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【结 构 式】 
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【分子编号】11182 【品名】2,5-Furandione; Maleic anhydride 【CA登记号】108-31-6 |
【 分 子 式 】C4H2O3 【 分 子 量 】98.05808 【元素组成】C 49% H 2.06% O 48.95% |
合成路线1
该中间体在本合成路线中的序号：(II)The copolymerization of ethylene (III) and maleic anhydride (II) in ethylbenzene (I) by means of benzoyl peroxide (IV) at 70 C gives an ethylene/maleic anhydride copolymer (V), which is ammoniated by treating with liquid ammonia in acetone yielding the ammoniated ethylene/maleic acid copolymer (VI). Finally, this product is imidated partially by heating in refluxing xylene.
| 【1】 Asculai, S.S.; Fields, J.E.; Johnson, R.K.; Johnson, J.H.; Carboxyimidate, a low-molecular-weight polyelectrolyte with antitumor properties and low toxixity. J Med Chem 1982, 25, 9, 1060-64. |
| 【2】 Hopkins, S.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; N-137. Drugs Fut 1983, 8, 3, 210. |
| 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) | 31977 | 1-ethylbenzene | 100-41-4 | C8H10 | 详情 | 详情 |
| (II) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (III) | 18363 | 4-chloro-2-methyl-5-(methylsulfonyl)benzoic acid | C9H9ClO4S | 详情 | 详情 | |
| (IV) | 35970 | benzoyl benzenecarboperoxoate | 94-36-0 | C14H10O4 | 详情 | 详情 |
| (V) | 35971 | 3-[2-(2,5-dioxotetrahydro-3-furanyl)ethyl]-4-(1-phenylethyl)dihydro-2,5-furandione | C18H18O6 | 详情 | 详情 | |
| (VI) | 35972 | C18H26N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The cyclization of trifluoroacetylmethylpyridinium bromide (I) with 3-(4-trifluoromethylbenzoyl)acrylic acid (II) by means of ammonium acetate in refluxing methanol gives 2-trifluoromethyl-6-(4-trifluoromethylphenyl)isonicotinic acid (III), which by condensation with 2-bromopyridine (IV) by means of butyllithium in ethyl ether yields 2-trifluoromethyl-6-(4-trifluoromethylphenyl)4-pyridyl-2'-pyridyl ketone (V). Finally, this compound is reduced with H2 over Pt in aqueous concentrated HCl. The starting products are prepared as follows: 1) The acrylic acid (II) is obtained by condensation of maleic anhydride (VI) with 4-trifluoromethylphenylmagnesium bromide (VII) by means of ZnCl2 in refluxing ethyl ether. An alternative method is the condensation of 4-trifluoromethylacetophenone (VIII) with glyoxylic acid (IX) by means of triethylamine at 135 C. 2) The pyridinium salt (I) is prepared by bromination of 1,1,1-trifluoroacetone (X) giving 1,1,1-trifluoro-3-bromoacetone (XI), which is then condensed with pyridine.
| 【1】 La Montagne, M.P.; et al.; Antimalarials. 6. Synthesis, antimalarial activity and configurations of rracemic alpha-(2-piperidyl)-4-pyridinemethanols. J Med Chem 1974, 17, 5, 219-523. |
| 【2】 Ash, A.B.; et al. (Department of the Army); 2-Substituted phenyl-6-trifluoromethyl-4-pyridylcarbinolamines. US 3940404 . |
| 【3】 Ash, A.B.; et al. (Department of the Army); 2-Aryl-6-trifluoromethyl-4-pyridylcarbinolamine antimalarials. US 3953463 . |
| 【4】 Ash, A.B.; et al. (Department of the Army); 2-Aryl-6-trifluoromethyl-4-pyridylcarbinolamine antimalarials. US 3886167 . |
| 【5】 Castaner, J.; Roberts, P.J.; WR-180,409. Drugs Fut 1978, 3, 9, 694. |
| 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) | 39908 | 1-(3,3,3-trifluoro-2-oxopropyl)pyridinium bromide | C8H7BrF3NO | 详情 | 详情 | |
| (II) | 39906 | (E)-4-oxo-4-[4-(trifluoromethyl)phenyl]-2-butenoic acid | C11H7F3O3 | 详情 | 详情 | |
| (III) | 39910 | 2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]isonicotinic acid | C14H7F6NO2 | 详情 | 详情 | |
| (IV) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (V) | 39911 | 2-pyridinyl[2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-4-pyridinyl]methanone | C19H10F6N2O | 详情 | 详情 | |
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 39311 | bromo[4-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (VIII) | 39907 | 1-[4-(trifluoromethyl)phenyl]-1-ethanone | 709-63-7 | C9H7F3O | 详情 | 详情 |
| (IX) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (X) | 35449 | 1,1,1-trifluoroacetone | 421-50-1 | C3H3F3O | 详情 | 详情 |
| (XI) | 39909 | 3-bromo-1,1,1-trifluoroacetone | 431-35-6 | C3H2BrF3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)An asymmetric synthesis of (-)-quinocarcin has been described: The acylation of 2-(2-methoxy-6-methylphenyl)-(R)- glycinol (I) with maleic anhydride (II) in ether gives the maleic monoamide (III), which is cyclized to the pyrrolidinedione (IV) by refluxing with acetic anhydride. The cyclization of (IV) with methyl azide in toluene affords the pyrrolotriazole (V), which is irradiated with UV light (Hg lamp), giving the aziridinopyrrole (VI). The cycloaddition of (VI) with the chiral acrylamide (VII) affords the diazabicyclo[3.2.1]octane (VIII). At this point, the hydroxyl group of (VIII) is protected with methoxymethyl chloride giving the methoxymethyl ether (IX), which is submitted to benzylic bromination with N-bromosuccinimide (NBS) in chloroform, yielding the bromo derivative (X). The reaction of (X) with triphenylphosphine affords the phosphonium salt (XI), which by treatment with potassium tert-butoxide and heat cyclizes to the tetracyclo compound (XII). Hydrogenation of (XII) with H2 over RaNi in ethanol affords the reduced compound (XIII), which is treated with LiOH in THF - water, affording the free acid derivative (XIV). The deprotection of the ether group of (XIV) with trimethylsilyl chloride and NaI in acetonitrile gives the hydroxymethyl derivative (XV), which is finally cyclized to (-)-quinocarcin with AgNO3 in methanol-water.
| 【1】 Ho, W.B.; Garner, P.; Shin, H.; Asymmetric synthesis of (-)-quinocarcin. J Am Chem Soc 1992, 114, 7, 2767. |
| 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) | 11194 | (2R)-2-Amino-2-(2-methoxy-6-methylphenyl)-1-ethanol | C10H15NO2 | 详情 | 详情 | |
| (II) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (III) | 11196 | (Z)-4-[[(1R)-2-Hydroxy-1-(2-methoxy-6-methylphenyl)ethyl]amino]-4-oxo-2-butenoic acid | C14H17NO5 | 详情 | 详情 | |
| (IV) | 11197 | 1-[(1R)-2-Hydroxy-1-(2-methoxy-6-methylphenyl)ethyl]-1H-pyrrole-2,5-dione | C14H15NO4 | 详情 | 详情 | |
| (V) | 11198 | 5-[(1R)-2-Hydroxy-1-(2-methoxy-6-methylphenyl)ethyl]-1-methyl-3a,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-4,6(1H,5H)-dione | C15H18N4O4 | 详情 | 详情 | |
| (VI) | 11199 | 3-[(1R)-2-Hydroxy-1-(2-methoxy-6-methylphenyl)ethyl]-6-methyl-3,6-diazabicyclo[3.1.0]hexane-2,4-dione | C15H18N2O4 | 详情 | 详情 | |
| (VII) | 11200 | (1R)-4-Acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (VIII) | 11201 | (1R)-4-([(1S,5S,6R)-3-[(1R)-2-Hydroxy-1-(2-methoxy-6-methylphenyl)ethyl]-8-methyl-2,4-dioxo-3,8-diazabicyclo[3.2.1]oct-6-yl]carbonyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C28H37N3O7S | 详情 | 详情 | |
| (IX) | 11202 | (1R)-4-([(1S,5S,6R)-3-[(1R)-2-(Methoxymethoxy)-1-(2-methoxy-6-methylphenyl)ethyl]-8-methyl-2,4-dioxo-3,8-diazabicyclo[3.2.1]oct-6-yl]carbonyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C30H41N3O8S | 详情 | 详情 | |
| (X) | 11203 | (1R)-4-([(1S,5S,6R)-3-[(1R)-1-[2-(Bromomethyl)-6-methoxyphenyl]-2-(methoxymethoxy)ethyl]-8-methyl-2,4-dioxo-3,8-diazabicyclo[3.2.1]oct-6-yl]carbonyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C30H40BrN3O8S | 详情 | 详情 | |
| (XI) | 11204 | [2-[(1R)-1-((1S,5S,6R)-6-[[(1R)-10,10-Dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-8-methyl-2,4-dioxo-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(methoxymethoxy)ethyl]-3-methoxybenzyl](triphenyl)phosphonium bromide | C48H55BrN3O8PS | 详情 | 详情 | |
| (XII) | 11205 | (1R)-4-([(1S,10R,13S,15R)-8-Methoxy-10-[(methoxymethoxy)methyl]-16-methyl-12-oxo-11,16-diazatetracyclo[11.2.1.0(2,11).0(4,9)]hexadeca-2,4,6,8-tetraen-15-yl]carbonyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C30H39N3O7S | 详情 | 详情 | |
| (XIII) | 11206 | (1R)-4-([(1S,2S,10R,13S,15R)-8-Methoxy-10-[(methoxymethoxy)methyl]-16-methyl-12-oxo-11,16-diazatetracyclo[11.2.1.0(2,11).0(4,9)]hexadeca-4,6,8-trien-15-yl]carbonyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C30H41N3O7S | 详情 | 详情 | |
| (XIV) | 11207 | (1S,2S,10R,13S,15R)-8-Methoxy-10-[(methoxymethoxy)methyl]-16-methyl-12-oxo-11,16-diazatetracyclo[11.2.1.0(2,11).0(4,9)]hexadeca-4,6,8-triene-15-carboxylic acid | C20H26N2O6 | 详情 | 详情 | |
| (XV) | 11208 | (1S,2S,10R,13S,15R)-10-(Hydroxymethyl)-8-methoxy-16-methyl-12-oxo-11,16-diazatetracyclo[11.2.1.0(2,11).0(4,9)]hexadeca-4,6,8-triene-15-carboxylic acid | C18H22N2O5 | 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 synthesis of SM-3997 labeled in the carbonyl groups or the pyrimidine ring has been reported: The Diels-Alder condensation of cyclopentadiene (II) with [14C]-labeled maleic anhydride (I) gives bicyclo[2.2.1]hept-5-ene-2,3-endo-di[14C]-carboxylic anhydride (III), which by treatment with ammonia in THF is converted to the corresponding imide (IV endo). Heating of (IV endo) at 190 C in diphenylether affords the corresponding exo isomer (IV exo), which is hydrogenated with H2 over Pd/C in ethanol - THF to give the saturated exo-imide (V). The condensation of (V) with 1,4-dibromobutane (VI) by means of K2CO3 in refluxing acetone yields the N-(4-bromobutyl)imide (VII), which is finally condensed with 1-(2-pyrimidinyl)piperazine (VIII) by means of K2CO3 and KI in hot DMF to afford SM-399 [14C]-labeled at the carbonyl groups.
| 【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV endo) | 11185 | (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H9NO2 | 详情 | 详情 | |
| (IV exo) | 11186 | (1R,2R,6S,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H9NO2 | 详情 | 详情 | |
| (IV endo) | 45052 | (1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H9NO2 | 详情 | 详情 | |
| (IV exo) | 45053 | (1R,2S,6R,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H9NO2 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (I) | 45050 | 2,5-furandione | C4H2O3 | 详情 | 详情 | |
| (II) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (III) | 11184 | (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (III) | 45051 | (1R,2R,6S,7S)-4-oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (V) | 11173 | (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C9H11NO2 | 详情 | 详情 | |
| (V) | 45054 | (1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C9H11NO2 | 详情 | 详情 | |
| (VII) | 11174 | (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C13H18BrNO2 | 详情 | 详情 | |
| (VII) | 45055 | (1R,2R,6S,7S)-4-(4-bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C13H18BrNO2 | 详情 | 详情 | |
| (VIII) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The oxidation of the primary alcohol group of (XI) with pyridinium chlorochromate (PCC) in dichloromethane affords the aldehyde (XII), which is finally reductocondensed with 4-phenylsemicarbazide (XIII) by means of NaBH3CN and hydrolyzed with LiOH to furnish the target semicarbazide.
| 【1】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347. |
| 【2】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590. |
| 【3】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153. |
| 【4】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 43719 | (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIb) | 43720 | (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIa) | 43721 | (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIb) | 43728 | (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 43717 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C8H6O4 | 详情 | 详情 | |
| (IV) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 | |
| (V) | 43718 | (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one | C8H10O3 | 详情 | 详情 | |
| (VIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (IX) | 43722 | (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol | C9H14O3 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 43723 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H24O4 | 详情 | 详情 | |
| (XII) | 43729 | methyl (Z)-7-[(1R,2R,3S,4S)-3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H22O4 | 详情 | 详情 | |
| (XIII) | 43730 | N-phenyl-1-hydrazinecarboxamide | 537-47-3 | C7H9N3O | 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 Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The oxidation of the primary alcohol group of (XI) with pyridinium chlorochromate (PCC) in dichloromethane affords the aldehyde (XII), which is condensed with dimethyl 2-oxobutylphosphonate (XIII) and NaH, providing the pentenone (XIV). Finally, the ketonic group of (XIV) is reduced with NaBH4/CeCl3, and the resulting ester hydrolyzed with LiOH to furnish the target hydroxyacid as a diastereomeric mixture that is separated by conventional methods.
| 【1】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293. |
| 【2】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153. |
| 【3】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347. |
| 【4】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 43719 | (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIb) | 43720 | (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIa) | 43721 | (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIb) | 43728 | (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 43717 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C8H6O4 | 详情 | 详情 | |
| (IV) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 | |
| (V) | 43718 | (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one | C8H10O3 | 详情 | 详情 | |
| (VIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (IX) | 43722 | (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol | C9H14O3 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 43723 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H24O4 | 详情 | 详情 | |
| (XII) | 43729 | methyl (Z)-7-[(1R,2R,3S,4S)-3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H22O4 | 详情 | 详情 | |
| (XIII) | 43731 | dimethyl 2-oxobutylphosphonate | C6H13O4P | 详情 | 详情 | |
| (XIV) | 43732 | (Z)-7-[(1R,2R,3S,4S)-3-[(E)-3-oxo-1-pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C18H26O4 | 详情 | 详情 | |
| (XV) | 43733 | (Z)-7-[(1R,2R,3S,4S)-3-[(E,3R)-3-hydroxy-1-pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C18H28O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)Reaction of 1,3,5,7-cyclooctatetraene (I) with maleimide (Step a, b), or maleic anhydride (Step c), in refluxing toluene affords the imide (II) or the anhydride (III) in 78 and 85% yields, respectively. Reaction of imide intermediate (II) with 1,4-dibromobutane gives the omega-haloalkylimide, which subsequently is reacted with 1-(2-pyrimidinyl)piperazine to yield Wy-47846 (Method A). Alternatively, Wy-47846 can be prepared via the reaction of (III) with 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in refluxing pyridine (Method B), as shown in scheme. Wy-47846 is achiral.
| 【2】 Abou-Gharbia, M.; Moyer, J.A.; Haskins, J.T.; WY-47846. Drugs Fut 1989, 14, 5, 442. |
| 【1】 Abou-Gharbia, M.; et al.; Polycyclic aryl- and heteroarylpiperazyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies. J Med Chem 1988, 31, 7, 1382. |
| 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) | 20923 | 1,3,5,7-cyclooctatetraene | 629-20-9 | C8H8 | 详情 | 详情 |
| (II) | 20924 | bicyclo[4.2.0]octa-2,4-diene | C8H10 | 详情 | 详情 | |
| (III) | 20925 | (2R,6S,8R,11S)-4-azatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione | C12H11NO2 | 详情 | 详情 | |
| (IV) | 20926 | (2R,6S,8R,11S)-4-oxatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione | C12H10O3 | 详情 | 详情 | |
| (V) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (VIII) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (IX) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The Diels-Alder condensation of maleic anhydride (I) with furan (II) gives the epoxytetrahydrophthalic anhydride (III), which is reduced with H2 over Pd/C, yielding the epoxyperhydrophthalic anhydride (IV). Further reduction of (IV) with NaBH4 affords the epoxyperhydrophthalide (V), which is submitted to a third reduction with DIBAL-H to provide the lactol (VI) as a racemic mixture that is resolved with menthol. The appropriate isomer (VIIa) is treated with triphenylphosphonium bromide (VIII) and potassium tert-amyloxide to give the 5,8-epoxyperhydro-2-benzopyran-3-ol (IX), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (X) by means of potassium tert-amyloxide and esterified with Amberlist-15/MeOH, yielding the cis-5-heptenoic acid methyl ester (XI). The sulfonation of the primary alcohol group of (XI) with TsOH affords the tosylate (XII), which is condensed with potassium phthalimide (XII) to provide the phthalimido derivative (XIV). The treatment of (XIV) with hydrazine gives the aminomethyl compound (XV), which is finally condensed with N-(heptanoyl)glycine (XVI) by means of CDI and hydrolyzed with LiOH to afford the target glycinamide compound.
| 【1】 Hedberg, A.; Hall, S.E.; Harris, D.N.; Ogletree, M.L.; 7-Oxabicycloheptane analogs: modulators of the arachidonate cascade. Drugs Fut 1988, 13, 2, 153. |
| 【2】 Haslanger, M.F.; Han, W.-C.; Ogletree, M.L.; Hall, S.E.; Harris, D.N.; 9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase. J Med Chem 1986, 29, 2335-2347. |
| 【3】 Haslanger, M.F.; Greenberg, M.J.; Ogletree, M.L.; Nakane, M.; Garber, D.P.; Harris, D.N.; Reid, J.C.; Aza-substituted omega side chain modification of 7-oxabicyclo[2.2.1]heptane TxA2 receptor antagonists: Structure-activity relationships. Advances in Prostaglandin, Thromboxane and Leukotriene Research, vol. 15; O. Hayaishi and S. Yamamoto (Eds.). Raven Press: New York 1985, 291-293. |
| 【4】 Gougoutas, J.Z.; Sprague, P.W.; Harris, D.N.; Malley, M.F.; Heikes, J.E.; Greenberg, R.; Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2. J Med Chem 1985, 28, 1580-1590. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 43719 | (1R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIb) | 43720 | (1R,3R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIa) | 43721 | (1R,2R,3S,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (VIIb) | 43728 | (1S,2S,3R,6S,7R)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-ol | C8H12O3 | 详情 | 详情 | |
| (I) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 43717 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C8H6O4 | 详情 | 详情 | |
| (IV) | 36472 | (1R,2R,6S,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 | |
| (V) | 43718 | (1R,2R,6R,7S)-4,10-dioxatricyclo[5.2.1.0(2,6)]decan-3-one | C8H10O3 | 详情 | 详情 | |
| (VIII) | 25649 | (methoxymethyl)(triphenyl)phosphonium bromide | C20H20BrOP | 详情 | 详情 | |
| (IX) | 43722 | (1S,2R,5R,7R,8R)-4,11-dioxatricyclo[6.2.1.0(2,7)]undecan-5-ol | C9H14O3 | 详情 | 详情 | |
| (X) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XI) | 43723 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H24O4 | 详情 | 详情 | |
| (XII) | 43724 | methyl (Z)-7-[(1R,2R,3R,4S)-3-([[(4-methylphenyl)sulfonyl]oxy]methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C22H30O6S | 详情 | 详情 | |
| (XIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XIV) | 43725 | methyl (Z)-7-[(1R,2R,3R,4S)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C23H27NO5 | 详情 | 详情 | |
| (XV) | 43726 | methyl (Z)-7-[(1R,2R,3R,4S)-3-(aminomethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H25NO3 | 详情 | 详情 | |
| (XVI) | 43727 | 2-(heptanoylamino)acetic acid | C9H17NO3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)1) The condensation of 4-fluoroanisole (I) with maleic anhydride (II) by means of AlCl3 in hot 1,2-dichloroethane gives (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid (III), which is cyclized by means of NaHCO3 in boiling water to yield racemic 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (IV). The reaction of (IV) with refluxing SOCl2 affords the corresponding acyl chloride (V), which is condensed with (S)-(-)-1-phenylethylamine (VI) affording the amide (VII) as a diastereomeric mixture (R,S + S,S), which is submitted to a fractional crystallization to give the suitable isomer (S,S)-(VII). The hydrolysis of (S,S)-(VII) with concentrated HCl in refluxing dioxane yields the corresponding acid (S)-(IV) as a pure enantiomer. The cyclization of (S)-(IV) with KCN and (NH4)2CO3 in hot water affords the acidic spiro compound (VIII), again as a diastereomeric mixture (2S,4R + 2S,4S), which is separated by fractional crystallization to obtain the desired (2S,4S)-(VIII) compound. The esterification of (2S,4S)-(VIII) with propanol/sulfuric acid affords the corresponding propyl ester (IX), which is finally treated with dry ammonia in methanol.
| 【1】 Mealy, N.; Castaner, J.; SNK-860. Drugs Fut 1996, 21, 3, 261. |
| 【2】 Yamaguchi, T.; Miura, K.; Usui, T.; Unno, R.; Matsumoto, Y.; Fukushima, M.; Mizuno, K.; Kondo, Y.; Baba, Y.; Kurono, M.; Synthesis and aldose reductase inhibitory activity of 2-substituted-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,4'--imidazolidine]-2',5'-diones. Arzneim-Forsch Drug Res 1994, 44, 3, 344-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| ((S)-IV) | 16064 | (2S)-6-fluoro-4-oxo-3,4-dihydro-2H-chromene-2-carboxylic acid | C10H7FO4 | 详情 | 详情 | |
| (I) | 16057 | 4-Fluoroanisole; 4-fluorophenyl methyl ether; 1-fluoro-4-methoxybenzene; p-Fluoroanisole | 459-60-9 | C7H7FO | 详情 | 详情 |
| (II) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (III) | 16059 | (E)-4-(5-fluoro-2-hydroxyphenyl)-4-oxo-2-butenoic acid | C10H7FO4 | 详情 | 详情 | |
| (IV) | 16060 | 6-fluoro-4-oxo-2-chromanecarboxylic acid | C10H7FO4 | 详情 | 详情 | |
| (V) | 16061 | 6-fluoro-4-oxo-2-chromanecarbonyl chloride | C10H6ClFO3 | 详情 | 详情 | |
| (VI) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VII) | 16063 | (2S)-6-fluoro-4-oxo-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide | C18H16FNO3 | 详情 | 详情 | |
| (VIII) | 16065 | (2S,4S)-6-fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]2-ylcarboxylic acid | C12H9FN2O5 | 详情 | 详情 | |
| (IX) | 16066 | (2S,4S)-6-Fluoro-2',5'-dioxo-3,4-dihydro-2H-spiro[1-benzopyran-4,4'-imidazolidin]-2-ylcarboxylic acid propyl ester | C15H15FN2O5 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)1-Bromo-3,5-dimethyladamantane (I) is subjected to Ritter reaction with acetonitrile in the presence of H2SO4 to produce acetamide (II). This is further hydrolyzed to the aminoadamantane (III) employing NaOH in refluxing diethyleneglycol. Condensation of amine (III) with maleic anhydride (IV) leads to the maleamic acid (V), which is finally cyclized to the target maleimide upon heating in acetic anhydride in the presence of NaOAc.
| 【1】 Wang, J.J.; Chern, Y.-T.; Liu, T.-Y.; Chi, C.-W.; In vitro and in vivo growth inhibition of cancer cells by adamantylmaleimide derivatives. Anti-Cancer Drug Des 1998, 13, 7, 779. |
| 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) | 52352 | 1-bromo-3,5-dimethyltricyclo[3.3.1.1~3,7~]decane | C12H19Br | 详情 | 详情 | |
| (II) | 63743 | N-(3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-yl)acetamide | C14H23NO | 详情 | 详情 | |
| (III) | 63744 | 3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-ylamine; 3,5-dimethyltricyclo[3.3.1.1~3,7~]decan-1-amine | C12H21N | 详情 | 详情 | |
| (IV) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (V) | 63745 | 4-[(3,5-dimethyltricyclo[3.3.1.1~3,7~]dec-1-yl)amino]-4-oxo-2-butenoic acid | C16H23NO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VI)The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords the title product as a mixture of two diastereomeric racemates that are separated by column chromatography.
| 【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 . |
| 【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707. |
| 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) | 53530 | 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione | 606-23-5 | C9H6O2 | 详情 | 详情 |
| (II) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (III) | 53531 | 2-Benzylidene-1,3-indandione | n/a | C16H10O2 | 详情 | 详情 |
| (IV) | 53532 | n/a | C16H10O3 | 详情 | 详情 | |
| (V) | 23629 | 3,4-dichloroaniline | 95-76-1 | C6H5Cl2N | 详情 | 详情 |
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 53533 | 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione | 19844-27-0 | C10H5Cl2NO2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VII)The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords the title product as a mixture of two diastereomeric racemates that are separated by column chromatography.
| 【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 . |
| 【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707. |
| 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) | 53530 | 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione | 606-23-5 | C9H6O2 | 详情 | 详情 |
| (II) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (III) | 53531 | 2-Benzylidene-1,3-indandione | n/a | C16H10O2 | 详情 | 详情 |
| (IV) | 53532 | n/a | C16H10O3 | 详情 | 详情 | |
| (V) | 53533 | 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione | 19844-27-0 | C10H5Cl2NO2 | 详情 | 详情 |
| (VI) | 23629 | 3,4-dichloroaniline | 95-76-1 | C6H5Cl2N | 详情 | 详情 |
| (VII) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XI)Alternatively, the condensation of 1,3-benzodioxole-5-carbaldehyde ethylene ketal (VIII) with carbaldehyde (V) by means of n-BuLi gives the hydroxy ketal (IX), which is treated with Ac2O, HOAc and maleic anhydride (XI) at 140 C to perform a Diels-Alder cyclization between the nonisolated isobenzofuran (X) (a reactive diene) and the maleic anhydride (the dienophile), giving rise to the cyclic anhydride (XII). Finally, this compound is reduced with NaBH4 to the target compound along with some structural isomer (XIII) that is separated by chromatography.
| 【1】 Urasaki, Y.; et al.; Activity of a novel camptothecin analogue, homocamptothecin, in camptothecin-resistant cell lines with topoisomerase I alterations. Cancer Res 2000, 60, 23, 6577. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (VIII) | 46637 | 5-(1,3-dioxolan-2-yl)-1,3-benzodioxole | C10H10O4 | 详情 | 详情 | |
| (IX) | 46638 | 1,3-benzodioxol-5-yl[5-(1,3-dioxolan-2-yl)-1,3-benzodioxol-4-yl]methanol | C18H16O7 | 详情 | 详情 | |
| (X) | 46639 | 8-(1,3-benzodioxol-5-yl)furo[3,4-e][1,3]benzodioxole | C16H10O5 | 详情 | 详情 | |
| (XI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (XII) | 46640 | 10-(1,3-benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d][1,3]dioxole-7,9-dione | C20H10O7 | 详情 | 详情 | |
| (XIII) | 46641 | 10-(1,3-benzodioxol-5-yl)furo[3',4':6,7]naphtho[1,2-d][1,3]dioxol-9(7H)-one | C20H12O6 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(VI)Hexachloroplatinic acid (I) was reduced to potassium tetrachloroplatinate (II) using hydrazine. Treatment of (II) with KI produced the tetraiodoplatinate (III), which was converted to the diamino compound (IV) by reaction with isopropylamine. Conversion to the dinitrate (V) was then effected by iodide ion exchange with silver nitrate. Diels-Alder condensation of maleic anhydride (VI) with furan (VII) furnished adduct (VIII), which was further hydrogenated to (IX) using Pd/C. Then, basic hydrolysis of the cyclic anhydride in the presence of the platinum complex (V) afforded the title compound.
| 【1】 Lin, G.; To, K.K.W.; Wang, X.; Han, X.; Au-Yeung, S.C.F.; Ho, Y.-P.; Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety. J Med Chem 2001, 44, 13, 2065. |
| 【2】 Ho, Y.P.; Au-Yeung, S.C.F.; Jiang, T.; Han, X.; Wang, X.; Lin, G.; Lu, S. (Chinese University of Hong Kong); Synthesis of platinum complexes and uses thereof. WO 9849174 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (VIII) | 49887 | exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride; exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride; 7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride | 6118-51-0 | C8H6O4 | 详情 | 详情 |
| (IX) | 49888 | 4,10-Dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(I)The Diels-Alder cycloaddition between maleic anhydride (I) and furan (II) produced adduct (III). Subsequent double-bond hydrogenation in the presence of Pd/C furnished the saturated anhydride (IV).
| 【1】 Lin, G.; To, K.K.W.; Wang, X.; Han, X.; Au-Yeung, S.C.F.; Ho, Y.-P.; Potential new antitumor agents from an innovative combination of demethylcantharidin, a modified traditional Chinese medicine, with a platinum moiety. J Med Chem 2001, 44, 13, 2065. |
| 【2】 Ho, Y.P.; Au-Yeung, S.C.F.; Jiang, T.; Han, X.; Wang, X.; Lin, G.; Lu, S. (Chinese University of Hong Kong); Synthesis of platinum complexes and uses thereof. WO 9849174 . |
| 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) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (II) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (III) | 49887 | exo-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride; exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride; 7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride | 6118-51-0 | C8H6O4 | 详情 | 详情 |
| (IV) | 49888 | 4,10-Dioxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C8H8O4 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(VII)The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords a mixture of two diastereomeric racemates from which the desired isomer (VIII) is separated by column chromatography (1-3). Finally, (VIII) is reduced with NaBH4 in methanol to provide a diastereomeric mixture from which the title product is separated by chromatography.
| 【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707. |
| 【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Tetracyclic heterocycles as antimicrobial agents. US 6153645; WO 0017206 . |
| 【3】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 . |
| 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) | 53530 | 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione | 606-23-5 | C9H6O2 | 详情 | 详情 |
| (II) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (III) | 53531 | 2-Benzylidene-1,3-indandione | n/a | C16H10O2 | 详情 | 详情 |
| (IV) | 53532 | n/a | C16H10O3 | 详情 | 详情 | |
| (V) | 53533 | 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione | 19844-27-0 | C10H5Cl2NO2 | 详情 | 详情 |
| (VI) | 23629 | 3,4-dichloroaniline | 95-76-1 | C6H5Cl2N | 详情 | 详情 |
| (VII) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VIII) | 53598 | n/a | C26H15Cl2NO5 | 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 condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (III), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords a mixture of two diastereomeric racemates from which the desired isomer (VIII) is separated by column chromatography (1-3). Finally, (VIII) is reduced with NaBH4 in methanol to provide a diastereomeric mixture from which the title product is separated by chromatography.
| 【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707. |
| 【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 . |
| 【3】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Tetracyclic heterocycles as antimicrobial agents. US 6153645; WO 0017206 . |
| 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) | 53530 | 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione | 606-23-5 | C9H6O2 | 详情 | 详情 |
| (II) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (III) | 53531 | 2-Benzylidene-1,3-indandione | n/a | C16H10O2 | 详情 | 详情 |
| (IV) | 53532 | n/a | C16H10O3 | 详情 | 详情 | |
| (V) | 53533 | 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione | 19844-27-0 | C10H5Cl2NO2 | 详情 | 详情 |
| (VI) | 23629 | 3,4-dichloroaniline | 95-76-1 | C6H5Cl2N | 详情 | 详情 |
| (VII) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VIII) | 53598 | n/a | C26H15Cl2NO5 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(II)6-Aminocaproic acid (I) is condensed with maleic anhydride (II) in refluxing AcOH to provide maleimidocaproic acid (III). After activation of acid (III) as the corresponding mixed anhydride with isobutyl chloroformate, coupling with tert-butyl carbazate (IV) affords the N-Boc hydrazide (V). Subsequent acidic cleavage of the Boc group of (V) furnishes hydrazide (VI). Finally, hydrazide (VI) is condensed with doxorubicin (VII) to produce the title hydrazone conjugate.
| 【1】 Willner, D.; Trail, P.A.; Hofstead, S.J.; King, H.D.; Lasch, S.J.; Braslawsky, G.R.; Greenfield, R.S.; Kaneko, T.; Firestone, R.A.; (6-Maleimidocaproyl)hydrazone of doxorubicin - A new derivative for the preparation of immunoconjugates of doxorubicin. Bioconjugate Chem 1993, 4, 6, 521. |
| 【2】 Willner, D.; Trail, P.A.; King, D.H.; Hofstead, S.J.; Greenfield, R.S.; Braslawsky, G.R. (Bristol-Myers Squibb Co.); Thioether conjugates. EP 0554708; JP 1994025012; US 5622929 . |
| 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) | 41170 | 6-aminohexanoic acid | 60-32-2 | C6H13NO2 | 详情 | 详情 |
| (II) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (III) | 63203 | 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid | C10H13NO4 | 详情 | 详情 | |
| (IV) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (V) | 63204 | tert-butyl 2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-1-hydrazinecarboxylate | C15H23N3O5 | 详情 | 详情 | |
| (VI) | 63205 | 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide | C10H15N3O3 | 详情 | 详情 | |
| (VII) | 11675 | (8S,10S)-10-[[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C27H29NO11 | 详情 | 详情 |