N4O | 详情 | 详情 | |
(XII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |