|
【结 构 式】 
|
【分子编号】21891 【品名】2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil 【CA登记号】118-75-2 |
【 分 子 式 】C6Cl4O2 【 分 子 量 】245.8756 【元素组成】C 29.31% Cl 57.68% O 13.01% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of chloranil (I) with ethyl carbamate (II) by means of Na in dry benzene gives 2,5-dichloro-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone (III), which is then condensed with aziridine (IV) by means of triethylamine in THF.
| 【1】 Driscoll, J.S.; et al.; Structure-antitumor activity relationships among quinone derivatives. Cancer Chemother Rep 1974, 4, 2, 1. |
| 【2】 Zubrod, C.G.; Rall, D.P.; Anu Rev Pharmacol 1962, 2, 109. |
| 【3】 Kahn, A.H.; Driscoll, J.S.; Potential central nervous system antitumor agents. Azirinylbenzoquinones. 1. J Med Chem 1976, 19, 2, 313-317. |
| 【4】 Driscoll, J.S.; et al. (US Department of Health & Human Services); Aziridinyl quinone anti-transplanted tumor agents. US 4146622 . |
| 【5】 Cabanillas, F.; Blancafort, P.; Serradell, M.N.; Castaner, J.; AZQ. Drugs Fut 1981, 6, 6, 338. |
| 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) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
| (II) | 24199 | Ethyl carbamate; Urethane | 51-79-6 | C3H7NO2 | 详情 | 详情 |
| (III) | 32193 | 2,5-Dichloro-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone; Ethyl 2,5-dichloro-4-[(ethoxycarbonyl)amino]-3,6-dioxo-1,4-cyclohexadien-1-ylcarbamate | C12H12Cl2N2O6 | 详情 | 详情 | |
| (IV) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III), which by cyclization with acetic acid is converted to the lactol (IV). Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V), which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI). Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.
| 【1】 Petzoldt, K.; Wiechert, R.; Laurent, H.; A new synthesis for aldosterone-antagonistic spirorenone. Angew Chem 1983, 95, 5, 413-414. |
| 【2】 Wiechert, R.; et al. (Schering AG); 6beta,7beta;15,16-Dimethylene-1,4-androstadien-3-ones, their preparation and use as medicinal agents. DE 2922500; EP 0019690; JP 55162799 . |
| 【3】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 | |
| 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 | |
| 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 | |
| (A) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (I) | 29688 | (4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O2 | 详情 | 详情 | |
| (II) | 29689 | 3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether | 36255-44-4 | C5H11BrO2 | 详情 | 详情 |
| (III) | 29690 | (4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3,3-dimethoxypropyl)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7-diol | C25H40O4 | 详情 | 详情 | |
| (IV) | 29691 | 3-Hydroxycyclopropa[1',2':15-beta,16-beta]pregn-5-ene-21,17-carbolactone | C23H34O3 | 详情 | 详情 | |
| (V) | 29692 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (VI) | 11776 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone | C23H28O3 | 详情 | 详情 | |
| (VII) | 29694 | 3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone | C24H30O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(B)The condensation of cyclohexenone (I) with diethyl alpha-methylmalonate (II) by means of sodium ethoxide in ethanol gives diethyl alpha-methyl-3-oxocyclohexanemalonate (III), oil b.p.(0.8) = 149-52 C, n(20)(D) = 1.4660, which is hydrolyzed and decarboxylated with refluxing dioxane-HCl to yield alpha-methyl-3-oxocyclohexaneacetic acid (IV), oil, b.p.(0.7) = 164-6 C, n(20)(D) = 1.4794. The condensation of (IV) with 4-chlorophenylhydrazine (A) in acetic acid-water atfords 6-chloro-alpha-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid (V), m.p. 193-202 C, which is esterified with ethanol-HCl to ethyl 6-chloro-alpha-methyl-1,2,3,4-tetrahydrocarbazole-2-acetate (VI) and aromatized with chloranil (B) in refluxing xylene to give ethyl 6-chloro-alpha-methylcarbazole-2-acetate (VII), m.p. 106.0-7.5 C. Finally, this ester is hydrolyzed with NaOH in refluxing ethanol.
| 【1】 Berger, L.; Corraz, A.J.; Carbazoles. ES 417167; ES 442684; ES 442685; US 3896145 . |
| 【2】 Weetman, D.F.; Castaner, J.; Carprofen. Drugs Fut 1977, 2, 1, 15. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
| (A) | 33345 | 1-(4-chlorophenyl)hydrazine; 4-Chlorophenylhydrazine | 1073-70-7 | C6H7ClN2 | 详情 | 详情 |
| (I) | 26253 | 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone | 930-68-7 | C6H8O | 详情 | 详情 |
| (II) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
| (III) | 33625 | diethyl 2-methyl-2-(3-oxocyclohexyl)malonate | C14H22O5 | 详情 | 详情 | |
| (IV) | 33626 | 2-(3-oxocyclohexyl)propionic acid | C9H14O3 | 详情 | 详情 | |
| (V) | 33627 | 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)propionic acid | C15H16ClNO2 | 详情 | 详情 | |
| (VI) | 33628 | ethyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)propanoate | C17H20ClNO2 | 详情 | 详情 | |
| (VII) | 33629 | ethyl 2-(6-chloro-9H-carbazol-2-yl)propanoate | C17H16ClNO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)The dehydrogenation of 3beta-hydroxycholest-5-en-24-one with dichlorodicyanobenzoquinone in refluxing dioxane, or of cholest-4-ene-3,24-dione (II) with chloranil in refluxing tert-butyl alcohol gives cholesta-1,4,6-triene-3,24-dione (III), which is epoxidized with 30% H2O2 and NaOH in methanol-dioxane-THF yielding 1 alpha,2alpha-epoxycholesta-4,6-diene-3,24-dione (IV). The reduction of (IV) with Li in liquid NH3 affords 1alpha,3beta,24-trihydroxycholest-5-ene (V), which is benzoylated with benzoyl chloride in pyridine and submitted to column chromatography on silica gel to give 1alpha,3beta,24R-tribenzoyloxycholest-5-ene (VI). The dehydrogenation of (VI) with dibromodimethylhydantoin of N-bromosuccinimide yields lalpha,3beta,24R-trihydroxy-cholesta-5,7-diene (VII), which is finally submitted to irradiation with a medium-pressure Hg lamp in ether.
| 【1】 Ikekawa, N.; Koizumi, N.; Morisaki, M.; Synthesis of active forms of vitamin D. Part IX. S. J Chem Soc - Perkins Trans I 1975, 1421. |
| 【2】 Takeshita, T.; Hashimoto, Y.; Kawashima, H.; Ishimoto, S.; Ikekawa, N.; Morisaki, M. (Teijin Ltd.); 1alpha,24-Dihydroxycholecalciferol derivs. and pro. DE 2526981; US 4022891 . |
| 【3】 Castaner, J.; Prous, J.; TV-02. Drugs Fut 1988, 13, 2, 133. |
| 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) | 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 |
| (B) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
| (I) | 21883 | 6-[(3S,10R,13R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanone | C27H44O2 | 详情 | 详情 | |
| (II) | 21884 | (10R,13R)-17-(1,5-dimethyl-4-oxohexyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C27H42O2 | 详情 | 详情 | |
| (III) | 21885 | (10S,13R)-17-(1,5-dimethyl-4-oxohexyl)-10,13-dimethyl-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one | C27H38O2 | 详情 | 详情 | |
| (IV) | 21886 | (2aR,3aR,3bR,5aR)-6-(1,5-dimethyl-4-oxohexyl)-3b,5a-dimethyl-2a,3a,3b,3c,4,5,5a,6,7,8,8a,8b-dodecahydro-2H-cyclopenta[7,8]phenanthro[3,4-b]oxiren-2-one | C27H38O3 | 详情 | 详情 | |
| (V) | 21887 | (1S,3R,10R,13R)-17-(4-hydroxy-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C27H46O3 | 详情 | 详情 | |
| (VI) | 21888 | (1S,3R,10R,13R)-1-(benzoyloxy)-17-[(4R)-4-(benzoyloxy)-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl benzoate | C48H58O6 | 详情 | 详情 | |
| (VII) | 21889 | (1S,3R,10R,13R)-17-[(4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C27H44O3 | 详情 | 详情 | |
| (C) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 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) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 23689 | 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione | C9H12O5 | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 23696 | S-ethyl 3-oxopentanethioate | C7H12O2S | 详情 | 详情 | |
| (VI) | 23692 | propyl 3-oxo-3-phenylpropanoate | C12H14O3 | 详情 | 详情 | |
| (VII) | 23693 | propyl (E)-3-amino-3-phenyl-2-propenoate | C12H15NO2 | 详情 | 详情 | |
| (VIII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (IX) | 23699 | ethyl 4,6-diethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-1,4-dihydro-3-pyridinecarboxylate | C21H27NO3S | 详情 | 详情 | |
| (X) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with propanethiol (IV), followed by decarboxylation provided S-propyl 3-oxothiovalerate (V). Propyl 3-amino-3-(m-chlorophenyl)-2-propenoate (VII) was prepared by reaction of (3-chlorobenzoyl)acetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 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) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 23689 | 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione | C9H12O5 | 详情 | 详情 | |
| (IV) | 23703 | propylhydrosulfide; 1-propanethiol | 107-03-9 | C3H8S | 详情 | 详情 |
| (V) | 23704 | S-propyl 3-oxopentanethioate | C8H14O2S | 详情 | 详情 | |
| (VI) | 23705 | propyl 3-(3-chlorophenyl)-3-oxopropanoate | C12H13ClO3 | 详情 | 详情 | |
| (VII) | 23706 | propyl (E)-3-amino-3-(3-chlorophenyl)-2-propenoate | C12H14ClNO2 | 详情 | 详情 | |
| (VIII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (IX) | 23708 | propyl 2-(3-chlorophenyl)-4,6-diethyl-5-[(propylsulfanyl)carbonyl]-1,4-dihydro-3-pyridinecarboxylate | C23H30ClNO3S | 详情 | 详情 | |
| (X) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(X)Acylation of Meldrum's acid (I) with butyryl chloride (II) in the presence of pyridine gave butyryl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiocaproate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), b-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 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) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 10792 | Butanoyl chloride; Butyryl chloride | 141-75-3 | C4H7ClO | 详情 | 详情 |
| (III) | 23711 | 5-butyryl-2,2-dimethyl-1,3-dioxane-4,6-dione | C10H14O5 | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 23713 | S-ethyl 3-oxohexanethioate | C8H14O2S | 详情 | 详情 | |
| (VI) | 10004 | Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester | 94-02-0 | C11H12O3 | 详情 | 详情 |
| (VII) | 23715 | ethyl (E)-3-amino-3-phenyl-2-propenoate | C11H13NO2 | 详情 | 详情 | |
| (VIII) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (IX) | 23716 | ethyl 4-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-6-propyl-1,4-dihydro-3-pyridinecarboxylate | C22H29NO3S | 详情 | 详情 | |
| (X) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |