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【结 构 式】 
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【分子编号】15866 【品名】ethanimidamide 【CA登记号】 |
【 分 子 式 】C2H6N2 【 分 子 量 】58.08312 【元素组成】C 41.36% H 10.41% N 48.23% |
合成路线1
该中间体在本合成路线中的序号：(C)Compound can be prepared in three different related ways: 1) The reaction of 5-(o-clorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine-2-one (I) with P2S5 in pyridine at 80 C gives the corresponding thioketone (II), which by reaction with hydrazine hydrate (A) in methanol yields 2-hydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (III). Finally, this compound is cyclized with acetic anhydride acetic acid in refluxing benzene. This cyclization can also be carried out with refluxing ethyl orthoacetate (E) and H2SO4, with acetimino ethyl ether (G) in refluxing chloroform, with acetamidine hydrochloride (C) and 2-methylimidazole (D) at 160 C or thioacetamide (F) and H2SO4 at 190 C. 2) The condensation of thioketone (II) with acetohydrazide (B) in refluxing chloroform gives 2-acetylhydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (IV), which is then cyclized with acetic acid in refluxing benzene or by heating at 205 C. 3) The acetylated compound (IV) can also be obtained by acetylation of (III) with acetic anhydride and triethylamine at room temperature.
| 【1】 Nakanishi, M.; et al.; ZA 7204610 . |
| 【2】 Thorpe, P.J.; Castaner, J.; Etizolam. Drugs Fut 1979, 4, 1, 22. |
| 【3】 Nakanishi, M.; et al.; US 3904641 . |
| 【4】 Tahara, T.; et al.; Syntheses and structure-activity relationship pf 6-aryl-4H-s-triazolo[3,4-c]thieno[2,3-e](1,4)diazepines. Arzneim-Forsch Drug Res 1978, 28, 7, 1153-58. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (D) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (F) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (A) | 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 |
| (B) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
| (E) | 39465 | 1-ethoxy-1,1-ethanediol | C4H10O3 | 详情 | 详情 | |
| (I) | 39461 | 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one | C15H13ClN2OS | 详情 | 详情 | |
| (II) | 39462 | 5-(2-chlorophenyl)-7-ethyl-1,3,5a,8a-tetrahydro-2H-thieno[2,3-e][1,4]diazepine-2-thione | C15H15ClN2S2 | 详情 | 详情 | |
| (III) | 39463 | 5-(2-chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno[2,3-e][1,4]diazepine | C15H15ClN4S | 详情 | 详情 | |
| (IV) | 39464 | N'-[5-(2-chlorophenyl)-7-ethyl-3H-thieno[2,3-e][1,4]diazepin-2-yl]acetohydrazide | C17H17ClN4OS | 详情 | 详情 | |
| (C) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The cyclization of acetamidine (I) with 2-cyano-3,3-bis(methylthio)-2-propenoic acid methyl ester (II) by means ot NaH in DMF gives 2-methyl-6-(methylthio)-4 oxo-1,4-dihydropyrimidine-5-carbonitrile (III), which is then condensed with 3-pyridylmethyl amine (IV) by refluxing in dimethoxyethane solution.
| 【1】 Bagli, J.F. (American Home Products Corp.); Amino-pyrimidine derivs.. EP 0130735; ES 8602694; JP 1985025974; US 4505910 . |
| 【2】 Prous, J.; Castaner, J.; Pelrinone hydrochloride. Drugs Fut 1988, 13, 8, 728. |
| 【3】 Bagli, J.; Bogri, T.; Palameta, B.; Rakhit, S.; Peseckis, S.; McQuillan, J.; Lee, D.K.; Chemistry and positive inotropic effect of pelrino. J Med Chem 1988, 31, 4, 814-23. |
| 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) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 | |
| (II) | 22737 | methyl 2-cyano-3,3-bis(methylsulfanyl)acrylate | C7H9NO2S2 | 详情 | 详情 | |
| (III) | 22738 | 2-methyl-6-(methylsulfanyl)-4-oxo-1,4-dihydro-5-pyrimidinecarbonitrile | C7H7N3OS | 详情 | 详情 | |
| (IV) | 18731 | 3-pyridinylmethanamine; 3-pyridinylmethylamine | 3731-52-0 | C6H8N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)1) The cyclization of 2-acetylglutaric acid diethyl ester (I) with acetamidine (II) by means of sodium ethoxide in refluxing ethyl ether gives the pyrimidinone derivative (III), which by treatment with refluxing phosphorus oxychloride is converted into the chloropyrimidine (IV). The cyclization of (IV) with 4-bromobenzylamine (V) by means of NaHCO3 in refluxing butanol affords 8-(4-bromobenzyl)-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VI), which is condensed with 2-(2-tert-butyltetrazol-5-yl)phenylboronic acid (VII) by means of tetrakis(triphenylphosphine)palladium in refluxing toluene/ethanol to give 8-[2'-(2-tert-butyltetrazol-5-yl)biphenyl-4-ylmethyl]-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VIII). Finally, this compound is deprotected with methanesulfonic acid in refluxing toluene. (1,2) 2) The boronic acid (VII) has been obtained as follows: The cyclization of 2-bromobenzonitrile (IX) with sodium azide in hot DMF, followed by protection with tert-butanol in trifluoroacetic acid/H2SO4 gives 5-(2-bromophenyl)-2-tertbutyltetrazole (X), which is finally condensed with triisopropyl borate by means of butyllithium in THF and hydrolyzed with HCl. (1,2)
| 【1】 Merlos, M.; Casas, A.; Castaner, J.; Tasosartan. Drugs Fut 1997, 22, 8, 850. |
| 【2】 Ellingboe, J.W.; Nikaido, M.; Bagli, J. (American Home Products Corp.); Substd. pyridopyrimidines useful as angiotensin II antagonists. EP 0539086; US 5149699; US 5256654 . |
| 【3】 Ellingboe, J.W.; Antane, M.; Nguyen, T.T.; et al.; Pyrido[2,3-p]pyrimidine angiotensin II antagonists. J Med Chem 1994, 37, 4, 542-50. |
| 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) | 15865 | Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate | 1501-06-0 | C11H18O5 | 详情 | 详情 |
| (II) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 | |
| (III) | 15867 | ethyl 3-(2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl)propanoate | C11H16N2O3 | 详情 | 详情 | |
| (IV) | 15868 | ethyl 3-(4-chloro-2,6-dimethyl-5-pyrimidinyl)propanoate | C11H15ClN2O2 | 详情 | 详情 | |
| (V) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (VI) | 15870 | 8-(4-bromobenzyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one | C16H16BrN3O | 详情 | 详情 | |
| (VII) | 15871 | 2-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl]phenylboronic acid | C11H15BN4O2 | 详情 | 详情 | |
| (VIII) | 15872 | 8-([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one | C27H29N7O | 详情 | 详情 | |
| (IX) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (X) | 15874 | 5-(2-bromophenyl)-2-(tert-butyl)-2H-1,2,3,4-tetraazole | C11H13BrN4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)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5
该中间体在本合成路线中的序号：(VIII)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6
该中间体在本合成路线中的序号：(III)Claisen condensation of diethyl carbonate with p-fluoroacetophenone (I) produced keto ester (II). This was cyclized to the pyrimidine (IV) by treatment with acetamidine hydrochloride (III) in the presence of K2CO3 in hot EtOH. Chlorination of hydroxypyrimidine (IV) by means of POCl3 furnished the 4-chloropyrimidine (V). Finally, chloride displacement in (V) with the sodium alkoxide of 5-piperidino-1-pentanol (VI) gave rise to the target pyrimidinyl ether, which was isolated as the corresponding hydrochloride salt.
| 【1】 Chokai, S.; Ukai, Y.; Aoki, T.; Ideguchi, K. (Nippon Shinyaku Co., Ltd.); Heterocyclic deriv. and medicine. EP 0781766; JP 2000136184; US 6191149; WO 9607641 . |
| 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) | 37684 | 1-(4-fluorophenyl)-1-ethanone | 403-42-9 | C8H7FO | 详情 | 详情 |
| (II) | 54647 | ethyl 3-(4-fluorophenyl)-3-oxopropanoate | C11H11FO3 | 详情 | 详情 | |
| (III) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 | |
| (IV) | 54648 | 6-(4-fluorophenyl)-2-methyl-4-pyrimidinol | C11H9FN2O | 详情 | 详情 | |
| (V) | 54649 | 4-chloro-6-(4-fluorophenyl)-2-methylpyrimidine | C11H8ClFN2 | 详情 | 详情 | |
| (VI) | 54650 | 5-(1-piperidinyl)-1-pentanol | C10H21NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)The condensation of diketone (I) with hydrazine (II) in refluxing EtOH gave pyrazole (III). Carboxylic acid (IV) was then obtained by oxidative cleavage of the furan ring with KMnO4. After conversion of (IV) to the corresponding acid chloride (V), coupling with the biphenyl amine (VI) provided amide (VII). Ring closure of the fluoronitrile group with acetamidine hydrochloride (VIII) with concomitant deprotection of the N-tert-butyl group furnished the title aminoquinazoline derivative.
| 【1】 Rossi, K.A.; Clark, C.G.; Li, R.; et al.; Discovery of aminoquinazoline and aminoindazole P1 side chains as benzamidine mimics for FXa inhibitors. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 50. |
| 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) | 47956 | 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione; 1-(2-Furanyl)-4,4,4-trifluoro-1,3-butanedione | 326-90-9 | C8H5F3O3 | 详情 | 详情 |
| (II) | 49135 | 2-fluoro-5-hydrazinobenzonitrile | C7H6FN3 | 详情 | 详情 | |
| (III) | 49136 | 2-fluoro-5-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile | C15H7F4N3O | 详情 | 详情 | |
| (IV) | 49137 | 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid | C12H5F4N3O2 | 详情 | 详情 | |
| (V) | 49138 | 1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride | C12H4ClF4N3O | 详情 | 详情 | |
| (VI) | 47966 | 4'-amino-N-(tert-butyl)-3'-fluoro[1,1'-biphenyl]-2-sulfonamide | C16H19FN2O2S | 详情 | 详情 | |
| (VII) | 49139 | N-[2'-[(tert-butylamino)sulfonyl]-3-fluoro[1,1'-biphenyl]-4-yl]-1-(3-cyano-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide | C28H22F5N5O3S | 详情 | 详情 | |
| (VIII) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 |