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【结 构 式】 
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【分子编号】12294 【品名】Aniline; Phenylamine 【CA登记号】62-53-3 |
【 分 子 式 】C6H7N 【 分 子 量 】93.12832 【元素组成】C 77.38% H 7.58% N 15.04% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of aniline (I) with 4-hydroxybenzoic acid (II) by means of P2O5 in refluxing toluene gives N-(4-hydroxybenzoyl)aniline (III), which is then condensed with pyrrolidine (IV) and formaldehyde (V) in refluxing ethanol.
| 【1】 Stout, D.M.; et al.; Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 3. Modifications to the linkage region (Region 3(. J Med Chem 1985, 28, 3, 295-298. |
| 【2】 Serradell, M.N.; Castaner, J.; ACC-9358. Drugs Fut 1986, 11, 3, 169. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 28208 | 3-thioxo-2,3-dihydro-1H-2H-thieno[3,4-d]isothiazole-1,1-dione | C5H3NO2S3 | 详情 | 详情 | |
| (III) | 28206 | 4-hydroxy-N-phenylbenzamide | C13H11NO2 | 详情 | 详情 | |
| (IV) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (V) | 22075 | Formaldehyde; Paraformaldehyde | 1118-66-7 | CH2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The hydrolysis of diethyl imidazole-4,5-dicarboxylate (I) with aqueous NaOH gives imidazole-4,5-dicarboxylic acid (II), which is partially decarboxylated by treatment with refluxing aniline yielding 4-anilinocarbonylimidazole (III). The hydrolysis of (III) with refluxing aqueous HCl affords imidazole-4-carboxylic acid (IV), which is finally esterified with ethanol and dry HCl at reflux temperature.
| 【1】 Schen, T.-T.; et al.; US 3438992 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Hillier, K.; Castaner, J.; C-751. Drugs Fut 1981, 6, 4, 218. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (I) | 37424 | diethyl 1H-imidazole-4,5-dicarboxylate | C9H12N2O4 | 详情 | 详情 | |
| (II) | 31951 | 1H-imidazole-4,5-dicarboxylic acid | 570-22-9 | C5H4N2O4 | 详情 | 详情 |
| (III) | 37425 | N-phenyl-1H-imidazole-4-carboxamide | C10H9N3O | 详情 | 详情 | |
| (IV) | 37426 | 1H-imidazole-4-carboxylic acid | C4H4N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)This compound can be obtained by several different ways: 1) By condensation of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylic acid (I) with phenylhydrazine (II) by means of N,N-dimethylaniline in DMSO. 2) By a coupling reaction between 6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylic acid (III) with phenyldiazonium chloride (IV) (prepared with aniline (V), NaNO2 and HCl). 3) The coupling reaction of (IV) with ethyl 6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine 3-carboxylate (VI) gives ethyl 6-methyl-4-oxo-9-(phenylhydrazono)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (VII), which is hydrolyzed with NaOH in water. 4) By reaction of ethyl 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylate (VIII) with (II) in refluxing ethanol, giving (VII), already obtained. 5) By condensation of ethyl 9-hydroxy-6-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-3-carboxylate (IX) with (II) in refluxing ethanol yielding (VII), already obtained.
| 【1】 Vasvari-Debreczy, L.; Horvath, A.; Dessy, F.; Hermecz, I.; De Vos, C.; Meszaros, Z.; Rodriguez, L.; Breining, T.; 18. New antiallergic 4H-pyridol[1,2-a]pyrimidin-4-ones. J Med Chem 1982, 25, 10, 1140-45. |
| 【2】 Bitter, I.; Breining, T.; Mandi, A.; Szucs, T.; Horvath, A.; Meszaros, Z.; Virag, S.; Hermecz, I.; Vasvari, L.; Nagy, G.; Sebestyen, G. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); Condensed pyrimidine derivs., their preparation and pharmaceutical compsns. containing them. GB 2011898 . |
| 【3】 Vasvari, L.; Horvath, A.; Hermecz, I.; Kokosi, J.; Breining, T. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); 9-Hydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidine-4-one derivs., their preparation and pharmaceutical compsns. containing them. GB 2051783 . |
| 【4】 Castaner, J.; Serradell, M.N.; Sneddon, J.M.; Blancafort, P.; UCB-L-140. Drugs Fut 1983, 8, 7, 612. |
| 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) | 36163 | 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid | C10H10Br2N2O3 | 详情 | 详情 | |
| (II) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (III) | 36162 | 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid | C10H12N2O3 | 详情 | 详情 | |
| (IV) | 25897 | benzenediazonium chloride | C6H5ClN2 | 详情 | 详情 | |
| (V) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VI) | 36161 | ethyl 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate | C12H16N2O3 | 详情 | 详情 | |
| (VII) | 36160 | ethyl 6-methyl-4-oxo-9-[(Z)-2-phenylhydrazono]-7,8-dihydro-4H-pyrido[1,2-a]pyrimidine-3(6H)-carboxylate | C18H20N4O3 | 详情 | 详情 | |
| (VIII) | 36158 | ethyl 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate | C12H15BrN2O3 | 详情 | 详情 | |
| (IX) | 36159 | ethyl 9-hydroxy-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate | C12H16N2O4 | 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 aniline (I) with ethyl bromoacetate (II) by means of triethylamine in benzene gives ethyl phenylaminoacetate (III), which is nitrosated with NaNO2 and HCl in water to yield ethyl N-nitrosophenylaminoacetate (IV). The reduction of (IV) with Zn in ethanol-water-acetic anhydride affords ethyl N1-phenylhydrazinoacetate (V), which is condensed with benzil (A) by means of HCl-sodium acetate in refluxing ethanol-water to yield ethyl alpha-benzoylbenzylidene-N1-phenylhydrazinoacetate (VI). The cyclization of (VI) by means of sodium ethoxide in refluxing ethanol gives 1,3,4-triphenylpyrazole-5-carboxylic acid (VII), which is reduced with LiAlH4 in ether-THF to produce 1,3,4-triphenyl-5-(hydroxymethyl)pyrazole (VIII). The reaction of (VIII) with SOCl2 in refluxing chloroform yields 1,3,4-triphenyl-5-(chloromethyl)pyrazole (IX), which by reaction with NaCN in hot DMSO is converted into 1,3,4-triphenylpyrazole-5-acetonitrile (X). Finally, this compound is hydrolyzed by means of NaOH in refluxing aqueous ethanol.
| 【1】 Gueremy, C.; Renault, C.; US 3984431 . |
| 【2】 Castaner, J.; Arrigoni, Martelli, E.; Isofezolac. Drugs Fut 1980, 5, 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 |
|---|---|---|---|---|---|---|
| (A) | 39056 | Dibenzoyl; benzil | 134-81-6 | C14H10O2 | 详情 | 详情 |
| (I) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 25701 | ethyl 2-anilinoacetate | 2216-92-4 | C10H13NO2 | 详情 | 详情 |
| (IV) | 39055 | C10H12N2O3 | 详情 | 详情 | ||
| (V) | 25702 | ethyl 2-(1-phenylhydrazino)acetate | C10H14N2O2 | 详情 | 详情 | |
| (VI) | 39057 | ethyl (Z)-4-oxo-3,4-diphenyl-2-(1-phenylhydrazino)-2-butenoate | C24H22N2O3 | 详情 | 详情 | |
| (VII) | 39058 | 1,3,4-triphenyl-1H-pyrazole-5-carboxylic acid | C22H16N2O2 | 详情 | 详情 | |
| (VIII) | 39059 | (1,3,4-triphenyl-1H-pyrazol-5-yl)methanol | C22H18N2O | 详情 | 详情 | |
| (IX) | 39060 | 5-(chloromethyl)-1,3,4-triphenyl-1H-pyrazole | C22H17ClN2 | 详情 | 详情 | |
| (X) | 39061 | 2-(1,3,4-triphenyl-1H-pyrazol-5-yl)acetonitrile | C23H17N3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(B)The reaction of (V) with 3-morpholinopropionitrile (X) by means of sodium methoxide in methanol - DMSO gives 4-bromo-3,5-dimethoxy-alpha-(morpholinomethyliden)hydrocinnamic acid nitrile (XI), which by reaction with aniline (B) and HCl in refluxing isopropanol is converted into 4-bromo-3,5-dimethoxy-alpha-(anilinomethyliden)hydrocinnamic acid nitrile (XII). Finally, this compound is condensed with guanidine (A) as before.
| 【1】 Sweetman, A.J.; Serradell, M.N.; Castaner, J.; Blancafort, P.; Brodimoprim. Drugs Fut 1982, 7, 2, 93. |
| 【2】 Kompis, I.; Wick, A.; Synthesis of 4-halo-substituted analogs of trimethropin. Helv Chim Acta 1977, 60, 8, 3025-34. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (A) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (V) | 31928 | 4-Bromo-3,5-dimethoxybenzaldehyde | C9H9BrO3 | 详情 | 详情 | |
| (X) | 31933 | 3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile | 4542-47-6 | C7H12N2O | 详情 | 详情 |
| (XI) | 31934 | (Z)-2-(4-bromo-3,5-dimethoxybenzyl)-3-(4-morpholinyl)-2-propenenitrile | C16H19BrN2O3 | 详情 | 详情 | |
| (XII) | 31935 | (Z)-3-anilino-2-(4-bromo-3,5-dimethoxybenzyl)-2-propenenitrile | C18H17BrN2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The condensation of aniline (I) with diethyl ethoxymethylenemalonate (II) by heating at 90 C gives diethyl anilinomethylenemalonate (III), which is cyclized to ethyl 4-hydroxyquinoline-3-carboxylate (IV) by heating at 240 C in diphenyl ether-biphenyl. The reaction of (IV) with hot POCl3 affords ethyl 4-chloro-quinoline-3-carboxylate (V), which is finally cyclized with phenylhydrazine (VI) by heating at 105 C in xylene. (VI) is prepared in the usual way starting from aniline (I) by diazotation with NaNO2-HCl to phenyldiazonium chloride (VII), and reduction with SnCl2-HCl.
| 【1】 Yokoyama, N.; EP 0022078 . |
| 【2】 Yokoyama, N.; US 4312870 . |
| 【3】 Ritter, B.; Yokoyama, N.; Neubert, A.D.; 2-Arylpyrazolo[4,3-c]quinolin-3-ones: A partial novel agonist and antagonist of benzodiazepines. J Med Chem 1982, 25, 4, 337-339. |
| 【4】 Serradell, M.N.; Grau, M.; Castaner, J.; Blancafort, P.; CGS-8216 and CGS-9896. Drugs Fut 1983, 8, 2, 99. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 35953 | diethyl 2-(anilinomethylene)malonate | C14H17NO4 | 详情 | 详情 | |
| (IV) | 35954 | ethyl 4-hydroxy-3-quinolinecarboxylate | C12H11NO3 | 详情 | 详情 | |
| (V) | 35955 | ethyl 4-chloro-3-quinolinecarboxylate | C12H10ClNO2 | 详情 | 详情 | |
| (VI) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (VII) | 25897 | benzenediazonium chloride | C6H5ClN2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The condensation of aniline (I) with diethyl ethoxymethylenemalonate (II) by heating at 90 C gives diethyl anilinomethylenemalonate (III), which is cyclized to ethyl 4-hydroxyquinoline-3carboxylate (IV) by heating at 240 C in diphenyl ether-biphenyl. The reaction of (IV) with hot POCl3 affords ethyl-4-chloroquinoline-3-carboxylate (V), which is finally cyclized with 4-chlorophenylhydrazine (VIII) by heating at 105 C in xylene. (VIII) is prepared in the usual way starting from 4-chloroaniline (IX) by diazotation with NaNO2-HCl to 4-chlorophenyldiazonium chloride (X), and reduction with SnCl2-HCl.
| 【1】 Yokoyama, N.; US 4312870 . |
| 【2】 Yokoyama, N.; EP 0022078 . |
| 【3】 Ritter, B.; Yokoyama, N.; Neubert, A.D.; 2-Arylpyrazolo[4,3-c]quinolin-3-ones: A partial novel agonist and antagonist of benzodiazepines. J Med Chem 1982, 25, 4, 337-339. |
| 【4】 Castaner, J.; Blancafort, P.; Grau, M.; Serradell, M.N.; CGS-8216 and CGS-9896. Drugs Fut 1983, 8, 2, 99. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 35953 | diethyl 2-(anilinomethylene)malonate | C14H17NO4 | 详情 | 详情 | |
| (IV) | 35954 | ethyl 4-hydroxy-3-quinolinecarboxylate | C12H11NO3 | 详情 | 详情 | |
| (V) | 35955 | ethyl 4-chloro-3-quinolinecarboxylate | C12H10ClNO2 | 详情 | 详情 | |
| (VIII) | 33345 | 1-(4-chlorophenyl)hydrazine; 4-Chlorophenylhydrazine | 1073-70-7 | C6H7ClN2 | 详情 | 详情 |
| (IX) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (X) | 10197 | 4-Chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)The neutralized diazonium salt of anthranilic acid (I) is treated with sodium diselenide yielding diselenosalicylic acid (II), which is treated with thionyl chloride to give the selenenyl chloride (III). Treatment of (III) with aniline (IV) in the presence of a base affords PZ-51.
| 【1】 Renson, M.; Etschenberg, E.; Winkelmann, J. (A. Nattermann & Cie. GmbH); 2-Phenyl-1,2-benzisoselenazol-3(2H)-one containing pharmaceutical preparations and process for the treatment or rheumatic diseases. DE 3027073; EP 0044971; JP 8256427; US 4352799 . |
| 【2】 Graf, E.; Dereu, N.; Ebselen. Drugs Fut 1984, 9, 10, 741. |
合成路线9
该中间体在本合成路线中的序号：(A)5epsilon-lodo-9-deoxy-6epsilon,9alpha-epoxy-PGF1alpha (I) is protected with tert-butyldimethylsilyl chloride in DMF containing imidazole yielding the disilylated compound (II), which is treated with diazabicyclononane (DBN) in DMF to give the hydroxy keto ester (III). Acetylation of (III) with acetic anhydride in pyridine affords the corresponding acetoxy compound (IV), which by hydrolysis with NaOH affords the free hydroxy acid (V). Oxidation of (V) with Jones' reagent yields the diketonic acid (VI), which by cyclization with aniline (A) in pyridine - methanol followed by esterification with diazomethane is converted into the protected ester (VII). Elimination of the silyl groups of (VII) with tetrabutylanimonium fluoride in THF gives the methyl ester of U-60,257 (VIII), which is finally hydrolyzed with NaOH in methanol.
| 【1】 Smith, H.W. (Pharmacia Corp.); Nitrogen-containing prostacyclin analogues, their preparation and compsns. containing them. EP 0029341 . |
| 【2】 Sneddon, J.M.; Castaner, J.; Serradell, M.N.; Blancafort, P.; U-60,257. Drugs Fut 1983, 8, 10, 877. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (I) | 36242 | methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate | C21H35IO5 | 详情 | 详情 | |
| (II) | 36243 | methyl 5-[(3aR,4R,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate | C33H63IO5Si2 | 详情 | 详情 | |
| (III) | 36244 | methyl 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-hydroxycyclopentyl]-7-oxoheptanoate | C33H64O6Si2 | 详情 | 详情 | |
| (IV) | 36245 | methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)cyclopentyl]-7-oxoheptanoate | C35H66O7Si2 | 详情 | 详情 | |
| (V) | 36246 | 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-hydroxycyclopentyl]-7-oxoheptanoic acid | C32H62O6Si2 | 详情 | 详情 | |
| (VI) | 36247 | 7-[(1S,2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-oxocyclopentyl]-7-oxoheptanoic acid | C32H60O6Si2 | 详情 | 详情 | |
| (VII) | 36248 | methyl 5-[(4R,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl]pentanoate | C39H65NO4Si2 | 详情 | 详情 | |
| (VIII) | 36249 | methyl 5-[(4R,5R)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]-1-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-yl]pentanoate | C27H37NO4 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(III)The reaction of guanosine-2',3',5'-triacetate (I) with amyl nitrite and bromoform at 90 C gives 2-bromoinosine-2',3',5'-triacetate (II), which is condensed with aniline (III) in refluxing methanol to afford N-phenylguanosine-2',3',5'-triacetate (IV). The reaction of (IV) with POCl3 and N,N-dimethylaniline in refluxing acetonitrile gives 6-chloro-N-phenyl-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine-2-amine (V), which is finally treated with ammonia in methanol to give CV-1808.
| 【1】 Trivedi, B.K.; Studies toward synthesis of C2-substituted adenosines: An efficient synthesis of 2-(phenylamino)adenosine [CV-1808]. Nucleosides Nucleotides 1988, 7, 3, 393. |
| 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) | 20827 | 1-nitrosopentane | C5H11NO | 详情 | 详情 | |
| (I) | 20822 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H19N5O8 | 详情 | 详情 | |
| (II) | 20823 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17BrN4O8 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 20825 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-anilino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C22H23N5O8 | 详情 | 详情 | |
| (V) | 20826 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-anilino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C22H22ClN5O7 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)This compound can be obtained in two different ways: 1) The acylation of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide (I) with propionic anhydride (A) in pyridine gives the corresponding tri-O-propionyl derivative (II), which by treatment with POCl3 and triethylamine in CHCl3 is converted into 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-beta-D-ribofuranosyl)imidazole (III). The hydrolysis of (III) with methanolic ammonia yields 5-amino-4-cyano-1-beta-D-ribofuranosylimidazole (IV), which is finally cyclized with phenylcyanamide (V) in methanolic ammonia at 180 C in a pressure vessel. This cyclization can also be performed with (III) and (V) directly, using the same procedure. 2) By reaction of 2-bromoadenosine (VI) with aniline (VII) in 2-methoxyethanol at 120 C.
| 【1】 Marumoto, R.; et al.; Synthesis and coronary vasodilating activity of 2-substituted adenosines. Chem Pharm Bull 1975, 23, 4, 759-774. |
| 【2】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); 2,6-Diaminonebularine derivs.. US 3936439 . |
| 【3】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); Production of 2,6-diaminonebularines. DE 2845435 . |
| 【4】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Thorpe, P.J.; CV-1808. Drugs Fut 1981, 6, 4, 222. |
| 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) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (I) | 37427 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carboxamide | C9H14N4O5 | 详情 | 详情 | |
| (II) | 37428 | [(2R,3R,4R,5R)-5-[5-amino-4-(aminocarbonyl)-1H-imidazol-1-yl]-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate | C18H26N4O8 | 详情 | 详情 | |
| (III) | 37429 | [(2R,3R,4R,5R)-5-(5-amino-4-cyano-1H-imidazol-1-yl)-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate | C18H24N4O7 | 详情 | 详情 | |
| (IV) | 37430 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile | C9H12N4O4 | 详情 | 详情 | |
| (V) | 37431 | phenylcyanamide | C7H6N2 | 详情 | 详情 | |
| (VI) | 37432 | (2R,3R,4S,5R)-2-(6-amino-2-bromo-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H12BrN5O4 | 详情 | 详情 | |
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.
| 【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 . |
| 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) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (II) | 49678 | ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate | C9H13Cl2NO3 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 49679 | ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate | C21H25N3O3 | 详情 | 详情 | |
| (V) | 49680 | ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate | C22H27N3O3 | 详情 | 详情 | |
| (VI) | 49681 | 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide | C19H23N3O | 详情 | 详情 | |
| (VII) | 49682 | (4-anilino-4-piperidinyl)methanol | C12H18N2O | 详情 | 详情 | |
| (VIII) | 14721 | 1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C5H9BrN4O | 详情 | 详情 | |
| (IX) | 32218 | 1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | 69048-98-2 | C3H6N4O | 详情 | 详情 |
| (X) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XI) | 49683 | 1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C17H26N6O2 | 详情 | 详情 | |
| (XII) | 49684 | 1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C18H28N6O2 | 详情 | 详情 | |
| (XIII) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)[U-14C]-Aniline (I) is converted to [U-14C]phenyldiazonium chloride (II), which is condensed in situ with ethyl 2-(ethoxyalyl)propionate (III) to give [U-14C]phenylhydrazone of ethyl pyruvate (IV). Cyclization of (IV) by polyphosphoric acid in xylene affords ethyl [U-14C-phenyl]indole-2-carboxylic acid (V). Catalytic hydrogenation of compound (V) in the presence of platinum gives ethyl [U-14C-cyclohexyl]-(RS)-perhydroindole-2-carboxylic acid (VI), which is saponified to the corresponding acid (VIII). Compound (VI) can also be prepared by reduction of compound (V) with tin and hydrochloric acid to give compound (VII), and hydrogenation of the latter in the presence of palladium. Compound (VIII) is reesterified to the benzyl ester (IX), which is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine (X) in the presence of DCC and 1-hydroxy-1-benzotriazole. The resulting compound (X) is separated fom the mixture of isomers by silica gel column chromatography. Hydrogenolysis of the latter compound gives [U-14C-cyclohexyl]perindopril, which is isolated as the tert-bytylamine salt.
| 【1】 Pichat, L.; et al.; Syntheses du S-9490-3. J Label Compd Radiopharm 1988, 25, 5, 553. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 25897 | benzenediazonium chloride | C6H5ClN2 | 详情 | 详情 | |
| (III) | 27781 | diethyl 2-methyl-3-oxosuccinate | 5965-53-7 | C9H14O5 | 详情 | 详情 |
| (IV) | 27782 | ethyl 2-[(E)-2-phenylhydrazono]propanoate | C11H14N2O2 | 详情 | 详情 | |
| (V) | 27783 | Indole-2-carboxylic acid ethyl ester; 2-Carbethoxyindole; 1H-indole-2-carboxylic acid ethyl ester | 3770-50-1 | C11H11NO2 | 详情 | 详情 |
| (VI) | 27784 | ethyl octahydro-1H-indole-2-carboxylate | C11H19NO2 | 详情 | 详情 | |
| (VII) | 27785 | ethyl 2-indolinecarboxylate | C11H13NO2 | 详情 | 详情 | |
| (VIII) | 27789 | octahydro-1H-indole-2-carboxylic acid | C9H15NO2 | 详情 | 详情 | |
| (IX) | 27790 | benzyl octahydro-1H-indole-2-carboxylate | C16H21NO2 | 详情 | 详情 | |
| (X) | 27786 | (2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propionic acid | C10H19NO4 | 详情 | 详情 | |
| (XI) | 27787 | benzyl (2S,3aS,7aS)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl)octahydro-1H-indole-2-carboxylate | C26H38N2O5 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VI)A total synthesis of sufentanil has been described: The cyclization of 2-(2-thienyl)ethylamine (I) with allyltrimethylsilane (II) and formaldehyde gives 4-hydroxy-1-[2-(2-thienyl)ethyl]piperidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane to 1-[2-(2-thienyl)ethyl]piperidin-4-one (IV). The epoxidation of (IV) by means of trimethylsulfonium iodide and the sodium salt of DMSO yields the spiro-epoxide (V), which is opened with aniline (VI) and boron trifluoride ethearate giving a 1.8:1 mixture of 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII) and 4-hydroxy-4-(phenylamino)piperidine (VIII) that are conveniently separated. The methylation of the OH group of (VII) with diazomethane and SiO2 affords the methoxymethyl compound (IX), which is finally acylated with propionic anhydride to provide sufentanil.
| 【1】 Park, H.J.; Jeon, R.O.; Ryu, J.S.; Hyun, S.S.; Suh, Y.G.; Shin, D.Y.; Total synthesis of sufentanil. Arch Pharmacal Res 1999, 22, 4, 398. |
| 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) | 35253 | 2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine | 30433-91-1 | C6H9NS | 详情 | 详情 |
| (II) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (III) | 35254 | 1-[2-(2-thienyl)ethyl]-4-piperidinol | C11H17NOS | 详情 | 详情 | |
| (IV) | 35255 | 1-[2-(2-thienyl)ethyl]-4-piperidinone | C11H15NOS | 详情 | 详情 | |
| (V) | 35256 | 6-[2-(2-thienyl)ethyl]-1-oxa-6-azaspiro[2.5]octane | C12H17NOS | 详情 | 详情 | |
| (VI) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VII) | 35257 | [4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol | C18H24N2OS | 详情 | 详情 | |
| (VIII) | 35258 | 4-(anilinomethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinol | C18H24N2OS | 详情 | 详情 | |
| (IX) | 35259 | N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylamine; 4-(methoxymethyl)-N-phenyl-1-[2-(2-thienyl)ethyl]-4-piperidinamine | C19H26N2OS | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(III)The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with 2-(2-thienyl)ethyl mesylate (VIII) by means of K2CO3 in refluxing acetonitrile yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (X). Finally, this compound is acylated with propionyl chloride (XI) in chloroform to provide the target compound.
| 【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 . |
| 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) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (II) | 49678 | ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate | C9H13Cl2NO3 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 49679 | ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate | C21H25N3O3 | 详情 | 详情 | |
| (V) | 49680 | ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate | C22H27N3O3 | 详情 | 详情 | |
| (VI) | 49681 | 4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide | C19H23N3O | 详情 | 详情 | |
| (VII) | 49682 | (4-anilino-4-piperidinyl)methanol | C12H18N2O | 详情 | 详情 | |
| (VIII) | 49685 | 2-(2-thienyl)ethyl methanesulfonate | C7H10O3S2 | 详情 | 详情 | |
| (IX) | 35257 | [4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol | C18H24N2OS | 详情 | 详情 | |
| (X) | 49686 | 1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-N-phenyl-4-piperidinamine; N-[1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine | C21H30N2OS | 详情 | 详情 | |
| (XI) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(X)The reaction of acid (I) with SOCl2 in ethyl ether containing triethylamine gives the corresponding acyl chloride (VII), which is condensed with ethyl cyanacetate (VIII) by means of NaH in glyme yielding ethyl 2-cyano-3-(1-methyl-2-pyrrolyl)-3-oxopropanoate (IX). The reaction of (IX) with aniline (X) in refluxing xylene affords the corresponding anilide (V) already obtained.
| 【1】 Walker, G.N. (Novartis AG); alpha-Carbamoyl-pyrrolpropionitriles, process fortheir preparation and pharmaceutical preparations containing them. EP 0143142 . |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Prinomide Triethanolamine. Drugs Fut 1987, 12, 8, 773. |
| 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) | 11286 | 1-Methyl-1H-pyrrole-2-carboxylic acid; 1-Methyl-2-pyrrolecarboxylic acid | 6973-60-0 | C6H7NO2 | 详情 | 详情 |
| (V) | 28167 | 2-cyano-3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-N-phenylpropanamide | C15H13N3O2 | 详情 | 详情 | |
| (VI) | 28168 | 2-[bis(2-hydroxyethyl)amino]-1-ethanol | 102-71-6 | C6H15NO3 | 详情 | 详情 |
| (VII) | 28169 | 1-methyl-1H-pyrrole-2-carbonyl chloride | C6H6ClNO | 详情 | 详情 | |
| (VIII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (IX) | 28170 | ethyl 2-cyano-3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanoate | C11H12N2O3 | 详情 | 详情 | |
| (X) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(VII)The cyclocondensation of aniline (VII) with ethyl 2-oxocyclo-hexanecarboxylate (VIII) by means of HCl in refluxing benzene gives 9-acridone (IX), which by treatment with refluxing POCl3 is converted to 9-chloroacridine (X). Finally, this compound is treated with anhydrous NH3 in p-cresol), or with ethanolic ammonia with a Cu catalyst.
| 【1】 Hottelart, C.; et al.; J Chem Soc 1947, 92, 3, 634-637. |
| 【2】 Sigal, M.V. Jr.; Brent, B.J.; Marchini, P.; 7,8,9,10-Tetrahalo-6H-cyclohepta[b]quinolines. US 3232945 . |
| 【3】 Castaner, R.M.; Serradell, M.N.; Castaner, J.; Tacrine. Drugs Fut 1987, 12, 11, 1032. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VIII) | 11889 | ethyl 2-oxocyclohexanecarboxylate; Ethyl 2-cyclohexanonecarboxylate | 1655-07-8 | C9H14O3 | 详情 | 详情 |
| (IX) | 28180 | 1,3,4,4a,9a,10-hexahydro-9(2H)-acridinone | C13H15NO | 详情 | 详情 | |
| (X) | 28181 | 9-chloro-1,2,3,4-tetrahydroacridine | C13H12ClN | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(I)The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher's indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.
| 【1】 Pleiss, U.; Radtke, M.; Rosentreter, U.; Boberg, M.; Synthesis of (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-C-14]carbazolepropanoic acid, [C-14]BAY u 3405. J Label Compd Radiopharm 1994, 34, 12, 1207. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (I) | 45117 | C6H7N | 详情 | 详情 | ||
| (II) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (II) | 45118 | C6H8N2 | 详情 | 详情 | ||
| (III) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (IV) | 12297 | 1,2,3,4-Tetrahydrospiro[9H-carbazole-3,2'-1,3-dioxolane] | C14H15NO2 | 详情 | 详情 | |
| (IV) | 45119 | C14H15NO2 | 详情 | 详情 | ||
| (V) | 12288 | 1,2,4,9-Tetrahydro-3H-carbazol-3-one | C12H11NO | 详情 | 详情 | |
| (V) | 45120 | C12H11NO | 详情 | 详情 | ||
| (VI) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VII) | 12290 | N-[(1S)-1-Phenylethyl]-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amine; (3R)-N-[(1S)-1-Phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine | C20H22N2 | 详情 | 详情 | |
| (VII) | 45121 | C20H22N2 | 详情 | 详情 | ||
| (VIII) | 12291 | (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-ylamine; (3R)-2,3,4,9-Tetrahydro-1H-carbazol-3-amine | C12H14N2 | 详情 | 详情 | |
| (VIII) | 45122 | C12H14N2 | 详情 | 详情 | ||
| (IX) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |
| (X) | 12293 | 4-Fluoro-N-[(3R)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]benzenesulfonamide | C18H17FN2O2S | 详情 | 详情 | |
| (X) | 45123 | C18H17FN2O2S | 详情 | 详情 | ||
| (XI) | 12304 | N-[(3R)-9-(2-cyanoethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-4-fluorobenzenesulfonamide | C21H20FN3O2S | 详情 | 详情 | |
| (XI) | 45124 | C21H20FN3O2S | 详情 | 详情 | ||
| (XII) | 12305 | methyl 3-((3R)-3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoate | C22H23FN2O4S | 详情 | 详情 | |
| (XII) | 45125 | C22H23FN2O4S | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(I)The mesylation of aniline (I) with methanesulfonyl chloride gives the sulfonamide (II), which is condensed with 1-acetylpiperidine-4-carbonyl chloride (III) by means of AlCl3 in dichloromethane to give N-[4-(1-acetylpiperidin-4-ylcarbonyl)phenyl]methanesulfonamide (IV). Deacetylation of (IV) with HCl in water yields the piperidine (V), which is finally condensed with 2-methyl-6-vinylpyridine by means of sodium acetate in methanol - water. The same procedure has been performed with [14C]-labeled aniline in order to obtain [14C]-labeled E-4031.
| 【1】 Oinuma, H.; Yamanaka, M.; Miyake, K.; Hoshiko, T.; Minami, N.; Shoji, T.; Daiku, Y.; Sawada, K.; Nomoto, K. (Eisai Co., Ltd.); Piperidine deriv., pharmaceutical compsn. containing the same and use. EP 0235752; US 4876262; US 4996215; US 5118689; US 5179095 . |
| 【2】 Miyake, K.; Yamanaka, M.; Katoh, H.; Shino, M.; Hamano, S.; Nomoto, K.-I.; Oinuma, H.; Sawada, K.; 4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents. J Med Chem 1990, 33, 3, 903. |
| 【3】 Shino, M.; Oinuma, H.; Hamano, S.; Miyake, K.; Yamanaka, M.; Synthesis of antiarrhythmic [phenyl-14C]4'-[(4-piperidyl)carbonyl]methanesulfonanilides. J Label Compd Radiopharm 1990, 28, 8, 921. |
| 【4】 Castaner, J.; Prous, J.; E-4031. Drugs Fut 1992, 17, 6, 455. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 13699 | N-Phenylmethanesulfonamide; N-Phenyl methanesulfonamide | 1197-22-4 | C7H9NO2S | 详情 | 详情 |
| (III) | 13700 | 1-Acetyl-4-piperidinecarbonyl chloride | C8H12ClNO2 | 详情 | 详情 | |
| (IV) | 13701 | N-[4-[(1-Acetyl-4-piperidinyl)carbonyl]phenyl]methanesulfonamide | C15H20N2O4S | 详情 | 详情 | |
| (V) | 13702 | N-[4-(4-Piperidinylcarbonyl)phenyl]methanesulfonamide | C13H18N2O3S | 详情 | 详情 | |
| (VI) | 13703 | 2-Methyl-6-vinylpyridine | 1122-70-9 | C8H9N | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(I)[14C]-Saquinavir: The cyclization of [ring-14C]-aniline (I) with crotonic aldehyde (II) by means of HCl and acetic anhydride gives labeled 2-methylquinoline (III), which is brominated with Br2 in acetic acid yielding the tribromo derivative (IV). The hydrolysis of (IV) with hot sulfuric acid afforded labeled quinoline-2-carboxylic acid (V), which is finally condensed with Ro-32-0445 (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC) in THF.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (I) | 22516 | aniline; phenylamine | C6H7N | 详情 | 详情 | |
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (III) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (III) | 22518 | 2-methylquinoline | C10H9N | 详情 | 详情 | |
| (IV) | 22519 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 | |
| (IV) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (V) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (V) | 22520 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 | |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(IX)Pentadeuterated saquinavir: The nitration of hexadeuterobenzene (VII) with HNO3/H2SO4 gives pentadeuteronitrobenzene (VIII), which is hydrogenated with deuterium/Pt in D1-methanol yielding heptadeuteroaniline (IX). The cyclization of (IX) with crotonic aldehyde (II) by means of DCI/D2O and acetic anhydride as before affords hexadeuterated quinoline (X), which is brominated with Br2 as before giving the tribromo derivative (XI). The hydrolysis of (XI) with sulfuric acid as before yields the acid (XII), which is finally condensed with Ro-32-0445 (VI) as before.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 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) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (VII) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (VII) | 63831 | benzene | C6H6 | 详情 | 详情 | |
| (VIII) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (VIII) | 63832 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IX) | 63833 | aniline; phenylamine | C6H7N | 详情 | 详情 | |
| (X) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (X) | 63834 | 2-methylquinoline | C10H9N | 详情 | 详情 | |
| (XI) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (XI) | 63835 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 | |
| (XII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XII) | 63836 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(IX)Tetradeuterated saquinavir: The cyclization of heptadeuteroaniline (IX) with crotonic aldehyde (II) by means of HCl and acetic anhydride as before gives the tetradeuteroquinoline (XIII), which is brominated as described yielding the tribromo derivative (XIV). The hydrolysis of (XIV) with sulfuric acid affords tetradeuterated acid (XV), which is finally condensed with Ro-32-0445 (VI) as indicated.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 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) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IX) | 63833 | aniline; phenylamine | C6H7N | 详情 | 详情 | |
| (XIII) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (XIII) | 63834 | 2-methylquinoline | C10H9N | 详情 | 详情 | |
| (XIV) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (XV) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XV) | 63836 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 | |
| (XVI) | 63835 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(XXIII)5)[15N,13C,2H]-Saquinavir: The nitration of [13C6]-benzene (XXI) with [15N]-nitric acid gives the corresponding nitrobenzene (XXII), which is reduced with Sn/HCl to the aniline (XXIII). The cyclization of (XXIII) with crotonic aldehyde (II) by means of ClD/D2O and acetic ahydride yields the tetradeuterated quinoline (XXIV), which is brominated as before givig the tribromo derivative (XXV). The hydrolysis of (XXV) with sulfuric acid as usual affords the [15N,13C6,2H3]-labeled quinoline-2-carboxylic acid (XXVI), which is finally condensed with Ro-32-0445 (VI) by means of HOBT and CDI as indicated.
| 【1】 Wiltshire, H.R.; et al.; The synthesis of labelled forms of saquinavir. J Label Compd Radiopharm 1998, 41, 12, 1103. |
| 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) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (VI) | 22521 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (XI) | 22526 | 2-(tribromomethyl)quinoline | 613-53-6 | C10H6Br3N | 详情 | 详情 |
| (XI) | 45225 | 2-(tribromomethyl)quinoline | C10H6Br3N | 详情 | 详情 | |
| (XII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
| (XII) | 45226 | 2-quinolinecarboxylic acid | C10H7NO2 | 详情 | 详情 | |
| (XXI) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (XXI) | 22536 | benzene | C6H6 | 详情 | 详情 | |
| (XXII) | 22523 | 1-nitrobenzene | 28250-14-8 | C6H5NO2 | 详情 | 详情 |
| (XXII) | 22537 | 1-nitrobenzene | C6H5NO2 | 详情 | 详情 | |
| (XXIII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (XXIII) | 22538 | phenylamine; aniline | C6H7N | 详情 | 详情 | |
| (XXIV) | 13161 | Quinaldine; 2-Methylquinoline | 91-63-4 | C10H9N | 详情 | 详情 |
| (XXIV) | 45224 | 2-methylquinoline | C10H9N | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(I)The acylation of aniline (I) with methanesulfonyl chloride (II) in pyridine gives the corresponding sulfonamide (III), which is submitted to a Friedel-Crafts condensation with succinic anhydride (IV) and AlCl3 in hot carbon disulfide to afford 4-[4-(methanesulfonyl)phenyl]-4-oxobutyric acid (V). The amidation of (V) with N-ethylheptylamine (VI) yields the corresponding amide (VII), which is finally reduced with LiAlH4 in THF and treated with an ethanolic solution of fumaric acid in order to precipitate the corresponding salt.
| 【1】 Stolle, W.T.; Stelzer, L.S.; Hester, J.B.; Perricone, S.C.; Hsi, R.S.P.; Synthesis of radiolabeled racemic and enantiomeric antiarrhythmic agents. J Label Compd Radiopharm 1994, 34, 10, 929. |
| 【2】 Robinson, C.; Robinson, K.; Castaner, J.; Ibutilide Fumarate. Drugs Fut 1996, 21, 9, 894. |
| 【3】 Hester, J.B. Jr. (Pharmacia Corp.); N-(Aminoalkylphenyl)sulfonamides their preparation and therapeutic use. EP 0164865; JP 1985239458; US 5155268 . |
| 【4】 Hester, J.B.; Gibson, J.K.; Cimini, M.G.; Emmert, D.E.; Locker, P.K.; Perricone, S.C.; Skaletzky, L.L.; Sykes, J.K.; West, B.E.; N-[(omega-Amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with Class III antiarrhythmic activity. J Med Chem 1991, 34, 1, 308-15. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (III) | 13699 | N-Phenylmethanesulfonamide; N-Phenyl methanesulfonamide | 1197-22-4 | C7H9NO2S | 详情 | 详情 |
| (IV) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (V) | 14625 | 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid | C11H13NO5S | 详情 | 详情 | |
| (VI) | 14626 | N-ethyl-1-heptanamine; N-ethyl-N-heptylamine | C9H21N | 详情 | 详情 | |
| (VII) | 14627 | N-ethyl-N-heptyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide | C20H32N2O4S | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(IX)1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R*,5R*)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R*,R*)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 Roth, B.D.; Blankley, C.J.; Chucholowski, A.W.; Ferguson, E.; Hoefle, M.L.; Ortwine, D.F.; Newton, R.S.; Sekerke, C.S.; Sliskovic, D.R.; Stratton, C.D.; Wilson, M.W.; Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34, 1, 357-66. |
| 【3】 Roth, B.D. (Pfizer Inc.); Trans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. EP 0247633; US 4681893 . |
| 【4】 Roth, B.D. (Pfizer Inc.); (R-(R*R*)-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereo. EP 0409281; JP 1991058967; US 5273995 . |
| 【5】 Mills, N.; Muhammad, N.A.; Weiss, J.; Nesbitt, R.U. (Pfizer Inc.); Stable oral CI-981 formulation and process for preparing same. EP 0680320; JP 1996505640; US 5686104; WO 9416693 . |
| 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) | 15376 | 2-(1,3-dioxolan-2-yl)ethylamine; 2-(1,3-dioxolan-2-yl)-1-ethanamine | 5754-35-8 | C5H11NO2 | 详情 | 详情 |
| (II) | 15377 | ethyl 2-bromo-2-(4-fluorophenyl)acetate | 712-52-7 | C10H10BrFO2 | 详情 | 详情 |
| (III) | 15378 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl]amino]-2-(4-fluorophenyl)acetate | C15H20FNO4 | 详情 | 详情 | |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 15380 | ethyl 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetate | C19H26FNO5 | 详情 | 详情 | |
| (VI) | 15381 | 2-[[2-(1,3-dioxolan-2-yl)ethyl](isobutyryl)amino]-2-(4-fluorophenyl)acetic acid | C17H22FNO5 | 详情 | 详情 | |
| (VII) | 15382 | N,3-diphenyl-2-propynamide | C15H11NO | 详情 | 详情 | |
| (VIII) | 15383 | 3-phenyl-2-propynoic acid; Phenylpropiolic acid | 637-44-5 | C9H6O2 | 详情 | 详情 |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (X) | 15385 | 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C31H31FN2O3 | 详情 | 详情 | |
| (XI) | 15386 | 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide | C29H27FN2O2 | 详情 | 详情 | |
| (XII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XIII) | 15388 | methyl 7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-5-hydroxy-3-oxoheptanoate | C34H35FN2O5 | 详情 | 详情 | |
| (XIV) | 15389 | methyl (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate | C34H37FN2O5 | 详情 | 详情 | |
| (XV) | 15390 | (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid | C33H35FN2O5 | 详情 | 详情 | |
| (XVI) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 | |
| (XVII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XVIII) | 15393 | 1-((3R,5R)-3,5-dihydroxy-7-oxo-7-[[(1R)-1-phenylethyl]amino]heptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C41H44FN3O4 | 详情 | 详情 | |
| (XIX) | 15391 | 5-(4-fluorophenyl)-1-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C33H33FN2O4 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(I)1) The cyclization of aniline (I) with propionylacetic acid methyl ester (II) by means of p-toluenesulfonic acid in refluxing cyclohexane gives 2-ethylquinolin-4(1H)-one (III), which is condensed with 5-[4'-(bromomethyl)biphenyl-2-yl]-2-(triphenylmethyl)tetrazole (IV) by means of NaH in DMF, yielding 2-ethyl-4-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (V). Finally, this compound is deprotected with HCl in ethanol - methanol. 2) The condensation of 4-methylphenylboronic acid (VI) with 2-bromobenzonitrile (VII) by means of Na2CO3 and PdCl2 in toluene - methanol gives 2-(4-methylphenyl)benzonitrile (VIII), which is brominated with N-bromosuccinimide (NBS) and azobis(isobutyronitrile) (AIBN) in hot chlorobenzene, yielding the bromomethyl derivative (IX). The condensation of (IX) with quinolone (III) by means of K2CO3 in N-methylpyrrolidone affords 4-(2'-cyanobiphenyl-4-ylmethoxy)-2-ethylquinoline (X), which is treated with tributyltin hydrazide in refluxing toluene to afford 2-ethyl-4-[2'-[2-(tributyltin)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XI). Finally, this compound is deprotected with NaNO2 and HCl in cool water.
| 【1】 Roberts, D.A.; Russell, S.T.; Pearce, R.J. (AstraZeneca plc); Quinoline derivs., process for their preparation and their use as medicaments. AU 9160955; EP 0412848; GB 2234748; JP 1991169863; US 5444071 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; ICI-D8731. Drugs Fut 1993, 18, 5, 428. |
| 【3】 Bradbury, R.H.; Allott, C.P.; Dennis, M.; et al.; New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives. J Med Chem 1992, 35, 22, 4027. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (III) | 15537 | 2-ethyl-4(1H)-quinolinone | C11H11NO | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 15539 | 2-ethyl-4-quinolinyl [2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methoxy]quinoline | C44H35N5O | 详情 | 详情 | |
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (VII) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (VIII) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 详情 | 详情 |
| (IX) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (X) | 15544 | 4'-[[(2-ethyl-4-quinolinyl)oxy]methyl][1,1'-biphenyl]-2-carbonitrile | C25H20N2O | 详情 | 详情 | |
| (XI) | 15545 | 5-[4'-(2-Ethylquinolin-4-yloxymethyl)biphenyl-2-yl]-2-(tributylstannyl)-2H-tetrazole | C37H47N5OSn | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(II)The reaction of 1-benzyl-4-piperidone (I) with aniline (II) and KCN in acetic acid gives the aminonitrile (III), which is treated with H2SO4 at room temperature to yield the carboxamide (IV). The hydrolysis of (IV) with refluxing aqueous HCl affords the carboxylic acid (V), which is esterified with Ms-OH and methanol to provide the methyl ester (VI). Acylation of the NH group of (VI) with propionic anhydride (VII) gives the propionamide (VIII), which is debenzylated with H2 over Pd/C to yield the piperidine (IX). Finally, this compound is condensed with methyl acrylate (XI) in acetonitrile to afford the target compound.
| 【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 . |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 49674 | 4-Anilino-1-benzyl-4-cyanopiperidine | C19H21N3 | 详情 | 详情 | |
| (IV) | 49675 | 4-Anilino-1-benzylisonipecotamide | C19H23N3O | 详情 | 详情 | |
| (V) | 33884 | 4-anilino-1-benzyl-4-piperidinecarboxylic acid | C19H22N2O2 | 详情 | 详情 | |
| (VI) | 49676 | methyl 4-anilino-1-benzyl-4-piperidinecarboxylate | C20H24N2O2 | 详情 | 详情 | |
| (VII) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (VIII) | 49677 | methyl 1-benzyl-4-(propionylanilino)-4-piperidinecarboxylate | C23H28N2O3 | 详情 | 详情 | |
| (IX) | 15668 | methyl 4-(propionylanilino)-4-piperidinecarboxylate | C16H22N2O3 | 详情 | 详情 | |
| (X) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(V)The silylation of butane-2,3-dione(I) with TMSCl and TEA in hot DMF gives the silylated enol (II), which is cyclized with dimethyl acetylenedicarboxylate (III) in refluxing toluene to yield 4,5-bis(trimethylsilyloxy)-3,6-dihydrophthalic acid dimethyl ester (IV). The condensation of (IV) with aniline (V), with simultaneous aromatization in refluxing acetic acid affords 4,5-bis(phenylamino)phthalic acid dimethyl ester (VI), which is hydrolyzed with LiOH in methanol and anhydrized with acetic anhydride in toluene giving the corresponding phthalic anhydride (VII). Finally this compound is treated with ammonium formate at 140-50 C to furnish the target phthalimide.
| 【1】 Traxler, P.; Lydon, N.; Recent advances in protein tyrosine kinase inhibitors. Drugs Fut 1995, 20, 12, 1261. |
| 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) | 37053 | biacetyl | 431-03-8 | C4H6O2 | 详情 | 详情 |
| (II) | 41193 | 2,2,7,7-tetramethyl-4,5-dimethylene-3,6-dioxa-2,7-disilaoctane; 1-methylene-2-[(trimethylsilyl)oxy]-2-propenyl trimethylsilyl ether | C10H22O2Si2 | 详情 | 详情 | |
| (III) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (IV) | 41194 | dimethyl 4,5-bis[(trimethylsilyl)oxy]-1,4-cyclohexadiene-1,2-dicarboxylate | C16H28O6Si2 | 详情 | 详情 | |
| (V) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VI) | 41195 | dimethyl 4,5-dianilinophthalate | C22H20N2O4 | 详情 | 详情 | |
| (VII) | 41196 | 5,6-dianilino-2-benzofuran-1,3-dione | C20H14N2O3 | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(XIII)The addition of thiophenol (II) to N-(benzyloxycarbonyl)-L-serine beta-lactone (I) by means of NaH in THF gives N-(benzyloxycarbonyl)-(S-phenyl)-L-cysteine (III), which is treated with isobutyl chloroformate, diazomethane and N-nitro-N-nitrosoguanidine in ethyl acetate/ethyl ether to yield the diazo intermediate (IV). The treatment of (IV) with dry HCl in ethyl ether affords the chloromethyl derivative (V), which is reduced with NaBH4 in THF giving the secondary alcohol (VI). The dehydrochlorination of (VI) with KOH in ethanol yields the corresponding epoxide (VII), which is submitted to ring opening with (3S,4aS,8aS)-N-(tert-butyl)decahydroisoquinoline-3-carboxamide (VIII) in hot isopropanol to afford the condensation product (IX). The deprotection of (IX) with 30% HBr in acetic acid gives compound (X) with a free amino group, which is finally acylated with 3-hydroxy-2-methylbenzoic acid (XI) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in THF. The benzoic acid (XI) has been obtained by the following sequence: The condensation of 3-methoxybenzoyl chloride (XII) with aniline (XIII) gives the corresponding anilide (XIV), which is methylated with butyllithium and methyl iodide in THF yielding 2-methyl-3-methoxybenzanilide (XV). Finally, this compound is treated with 5N HCl and 30% HBr in refluxing acetic acid.
| 【1】 Rabasseda, X.; Martel, A.M.; Castañer, J.; Nelfinavir Mesylate. Drugs Fut 1997, 22, 4, 371. |
| 【2】 Dressman, B.A.; Fritz, J.E.; Hammond, M.; Hornback, W.J.; Kaldor, S.W.; Kalish, V.J.; Munroe, J.E.; Reich, S.H.; Tatlock, J.H.; Shepherd, T.A.; Rodriguez, M.J. (Agouron Pharmaceuticals, Inc.); HIV protease inhibitors. EP 0889036; JP 1997501443; JP 1999310573; US 5484926; WO 9509843 . |
| 【3】 Jungheim, L.N.; Shepherd, T.A. (Eli Lilly and Company); Intermediate and process for making. WO 9521164 . |
| 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) | 16749 | benzyl N-[(3S)-2-oxooxetanyl]carbamate | C11H11NO4 | 详情 | 详情 | |
| (II) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (III) | 16751 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(phenylsulfanyl)propionic acid | 159453-24-4 | C17H17NO4S | 详情 | 详情 |
| (IV) | 16752 | benzyl N-[(1R)-3-diazo-2-oxo-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H17N3O3S | 详情 | 详情 | |
| (V) | 16753 | benzyl N-[(1R)-3-chloro-2-oxo-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H18ClNO3S | 详情 | 详情 | |
| (VI) | 16754 | benzyl N-[(1R,2S)-3-chloro-2-hydroxy-1-[(phenylsulfanyl)methyl]propyl]carbamate | C18H20ClNO3S | 详情 | 详情 | |
| (VII) | 16755 | benzyl N-[(1R)-1-[(2S)oxiranyl]-2-(phenylsulfanyl)ethyl]carbamate | C18H19NO3S | 详情 | 详情 | |
| (VIII) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (IX) | 16757 | benzyl (1R,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-2-hydroxy-1-[(phenylsulfanyl)methyl]propylcarbamate | C32H45N3O4S | 详情 | 详情 | |
| (X) | 16758 | (3S,4aS,8aS)-2-[(2R,3R)-3-amino-2-hydroxy-4-(phenylsulfanyl)butyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2S | 详情 | 详情 | |
| (XI) | 16759 | 3-hydroxy-2-methylbenzoic acid | 603-80-5 | C8H8O3 | 详情 | 详情 |
| (XII) | 16760 | 3-methoxybenzoyl chloride | 1711-05-3 | C8H7ClO2 | 详情 | 详情 |
| (XIII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (XIV) | 16762 | 3-methoxy-N-phenylbenzamide | C14H13NO2 | 详情 | 详情 | |
| (XV) | 16763 | 3-methoxy-2-methyl-N-phenylbenzamide | C15H15NO2 | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(II)1. A mixture of diacid dichloride (I), aniline (II), hydroxylamine (III) and KOH in 50% THF/water gives, after chromatographic purification, the title product with yields of 15-30%.
| 【1】 Breslow, R.; Rifkind, R.A.; Jursic, B. (Columbia University; Sloan-Kettering Institute); Novel potent inducers of terminal differentiation and methods of use thereof. WO 9307148 . |
合成路线31
该中间体在本合成路线中的序号：(II)2. The reaction of the diacid monoester (IV) with oxalyl chloride in benzene gives the corresponding acyl chloride (V), which is treated with aniline (II) and pyridine in THF, yielding the monoester monoamide (VI). The hydrolysis of the ester group of (VI) with OH in refluxing methanol affords the monoamide carboxylic acid (VII), which is condensed with O-benzylhydroxylamine (VIII) by means of DCC in pyridine to provide the protected hydroxamic acid (IX). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish the target hydroxamic acid with yields of 35-65%. 3. A mixture of diacid dichloride (I), aniline (II) and O-benzylhydroxylamine (VIII) in pyridine gives, after chromatographic purification, the protected hydroxamic acid (IX), which is debenzylated as before to provide the target hydroxamic acid with yields of 20-35%. 4. The reaction of acid dichloride (I) with aniline (II) and O-(trimethylsilyl)hydroxylamine (X) by means of TEA in chloroform gives the trimethylsilyl protected compound (XI), which is desilylated with NH4Cl in hot methanol to afford the target hydroxamic acid with yields of 20-33%.
| 【1】 Breslow, R.; Rifkind, R.A.; Jursic, B. (Columbia University; Sloan-Kettering Institute); Novel potent inducers of terminal differentiation and methods of use thereof. WO 9307148 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 53943 | Ethyl hydrogen suberate; Monoethyl suberate; Suberic acid monoethyl ester | 14113-01-0 | C10H18O4 | 详情 | 详情 |
| (V) | 53944 | ethyl 8-chloro-8-oxooctanoate | C10H17ClO3 | 详情 | 详情 | |
| (VI) | 53945 | ethyl 8-anilino-8-oxooctanoate | C16H23NO3 | 详情 | 详情 | |
| (VII) | 53946 | 8-anilino-8-oxooctanoic acid | C14H19NO3 | 详情 | 详情 | |
| (VIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (IX) | 53947 | N~1~-(benzyloxy)-N~8~-phenyloctanediamide | C21H26N2O3 | 详情 | 详情 | |
| (X) | 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 |
| (XI) | 53948 | N~1~-phenyl-N~8~-[(trimethylsilyl)oxy]octanediamide | C17H28N2O3Si | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(II)5. The condensation of diacid (XII) with aniline (II) by heating at 190 C gives the monoamide (VII), which is esterified by means of Dowex 50W-X2 in refluxing methanol to yield the monoamide monoester (XIII). Finally, this compound is treated with hydroxylamine and NaOMe in methanol to afford the target hydroxamic acid with overall yields of around 37%.
| 【1】 Stowell, J.C.; et al.; The synthesis of N-hydroxy-N'-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J Med Chem 1995, 38, 8, 1411. |
合成路线33
该中间体在本合成路线中的序号：(II)6. The reaction of acid (XII) with refluxing acetic anhydride gives the cyclic anhydride (XIV), which is treated with aniline (II) in THF to yield the monoamide (VII). The reaction of (VII) with ethyl chloroformate and TEA in THF affords the mixed anhydride (XV), which is finally treated with hydroxylamine in methanol to afford the target hydroxamic acid with overall yields of around 58%.
| 【1】 Mai, A.; et al.; A new facile and expeditious synthesis of N-hydroxy-N'-phenyloctanediamide, a potent inducer of terminal cytodifferentiation. Org Prep Proced Int 2001, 33, 4, 391. |
合成路线34
该中间体在本合成路线中的序号：(I)The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the final intermediate (VIII). Finally, this compound is deprotected with TFA in dichloromethane to give the labeled target compound.
| 【1】 Fiore, P.J.; et al.; Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7. Org Process Res Dev 1998, 2, 3, 151. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 32735 | tert-butyl phenylcarbamate | 3422-01-3 | C11H15NO2 | 详情 | 详情 |
| (III) | 32736 | 2-[(tert-butoxycarbonyl)amino]benzoic acid | 68790-38-5 | C12H15NO4 | 详情 | 详情 |
| (III) | 45324 | 2-[(tert-butoxycarbonyl)amino]benzoic acid | C12H15NO4 | 详情 | 详情 | |
| (IV) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (IV) | 45325 | 2-aminobenzoic acid | C7H7NO2 | 详情 | 详情 | |
| (V) | 20404 | 2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid | 119-80-2 | C14H10O4S2 | 详情 | 详情 |
| (V) | 45326 | 2-[(2-carboxyphenyl)disulfanyl]benzoic acid | C14H10O4S2 | 详情 | 详情 | |
| (VI) | 20405 | 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride | C14H8Cl2O2S2 | 详情 | 详情 | |
| (VI) | 45327 | 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride | C14H8Cl2O2S2 | 详情 | 详情 | |
| (VII) | 32737 | tert-butyl (2S,3S)-2-amino-3-methylpentanoate | C10H21NO2 | 详情 | 详情 | |
| (VIII) | 32738 | tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate | C34H48N2O6S2 | 详情 | 详情 | |
| (VIII) | 45328 | tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate | C34H48N2O6S2 | 详情 | 详情 |
合成路线35
该中间体在本合成路线中的序号：(I)The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the intermediate (VIII). The deprotectionof (VIII) with TFA in dichloromethane to give the labeled dimeric isoleucine derivative (IX), which is finally cyclized to the target benazoisothiazolone by oxidative cyclization with Br2 in dichloromethane.
| 【1】 Fiore, P.J.; et al.; Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7. Org Process Res Dev 1998, 2, 3, 151. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 32735 | tert-butyl phenylcarbamate | 3422-01-3 | C11H15NO2 | 详情 | 详情 |
| (III) | 32736 | 2-[(tert-butoxycarbonyl)amino]benzoic acid | 68790-38-5 | C12H15NO4 | 详情 | 详情 |
| (III) | 45324 | 2-[(tert-butoxycarbonyl)amino]benzoic acid | C12H15NO4 | 详情 | 详情 | |
| (IV) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (IV) | 45325 | 2-aminobenzoic acid | C7H7NO2 | 详情 | 详情 | |
| (V) | 20404 | 2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid | 119-80-2 | C14H10O4S2 | 详情 | 详情 |
| (V) | 45326 | 2-[(2-carboxyphenyl)disulfanyl]benzoic acid | C14H10O4S2 | 详情 | 详情 | |
| (VI) | 20405 | 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride | C14H8Cl2O2S2 | 详情 | 详情 | |
| (VI) | 45327 | 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride | C14H8Cl2O2S2 | 详情 | 详情 | |
| (VII) | 32737 | tert-butyl (2S,3S)-2-amino-3-methylpentanoate | C10H21NO2 | 详情 | 详情 | |
| (VIII) | 32738 | tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate | C34H48N2O6S2 | 详情 | 详情 | |
| (VIII) | 45328 | tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate | C34H48N2O6S2 | 详情 | 详情 | |
| (IX) | 32740 | (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-carboxy-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoic acid | C26H32N2O6S2 | 详情 | 详情 | |
| (IX) | 45329 | (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-carboxy-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoic acid | C26H32N2O6S2 | 详情 | 详情 |
合成路线36
该中间体在本合成路线中的序号：(II)The title amide was prepared by coupling of the previously reported 5-carboxymethyl-2-isopropylidenehydrazonothiazolidin-4-one (I) with aniline (II) in the presence of EDC and HOBt.
| 【1】 Yasumura, K.; Miyajima, K.; Nagahama, T.; Ishikawa, S.; Tohyama, Y.; Sugiyama, K. (Otsuka Pharmaceutical Co., Ltd.); Thiazole or imidazole derivs. as Maillard reaction inhibitors. EP 0638075; JP 1995133264; JP 1998167965; WO 9419335 . |
合成路线37
该中间体在本合成路线中的序号：(C)Ethyl 2,3-dibromopropionate (I) is condensed with N-tosyl-O-benzylhydroxylamine (A) by means of NaOEt in ethanol to give after a treatment with ammonia, propionic acid (II), which is detosylated by treatment with phenol and 36% HBr- yielding D,L-2-amino-3-(benzyloxyamino)propionic acid (III). The benzoylation of (III) with N-benzoyloxysuccinimide (B) by means of Triton B - in methanol affords D,L-2-benzoylamino-3-benzyloxyaminopropionic acid (IV), which is resolved into its optical isomers by treatment with aniline (C) and papain in 0.5M NaOH - 0.5M citric acid and L-cysteine hydrochloride; L-2-benzoylamino-3-benzyloxyaminopropionanilide (L)-(V) was isolated. The benzoylation of (L)-(V) with benzoyl chloride (D) in pyridine affords L-2-benzoylamino-3-(N-benzoyl-N-benzyloxyamino)propionanilide (L)-(VI), which is debenzylated by hydrogenation with H2 over Pd/C in methanol giving L-2-benzoylamino-3-(N-benzoyl-N-hydroxyamino)propionanilide (L)-(VII). The protecting groups of (L)-(VII) are eliminated by treatment with 6M HCl at 90-5 C yielding L-2-amino-3-hydroxyaminopropionic acid (L)-(VIII), which is finally nitrosated with NaNO2 and HCl.
| 【1】 Serradell, M.N.; Castañer, J.; Cabanillas, F.; Blancafort, P.; Alanosine. Drugs Fut 1979, 4, 7, 469. |
| 【2】 Yoshikazu, I.; et al.; Synthesis of alanosine. Bull Chem Soc Jpn 1973, 46, 1847-50. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (A) | 39517 | N-(benzyloxy)-4-methylbenzenesulfonamide | C14H15NO3S | 详情 | 详情 | |
| (B) | 39520 | 1-(benzoyloxy)-2,5-pyrrolidinedione | C11H9NO4 | 详情 | 详情 | |
| (L)-(V) | 39522 | N-((1S)-2-anilino-1-[[(benzyloxy)amino]methyl]-2-oxoethyl)benzamide | C23H23N3O3 | 详情 | 详情 | |
| (L)-(VI) | 39523 | N-[(2S)-3-anilino-3-oxo-2-(propionylamino)propyl]-N-(benzyloxy)benzamide | C26H27N3O4 | 详情 | 详情 | |
| (L)-(VII) | 39524 | N-((1S)-2-anilino-1-[[benzoyl(hydroxy)amino]methyl]-2-oxoethyl)benzamide | C23H21N3O4 | 详情 | 详情 | |
| (L)-(VIII) | 39525 | (2S)-2-amino-3-(hydroxyamino)propionic acid | C3H8N2O3 | 详情 | 详情 | |
| (I) | 18341 | ethyl 2,3-dibromopropanoate | 3674-13-3 | C5H8Br2O2 | 详情 | 详情 |
| (II) | 39518 | 3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]alanine | C17H20N2O5S | 详情 | 详情 | |
| (III) | 39519 | 3-[(benzyloxy)amino]alanine | C10H14N2O3 | 详情 | 详情 | |
| (IV) | 39521 | N-benzoyl-3-[(benzyloxy)amino]alanine | C17H18N2O4 | 详情 | 详情 | |
| (C) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
合成路线38
该中间体在本合成路线中的序号：(III)Photochemical bromination of 7-methylcoumarin (I) using N-bromosuccinimide and azobis(isobutyronitrile) provided the benzylic bromide (II). N-Phenyl ethylenediamine (V) was prepared by reaction between aniline (III) and oxazolidone (IV) at 140 C. Then, alkylation of amine (V) with bromide (II) in the presence of K2CO3 in refluxing acetonitrile provided the title compound.
| 【1】 Kesten, S.R.; et al.; Design, synthesis, and evaluation of coumarins as potent and selective dopamine D4 antagonists. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 123. |
| 【2】 Johnson, S.J.; Heffner, T.G.; Kesten, S.R.; Wise, L.D.; Wright, J.L.; Pugsley, T.A.; Design, synthesis, and evaluation of chromen-2-ones as potent and selective human dopamine D4 antagonists. J Med Chem 1999, 42, 18, 3718. |
| 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) | 21453 | 7-methyl-2H-chromen-2-one | 2445-83-2 | C10H8O2 | 详情 | 详情 |
| (II) | 21454 | 7-(bromomethyl)-2H-chromen-2-one | C10H7BrO2 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 21456 | 1,3-oxazolidin-2-one | 497-25-6 | C3H5NO2 | 详情 | 详情 |
| (V) | 21457 | N(1)-phenyl-1,2-ethanediamine; N-(2-aminoethyl)-N-phenylamine | 1664-40-0 | C8H12N2 | 详情 | 详情 |
合成路线39
该中间体在本合成路线中的序号：(VI)Serinol (I) was protected with triphenylmethyl chloride giving the N-trityl derivative (II), which was O-methylated using CH3I and NaH to afford the bis(methyl ether) (III). Subsequent acid deprotection of the trityl group of (III) provided 1,3-dimethoxy-2-aminopropane (IV). The hydroxypyridone (V) was converted to the salt with cyclohexylamine (VI), and then treated with phosphoryl chloride to produce the 4-chloropyridone (VII), which was condensed with amine (IV) to yield the aminopyridone (VIII). Further treatment of (VIII) with phosphoryl chloride gave 2-chloropyridine (IX). The nitro group of (IX) was then reduced with iron powder and AcOH, and the resulting diamino pyridine (X) was treated with NaNO2 and AcOH to produce the triazolopyridine (XI). Finally, coupling of (XI) with 2-chloro-4,6-dimethylaniline (XII) in the presence of p-TsOH provided the title compound, which was isolated as the mesylate salt.
| 【1】 Bakthavatchalam, R.; Arvanitis, A.G.; Beck, J.P.; Cain, G.A.; Chorvat, R.J.; Gilligan, P.J.; Olson, R.E. (DuPont Pharmaceuticals Co.); Arylamino fused pyridines and pyrimidines. EP 0935601; WO 9735539 . |
| 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) | 23333 | 2-amino-1,3-propanediol; serinol | 534-03-2 | C3H9NO2 | 详情 | 详情 |
| (II) | 23334 | 2-(tritylamino)-1,3-propanediol | C22H23NO2 | 详情 | 详情 | |
| (III) | 23335 | 1,3-dimethoxy-N-trityl-2-propanamine | C24H27NO2 | 详情 | 详情 | |
| (IV) | 23336 | 1,3-dimethoxy-2-propanamine | C5H13NO2 | 详情 | 详情 | |
| (V) | 23337 | 4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone | 4966-90-9 | C6H6N2O4 | 详情 | 详情 |
| (VI) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VII) | 23339 | 4-chloro-6-methyl-3-nitro-2(1H)-pyridinone | C6H5ClN2O3 | 详情 | 详情 | |
| (VIII) | 23340 | 4-[[2-methoxy-1-(methoxymethyl)ethyl]amino]-6-methyl-3-nitro-2(1H)-pyridinone | C11H17N3O5 | 详情 | 详情 | |
| (IX) | 23341 | 2-chloro-N-[2-methoxy-1-(methoxymethyl)ethyl]-6-methyl-3-nitro-4-pyridinamine | C11H16ClN3O4 | 详情 | 详情 | |
| (X) | 23342 | 2-chloro-N(4)-[2-methoxy-1-(methoxymethyl)ethyl]-6-methyl-3,4-pyridinediamine | C11H18ClN3O2 | 详情 | 详情 | |
| (XI) | 23343 | 2-(4-chloro-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-3-methoxypropyl methyl ether | C11H15ClN4O2 | 详情 | 详情 | |
| (XII) | 23344 | 2-chloro-4,6-dimethylaniline | C8H10ClN | 详情 | 详情 |
合成路线40
该中间体在本合成路线中的序号：(II)The reaction of 2-chloro-5-methoxynitrobenzene (I) with aniline (II) in basic medium gives the diphenylamine (III), which is reduced at the NO2 group with H2 over Pd/C in methanol yielding the o-phenylenediamine (IV). Finally, this compoud is cyclized with formamidine (V) in refluxing 2-methoxyethanol.
| 【1】 Palmer, B.D.; Smaill, J.B.; Boyd, M.; Boschelli, D.H.; Doherty, A.M.; Hamby, J.M.; Khatana, S.S.; Kramer, J.B.; Kraker, A.J.; Panek, R.L.; Lu, G.H.; Dahring, T.K.; Winters, R.T.; Showalter, H.D.; Denny, W.A.; Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor. J Med Chem 1998, 41, 27, 5457. |
| 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) | 24772 | 1-chloro-4-methoxy-2-nitrobenzene | 10298-80-3 | C7H6ClNO3 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 24774 | 4-methoxy-2-nitro-N-phenylaniline | C13H12N2O3 | 详情 | 详情 | |
| (IV) | 24775 | 4-methoxy-N(1)-phenyl-1,2-benzenediamine | C13H14N2O | 详情 | 详情 | |
| (V) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
合成路线41
该中间体在本合成路线中的序号：(I)The intermediate 4-ethyltetrahydroquinoline (VII) has been prepared by two procedures: 1.- Conjugate addition of acrylic acid (II) to aniline (I) gave 3-(phenylamino)propionic acid (III), which was cyclized with PPA at 100 C to afford quinolinone (IV). After protection of (IV) as the tert-butyl carbamate (V), addition of ethylmagnesium bromide provided carbinol (VI). Hydrogenolysis of the hydroxyl group of (VI), followed by deprotection with trifluoroacetic acid then furnished tetrahydroquinoline (VII). 2.- In an alternative procedure, side-chain alkylation of lepidine (VIII) with CH3I and LDA provided 4-ethylquinoline (IX). This was then reduced to the desired tetrahydroquinoline (VII) using NaBH4 and NiCl2. 3.- After nitration of (VII) with HNO3 and H2SO4, the resulting 7-nitroquinoline (X) was reduced to diamine (XI) by catalytic hydrogenation over Pd/C. Finally, Knorr cyclization of (XI) with ethyl 4,4,4-trifluoroacetylacetate (XII) and ZnCl2 produced the target pyridoquinoline.
| 【1】 Hamann, L.G.; Mani, N.S.; Davis, R.L.; Marschke, K.B.; Wang, X.-N.; Jones, T.K.; Discovery of a potent, orally active, nonsteroidal androgen receptor agonist: 4-Ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6-g]quinoline (LG121071). J Med Chem 1999, 42, 2, 210. |
| 【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 . |
| 【3】 Edwards, J.P.; Higuchi, R.; Jones, T. (Ligand Pharmaceuticals, Inc.); Androgen receptor modulator cpds. and methods. EP 0918774; US 6017924; WO 9749709 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (III) | 25423 | 3-anilinopropionic acid | 5652-38-0 | C9H11NO2 | 详情 | 详情 |
| (IV) | 25424 | 2,3-dihydro-4(1H)-quinolinone | 4295-36-7 | C9H9NO | 详情 | 详情 |
| (V) | 25425 | tert-butyl 4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 25426 | tert-butyl 4-ethyl-4-hydroxy-3,4-dihydro-1(2H)-quinolinecarboxylate | C16H23NO3 | 详情 | 详情 | |
| (VII) | 25427 | 4-ethyl-1,2,3,4-tetrahydroquinoline | C11H15N | 详情 | 详情 | |
| (VIII) | 25428 | 4-methylquinoline | 491-35-0 | C10H9N | 详情 | 详情 |
| (IX) | 25429 | 4-ethylquinoline | C11H11N | 详情 | 详情 | |
| (X) | 25430 | 4-ethyl-7-nitro-1,2,3,4-tetrahydroquinoline | C11H14N2O2 | 详情 | 详情 | |
| (XI) | 25431 | 4-ethyl-1,2,3,4-tetrahydro-7-quinolinamine; 4-ethyl-1,2,3,4-tetrahydro-7-quinolinylamine | C11H16N2 | 详情 | 详情 | |
| (XII) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线42
该中间体在本合成路线中的序号：(II)Conjugate addition of crotonic acid (I) to aniline (II) gave amino acid (III), which was cyclized to the quinolinone (IV) with polyphosphoric acid at 110 C. Protection of the amino group of (IV) with Boc2O gave carbamate (V), which was subsequenty alkylated with iodoethane in the presence of NaH to yield (VI) as a diastereomeric mixture. Acid deprotection of the Boc group of (VI) gave amine (VII). The ketone group was then reduced with triethylsilane and boron trifluoride to the tetrahydroquinoline (VIII). Nitration of (VIII), followed by hydrogenation of the resulting nitro derivative (IX) furnished the aminoquinoline (X). Further Knorr cyclization of (X) with ethyl 4,4,4-trifluoroacetoacetate (XI) by means of ZnCl2 in refluxing EtOH yielded the corresponding pyridoquinoline. The required trans isomer was finally isolated by preparative HPLC.
| 【1】 Zhi, L.; Marschke, K.B.; Jones, T.K.; Tegley, C.M.; Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone. Bioorg Med Chem Lett 1999, 9, 7, 1009. |
| 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) | 20599 | (E)-2-butenoic acid; crotonic acid | 3724-65-0 | C4H6O2 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 31314 | 3-anilinobutyric acid | 14676-01-8 | C10H13NO2 | 详情 | 详情 |
| (IV) | 31315 | 2-methyl-2,3-dihydro-4(1H)-quinolinone | C10H11NO | 详情 | 详情 | |
| (V) | 31316 | tert-butyl 2-methyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (VI) | 31317 | tert-butyl 3-ethyl-2-methyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C17H23NO3 | 详情 | 详情 | |
| (VII) | 31318 | 3-ethyl-2-methyl-2,3-dihydro-4(1H)-quinolinone | C12H15NO | 详情 | 详情 | |
| (VIII) | 31319 | 3-ethyl-2-methyl-1,2,3,4-tetrahydroquinoline | C12H17N | 详情 | 详情 | |
| (IX) | 31320 | 3-ethyl-2-methyl-7-nitro-1,2,3,4-tetrahydroquinoline | C12H16N2O2 | 详情 | 详情 | |
| (X) | 31321 | 3-ethyl-2-methyl-1,2,3,4-tetrahydro-7-quinolinylamine; 3-ethyl-2-methyl-1,2,3,4-tetrahydro-7-quinolinamine | C12H18N2 | 详情 | 详情 | |
| (XI) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线43
该中间体在本合成路线中的序号：(II)Conjugate addition of pentenoic acid (I) to aniline (II) gave amino acid (III), which was cyclized to the quinolinone (IV) with polyphosphoric acid at 110 C. Protection of the amino group of (IV) with Boc2O gave carbamate (V), which was subsequenty alkylated with iodoethane in the presence of NaH to yield (VI) as a diastereomeric mixture. Acid deprotection of the Boc group of (VI) gave amine (VII). The ketone group of (VII) was then reduced with triethylsilane and boron trifluoride to the tetrahydroquinoline (VIII). Nitration of (VIII), followed by hydrogenation of the resulting nitro derivative (IX) furnished the aminoquinoline (X). Further Knorr cyclization of (X) with ethyl 4,4,4-trifluoroacetoacetate (XI) by means of ZnCl2 in refluxing EtOH yielded the corresponding pyridoquinoline. The required trans isomer was finally isolated by preparative HPLC.
| 【1】 Zhi, L.; Marschke, K.B.; Jones, T.K.; Tegley, C.M.; Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone. Bioorg Med Chem Lett 1999, 9, 7, 1009. |
| 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) | 31305 | (E)-2-pentenoic acid | 13991-37-2 | C5H8O2 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 31306 | 3-anilinopentanoic acid | C11H15NO2 | 详情 | 详情 | |
| (IV) | 31307 | 2-ethyl-2,3-dihydro-4(1H)-quinolinone | C11H13NO | 详情 | 详情 | |
| (V) | 31308 | tert-butyl 2-ethyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VI) | 31309 | tert-butyl 2,3-diethyl-4-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C18H25NO3 | 详情 | 详情 | |
| (VII) | 31310 | 2,3-diethyl-2,3-dihydro-4(1H)-quinolinone | C13H17NO | 详情 | 详情 | |
| (VIII) | 31311 | 2,3-diethyl-1,2,3,4-tetrahydroquinoline | C13H19N | 详情 | 详情 | |
| (IX) | 31313 | 2,3-diethyl-7-nitro-1,2,3,4-tetrahydroquinoline | C13H18N2O2 | 详情 | 详情 | |
| (X) | 31312 | 2,3-diethyl-1,2,3,4-tetrahydro-7-quinolinylamine; 2,3-diethyl-1,2,3,4-tetrahydro-7-quinolinamine | C13H20N2 | 详情 | 详情 | |
| (XI) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
合成路线44
该中间体在本合成路线中的序号：(II)The reductocondensation of 3-methyl-4-oxopiperidine-1-carboxylic acid methyl ester (I) with aniline (II) by means of TsOH and NaBH4 in refluxing toluene gives 3-methyl-4-(phenylamino)piperidine-1-carboxylic acid methyl ester (III), which is acylated with propionyl anhydride yielding the corresponding propionamide as a mixture of cis and trans isomers, from which the racemic cis isomer (rac)-(IV) is isolated by crystallization. The optical resolution of (rac)-(IV) with d-tartaric acid followed by treatment with NaOH affords (3S.4R)-3-methyl-4-(phenylamino)piperidine (3S,4R)-(V), which is methylated with methyl iodide and K2CO3 to provide (3S,4R)-1,3-dimethyl-4-(phenylamino)piperidine (VI) (1). The condensation of (VI) with the 4-fluorobenzoate (VII) by means of BuLi in THF furnishes the corresponding tertiary amine (VIII), which is transesterified with NaOMe and hydrolyzed with ethanol/water to give the free benzoic acid (IX). The condensation of (IX) with diethylamine by means of BOP and TEA yields the corresponding diethylamide (X), which is demethylated by acylation with phenyl chloroformate and cleavage with KOH to afford the free piperidine NH compound (XI). Finally this piperidine derivative is allylated with allyl bromide (XII) and K2CO3 in ethanol.
| 【1】 Niemegeers, C.J.E.; Van Bever, W.F.M.; Janssen, P.A.J.; Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J Med Chem 1974, 17, 10, 1047-1051. |
| 【2】 Carroll, F.I.; Thomas, J.B.; Dersch, C.M.; Rothman, R.B.; Mascarella, S.W.; Burges, J.P.; Xu, H.; Herault, X.M.; Horel, R.B.; (±)-4-[(N-Allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 20, 3053. |
| 【3】 Carroll, F.I.; Horel, R.B.; Rothman, R.B.; Mascarella, S.W.; Dersch, C.M.; Atkinson, R.N.; Xu, H.; Herault, X.M.; Thomas, J.B.; Optically pure (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding and full agonist activity for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 23, 3347. |
| 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) | 41454 | methyl 3-methyl-4-oxo-1-piperidinecarboxylate | C8H13NO3 | 详情 | 详情 | |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 41455 | methyl 4-anilino-3-methyl-1-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IV) | 41456 | methyl (3S,4R)-3-methyl-4-(propionylanilino)-1-piperidinecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (V) | 41457 | N-[(3S,4R)-3-methylpiperidinyl]-N-phenylamine; (3S,4R)-3-methyl-N-phenyl-4-piperidinamine | C12H18N2 | 详情 | 详情 | |
| (VI) | 41459 | N-[(3S,4R)-1,3-dimethylpiperidinyl]-N-phenylamine; (3S,4R)-1,3-dimethyl-N-phenyl-4-piperidinamine | C13H20N2 | 详情 | 详情 | |
| (VII) | 41458 | 2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate | C22H27FO3 | 详情 | 详情 | |
| (VIII) | 41460 | 2,6-di(tert-butyl)-4-methoxyphenyl 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoate | C35H46N2O3 | 详情 | 详情 | |
| (IX) | 41461 | 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoic acid | C20H24N2O2 | 详情 | 详情 | |
| (X) | 41462 | 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]-N,N-diethylbenzamide | C24H33N3O | 详情 | 详情 | |
| (XI) | 41463 | N,N-diethyl-4-[[(3S,4R)-3-methylpiperidinyl]anilino]benzamide | C23H31N3O | 详情 | 详情 | |
| (XII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
合成路线45
该中间体在本合成路线中的序号：(VIII)2-Chloronicotinic acid (I) was reduced to alcohol (II) employing borane, generated from NaBH4 and BF3.Et2O. Subsequent oxidation of (II) with N-bromosuccinimide produced aldehyde (III), which was condensed with N-Boc-4-aminopiperidine (IV), yielding imine (V). Addition to (V) of (4-fluorophenyl)-toluenesulfonylmethyl isocyanide (VI) gave rise to imidazole (VII). Then, displacement of the 2-chloro of (VII) by means of aniline (VIII) in the presence of NaH furnished the 2-anilinopyridine derivative (IX). The Boc protecting group of (IX) was finally removed by treatment with trifluoroacetic acid.
| 【1】 Adams, J.L.; Gallagher, T.F.; Sisko, J.; Peng, Z.-Q.; Osifo, I.K.; Boehm, J.C. (SmithKline Beecham plc); Imidazole cpds.. EP 0831830; JP 1999513017; US 5658903; WO 9640143 . |
| 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) | 40032 | 2-chloroisonicotinic acid | 6313-54-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 40033 | (2-chloro-4-pyridinyl)methanol | 100704-10-7 | C6H6ClNO | 详情 | 详情 |
| (III) | 29234 | 2-chloroisonicotinaldehyde | C6H4ClNO | 详情 | 详情 | |
| (IV) | 28414 | 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine | 87120-72-7 | C10H20N2O2 | 详情 | 详情 |
| (V) | 40034 | tert-butyl 4-[[(E)-(2-chloro-4-pyridinyl)methylidene]amino]-1-piperidinecarboxylate | C16H22ClN3O2 | 详情 | 详情 | |
| (VI) | 40035 | 2-(4-fluorophenyl)-2-[(4-methylphenyl)sulfonyl]acetonitrile | C15H12FNO2S | 详情 | 详情 | |
| (VII) | 40036 | tert-butyl 4-[5-(2-chloro-4-pyridinyl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]-1-piperidinecarboxylate | C24H26ClFN4O2 | 详情 | 详情 | |
| (VIII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IX) | 40037 | tert-butyl 4-[5-(2-anilino-4-pyridinyl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]-1-piperidinecarboxylate | C30H32FN5O2 | 详情 | 详情 |
合成路线46
该中间体在本合成路线中的序号：(II)The reductive alkylation of tropinone (I) with aniline (II) using either NaBH4 or NaBH(OAc)3 as the reducing agent furnished the endo-isomer (III). Arylation of amine (III) with t-butyl 4-bromobenzoate (IV) produced the (diarylamino)tropane (V). Acid cleavage of the tert-butyl ester of (V) gave acid (VI), which was further coupled to diethylamine, yielding amide (VII). Demethylation of tropane (VII) with 1-chloroethyl chloroformate, followed by methanolysis of the resulting carbamate (VIII), provided the secondary amine (IX). This was finally subjected to reductive alkylation with 3,4-methylenedioxybenzaldehyde (X) to give the title compound.
| 【1】 Gauthier, A.D.; Neilson, L.A.; Carson, J.R.; Codd, E.E.; Zhang, S.-P.; Boyd, R.E.; Synthesis and binding affinities of 4-diarylaminotropanes, a new class of delta opioid agonists. Bioorg Med Chem Lett 2000, 10, 10, 1109. |
| 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) | 16443 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one | C8H13NO | 详情 | 详情 | |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 51368 | (1R,5S)-8-methyl-N-phenyl-8-azabicyclo[3.2.1]octan-3-amine; N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N-phenylamine | C14H20N2 | 详情 | 详情 | |
| (IV) | 14286 | tert-butyl 4-bromobenzoate | C11H13BrO2 | 详情 | 详情 | |
| (V) | 51369 | tert-butyl 4-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]anilino]benzoate | C25H32N2O2 | 详情 | 详情 | |
| (VI) | 51370 | 4-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]anilino]benzoic acid | C21H24N2O2 | 详情 | 详情 | |
| (VII) | 51371 | N,N-diethyl-4-[[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]anilino]benzamide | C25H33N3O | 详情 | 详情 | |
| (VIII) | 51372 | 1-chloroethyl (1R,5S)-3-[4-[(diethylamino)carbonyl](phenyl)anilino]-8-azabicyclo[3.2.1]octane-8-carboxylate | C27H34ClN3O3 | 详情 | 详情 | |
| (IX) | 51373 | 4-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylanilino]-N,N-diethylbenzamide | C24H31N3O | 详情 | 详情 | |
| (X) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
合成路线47
该中间体在本合成路线中的序号：(VII)Condensation between 4-fluorophenylhydrazine (I) and 2-ketoglutaric acid (II) produced the intermediate hydrazone (III), which was cyclized and esterified to the indole diester (IV) under Fischer synthesis conditions. Alkylation of the indole nitrogen with iodomethane and NaH produced the N-methyl indole (V). This was condensed with dimethylformamide-dimethylacetal in refluxing DMF to furnish the enamino ester (VI). Condensation of enamine (VI) with aniline (VII), followed by cyclization of the intermediate enamino ester under basic conditions, gave rise to the pyridoindole (VIII). The remaining ester group of (VIII) was then hydrolyzed with NaOH to the corresponding carboxylic acid (IX), which was finally coupled with pyrrolidine (X) via activation with carbonyldiimidazole.
| 【1】 Sevrin, M.; Maloizel, C.; Evanno, Y.; Legalloudec, O.; George, P. (Sanofi-Synthelabo); 1H-Pyrido[3,4-b]indole-4-carboxamide derivs., preparation and application thereof in therapeutics. FR 2754262; JP 2001508403; US 6075021; WO 9815552 . |
| 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) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (II) | 52267 | 2-Ketoglutaric acid; 2-Oxoglutaric acid; alpha-Ketoglutaric acid; 2-Oxopentanedioic acid | 328-50-7 | C5H6O5 | 详情 | 详情 |
| (III) | 52268 | 2-[2-(4-fluorophenyl)hydrazono]pentanedioic acid | C11H11FN2O4 | 详情 | 详情 | |
| (IV) | 52269 | ethyl 3-[2-(ethyloxy)-2-oxoethyl]-5-fluoro-1H-indole-2-carboxylate | C15H16FNO4 | 详情 | 详情 | |
| (V) | 52270 | ethyl 3-[2-(ethyloxy)-2-oxoethyl]-5-fluoro-1-methyl-1H-indole-2-carboxylate | C16H18FNO4 | 详情 | 详情 | |
| (VI) | 52271 | ethyl 3-{2-(dimethylamino)-1-[(ethyloxy)carbonyl]ethenyl}-5-fluoro-1-methyl-1H-indole-2-carboxylate | C19H23FN2O4 | 详情 | 详情 | |
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VIII) | 52272 | ethyl 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-beta-carboline-4-carboxylate | C21H17FN2O3 | 详情 | 详情 | |
| (IX) | 52273 | 6-fluoro-9-methyl-1-oxo-2-phenyl-2,9-dihydro-1H-beta-carboline-4-carboxylic acid | C19H13FN2O3 | 详情 | 详情 | |
| (X) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
合成路线48
该中间体在本合成路线中的序号：(I)Acetylation of aniline (I) with acetic anhydride (Ac2O) in HOAc followed by reaction with mercurium acetate (Hg(OAc)2) and HClO4 in HOAc provides derivative (II), which is first subjected to dimerization by treatment with Cu and PdCl2 in pyridine and then nitrated by means of HNO3 in HOAc to afford substituted biphenyl (III). Hydrolysis of (III) with H2SO4 gives 4,4'-diamino-3,3'-dinitrobiphenyl (IV), which is converted into tetraaminobiphenyl (V) by hydrogenation over Raney-Ni in acetone. Mitsunobu reaction between p-hydroxybenzaldehyde (VI) and 3-dimethylamino propan-1-ol (VII) with PPh3 and DEAD in THF gives substituted benzaldehyde (VIII), which is finally cyclized with biphenyl derivative (V) by heating in nitrobenzene to furnish the target product.
| 【1】 Neidle, S.; et al.; Symmetric bis-benzimidazoles: New sequence-selective DNA-binding molecules. Chem Commun (London) 1999, 10, 929. |
| 【2】 Kelland, L.R.; Opoku-Boahen, Y.; Mann, J.; Baron, A.; johansson, E.; Parkinson, G.; Neidle, S.; A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity. J Med Chem 2001, 44, 2, 138. |
| 【3】 Mann, J.; Neidle, S. (Institute of Cancer Research; Queen's University of Belfast; University of Reading); Bis-benzazoles and their use as antineoplastic agents. WO 0063180 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 47202 | C10H11HgNO3 | 详情 | 详情 | ||
| (III) | 47203 | N-[4'-(acetamido)-3,3'-dinitro[1,1'-biphenyl]-4-yl]acetamide | C16H14N4O6 | 详情 | 详情 | |
| (IV) | 47204 | 3,3'-dinitro[1,1'-biphenyl]-4,4'-diamine; 4'-amino-3,3'-dinitro[1,1'-biphenyl]-4-ylamine | 6271-79-0 | C12H10N4O4 | 详情 | 详情 |
| (V) | 47205 | 3',4,4'-triamino[1,1'-biphenyl]-3-ylamine; [1,1'-biphenyl]-3,3',4,4'-tetramine | 91-95-2 | C12H14N4 | 详情 | 详情 |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (VIII) | 47206 | 4-[3-(dimethylamino)propoxy]benzaldehyde | C12H17NO2 | 详情 | 详情 |
合成路线49
该中间体在本合成路线中的序号：(II)The title imine derivative was prepared by condensation of the known 7-formylcamptothecin (I) with aniline (II) in the presence of ytterbium triflate and molecular sieves in CH2Cl2.
| 【1】 De Cesare, M.; Pratesi, G.; Carenini, N.; Dallavalle, S.; Penco, S.; Ferrari, A.; Merlini, L.; Zunino, F.; Perego, P.; Novel cytotoxic 7-iminomethyl and 7-aminomethyl derivatives of camptothecin. Bioorg Med Chem Lett 2001, 11, 3, 291. |
| 【2】 Carminati, P.; Penco, S.; Zunino, F.; Merlini, L. (Istituto Nazionale per lo Studio e la Cura dei Tumori; Sigma-Tau Industrie Farmaceutiche Riunite SpA); Camptothecin derivs. having antitumor activity. EP 1044977; WO 0053607 . |
合成路线50
该中间体在本合成路线中的序号：(I)Treatment of aniline (I) with hexafluoroacetone trihydrate (II) and p-toluenesulfonic acid affords derivative (III), which is then derivatized with trifluoroacetic anhydride (IV) to provide trifluoroacetanilide derivative (V). Reduction of (V) by means of LiAlH4 in refluxing THF yields N-trifluoroethylaniline derivative (VI), which is finally converted into the target sulfonamide by reaction with benzenesulfonyl chloride (VII) in pyridine.
| 【1】 Shan, B. (Tularik Inc.); Compsns. and methods for raising HDL cholesterol levels. WO 0103705 . |
| 【2】 Liu, J.; Li, L.; Cutler, S.T.; Zhu, L.; Shan, B.; Medina, J.C.; Hasegawa, H.; Lustig, K. (Tularik Inc.); LXR modulators. EP 1161233; WO 0054759 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (III) | 50005 | 2-(4-Aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 4-(Hexafluoro-2-hydroxyisopropyl)aniline | 722-92-9 | C9H7F6NO | 详情 | 详情 |
| (IV) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (V) | 50006 | 2,2,2-trifluoro-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide | C11H6F9NO2 | 详情 | 详情 | |
| (VI) | 50007 | 1,1,1,3,3,3-hexafluoro-2-[4-[(2,2,2-trifluoroethyl)amino]phenyl]-2-propanol | C11H8F9NO | 详情 | 详情 | |
| (VII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
合成路线51
该中间体在本合成路线中的序号：(II)The condensation of phthalic anhydride (I) with aniline (II) in refluxing HOAc produced N-phenyl phthalimide (III). Aromatic sulfonation of (III) with chlorosulfonic acid in the presence of PCl5 afforded the sulfonyl chloride (IV). This was finally condensed with thiomorpholine (V) to furnish the target sulfonamide.
| 【1】 Legora, A.M.; et al.; Anti-inflammatory effects of thalidomide-derived compounds on LPS-induced inflammation in mouse lung. Inflamm Res 2001, 50, Suppl. 3, Abst 083. |
| 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) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 53124 | N-Phenylphthalimide | 520-03-6 | C14H9NO2 | 详情 | 详情 |
| (IV) | 53125 | 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzenesulfonyl chloride | n/a | C14H8ClNO4S | 详情 | 详情 |
| (V) | 36317 | thiomorpholine | 123-90-0 | C4H9NS | 详情 | 详情 |
合成路线52
该中间体在本合成路线中的序号：(I)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-cyclopropylethanone (IV) (obtained by bromination of acetylcyclopropane (V)) by means of NaOMe to yield the adduct (VI). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 12436 | 2-Bromo-1-cyclopropyl-1-ethanone | 69267-75-0 | C5H7BrO | 详情 | 详情 |
| (V) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (VI) | 53529 | (Z)-3-anilino-3-[(2-cyclopropyl-2-oxoethyl)sulfanyl]-2-propenenitrile | n/a | C14H14N2OS | 详情 | 详情 |
合成路线53
该中间体在本合成路线中的序号：(II)2,6-Dichloro-3-nitrobenzoic acid (I) was condensed with aniline (II) to produce the anilinobenzoic acid (III), which was subsequently cyclized to the acridinone (IV) upon treatment with POCl3. Displacement of the chloride group of (IV) with 1,4-bis(3-aminopropyl)piperazine (V) in DMF afforded adduct (VI). The nitro group of (VI) was reduced by catalytic hydrogenation in the presence of Raney-Ni and formic acid, and the intermediate formamide was further cyclized under acidic conditions to the imidazoacridinone (VII). Finally, conversion of the primary amino group of (VII) to the target imide was achieved by heating with 3-nitro-1,8-naphthalenedicarboxylic anhydride (VIII) in DMF.
| 【1】 Cholody, W.M.; Michejda, C.J.; Kosakowska-Cholody, T. (US Department of Health & Human Services); 1,8-Naphthalimide imidazo[4,5,1-de]acridones with anti-tumor activity. WO 0166545 . |
| 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) | 52274 | 2,5-Dichloro-3-nitrobenzoic acid | 88-86-8 | C7H3Cl2NO4 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 52275 | 6-chloro-3-nitro-2-(phenylamino)benzoic acid | C13H9ClN2O4 | 详情 | 详情 | |
| (IV) | 52276 | 1-chloro-4-nitro-9(10H)-acridinone | C13H7ClN2O3 | 详情 | 详情 | |
| (V) | 52277 | 1,4-Bis(3-aminopropyl)piperazine; N,N'-Bis(3-Aminopropyl)piperazine; Bis aminopropyl piperazine; 1,4-Di(3-aminopropyl)piperazine | 7209-38-3 | C10H24N4 | 详情 | 详情 |
| (VI) | 52278 | 1-({3-[4-(3-aminopropyl)-1-piperazinyl]propyl}amino)-4-nitro-9(10H)-acridinone | C23H30N6O3 | 详情 | 详情 | |
| (VII) | 52279 | 5-({3-[4-(3-aminopropyl)-1-piperazinyl]propyl}amino)-6H-imidazo[4,5,1-de]acridin-6-one | C24H30N6O | 详情 | 详情 | |
| (VIII) | 15864 | 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride | 3027-38-1 | C12H5NO5 | 详情 | 详情 |
合成路线54
该中间体在本合成路线中的序号：(I)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-pyridyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (IV) | 53085 | 2-bromo-1-(3-pyridinyl)-1-ethanone | n/a | C7H6BrNO | 详情 | 详情 |
| (V) | 53539 | (Z)-3-anilino-3-{[2-oxo-2-(3-pyridinyl)ethyl]sulfanyl}-2-propenenitrile | n/a | C16H13N3OS | 详情 | 详情 |
合成路线55
该中间体在本合成路线中的序号：(I)The reaction of aniline (I) with di(2-pyridyl)thione (DPT) gives the corresponding isothiocyanate (II), which is condensed with cyanamide (III) and 2-bromo-1-(3-benzyloxyphenyl)ethanone (IV) by means of NaOMe to yield the adduct (V). This compound, without isolation, cyclizes to the target thiazole.
| 【1】 Sorensen, A.R.; Engelhardt, S.; Kurtzhals, P.; Urso, B.; Bowler, A.N.; 2,4-Diaminothiazoles: A novel class of glycogen synthase kinase-3 (GSK-3) inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P20. |
| 【2】 Olesen, P.H.; Kurtzhals, P.; Bowler, A.N.; Soerensen, A.R.; Worsaae, H.; Hansen, B.F. (Novo Nordisk A/S); 2,4-Diaminothiazole derivs.. WO 0156567 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (III) | 53541 | 1-[3-(benzyloxy)phenyl]-2-bromo-1-ethanone | n/a | C15H13BrO2 | 详情 | 详情 |
| (IV) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (V) | 53545 | (Z)-3-({2-[3-(benzyloxy)phenyl]-2-oxoethyl}sulfanyl)-3-(4-chloroanilino)-2-propenenitrile | n/a | C24H19ClN2O2S | 详情 | 详情 |
合成路线56
该中间体在本合成路线中的序号：(I)Acylation of aniline (I) with chloroacetyl chloride (II) in cold CH2Cl2 provides 2-chloro-N-phenylacetamide (III). Then, condensation of (III) with 4-aminoquinaldine (IV) in the presence of NaH in an inert atmosphere furnishes the title compound
| 【1】 Sahu, N.P.; et al.; Synthesis of a novel quinoline derivative, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide- A potential antileishmanial agent. Bioorg. Med. Chem. 2002, 10, 6, 1687. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 60932 | 2-chloro-N-phenylacetamide | C8H8ClNO | 详情 | 详情 | |
| (IV) | 61469 | 4-Aminoquinaldine; 4-Amino-2-methylquinoline; 4-Amino-2-Methylquinoline; 4-Aminoquinaldine; 4-Amino-2-methylchinolin | 6628-04-2 | C10H10N2 | 详情 | 详情 |
合成路线57
该中间体在本合成路线中的序号：(IX)O-Protection of 2,4-di-tert-butylphenol (I) with methyl chloroformate (II) in the presence of Et3N and DMAP in CH2Cl2 gives 2,4-ditert-butylphenyl methyl carbonate (III), which by nitration with HNO3 and H2SO4 provides a mixture of the 5- and 6-nitrophenyl carbonates (IVa) and (IVb), respectively. Hydrolysis of the mixture of carbonates (IVa) and (IVb) by means of KOH in MeOH followed by chromatographic separation of the resulting mixture of nitrophenols affords 2,4-di-tert-butyl-5-nitrophenol (V), which is reduced by transfer hydrogenation with HCOONH4 in the presence of Pd/C in refluxing EtOH to the amine (VI). Finally, amine (VI) is condensed with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) by means of HBTU and Et3N in DMF or CH2Cl2 .
4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (VII) is prepared by coupling of diethyl 2-(ethoxymethylene)malonate (VIII) with aniline (IX) by heating at 140-150 °C to afford diethyl 2-(anilinomethylene) malonate (X), which by cyclization by means of PPA and POCl3 at 70 °C yields ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (XI). Finally, ethyl ester derivative (XI) is saponified with NaOH at reflux, followed by acidification with HCl .
| 【1】 Hadida Ruah, S.S., Hazlewood, A.R., Grootenhuis, P.D.J., Van Goor, F.F., Singh, A.K., Zhou, J., McCartney, J. (Vertex Pharmaceuticals, Inc.).Modulators of ATP-binding cassette transporters. CN 10193301, EP 1773816, JP 2008504291, US 2006074075, US 7495013, US 8101767, WO 2006002421. |
| 【2】 Hurter, P. (Vertex Pharmaceuticals, Inc.). Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide. EP 1993360, JP 200952278, US 011064811, WO 2007079139. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 68207 | 2,4-di-tert-butyl-5-nitrophenyl methyl carbonate | 873055-55-1 | C16H23NO5 | 详情 | 详情 |
| (IVb) | 68208 | 2,4-di-tert-butyl-6-nitrophenyl methyl carbonate | 详情 | 详情 | ||
| (I) | 68205 | 2,4-di-tert-butylphenol;2,4-Bis(1,1-dimethylethyl)-phenol | 96-76-4 | C14H22O | 详情 | 详情 |
| (II) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (III) | 68206 | 2,4-ditert-butylphenyl methyl carbonate | C16H24O3 | 详情 | 详情 | |
| (V) | 68209 | 2,4-di-tert-butyl-5-nitrophenol | C14H21NO3 | 详情 | 详情 | |
| (VI) | 68210 | 5-amino-2,4-di-tert-butylphenol | C14H23NO | 详情 | 详情 | |
| (VII) | 68211 | 4-oxo-1,4-dihydroquinoline-3-carboxylic acid | 13721-01-2 | C10H7NO3 | 详情 | 详情 |
| (VIII) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (IX) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (X) | 35953 | diethyl 2-(anilinomethylene)malonate | C14H17NO4 | 详情 | 详情 | |
| (XI) | 68212 | ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate | C12H11NO3 | 详情 | 详情 |
合成路线58
该中间体在本合成路线中的序号：(III)Chlorination of 2-fluoro-6-nitrobenzoic acid (I) with (COCl)2 by means of DMF in CH2Cl2 gives 2-fluoro-6-nitrobenzoyl chloride (II), which is then coupled with aniline (III) in the presence of NaHCO3 in dioxane/H2O to yield 2-fluoro-6-nitro-N-phenylbenzamide (IV). Activation of amide (IV) as the corresponding imidoyl chloride (V) by means of SOCl2 and DMF at 85 °C, and subsequent coupling with NBoc-2(S)-aminobutyric acid (VI) by means of Et3N in CH2Cl2 affords imide (VII). Reductive cyclization of compound (VII) in the presence of Zn in AcOH affords quinazolinone (VIII), which is N-deprotected with TFA in CH2Cl2 to obtain amine (IX). Finally, amine (IX) is condensed with 6-bromopurine (X) by means of DIEA in t-BuOH at 80 °C .
| 【1】 Kesicki, E.A., Zhichkin, P. (Icos Corp.). Method of preparing 3-phenyl-2-[(9H-purin-6-ylamino)-methyl]-3H-quinazolin-4-one and substituted and related compounds. WO 2005113554. |
| 【2】 Fowler, K.W., Huang, D., Kesicki, E.A., Ooi, H.C., Oliver, A.R., Ruan, F., Treiberg, J. (Icos. Corp.). Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta. CA 2566609, CN 102229609, EP 1761540, JP 2007537291, US 2008275067, US 7932260, US 2012015964, WO 2005113556. |
| 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) | 68438 | 2-fluoro-6-nitrobenzoic acid;6-Fluoro-2-nitrobenzoic acid | 385-02-4 | C7H4FNO4 | 详情 | 详情 |
| (II) | 68461 | 2-methyl-6-nitrobenzoyl chloride | 66232-57-3 | C8H6ClNO3 | 详情 | 详情 |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 68462 | 2-fluoro-6-nitro-N-phenylbenzamide | C13H9FN2O3 | 详情 | 详情 | |
| (V) | 68464 | (Z)-2-fluoro-6-nitro-N-phenylbenzimidoyl chloride | C13H8ClFN2O2 | 详情 | 详情 | |
| (VI) | 68463 | (S)-2-((tert-butoxycarbonyl)amino)butanoic acid | 34306-42-8 | C9H17NO4 | 详情 | 详情 |
| (VII) | 68465 | (S)-tert-butyl (1-(2-fluoro-6-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate | C22H24FN3O6 | 详情 | 详情 | |
| (VIII) | 68466 | (S)-tert-butyl (1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate | C22H24FN3O3 | 详情 | 详情 | |
| (IX) | 68467 | (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one | C17H16FN3O | 详情 | 详情 | |
| (X) | 68468 | 6-bromopurine;6-Bromo-1H-purine | 767-69-1 | C5H3BrN4 | 详情 | 详情 |