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【结 构 式】

【分子编号】15670

【品名】2-Methylimidazole; 2-Methyl-1H-imidazole

【CA登记号】693-98-1

【 分 子 式 】C4H6N2

【 分 子 量 】82.10512

【元素组成】C 58.52% H 7.37% N 34.12%
与该中间体有关的原料药合成路线共 17 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线1

该中间体在本合成路线中的序号：(I)

2-Methylimidazole (I) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in Ac2O to produce 2-methyl-4-nitroimidazole (II) . In a variant of this procedure, 2-methylimidazole (I) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. Imidazole (II) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. Alternatively, the alkylation of (II) has been reported by treatment with ethylene oxide (III) under acidic conditions.

参考文献 中间体
合成目标
【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 .
【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 .
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) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(II) 33273 2-methyl-5-nitro-1H-imidazole; 2-methyl-5-nitroimidazole 696-23-1 C4H5N3O2 详情 详情
(III) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 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 nitration of (I) with HNO3 and H2SO4 gives 2-methyl-4(5)-nitroimidazole (II), which is then condensed with refluxing 1-chloroisopropanol (B) or with propylene oxide in 85% formic acid (A).

参考文献 中间体
合成目标
【1】 Nouveaux derives de l'imidazole et compositions les contenant. FR 3270M .
【2】 Cosar, C.; Crisan, C.; Horclois, R.; Jacob, R.M.; Robert, J.; Tchelitcheff, S.; Vaupre,R.; Nitroimidazoles. Arzneim-Forsch Drug Res 1966, 16, 1, 23-29.
【3】 Hillier, K.; Secnidazole. Drugs Fut 1979, 4, 4, 280.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 24485 Propylene oxide; 2-Methyloxirane C3H6O 详情 详情
(B) 33274 1-chloro-2-propanol; 1-chloroisopropanol 127-00-4 C3H7ClO 详情 详情
(I) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(II) 33273 2-methyl-5-nitro-1H-imidazole; 2-methyl-5-nitroimidazole 696-23-1 C4H5N3O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of (I) with propylene oxide (A) in ethanol at 20 C gives 1-(2-hydroxypropyl)-2-methylimidazole (III), which is acetylated with acetyl chloride in refluxing acetonitrile yielding the corresponding acetate (IV). The nitration of (IV) by means of HNO3 and P2O5 affords 1-(2-acetoxypropyl)-2-methyl-4-nitroimidazole (V), which is finally hydrolyzed with 4N HCl at 90 C.

参考文献 中间体
合成目标
【1】 Cosar, C.; Crisan, C.; Horclois, R.; Jacob, R.M.; Robert, J.; Tchelitcheff, S.; Vaupre,R.; Nitroimidazoles. Arzneim-Forsch Drug Res 1966, 16, 1, 23-29.
【2】 Jeanmart, C.; Messer, M. (Aventis Pharma SA); New process for the preparation of 5-nitroimidazole derivatives. DE 2107405; FR 2079880; GB 1278757; JP 49080066 .
【3】 Hillier, K.; Secnidazole. Drugs Fut 1979, 4, 4, 280.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 24485 Propylene oxide; 2-Methyloxirane C3H6O 详情 详情
(I) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(III) 33275 1-(2-methyl-1H-imidazol-1-yl)-2-propanol; 1-(2-hydroxypropyl)-2-methylimidazole C7H12N2O 详情 详情
(IV) 33276 1-methyl-2-(2-methyl-1H-imidazol-1-yl)ethyl acetate C9H14N2O2 详情 详情
(V) 33277 1-(2-Acetoxypropyl)-2-methyl-4-nitroimidazole; 1-Methyl-2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl acetate C9H13N3O4 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

The reaction of (I) with chloroacetone (C) by means of K2CO3 in refluxing acetone gives (2-methylimidazol-1-yl)acetone (VI), which is nitrated with HNO3 and P2O5 affording the corresponding nitro compound (VII). Finally, this product is reduced with NaBH4 in methanol at room temperature.

参考文献 中间体
合成目标
【1】 Cosar, C.; Crisan, C.; Horclois, R.; Jacob, R.M.; Robert, J.; Tchelitcheff, S.; Vaupre,R.; Nitroimidazoles. Arzneim-Forsch Drug Res 1966, 16, 1, 23-29.
【2】 Jeanmart, C.; Messer, M. (Aventis Pharma SA); Process for the preparation of 5-nitroimidazole derivatives. CH 513177; DE 2107423; FR 2079879; GB 1278758; NL 7101641 .
【3】 Hillier, K.; Secnidazole. Drugs Fut 1979, 4, 4, 280.
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) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(VI) 33278 (2-methylimidazol-1-yl)acetone; 1-(2-methyl-1H-imidazol-1-yl)acetone C7H10N2O 详情 详情
(VII) 33279 1-(2-methyl-5-nitro-1H-imidazol-1-yl)acetone C7H9N3O3 详情 详情
(C) 15288 1-Chloroacetone; Chloroacetone 78-95-5 C3H5ClO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(D)

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.

参考文献 中间体
合成目标
【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6

该中间体在本合成路线中的序号：(IX)

Condensation of 2-bromo-p-toluidine (I) with cyclohexane-1,3-dione (II) gives bromo enaminone (III), which is N-methylated with iodomethane and NaH, affording tertiary enaminone (IV). Treatment of (IV) with triphenylphosphine-palladium acetate complex/NHCO3 or palladium acetate in acetonitrile provides carbazolone (V). Treatment of carbazolone (V) with sodium metal in EtOH/dioxane (or sodium methoxide in 1,2-dimethoxyethane) and diethyl oxalate (VI) provides ethoxallyl derivative (VII), which is then converted into glyoxylic acid lactone (VIII). Coupling of (VIII) with 2-methylimidazol (IX) by means of benzyltriethylammonium chloride in CHCl3/H2O furnishes glyoxylate (X), which is converted into the target product by reaction again with 2-methylimidazol (IX) in dioxane and final treatment with HCl. Alternatively, glyoxylate (X) can be directly obtained from (VIII) by reaction with formaldehyde and 2-methylimidazol (IX) in dioxane.

参考文献 中间体
合成目标
【1】 Iida, H.; et al.; Intramolecular cyclization of enaminones involving arylpalladium complexes. Synthesis of carbazoles. J Org Chem 1980, 45, 15, 2938.
【2】 Harsanyi, K.; Bod, P.; Trischler, F.; Fekecs, E.; Horvath, E.; Csehl, A.; Hegedus, B.; Mersich, E.; Szabo, G. (Gedeon Richter Ltd.); Carbazolone derivs. and process for preparing the same. EP 0595111 .
【3】 Dobay, L.; Czibula, L.; Szantay, C.; Gazdag, M.; Greiner, I.; Werkne Papp, E.; Tarkanyi, G.; Zsoldosne Babjak, M.; Mihalyfi, K. (Gedeon Richter Ltd.); An intermediate and process for its synthesis. WO 0172716 .
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) 27739 2-bromoaniline 615-36-1 C6H6BrN 详情 详情
(II) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(III) 53887 3-(2-bromoanilino)-2-cyclohexen-1-one n/a C12H12BrNO 详情 详情
(IV) 53888 3-[2-bromo(methyl)anilino]-2-cyclohexen-1-one n/a C13H14BrNO 详情 详情
(V) 53889 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 27387-31-1 C13H13NO 详情 详情
(VI) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(VII) 53890 ethyl 2-hydroxy-2-(9-methyl-4-oxo-1,2,4,9-tetrahydro-3H-carbazol-3-ylidene)acetate n/a C17H17NO4 详情 详情
(VIII) 53891 　 n/a C16H13NO4 详情 详情
(IX) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(X) 53892 2-methyl-1H-imidazol-3-ium 2-[3-(hydroxymethyl)-9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-2-oxoacetate n/a C20H21N3O5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(III)

Mannich alpha-methylenation of N-methyltetrahydrocarbazolone (I) with morpholine in refluxing acetic and acid formaldehyde provides methylenecarbazolone derivative (II), which is then subjected to Michael addition with 2-methylimidazole (III) by means of alumina in refluxing toluene. Finally, formation of the desired hydrochloride dihydrate salt is obtained by treatment with HCl.

参考文献 中间体
合成目标
【1】 Kim, M.Y.; et al.; An efficient process of ondansetron synthesis. Heterocycles 1997, 45, 10, 2041.
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) 53889 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 27387-31-1 C13H13NO 详情 详情
(II) 53893 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C14H13NO 详情 详情
(III) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(V)

Condensation of the lithium salt of indole derivative (I) with bromomethyl acrylic acid (II) in THF affords butyric acid derivative (III), which is then subjected to saponification with KOH in a refluxing mixture of MeOH /H2O to provide diacid compound (IV). Treatment of (IV) with 2-methylindole (V) at 160 C yields derivative (VI), which is finally converted into the desired product by first reaction with phosphoric acid and trifluoroacetic anhydride in acetonitrile, followed by hydrochloride dihydrate salt formation by treatment with HCl.

参考文献 中间体
合成目标
【1】 Caldero Ges, J.M.; Huguet Clotet, J. (Vita-Invest, SA); Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. ES 2043535 .
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) 53894 ethyl 1,2-dimethyl-1H-indole-3-carboxylate n/a C13H15NO2 详情 详情
(II) 53895 2-(Bromomethyl)acrylic acid; alpha-(Bromomethyl)acrylic acid 72707-66-5 C4H5BrO2 详情 详情
(III) 53896 2-{2-[3-(ethoxycarbonyl)-1-methyl-1H-indol-2-yl]ethyl}acrylic acid n/a C17H19NO4 详情 详情
(IV) 53897 2-(3-carboxy-3-butenyl)-1-methyl-1H-indole-3-carboxylic acid n/a C15H15NO4 详情 详情
(V) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(VI) 53898 2-[(2-methyl-1H-imidazol-1-yl)methyl]-4-(1-methyl-1H-indol-2-yl)butanoic acid n/a C18H21N3O2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VII)

Condensation of 2-iodoaniline (I) with cyclohexane-1,3-dione (II) at 120 C yields secondary amine (III), which is then methylated with iodomethane by means of sodium hydride in refluxing benzene to provide tertiary amine (IV). Treatment of (IV) with lithium diisopropylamide (LDA) and dimethylaminomethylene iodide (Eschenmoser's salt) (V) in THF yields dimethylaminomethyl derivative (VI), which is then coupled with 2-methylindole (VII) in DMF to give compound (VIII). Cyclization of cyclohexenone derivative (VIII) by means of palladium (II) acetate and triethylamine in acetonitrile provides carbazolone derivative (IX), which is finally converted into the desired hydrochloride salt by treatment with HCl.

参考文献 中间体
合成目标
【1】 Bell, J.A.; Ewan, G.B.; Humber, D.C.; Costes, I.H.; Godfrey, N. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0221629 .
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) 27725 2-iodoaniline 615-43-0 C6H6IN 详情 详情
(II) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(III) 53899 3-(2-iodoanilino)-2-cyclohexen-1-one n/a C12H12INO 详情 详情
(IV) 53900 3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one n/a C13H14INO 详情 详情
(V) 48555 Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide C3H8IN 详情 详情
(VI) 53901 6-[(dimethylamino)methyl]-3-[2-iodo(methyl)anilino]-2-cyclohexen-1-one n/a C16H21IN2O 详情 详情
(VII) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(VIII) 53902 3-[2-iodo(methyl)anilino]-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one n/a C18H20IN3O 详情 详情
(IX) 53903 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C18H19N3O 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

Treatment of tetrahydrocarbazolone (I) with formaldehyde and dimethylamine in EtOH provides tertiary amine (II), which is then methylated with refluxing iodomethane to furnish methanaminium iodide (III). Condensation of (III) with 2-methylimidazole (IV) in DMF affords free base (V), which is converted into the desired product, the hydrochloride dihydrate, by treatment with HCl in isopropanol/water. Alternatively, free base (V) can be obtained by other related procedures: (a) treatment of methanaminium iodide (III) with sodium carbonate in water to furnish methylene derivative (VI) followed by condensation with 2-methylimidazole (IV) in refluxing water; (b) conversion of (VI) into chloromethyl derivative (VII) by treatment with ethereal HCl in CHCl3, followed by reaction of (VII) with 2-methylimidazole (IV) in DMF; (c) treatment of dimethylamino derivative (VIII) with 2-methylimidazole (IV) in refluxing water; or (d) methylation of carbazolone (IX) with dimethylsulfate and sodium hydride in DMF.

参考文献 中间体
合成目标
【1】 Tyers, M.B. (GlaxoSmithKline plc); Ketone derivs.. EP 0275668; JP 1988253083; US 4845115 .
【2】 Coates, I.H.; Bell, J.A.; Ewan, G.B.; Humber, D.C. (GlaxoSmithKline plc); 1,2,3,9-Tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, compsn. containing them, and method of using them to treat neuronal 5HT function disturbances. AU 8652614; EP 0191562; JP 1986210083; US 4695578 .
【3】 Coates, I.H.; Bell, J.A.; Hunber, D.C.; Ewan, G.B. (GlaxoSmithKline plc); Imidazolylmethyl substd. carbazoles. AU 8538097; BE 0901576; CH 664152; ES 8609309; ES 8708224; ES 8801247; FR 2561244; GB 2153821; JP 1985214784 .
【4】 Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc); Pharmaceutical product. DE 3740351 .
【5】 Kraus, W.; Weisert, A.; Spies, J. (GlaxoSmithKline plc); Pharmaceutical product. DE 3906883 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II),(VIII) 53904 3-[(dimethylamino)methyl]-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C16H20N2O 详情 详情
(I) 53889 9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 27387-31-1 C13H13NO 详情 详情
(III) 53905 N,N,N-trimethyl(9-methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanaminium iodide n/a C17H23IN2O 详情 详情
(IV) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(V) 53903 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C18H19N3O 详情 详情
(VI) 53893 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C14H13NO 详情 详情
(VII) 53906 3-(chloromethyl)-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C14H14ClNO 详情 详情
(IX) 53907 3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C17H17N3O 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IV)

Treatment of 3-methoxy-2-cyclohexen-1-one (I) with n-butyllithium and diisopropylamine in THF, followed by addition of N,N-dimethylmethylene ammonium iodide (Eschenmoser's salt) (II) and precipitation with maleic acid, furnishes maleate (III). Methylation of (III) with iodomethane in DMF, followed by condensation with 2-methylimidazole (IV), affords compound (V), which is then converted into methylphenyl hydrazino derivative (VII) by first treatment with HCl in H2O followed by reaction with 1-methyl-1-phenylhydrazine (VI). Cyclization of (VII) is then performed by means of ZnCl2 in HOAc at 85 C to give carbazolone (VIII), and finally the target product is obtained by formation of the hydrochloride dihydrate salt.

参考文献 中间体
合成目标
【1】 Bell, J.A.; Ewan, G.B.; Oxford, A.W.; Humber, D.C.; Eldred, C.D.; Costes, I.H. (GlaxoSmithKline plc); Process for the preparation of 3-imidazolylmethyltetrahydrocarbazolones. EP 0219929 .
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) 53908 3-Methoxy-2-cyclohexen-1-one 16807-60-6 C7H10O2 详情 详情
(II) 48555 Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide C3H8IN 详情 详情
(III) 55373 　 C14H21NO6 详情 详情
(IV) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(V) 53910 3-methoxy-6-[(2-methyl-1H-imidazol-1-yl)methyl]-2-cyclohexen-1-one C12H16N2O2 详情 详情
(VI) 53911 1-Methyl-1-phenylhydrazine; 1-Methylphenylhydrazine 618-40-6 C7H10N2 详情 详情
(VII) 53912 6-[(2-methyl-1H-imidazol-1-yl)methyl]-3-(2-methyl-2-phenylhydrazino)-2-cyclohexen-1-one n/a C18H22N4O 详情 详情
(VIII) 53903 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one n/a C18H19N3O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(X)

The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II), which is reduced with LiAlH4 in THF, yielding the tetrahydroquinoline (III). The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV), which is reduced wiith LiAlH4 in THF to the N-amino compound (V). The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII), which is cyclized by means of HCl in refluxing acetic acid, yielding the tetracyclic compound (VIII). The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX), which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI). Finally, this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.

参考文献 中间体
合成目标
【1】 Castaner, J.; Rabasseda, X.; Silvestre, J.S.; Graul, A.; Cilansetron. Drugs Fut 1999, 24, 5, 475.
【2】 Haeck, H.H.; Hamminga, D.; Van Wijngaarden, I.; Wouters, W. (Duphar International Research BV); New anellated indole derivs.. AU 8818414; EP 0297651; JP 1989022870; US 4939136 .
【3】 Verbeek, J.-M.; Van der Meij, P.F.C. (Duphar International Research BV); Process for the preparation of enantiomerically pure imidazolyl cpds.. EP 0768309 .
【4】 de Jonge, A.; Tulp, M.T.M.; Olivier, B.; Tipker, J.; van Hes, R.; Mol, F.; Hamminga, D.; Standaar, P.J.; Van Wijngaarden, I.; Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. 1. J Med Chem 1993, 36, 23, 3693.
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) 23857 1-indanone 83-33-0 C9H8O 详情 详情
(II) 18553 3,4-dihydro-2(1H)-quinolinone 553-03-7 C9H9NO 详情 详情
(III) 23859 1,2,3,4-tetrahydroquinoline 635-46-1 C9H11N 详情 详情
(IV) 23860 1-nitroso-1,2,3,4-tetrahydroquinoline C9H10N2O 详情 详情
(V) 23861 3,4-dihydro-1(2H)-quinolinylamine; 3,4-dihydro-1(2H)-quinolinamine C9H12N2 详情 详情
(VI) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(VII) 23863 3-[3,4-dihydro-1(2H)-quinolinylimino]cyclohexanone C15H18N2O 详情 详情
(VIII) 23864 5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one C15H15NO 详情 详情
(IX) 23865 10-[(dimethylamino)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one C18H22N2O 详情 详情
(X) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(XI) 23867 10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one C20H21N3O 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

MCI-196 is synthesized by condensation of 2-methylimidazole (I) with epichlorohydrin (II) as follows: Equimolecular parts (0.5 M: 0.5 M) of (I) and (II) were allowed to condense in water (100 ml) at 90 C for 14 h; then 0.094 mol of (II) wa added and the reaction continued for 2 h at 45 C. The resulting resin was treated with 0.094 M of a 20% aqueous solution of NaOH and heated at 45 C for 2 h more. Finally, heat curing of the resin at 120 C for 5 h was performed. The resin was isolated by precipitation with water.

参考文献 中间体
合成目标
【1】 Toda, H. (Mitsubishi Chemical Corp.); Process for the preparation of granular basic ion exchange resins. JP 1985245626 .
【2】 Nomura, T.; Hamada, Y.; Kurihara, Y. (Mitsubishi Chemical Corp.); Oral hypocholesterolemic agents. JP 1992013627 .
【3】 Nomura, T.; Hamada, Y.; Kurihara, Y. (Mitsubishi Chemical Corp.); Oral hypocholesterolemic agents. JP 1990124819 .
【4】 Toda, H.; Kihara, K. (Bristol-Myers Squibb Co.); Novel quaternary salt of polymer. BE 0898807; CH 663415; DE 3403125; GB 2134119; NL 8400237 .
【5】 Toda, H.; Kihara, K. (Mitsubishi Chemical Corp.); Improved preparation process for anion exchange resins. JP 1984155421 .
【6】 Toda, H.; Mizogami, S.; Kihara, K.; Hashimoto, M.; Bile acid binding and hypocholesterolemic activity of a new anion exchange resin from 2-methylimidazol and epichlorohydrin. J Pharm Sci 1988, 77, 6, 531.
【7】 Castaner, J.; Prous, J.; MCI-196. Drugs Fut 1993, 18, 1, 15.
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) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(III)

Alkylation of diphenylacetonitrile (I) with dibromoethane provided bromide (II). This was condensed with 2-methylimidazole (III) in the presence of Et3N in DMF to afford the substituted imidazole (IV). Finally, hydrolysis of the cyano group of (IV) with 70% sulfuric acid produced the target amide.

参考文献 中间体
合成目标
【1】 Miyachi, H.; et al.; Synthesis and antimuscarinic activity of a series of 4-(1-imidazolyl)-2,2-diphenylbutyramides: Discovery of potent and subtype-selective antimuscarinic agents. Bioorg Med Chem 1999, 7, 6, 1151.
【2】 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(I) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 26217 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile 39186-58-8 C16H14BrN 详情 详情
(III) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(IV) 26218 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile C20H19N3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The compound was obtained by condensation of 2-(chloromethyl)pyridine (I) with 2-methylimidazole (II) in hot DMF. The free base (III) was then treated with fumaric acid in EtOH to produce the title fumarate salt.

参考文献 中间体
合成目标
【1】 Giger, R.K.A. (Novartis AG; Novartis Deutschland GmbH); Imidazolylmethyl-pyridines. DE 4131584; EP 0534904; JP 1993194491; US 5635521 .
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) 26187 2-(Chloromethyl)pyridine 4377-33-7 C6H6ClN 详情 详情
(II) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(III) 37793 2-[(2-methyl-1H-imidazol-1-yl)methyl]pyridine C10H11N3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IV)

Treatment of acetonitrile derivative (I) with dibromoethane (II) in toluene in the presence of NaNH2 affords bromo compound (III), which is then condensed with imidazole derivative (IV) by means of Et3N in DMF to provide compound (V). Hydrolysis of the cyano group of (V) with aqueous H2SO4 yields amide derivative (VI), which is finally subjected to alkyl quaternization by reaction with bromobenzyl bromide (VI) in acetone to furnish the desired product.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Kiyota, H.; Segawa, M.; Design, synthesis and antimuscarinic activity of some imidazolium derivatives. Bioorg Med Chem Lett 1999, 9, 20, 3003.
【2】 Miyachi, H.; Okazaki, K.; Kiyota, H.; Segawa, M. (Kyorin Pharmaceutical Co., Ltd.); Novel imidazole deriv. and process for producing the same. EP 0733621; US 5932607; US 6103747; WO 9515951 .
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) 14493 alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile 86-29-3 C14H11N 详情 详情
(II) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(III) 26217 4-Bromo-2,2-diphenylbutyronitrile; 4-Bromo-2,2-diphenylbutanenitrile 39186-58-8 C16H14BrN 详情 详情
(IV) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(V) 26218 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanenitrile C20H19N3 详情 详情
(VI) 47152 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide 170105-16-5 C20H21N3O 详情 详情
(VII) 16109 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide 589-15-1 C7H6Br2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VII)

Arylation of 2-methylimidazole (VII) with1-fluoro-4-iodobenzene (VIII) gives the iodophenyl imidazole (IX). Then, condensation of aryl iodide (IX) with thiophenol (VI) produces the diaryl sulfide (X). Finally, partial hydrolysis of the cyano group of (X) employing KOH in t-butanol yields the target carboxamide

参考文献 中间体
合成目标
【1】 Stevens, R.W.; Mano, T.; Nakao, K.; Okumura, Y. (Pfizer Inc.); 5-Lipoxygenase inhibitors. EP 0787127; JP 1999507322; US 5883106; WO 9611911 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 60260 4-(3-fluoro-5-sulfanylphenyl)tetrahydro-2H-pyran-4-carbonitrile C12H12FNOS 详情 详情
(VII) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(VIII) 54686 1-Fluoro-4-iodobenzene; 4-Fluoroiodobenzene; 4-Iodofluorobenzene; p-Fluoroiodobenzene 352-34-1 C6H4FI 详情 详情
(IX) 60261 1-(4-iodophenyl)-2-methyl-1H-imidazole C10H9IN2 详情 详情
(X) 60262 4-(3-fluoro-5-{[4-(2-methyl-1H-imidazol-1-yl)phenyl]sulfanyl}phenyl)tetrahydro-2H-pyran-4-carbonitrile C22H20FN3OS 详情 详情
Extended Information