5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one -Drug Synthesis Database

【结构式】

【分子编号】22407

【品名】5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one

【CA登记号】

【分子式】C₁₅H₁₆O₅

【分子量】276.28904

【元素组成】C 65.21% H 5.84% O 28.95%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(III)

An improved synthesis of 5,7-dihydroxy-8-propionyl-4-propyl-2H-1-benzopyran-2-one, a key intermediate in the synthesis of (+)-calanolide A, has been reported: Friedel-Crafts acylation of 5,7-dihydroxy-4-propyl-2H-1-benzopyran-2-one (I) with propionic anhydride (II) by means of AlCl3 in refluxing nitromethane.

参考文献中间体

合成目标

【1】 Xu, Z.-Q.; Zembower, D.E.; Flavin, M.T.; Jimenez, N.; Kirchhoff, E.W.; Zhang, J.; Sen, P.; Automated process research. An example of accelerated optimization of the friedel-grafts acylation reaction, a key step for the synthesis of anti-HIV (+)-calanolide A. Org Process Res Dev 2000, 4, 6, 577.

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)	22405	5,7-dihydroxy-4-propyl-2H-chromen-2-one		C₁₂H₁₂O₄	详情	详情
(II)	20095	propionic anhydride	123-62-6	C₆H₁₀O₃	详情	详情
(III)	22407	5,7-dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one		C₁₅H₁₆O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

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.

参考文献中间体

合成目标

【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

Extended Information