5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one -Drug Synthesis Database

【结构式】

【分子编号】22409

【品名】5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one

【CA登记号】

【分子式】C₂₀H₂₂O₅

【分子量】342.39168

【元素组成】C 70.16% H 6.48% O 23.36%

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：(VII)

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：(VII)

4) The aldol condensation of the previously described benzodipyran (VII) with acetaldehyde catalyzed by TiCl4/lithium diisopropylamide (LDA) in heptane/THF/ethylbenzene gives a racemic mixture of the enantiomers (XXXI) and (XXXII), which is enzymatically resolved with lipase PS-30 or lipase-AK and vinyl acetate in tert-butyl methyl ether to yield a mixture of unchanged 3(S)-hydroxy-2(R)-methylbutyryl-enantiomer (XXXI) and acetylated enantiomer (XXXIII), which are easily separated by column chromatography. The cyclization of (XXXI) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives the (10R,11R)-precursor (XXXIV), which is finally reduced with NaBH4/triphenylphosphine oxide /CeCl3 in ethanol and purified by chiral HPLC.

参考文献中间体

合成目标

【1】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235.
【2】 Khilevich, A.; Mar, A.; Flavin, M.T.; et al.; Synthesis of (+)-calanolide A, an anti-HIV agent, via enzyme-catalyzed resolution of the aldol products. Tetrahedron Asymmetry 1996, 7, 11, 3315.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(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
(XXXI)	22432	5-hydroxy-6-[(2R,3S)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one	C₂₂H₂₆O₆	详情	详情
(XXXII)	22433	5-hydroxy-6-[(2S,3R)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one	C₂₂H₂₆O₆	详情	详情
(XXXIII)	22434	(1R,2S)-3-(5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-1,2-dimethyl-3-oxopropyl acetate	C₂₄H₂₈O₇	详情	详情
(XXXIV)	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

合成路线3

该中间体在本合成路线中的序号：(VII)

5) Synthesis of [14C]-labeled calanolide A: The aldol condensation of benzodipyran (VII) with [1,2-14C]-labeled acetaldehyde catalyzed by TiCl4/lithium diisopropylamide (LDA) in heptane/THF/ethylbenzene gives a racemic mixture of enantiomers (XXXV) and (XXXVI), which is enzymatically resolved with lipase-AK and vinyl acetate in tert-butyl methyl ether to yield a mixture of unchanged 3(S)-hydroxy-2(R)-methylbutyryl enantiomer (XXXVI) and acetylated enantiomer (XXXVII), which are easily separated by column chromatography. The cyclization of (XXXVI) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives the (10R,11R)-precursor (XXXVIII), which is finally reduced with NaBH4/triphenylphosphine oxide /CeCl3 in ethanol and purified by chiral HPLC.

参考文献中间体

合成目标

【1】 Rizzo, J.D.; Filer, C.; Khilevich, A.; Giltner, J.; Xu, Z.-Q.; Flavin, M.T.; Gaddam, S.; Synthesis of dual C-14-labeled (+)-calanolide A, a. J Label Compd Radiopharm 1997, 39, 11, 901.
【2】 Castañer, J.; Leeson, P.; Sorbera, L.A.; Calanolide A. Drugs Fut 1999, 24, 3, 235.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(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
(XXXV)	22433	5-hydroxy-6-[(2S,3R)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one	C₂₂H₂₆O₆	详情	详情
(XXXV)	45297	5-hydroxy-6-[(2S,3R)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one	C₂₂H₂₆O₆	详情	详情
(XXXVI)	22432	5-hydroxy-6-[(2R,3S)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one	C₂₂H₂₆O₆	详情	详情
(XXXVI)	45296	5-hydroxy-6-[(2R,3S)-3-hydroxy-2-methylbutanoyl]-2,2-dimethyl-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one	C₂₂H₂₆O₆	详情	详情
(XXXVII)	22434	(1R,2S)-3-(5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-1,2-dimethyl-3-oxopropyl acetate	C₂₄H₂₈O₇	详情	详情
(XXXVII)	45298	(1R,2S)-3-(5-hydroxy-2,2-dimethyl-8-oxo-10-propyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-1,2-dimethyl-3-oxopropyl acetate	C₂₄H₂₈O₇	详情	详情
(XXXVIII)	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
(XXXVIII)	45299	(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

Extended Information