• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】22411

【品名】(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

【CA登记号】

【 分 子 式 】C22H24O5

【 分 子 量 】368.42956

【元素组成】C 71.72% H 6.57% O 21.71%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IX)

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2

该中间体在本合成路线中的序号:(XII)

An enantioselective total synthesis of (+)-calanolide A has been reported: The silylation of 2'-hydroxy-4',6'-dimethoxybutyrophenone (I) with TIPS-Cl by means of benzylltriethylammonium chloride and NaOH in benzene gives the silyl ether (II), which is demethylated with BCl3 in dichloromethane yielding 2'-hydroxy-4'-methoxy-6'-(triisopropylsilyloxy)butyrophenone (III). The Wittig condensation of (III) with the phosphorane (IV) in N,N-diethylaniline with simultaneous cyclization, affords the benzopyranone (V), which is submitted to a Friedel-Crafts condensation with the acyl chloride (VI) by means of SnCl4 in dichloromethane to provide the 8-acylbenzopyranone (VII). The desilylation of (VII) by means of TBAF in THF/dichloromethane gives the 5-hydroxy compound (VIII) which is submitted to a propargylation with alcohol (IX) and DBU and then to a Claisen rearrangement with N,N-diethylaniline affording the pyrano-benzopyran (X). Demethylation of (X) with MgI2 in refluxing benzene gives the phenol (XI), which is submitted to a (-)-quinine-catalyzed asymmetric intramolecular oxo-Michael addition in chlorobenzene yielding an 80:20 mixture of the chiral cis- and trans-benzotripyrans (XII) (94% ee) and (XIII), respectively. Since the desired compound is the minor component (XIII), the preceding mixture is treated with MgI2 in refluxing benzene to afford an equilibrated 50:50 mixture that is separated by chromatography, and the undesired cis-isomer can be recycled by repeating the MgI2 treatment. The enantiomerically rich trans-isomer (XIII) is finally reduced with LiAlH(Ot-Bu)3 in THF.

1 Tanaka, T.; et al.; Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intramolecular oxo-Michael addition. Tetrahedron Lett 2000, 41, 52, 10229.
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) 45726 1-(2-hydroxy-4,6-dimethoxyphenyl)-1-butanone C12H16O4 详情 详情
(II) 45727 1-[2,4-dimethoxy-6-[(triisopropylsilyl)oxy]phenyl]-1-butanone C21H36O4Si 详情 详情
(III) 45728 1-[2-hydroxy-4-methoxy-6-[(triisopropylsilyl)oxy]phenyl]-1-butanone C20H34O4Si 详情 详情
(IV) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane;Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(V) 45729 7-methoxy-4-propyl-5-[(triisopropylsilyl)oxy]-2H-chromen-2-one C22H34O4Si 详情 详情
(VI) 45730 Tigloyl chloride; (E)-2-methyl-2-butenoyl chloride 35660-94-7 C5H7ClO 详情 详情
(VII) 45731 7-methoxy-8-[(E)-2-methyl-2-butenoyl]-4-propyl-5-[(triisopropylsilyl)oxy]-2H-chromen-2-one C27H40O5Si 详情 详情
(VIII) 45732 5-hydroxy-7-methoxy-8-[(E)-2-methyl-2-butenoyl]-4-propyl-2H-chromen-2-one C18H20O5 详情 详情
(IX) 22416 3-chloro-3-methyl-1-butyne 1111-97-3 C5H7Cl 详情 详情
(X) 45733 5-methoxy-2,2-dimethyl-6-[(E)-2-methyl-2-butenoyl]-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one C23H26O5 详情 详情
(XI) 45734 5-hydroxy-2,2-dimethyl-6-[(E)-2-methyl-2-butenoyl]-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one C22H24O5 详情 详情
(XII) 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
(XIII) 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
Extended Information