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【结 构 式】 
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【分子编号】12516 【品名】ethyl 3-oxohexanoate; ethyl butyrylacetate 【CA登记号】3249-68-1 |
【 分 子 式 】C8H14O3 【 分 子 量 】158.19736 【元素组成】C 60.74% H 8.92% O 30.34% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis of SK&F 96067 can be achieved in five stages: Reaction of ethyl butyrylacetate with triethyl orthoformate and acetic anhydride gives ethyl 2-butyryl-3-ethoxyacrylate (II) as a mixture of (E)- and (Z)-isomers. Treatment of (II) with o-anisidine provides the acyclic quinolone precursor (III), which on thermal cyclization in diphenyl ether gives the quinolone (IV). Conversion to the 4-chloroquinoline (V) is achieved by treatment with phosphorus oxychloride. Reaction of the chloroquinoline (V) with o-toluidine gives SK&F 96067 (VI).
| 【1】 Ife, R.J.; Brown, T.H.; Leach, C.A. (SmithKline Beecham plc); 4-Amino-3-substituted quinolines as inhibitors of gastric acid secretion. AU 8778741; EP 0259174; JP 1989500664; US 4806549; US 4806550; WO 8801621 . |
| 【2】 Brown, T.H.; Reavill, D.R.; Wiggall, K.J.; Ife, R.J.; Keeling, D.J.; Leach, C.A.; Meeson, M.L.; Parsons, M.E.; Theobald, C.J.; Reversible inhibitors of the gastric (H+/K+)-ATPase. 3. 3-Substituted-4-phenylaminoquinolines. J Med Chem 1992, 35, 18, 3413. |
| 【3】 Ife, R.J.; SK&F-96067. Drugs Fut 1992, 17, 9, 796. |
| 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) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (II) | 12517 | ethyl (E)-2-butyryl-3-ethoxy-2-propenoate | C11H18O4 | 详情 | 详情 | |
| (III) | 12518 | ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate | C16H21NO4 | 详情 | 详情 | |
| (IV) | 12519 | 3-Butyryl-8-methoxy-4(1H)-quinolinone | C14H15NO3 | 详情 | 详情 | |
| (V) | 12520 | 1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone | C14H14ClNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)This compound has been obtained by several related ways: 1) The reaction of ethyl butyrylacetate (I) with triethyl orthoformate and Ac2O gives acrylate (II), which by reaction with o-toluidine (III) yields the aminoacrylate (IV). The cyclization of (IV) by heating at 255 C in diphenyl ether affords the quinolone (V), which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI). The demethylation of (VI) with AlCl3 or BBr3 yields the 8-hydroxyquinoline (VII), which is condensed with o-toluidine (VIII) in refluxing dioxane affording 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX). Finally, this compound is condensed with 2-bromomethanol (X) by means of potassium tert-butoxide or with ethylene carbonate (XI) by means of K2CO3. 2) The condensation of chloroquinoline (VI) with o-toluidine (VIII) in refluxing dioxane gives 1-[8-methoxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (XII), which is demethylated with AlCl3 or BBr3 as before yielding the previously reported 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).
| 【1】 Atkins, R.J.; et al.; Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin. Org Process Res Dev 1997, 1, 3, 185. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 | |
| (I) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (II) | 12517 | ethyl (E)-2-butyryl-3-ethoxy-2-propenoate | C11H18O4 | 详情 | 详情 | |
| (III) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (IV) | 12518 | ethyl (Z)-2-butyryl-3-(2-methoxyanilino)-2-propenoate | C16H21NO4 | 详情 | 详情 | |
| (V) | 12519 | 3-Butyryl-8-methoxy-4(1H)-quinolinone | C14H15NO3 | 详情 | 详情 | |
| (VI) | 12520 | 1-(4-Chloro-8-methoxy-3-quinolinyl)-1-butanone | C14H14ClNO2 | 详情 | 详情 | |
| (VII) | 32800 | 1-(4-chloro-8-hydroxy-3-quinolinyl)-1-butanone | C13H12ClNO2 | 详情 | 详情 | |
| (VIII) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (IX) | 32801 | 1-[8-hydroxy-4-(2-toluidino)-3-quinolinyl]-1-butanone | C20H20N2O2 | 详情 | 详情 | |
| (X) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (XI) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (XII) | 32799 | 1-[8-methoxy-4-(2-toluidino)-3-quinolinyl]-1-butanone | C21H22N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)1) The cyclization of phloroglucinol (I) with butyrylacetic acid ethyl ester (II) by means of concentrated sulfuric acid gives 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III), which is condensed with propionyl chloride by means of AlCl3 in nitrobenzene, yielding the 8-propionyl derivative (V). The cyclization of (V) with 3-hydroxy-3-methylbuytyraldehyde dimethylacetal (VI) in refluxing pyridine affords the benzodipyran (VII), which is cyclized again with paraldehyde or acetaldehyde dimethylacetal by means of p-toluenesulfonic acid and trifluoroacetic acid in pyridine at 140 C to give a mixture of the diastereomeric racemates (VIII) and (IX), which are separated by column chromatography. The reduction of racemate (VIII) with NaBH4 /CeCl3 in ethanol yields a new mixture of the racemic hydroxy epimers (X) (racemic calanolide A) and (XI), which are separated by semipreparative HPLC. Racemic calanolide A (X) is finally submitted to optical resolution by semipreparative chiral HPLC.
| 【1】 Flavin, M.T.; Sheinkman, A.K.; Boulanger, W.A.; Khilevich, A.; Shone, R.L.; Rizzo, J.D.; Xu, Z.-Q.; Kucherenko, A.; Novel approach for synthesis of (±)-calanolide A a. Tetrahedron Lett 1995, 36, 31, 5475. |
| 【2】 Flavin, M.T.; Rizzo, J.D.; Khilevich, A.; et al.; Synthesis, chromatographic resolution, and anti-hu. J Med Chem 1996, 39, 6, 1303. |
| 【3】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235. |
| 【4】 Bokesch, H.R.; Cardellina, J.H. II; Boyd, M.R.; McKee, T.C.; Resolution and comparative anti-HIV evaluation of the enantiomers of calanolides A and B. Bioorg Med Chem Lett 1995, 5, 9, 1011. |
| 【5】 Boyd, M.R.; Cardellina, J.H. II; Gustafson, K.R.; McMahon, J.B.; Fuller, R.W.; Cragg, G.M.; Kashman, Y. (US Department of Health & Human Services); Calanolide antiviral cpds., compsns. and uses ther. EP 0633887; JP 1996502948; JP 1996507311; US 5591770; WO 9320082; WO 9428000 . |
| 【6】 Brankovic, D.; Flavin, M.T.; Vilaychack, V.; Liao, S.; Zembower, D.; Lin, L.; Dzekhster, S.; Rizzo, J.D.; Mar, A.; Xu, Z.-Q.; Khilevich, A.; Liu, J. (MediChem Research, Inc.); Method for the preparation of (+)-calanolide A and. WO 9838193 . |
| 【7】 Cragg, G.M.; Buckheit, R.W. Jr.; Fuller, R.W.; Gustafson, K.R.; Boyd, M.R.; Currens, M.J.; Cardellina, J.H. II; McMahon, J.B.; Hughes, S.H.; Kashman, Y.; The calanolides, a novel HIV-inhibitory class of c. J Med Chem 1992, 35, 15, 2735. |
| 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) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (IV) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (V) | 22407 | 5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one | C15H16O5 | 详情 | 详情 | |
| (VI) | 22408 | 4,4-dimethoxy-2-methyl-2-butanol | C7H16O3 | 详情 | 详情 | |
| (VII) | 22409 | 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one | C20H22O5 | 详情 | 详情 | |
| (VIII) | 22410 | (10R,11R)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione | C22H24O5 | 详情 | 详情 | |
| (IX) | 22411 | (10R,11S)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione | C22H24O5 | 详情 | 详情 | |
| (X) | 22412 | (10R,11S,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 | |
| (XI) | 22413 | (10R,11S,12R)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-dipyrano[2,3-f:2,3-h]chromen-2-one | C22H26O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The cyclization of phloroglucinol (I) with 3-oxohexanoic acid methyl ester (II) by means of conc. sulfuric acid gives the benzopyranone (III), which is acylated with 2-methyl-2-butenoyl chloride (IV) and AlCl3 in dichloroethane to yield the 5-hydroxy-7-(2-methyl-2-butenoyloxy)-4-propylbenzopyran-2-one (V). This compound, without isolation, rearranges under the reaction conditions to afford 5,7-dihydroxy-8-(2-methyl-2-butenoyloxy)-4-propylbenzopyran-2-one (VI). The cyclization of (VI) with 3-methyl-2-butenal (VII) in refluxing pyridine provides the benzo-tripyran-2,12-dione derivative (VIII) -alternatively, conversion of (VI) into (VIII) can be performed by first cyclization of (VI) by means of TEA to furnish compound (IX), which is then subjected to cyclization with 3-methyl-2-butenal (VII)-. Finally, reduction of (VIII) with LiAlH(OBu)3 in THF provides the target calanolide A.
| 【1】 Terashima, S.; Koyakumaru, K. (Kuraray Co., Ltd.; Sagami Chemical Research Center); Processes for preparing calanolide A and intermediates thereof. JP 2002193971; WO 0251847 . |
| 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) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (IV) | 45730 | Tigloyl chloride; (E)-2-methyl-2-butenoyl chloride | 35660-94-7 | C5H7ClO | 详情 | 详情 |
| (V) | 56901 | 5-hydroxy-2-oxo-4-propyl-2H-chromen-7-yl (E)-2-methyl-2-butenoate | C17H18O5 | 详情 | 详情 | |
| (VI) | 56902 | 5,7-dihydroxy-8-[(E)-2-methyl-2-butenoyl]-4-propyl-2H-chromen-2-one | C17H18O5 | 详情 | 详情 | |
| (VII) | 19512 | (2S,3aR,7aS)octahydro-1H-indole-2-carboxylic acid | 145438-94-4 | C9H15NO2 | 详情 | 详情 |
| (VIII) | 22410 | (10R,11R)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione | C22H24O5 | 详情 | 详情 | |
| (IX) | 56903 | (8R,9R)-5-hydroxy-8,9-dimethyl-4-propyl-8,9-dihydro-2H,10H-pyrano[2,3-f]chromene-2,10-dione | C17H18O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The cyclization of floroglucinol (I) with ethyl 2-oxohexanoate (II) in acidic medium gives 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (III), which is submitted to a Friedel Crafts condensation with propionyl chloride (IV) / AlCl3 to yield the 8-propionyl derivative (V). Finally, the cyclization of (V) with 3-hydroxy-3-methylbutyraldehyde dimethyl acetal (VI) in refluxing pyridine affords the target compound.
| 【1】 Sudbeck, E.A.; Uckun, F.M. (Parker Hughes Institute); Calanolides for inhibiting BTK. WO 0056737 . |
| 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) | 11799 | 1,3,5-Benzenetriol; Fluoroglucinol | 108-73-6 | C6H6O3 | 详情 | 详情 |
| (II) | 12516 | ethyl 3-oxohexanoate; ethyl butyrylacetate | 3249-68-1 | C8H14O3 | 详情 | 详情 |
| (III) | 22405 | 5,7-dihydroxy-4-propyl-2H-chromen-2-one | C12H12O4 | 详情 | 详情 | |
| (IV) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (V) | 22407 | 5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one | C15H16O5 | 详情 | 详情 | |
| (VI) | 22408 | 4,4-dimethoxy-2-methyl-2-butanol | C7H16O3 | 详情 | 详情 |