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【结 构 式】 
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【分子编号】25904 【品名】benzonitrile 【CA登记号】100-47-0 |
【 分 子 式 】C7H5N 【 分 子 量 】103.12344 【元素组成】C 81.53% H 4.89% N 13.58% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol monobenzoate (III), which is chloromethylated with formaldehyde and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The condensation of (IV) with 2,6-dichloropurine (V) by means of triethylamine in DMF yields 2,6-dichloro-9-(2-benzoyloxyethoxymethyl)purine (VI), which is aminated and debenzoylated by treatment with NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2-hydroxyethoxymethyl)adenine (VII). The Sandmeyer reaction of (VII) with NaNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII), which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.
| 【1】 Schaeffer, H.J.; et al.; 9-(2-Hydroxyethoxy)guanine activity aganist viruses of the herpes group. Nature 1978, 272, 583-585. |
| 【2】 Castaner, J.; Hillier, K.; Acycloguanosine. Drugs Fut 1978, 3, 11, 788. |
| 【3】 Schaeffer, H.J. (Glaxo Wellcome plc); Purine derivs.. US 4294831 . |
| 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) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (II) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (III) | 39965 | 2-hydroxyethyl benzoate | C9H10O3 | 详情 | 详情 | |
| (IV) | 39966 | 2-(chloromethoxy)ethyl benzoate | C10H11ClO3 | 详情 | 详情 | |
| (V) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (VI) | 39967 | 2-[(2,6-dichloro-9H-purin-9-yl)methoxy]ethyl benzoate | C15H12Cl2N4O3 | 详情 | 详情 | |
| (VII) | 39968 | 2-[(6-amino-2-chloro-9H-purin-9-yl)methoxy]-1-ethanol | C8H10ClN5O2 | 详情 | 详情 | |
| (VIII) | 39969 | 2-chloro-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol | C8H9ClN4O3 | 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 cyclization of 2(R),3(S)-dihydroxy-3-phenylpropionic acid methyl ester (I) with benzonitrile (II) by means of conc. H2SO4 gives 2,4(S)-diphenyloxazolidine-5(S)-carboxylic acid methyl ester (III). Finally, this compound is submitted to an hydrolytic treatment with aq. H2SO4 to afford the target 3(S)-benzamido-2(R)-hydroxy-3-phenylpropionic acid (IV).
| 【1】 Voronkov, M.V.; et al.; Improved large-scale synthesis of phenylisoserine and the taxol C-13 side chain. Tetrahedron Lett 2003, 44, 2, 407. |
| 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) | 23889 | methyl (2S,3R)-2,3-dihydroxy-3-phenylpropanoate | C10H12O4 | 详情 | 详情 | |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 61751 | methyl (4S,5R)-2,4-diphenyl-4,5-dihydro-1,3-oxazole-5-carboxylate | C17H15NO3 | 详情 | 详情 | |
| (IV) | 31988 | (2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropionic acid | C16H15NO4 | 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 cyclization of benzonitrile (I) with sodium azide by means of ZnCl2 in hot DMF gives 5-phenyltetrazole (II), which is condensed with trityl chloride (III) by means of TEA in THF to yield 5-phenyl-2-(triphenylmethyl)tetrazole (IV). The condensation of (IV) with 4-iodotoluene (V) by means of n-BuLi, ZnCl2, (PPh3)2NiCl2 and CH3MgCl in THF affords 5-(4'-methylbiphenyl-2-yl)-2-triphenylmethyltetrazole ?VI), which is finally brominated with N-bromosuccinimide (NBS) and AIBN in refluxing acetic acid to provide the target intermediate 5-[4'-(bromomethyl)biphenyl-2-yl]-2-(triphenylmethyl)tetrazole (VII).
| 【1】 Fisher, M.H.; Wyvratt, M.J.; Schoen, W.R.; DeVita, R.J. (Merck & Co., Inc.); Benzo-fused lactams promote release of growth hormone. EP 0513974; JP 1994172316; US 5206235; WO 9216524 . |
| 【2】 Anderson, R.K.; King, A.O.; Shuman, R.F. (Merck & Co., Inc.); Ortho-lithiation process for the synthesis of 2-substd. 1-(tetrazol-5-yl)benzenes. US 5039814 . |
| 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) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (II) | 36353 | 5-phenyl-2H-1,2,3,4-tetraazole | 18039-42-4 | C7H6N4 | 详情 | 详情 |
| (III) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (IV) | 36354 | 5-phenyl-2-trityl-2H-1,2,3,4-tetraazole | C26H20N4 | 详情 | 详情 | |
| (V) | 46620 | 1-iodo-4-methylbenzene | C7H7I | 详情 | 详情 | |
| (VI) | 46621 | 5-(4'-methyl[1,1'-biphenyl]-2-yl)-2-trityl-2H-1,2,3,4-tetraazole | C33H26N4 | 详情 | 详情 | |
| (VII) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of 5-methylindoline (I) with benzonitrile (II) by means of BCl3 and AlCl3 in dichloroethane gives the 7-benzoyl-5-methylindoline (III), which is cyclized with glycine methyl ester (IV) in pyridine yielding the tricyclic pyrrolobenzodiazepinone (V). The reaction of (V) with isoamyl nitrite and potassium tert-butoxide in THF affords the oxime (VI), which is reduced with H2 over Ru/C in methanol providing the racemic amine (VII). The optical resolution of (VII) with N-acetyl-L-phenylalanine gives the desired isomer (VIII), which is finally condensed with pyridine-4-carboxylic acid (IX) by means of O-[1-(ethoxycarbonyl)-1-cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and DIEA in dichloromethane.
| 【1】 Andrianjara, C.R.; Auclair, E.; Pascal, Y.; et al.; Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: Novel PDE4 inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 35. |
| 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) | 31641 | 5-methylindoline | C9H11N | 详情 | 详情 | |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 31642 | (5-methyl-2,3-dihydro-1H-indol-7-yl)(phenyl)methanone | C16H15NO | 详情 | 详情 | |
| (IV) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (V) | 31643 | 9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H16N2O | 详情 | 详情 | |
| (VI) | 31644 | 9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C18H15N3O2 | 详情 | 详情 | |
| (VII) | 31645 | 3-amino-9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O | 详情 | 详情 | |
| (VIII) | 31646 | (3R)-3-amino-9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O | 详情 | 详情 | |
| (IX) | 25028 | isonicotinic acid | 55-22-1 | C6H5NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The hydrogenation of 5-methoxy-1H-indole (I) by means of NaCNBH3 in acetic acid gives 5-methoxyindoline (II), which is benzoylated with benzonitrile (III) by means of BCl3/AlCl3 in dichloroethane yielding 7-benzoyl-5-methoxyindoline (IV). The cyclization of (IV) with glycine ethyl ester (V) in pyridine affords the pyrrolo[1,4]benzodiazepine (VI), which is treated with amyl nitrite in toluene/THF to provide the oxime (VII). The reduction of (VII) with H2 over Ru/C in methanol gives the racemic amine (VIII), which is submitted to optical resolution with di-p-toluoyl-D-tartaric acid yielding the corresponding (R)-isomer (IX). Finally, this compound is condensed with 1H-indole-2-carboxylic acid (X) by means of TOTU and DIEA in dichloromethane.
| 【1】 Feru, F.; et al.; Synthesis and structure-activity relationships of 9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indolines: Novel PDE 4 inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 049. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40665 | cyclopentyl nitrite | C5H9NO2 | 详情 | 详情 | ||
| (I) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (II) | 25903 | 5-methoxyindoline; 2,3-dihydro-1H-indol-5-yl methyl ether | C9H11NO | 详情 | 详情 | |
| (III) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (IV) | 25905 | (5-methoxy-2,3-dihydro-1H-indol-7-yl)(phenyl)methanone | C16H15NO2 | 详情 | 详情 | |
| (V) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (VI) | 25906 | 9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H16N2O2 | 详情 | 详情 | |
| (VII) | 25907 | 9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C18H15N3O3 | 详情 | 详情 | |
| (VIII) | 25908 | 3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O2 | 详情 | 详情 | |
| (IX) | 25909 | (3R)-3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O2 | 详情 | 详情 | |
| (X) | 25226 | 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid | 1477-50-5 | C9H7NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.
| 【2】 Pascal, Y.; Jacobelli, H.; Calvet, A.; Payne, A.; Dahl, S.G. (Institut de Recherche Jouveinal); Diazepino-indoles as phosphodiesterase IV inhibitors. EP 0828742; US 5972927; WO 9736905 . |
| 【1】 Burnouf, C.; Auclair, E.; Avenel, N.; et al.; Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent, selective phosphodiesterase type 4 inhibitors. J Med Chem 2000, 43, 25, 4850. |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 47455 | 2,3-dihydro-1H-indol-7-yl(phenyl)methanone | C15H13NO | 详情 | 详情 | |
| (IV) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (V) | 47456 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N2O | 详情 | 详情 | |
| (VI) | 47457 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C17H13N3O2 | 详情 | 详情 | |
| (VII) | 47458 | 3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (VIII) | 47459 | (3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (IX) | 47460 | (3R)-3-amino-9-nitro-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N4O3 | 详情 | 详情 | |
| (X) | 47461 | (3R)-3,9-diamino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H16N4O | 详情 | 详情 | |
| (XI) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Condensation between ortho-anisidine (I) and benzonitrile (II) in the presence of NaNH2 furnishes N-(2-methoxyphenyl)benzamidine (III). Subsequent condensation of (III) with p-tolyl isothiocyanate (IV) produces the imidoyl thiourea (V). This is then oxidized by bromine in CHCl3 to form the target thiadiazolium salt.
| 【1】 Pan, K.; Scott, M.K.; Lee, D.H.S.; Fitzpatrick, L.J.; Crooke, J.J.; Rivero, R.A.; Rosenthal, D.I.; Vaidya, A.H.; Zhao, B.; Reitz, A.B.; 2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats. Bioorg Med Chem 2003, 11, 2, 185. |
| 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) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 65126 | N-(2-methoxyphenyl)benzenecarboximidamide | C14H14N2O | 详情 | 详情 | |
| (IV) | 51389 | 1-isothiocyanato-4-methylbenzene; 4-methylphenyl isothiocyanate | C8H7NS | 详情 | 详情 | |
| (V) | 65128 | N-[(Z)-(2-methoxyanilino)(phenyl)methylidene]-N'-(4-methylphenyl)thiourea | C22H21N3OS | 详情 | 详情 |