CN1221540C - Chird sugarapple lactone compound modified by ether bond, its synthesis method and application - Google Patents
Chird sugarapple lactone compound modified by ether bond, its synthesis method and application Download PDFInfo
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- CN1221540C CN1221540C CNB031416330A CN03141633A CN1221540C CN 1221540 C CN1221540 C CN 1221540C CN B031416330 A CNB031416330 A CN B031416330A CN 03141633 A CN03141633 A CN 03141633A CN 1221540 C CN1221540 C CN 1221540C
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- chiral
- lactone
- compound
- anonace
- ehter bond
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a chiral cherimoya lactone compound with changed ether linkage, a synthetic method thereof and a purpose thereof. The molecular formula of the compound is disclosed in the specification, wherein X=alkyl groups of C6 to C20, n=1-3, m=0-5, k=1-10 and j=0-10. The compound can be prepared by that chiral epoxy-lactone fragments and alkyne compounds generate a coupling reaction under the condition of the existence of alkyl lithium and boron reagents, and obtainedproducts and chiral epoxy-lactone compounds generate a coupling reaction under the condition of the existence of alkyl lithium and boron reagents; tri-lnkage is reduced into single linkage by p-toluenesulfonyl hydrazide, and final products are obtained by releasing protective groups by inorganic acid. The compound of the present invention has high anticancer activities which can reach 0.42 to the IC50(mug/ml) of liver cancer Bel7402 and also has high selectivity to different tumor cells; therefore, the compound can be used for developing anticancer drugs. Moreover, the present invention is simple and is also suitably developed into an industrialized production method.
Description
Technical field
The present invention relates to a kind of lactone compound, specifically a kind of chirality analogue, synthetic method and purposes of natural Annona lactone.
Background technology
Annona lactone (annonaceous acetogenins) is a class natural product of finding from the annonaceae plant, because it has antitumour activity and is paid attention to by people.People such as Wu Yulin had once reported a kind of Annona lactone analogue (CN1263890A) with antitumour activity, had following molecular formula:
The alkyl of Y=C6-20 wherein, n=1-3, m=7-19.This series of compounds is by chirality haloalkane and chirality dihydroxyl alkyl carboxylic acid ester, at dialkyltin R
2SnO takes place and the monovalence metal fluoride exists linked reaction takes place down, with behind the methoxychlor methane protection hydroxyl, obtains the aldol condensation product with the chiral aldehydes reaction again, eliminate react, deprotection gets final product.But this method does not have to obtain to have the product of chiral hydroxyl group on ehter bond, people's expectation is by new synthetic method and approach, obtain the chiral anonace-lactone compounds that ehter bond changes,, finally be developed to the new cancer therapy drug of a class so that further improve its antitumour activity.
Summary of the invention
The object of the invention provides the chiral anonace-lactone compounds that ehter bond changes, and its characteristic is to have optically active compound.
The object of the invention also provides the preparation method of above-claimed cpd.
Another purpose of the present invention provides the purposes of above-claimed cpd.
The chiral anonace-lactone compounds that ehter bond of the present invention changes is the optically active compound with following molecular formula:
In other words, this compound is
Refer in particular to
Deng compound, X=C wherein
6-C
20Alkyl, n=0-3, m=0-5, k=1-13, j=0-10.
The chiral anonace-lactone compounds that above-mentioned ehter bond of the present invention changes can be 15 chiral epoxy lactone fragments with molecular formula, and molecular formula is that 16 chiral epoxy fragments and molecular formula are that 17 alkynes fragment is a starting raw material.
Above-mentioned chiral epoxy and alkine compounds; linked reaction takes place in the presence of lithium alkylide and borane reagent; products therefrom and chiral epoxy lactone compound; linked reaction takes place in the presence of lithium alkylide and borane reagent; with p-toluene sulfonyl hydrazide reduction triple bond is singly-bound, obtains final product with mineral acid deprotection group.Available following reaction formula is represented:
X=C wherein
6-C
20Alkyl, n=1-3, m=0-5, k=3-13, j=0-10, l=1-8.P=MOM, THP, TBS or TMS, the MOM=methoxymethyl, the THP=THP trtrahydropyranyl, the TBS=dimethyl tertiary butyl is silica-based, and TMS=is trimethyl silicon based.R is an alkyl among the described lithium alkylide RLi, recommends C
1～C
10Alkyl.
Preparation method of the present invention can further describe: above-mentioned chiral epoxy compound (16), alkine compounds (17), n-BuLi, and BF
3Et
2The O mol ratio is 1: 1.1-1.5: 1-1.2: 1-1.2, under-100 ℃-0 ℃ of one or more polar solvent neutralization, reaction 1-5h generates chirality alkine compounds (18,19).Above-mentioned chirality alkynes (18,19), chiral epoxy lactone (15), n-BuLi, and BF
3Et
2The O mol ratio is 1: 1.1-1.5: 1-1.2: 1-1.2, under-100 ℃-0 ℃ of one or more polar solvent neutralization, reaction 1-7h generates chipal compounds (20,21).Chipal compounds 20,21, p-toluene sulfonyl hydrazide, the sodium-acetate mol ratio is 1: 2-10: during 2-10, react 1-10h with room temperature to reflux temperature in polar solvent, obtain compound 22.Chipal compounds 22 in one or more polar solvents, under the acid catalysis, 0 ℃ to the room temperature reaction 30min-5h get deprotection compound 2.Described acid can be H
2SO
4, HCl, BF
3Et
2O etc.Described polar solvent can be CH
2Cl
2, CHCl
3, CH
3OH, C
2H
5OH, ether, toluene, dimethyl sulphide, N, dinethylformamide (DMF) etc.
Compound of the present invention has high antitumour activity, as the IC to liver cancer Bel7402
50(μ g/ml) reaches 0.42; And different tumour cells there is selectivity preferably, can be used for developing cancer therapy drug.And the preparation method is simple and easy, is a kind of method that is suitable for developing into suitability for industrialized production.
Embodiment
To help reason to connect by following embodiment and separate the present invention, but can not limit content of the present invention.
Embodiment 1
Synthesizing of target compound basic framework is example with following reaction and compound
(0.962ml 6.75mmol) is dissolved in THF (7.5ml) to the trimethyl silicane ethyl-acetylene, and (1.6M, 4.22ml 6.75mmol), stir 2-3hr to-78 ℃ of following dropping n-BuLi, add BF
3Et
2(0.86ml 6.75mmol), stirs after 30 minutes O, adds 23 (1.112g, THF 2.25mmol) (7.5ml) solution.After stirring 3 hours under this temperature, add saturated NH
4Cl is back to room temperature naturally.Ether extraction three times merges organic phase, the saturated nacl aqueous solution washing, drying, concentrate the product intermediate.Be dissolved in the 11ml methylene dichloride, and the adding diisopropyl ethyl amine (3.14ml, 18mmol), be cooled to 0 ℃, injection MOMCl (1.35ml, 18mmol), reaction is 8 hours under the room temperature, add the ether dilution, organic phase water, saturated nacl aqueous solution washing, drying concentrates, product intermediate 0.86g, productive rate 60%.With intermediate (0.313g, 0.5mmol) be dissolved among the 2.5mlTHF, 0 ℃ drips tetrabutyl ammonium fluoride (1.0M, 0.6ml down, 0.6mmol), mixture stirred 3 hours down for 0 ℃, the dilution of 15ml ether, organic phase water, saturated nacl aqueous solution washing, dry, concentrate, column chromatography gets product 0.26g, productive rate 92%.
[α]
D 25＝-9.73(c 1.45，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.91(3H，t，J＝6.6Hz)，1.29(16H，brs)，1.53(3H，m)，2.04(1H，t，J＝2.4Hz)，2.54(2H，m)，3.40(3H，s)，3.41(3H，s)，3.42(3H，s)，3.43(3H，s)，3.51(2H，d，J＝5.4Hz)，3.59~3.75(7H，m)，3.86~3.97(3H，m)，4.67~4.82(8H，m)ppm；
IR(neat)：3270，2928，2856，1467，1215，1037，919，635cm
-1；
MS(ESI，m/z)：587(M
++Na).
Anal.calcd for C
29H
56O
10(％)：C，61.68；H，9.99.Found：C，61.61；H，9.75.
Embodiment 2
(0.14g 0.248mmol) is dissolved among the anhydrous THF of 1.2ml compound 25, and dry ice-propanone is chilled to-78 ℃, and (1.6M, 0.17mL 0.273mmol), behind the stirring 1-2hr, add BF slowly to splash into n-BuLi
3Et
2(0.035mL 0.273mmol), stirred 30 minutes O, and (0.066g, 0.273mmol) solution that is dissolved in 1ml THF reacted 3 hours under this temperature in reaction system, with saturated ammonium chloride 1ml cancellation reaction to add 26.Rise to room temperature, ethyl acetate extraction 3 times (10ml * 3).The organic phase water, the saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters, and concentrated, column chromatography get yellow liquid 63mg, productive rate 67%.
[α]
D 25＝+3.0(c 0.66，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.88(3H，t，J＝6.9Hz)，1.32~1.55(28H，m)，1.41(3H，d，J＝6.9Hz)，2.24-2.50(8H，m)，3.38~3.39(12H，m)，3.47(2H，d，J＝5.2Hz)，3.57~3.71(8H，m)，3.82~3.92(3H，m)，4.64~4.78(8H，m)，5.00(1H，dq，J＝1.7，6.9Hz)，6.99(1H，d，J＝1.4Hz)ppm；
13C NMR(100MHz，CDCl
3)：173.8，148.9，134.3，97.1，96.1，95.9，78.9，78.4，76.3，75.9，74.7，74.2，72.7，71.1，71.0，55.7，55.5，36.3，32.1，31.9，29.7，29.6，29.4，29.3，29.1，27.8，27.3，25.6，25.4，25.2，22.7，22.2，19.2，14.1ppm；
IR(neat)：3485，2928，2856，1758，1467，1319，1213，1151，1106，1034，919cm
-1；
MS(ESI，m/z)：825(M
++Na).
HRMS(ESI)calcd for C
43H
78O
13Na[M
++Na]825.5335，Found 825.5346.
Embodiment 3
With compound 27 (147mg, 0.183mmol) and p-toluene sulfonyl hydrazide (2.425g, 97%, 12.6mmol), be dissolved in reflux among the 7 glycol dimethyl ether 24ml, (1.172g 14.3mmol) is dissolved in the 20ml aqueous solution, slowly splashes in the reaction solution in 5 hours with sodium-acetate, the while stirring and refluxing, mixture is chilled to room temperature, in the impouring water, and extracted with diethyl ether 3 times (15ml * 3).Merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters, and concentrates, and column chromatography gets liquid 0.13g, productive rate 88%.
[α]
D 25＝+4.3(c 1.12，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.88(3H，t，J＝6.6Hz)，1.25~1.55(38H，m)，1.41(3H，d，J＝6.9Hz)，2.27(2H，t，J＝7.2Hz)，3.36~3.39(12H，m)，3.47(2H，d，J＝5.2Hz)，3.55~3.71(9H，m)，3.90(2H，m)，4.62~4.78(8H，m)，5.00(1H，dq，J＝1.8，6.9Hz)，6.99(1H，d，J＝1.5Hz)ppm；
13C NMR(100MHz，CDCl
3)：173.8，148.8，134.3，97.1，96.0，76.3，75.9，74.2，74.1，71.7，71.1，55.7，55.4，37.4，32.1，31.7，31.4，30.2，29.6，29.3，29.1，27.4，25.6，25.4，25.1，22.6，19.2，14.1ppm；
IR(neat)：3495，2928，2856，1758，1466，1319，1213，1150，1106，1036，919cm
-1；MS(ESI，m/z)：829(M
++Na).
HRMS(ESI)calcd for C
43H
82O
13Na[M
++Na]829.5668，Found 829.5647.
Embodiment 4
(0.1g 0.124mmol) is dissolved in the 11ml dimethyl sulphide, and frozen water is cooled to 0 ℃, adds BF with compound 28
3Et
2O (0.941mL, 7.29mmol).Mixture stirred after 40 minutes, with saturated sodium bicarbonate (3mL) cancellation, ethyl acetate extraction (15ml * 3).Organic phase water, saturated common salt water washing, anhydrous sodium sulfate drying spends the night, and filters, concentrate white solid, column chromatography gets product 41mg, productive rate 53%.
[α]
D 25＝+14.6(c 0.89，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.88(3H，t，J＝6.6Hz)，1.26~1.55(38H，m)，1.41(3H，d，J＝6.9Hz)，2.26(2H，t，J＝7.8Hz)，3.36(2H，m)，3.52~3.68(8H，m)，3.79~3.85(3H，m)，5.00(1H，dq，J＝1.2，6.9Hz)，6.99(1H，d，J＝1.2Hz)ppm；
13C NMR(100MHz，CDCl
3)：173.9，149.0，134.2，76.1，73.0，71.5，70.8，70.2，69.9，37.4，37.2，33.1，32.9，31.9，29.6，29.3，29.1，27.4，25.6，25.3，25.1，22.7，19.2，14.1ppm；
IR(neat)：3419，2924，2852，1752，1467，1324，1147，1080，1029cm
-1；
MS(ESI，m/z)：653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4593.
Embodiment 5
Adopt chiral epoxy compound 23,29,30 respectively with trimethylsilyl acetylene, 1,7 hot two alkyne reactions, products therefrom are chirality alkine compounds 25,31,32,33,34,35.With chirality alkine compounds 25,31,32,33,34,35 react with epoxy lactone compound 26,36,37,38 respectively, and operation obtains 4,5,6,7,8,9,10,11,12,13,14 products respectively with implementing 1,2,3,4 results.
Compound 4
[α]
D 25＝+14.5(c 0.33，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.88(3H，t，J＝6.8Hz)，1.26~1.58(38H，m)，1.41(3H，d，J＝6.6Hz)，2.27(2H，t，J＝7.5Hz)，3.37(2H，m)，3.47~3.73(8H，m)，3.79~3.85(3H，m)，5.00(1H，dq，J＝1.5，6.9Hz)，7.00(1H，d，J＝1.2Hz)ppm；
13C NMR(100MHz，CDCl
3)：173.9，148.9，134.3，76.6，76.2，73.1，73.0，70.7，70.3，37.5，33.1，33.0，31.9，29.7，29.6，29.5，29.3，29.2，29.1，27.4，25.6，25.4，25.1，22.7，19.2，14.1ppm；
IR(neat)：3418，2922，2852，1751，1470，1325，1148，1120，1078，856cm
-1；
MS(ESI，m/z)：653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4602.
Compound 5
[α]
D 25＝+20.1(c 1.41，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.90(3H，t，J＝6.6Hz)，1.28~1.57(38H，m)，1.43(3H，d，J＝6.6Hz)，2.29(2H，t，J＝7.5Hz)，3.38(2H，m)，3.51~3.69(7H，m)，3.79~3.87(4H，m)，5.00(1H，q，J＝6.6Hz)，7.03(1H，s)ppm；
13C NMR(100MHz，CDCl
3)：173.9，149.0，134.2，76.1，72.9，71.4，70.6，70.3，69.9，37.4，37.2，36.3，33.1，32.9，31.9，29.7，29.6，29.3，29.1，27.4，25.6，25.3，25.1，22.7，19.2，14.1ppm；
IR(neat)：3433，2922，2852，1751，1467，1326，1147，1081，1029cm
-1；
MS(ESI，m/z)：653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4616.
Compound 6
[α]
D 25＝+22.7(c 1.59，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.86(3H，t，J＝6.5Hz)，1.24~1.50(38H，m)，1.39(3H，d，J＝6.6Hz)，2.24(2H，t，J＝7.5Hz)，3.31~3.38(2H，m)，3.48~3.62(7H，m)，3.77~3.87(4H，m)，4.98(1H，q，J＝6.9Hz)，6.99(1H，s)ppm；
13C NMR(100MHz，CDCl
3)：173.9，150.0，134.2，76.0，72.8，71.6，70.6，70.4，70.2，37.4，37.2，33.0，32.8，31.9，29.6，29.3，29.2，29.1，27.3，25.6，25.1，22.6，19.1，14.1ppm；
IR(neat)：3421，2924，2852，1741，1465，1375，1324，1085cm
-1；
MS(ESI，m/z)：653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4583.
Compound 7
[α]
D 25＝+18.68(c 0.43，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.89(3H，t，J＝6.6Hz)，1.27(36H，brs)，1.44(3H，d，J＝6.9Hz)，2.39~2.56(2H，m)，3.35(2H，m)，3.51~3.72(7H，m)，3.77~3.85(4H，m)，5.08(1H，dq，J＝1.5，6.9Hz)，7.20(1H，dd，J＝1.2Hz)ppm；
13C NMR(100MHz，CDCl
3)：174.3，151.8，131.2，78.0，76.2，73.1，70.8，70.3，70.0，37.4，33.3，33.1，31.9，29.6，29.4，25.6，22.7，19.1，14.1ppm；
IR(neat)：3428，2920，2852，1744，1469，1323，1148，1075，1030，896cm
-1；
MS(ESI，m/z)：631(M
++1)，653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4597.
Compound 8
[α]
D 25＝+14.2(c 0.37，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.87(3H，t，J＝6.6Hz)，1.25(36H，brs)，1.42(3H，d，J＝6.6Hz)，2.38~2.55(2H，m)，3.33(2H，m)，3.51~3.65(7H，m)，3.77~3.83(4H，m)，5.05(1H，q，J＝1.2，6.9Hz)，7.18(1H，s)ppm；
13C NMR(100MHz，CDCl
3)：173.3，151.9，131.1，77.9，76.2，73.1，70.8，70.3，69.9，37.4，33.4，33.1，31.9，29.6，25.6，23.8，22.7，19.0，14.1ppm；
IR(neat)：3456，2921，2851，1751，1469，1324，1148，1074，896cm
-1；
MS(ESI，m/z)：631(630+1)，653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4601.
Compound 9
[α]
D 25＝+19.0(c 0.95，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.89(3H，t，J＝6.5Hz)，1.27(36H，brs)，1.45(3H，d，J＝6.9Hz)，2.37~2.58(2H，m)，3.36(2H，t，J＝9Hz)，3.53~3.56(3H，m)，3.61~3.68(4H，m)，3.80~3.86(4H，m)，5.05(1H，dq，J＝1.2，6.9Hz)，7.20(1H，d，J＝1.2Hz)ppm；
13C NMR(100MHz，CDCl
3)：174.6，151.8，131.1，78.0，76.2，73.0，70.7，70.2，69.9，37.4，33.3，33.0，31.9，29.6，29.3，25.5，22.7，19.1，14.1ppm；
IR(neat)：3490，2924，2851，1740，1467，1146，1119，1068，867cm
-1；
MS(ESI，m/z)：653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4567.
Compound 10
[α]
D 25＝+84.8(c 0.97，CHCl
3)；
1H NMR(CDCl
3，300MHz)：0.91(3H，t，J＝6.6Hz)，1.29(36H，brs)，1.47(3H，d，J＝6.9Hz)，2.43~2.55(2H，m)，3.38(2H，t，J＝8.9Hz)，3.54~3.59(3H，m)，3.63~3.70(4H，m)，3.80~3.88(4H，m)，5.08(1H，dq，J＝1.2，6.9Hz)，7.22(1H，d，J＝1.5Hz)ppm；
13C NMR(100MHz，CDCl
3)：174.6，151.9，131.1，78.0，76.2，73.1，70.7，70.2，69.8，37.4，33.4，33.0，31.9，29.6，29.3，25.6，22.7，19.1，14.1ppm；
IR(neat)：3444，2923，2850，1721，1469，1328，1141，1120，1071cm
-1；
MS(ESI，m/z)：653(M
++Na).
HRMS(ESI)calcd for C
35H
66O
9Na[M
++Na]653.4599，Found 653.4602.
Compound 11
[α]
D 20+18.7(c 0.57，CHCl
3).
IR(KBr)3420，2922，2852，1741，1465，1325，1150，1084cm
-1.
1H NMR(300MHz，CDCl
3)0.88(t，J＝6.7Hz，3H)，1.26～1.60(m，38H)，1.41(d，J＝6.9Hz，3H)，2.27(dt，J＝1.7Hz，6.6Hz，2H)，2.86(brs，3OH)，3.32(dt，J＝2.8Hz，8.9Hz，2H)，3.52～3.73(m，7H)，3.79(m，2H)，5.01(dq，J＝1.7Hz，6.9Hz，1H)，6.99(d，J＝1.4Hz，1H).
13C NMR(75MHz，CDCl
3)14.128，19.237，22.703，25.185，25.495，25.568，25.633，27.410，29.130，29.281，29.346，29.559，29.584，29.630，29.710，31.924，32.885，33.036，37.346，37.497，70.094，70.315，70.510，70.561，71.736，75.855，75.903，76.614，134.317，148.908，173.895.
MS(EI)m/z 571(MH
+).
HRMS(FAB)for C
33H
62O
7+Na：593.4387；Found：593.4397.
Compound 12
m.p.：58-60℃
[α]
D 20＝+18.5(c 0.35，CHCl
3).
1H NMR(CDCl
3，300MHz)：0.88(3H，t，J＝6.6Hz)，1.26~1.57(38H，m)，1.41(3H，d，J＝6.9Hz)，2.27(2H+3OH，m)，3.32(2H，m)，3.52~3.82(9H，m)，5.00(1H，dq，J＝1.8，6.6Hz)，6.99(1H，d，J＝1.5Hz)ppm；
13C NMR(100MHz，CDCl
3)：174.1，149.0，134.5，77.6，76.1，76.0，72.0，70.7，70.5，70.4，37.7，37.6，32.2，32.1，29.9，29.8，29.7，29.6，29.5，29.4，29.3，27.8，25.8，25.7，25.4，22.9，19.4，14.3ppm；
IR(neat)：3422，2923，2852，1749，1468，1321，1116，1083，909cm
-1；
MS(ESI，m/z)：593(M
++Na).
HRMS(ESI)calcd for C
33H
62O
7Na[M
++Na]593.4388，Found 593.4412.
Compound 13
[α]
D 25＝+6.6(c 0.63，CHCl
3).
1H NMR(400MHz，CDCl
3)：0.88(3H，t，J＝6.8Hz)，1.26-1.60(30H，m)，1.42(3H，d，J＝5.9Hz)，2.04(1H，m)，2.28(2H，m)，2.40(2H，dd，J＝8.2，15.2Hz)，2.53(2H，dt，J＝1.7，16.0Hz)，3.32(3H，m)，3.54(2H，dd，J＝2.7，9.8Hz)，3.63-3.71(5H，m)，3.77-3.81(4H，m)，5.05(1H，qd，J＝6.8，1.3Hz)，7.18(1H，d，J＝1.0Hz)ppm.
13C NMR(100MHz，CDCl
3)：171.2，151.9，131.3，78.1，75.9，70.6，70.3，70.1，60.5，37.5，33.4，33.1，29.8，29.6，29.4，25.6，22.8，21.1，19.2，14.3，14.2ppm.
IR(film)：3500，2919，2850，1751，1470，1156，1028，720cm
-1.
MS(ESI，m/z)：571(M
++1)，593(M
++Na).
HRMS(ESI)calcd for C
33H
63O
7[M
++H]571.4562，Found 571.4567.
Compound 14
[α]
D 25＝+27.5(c 1.03，CHCl
3).
1H NMR(300MHz，CDCl
3)：0.87(3H，t，J＝6.6Hz)，1.25-1.60(34H，m)，1.43(3H，d，J＝6.9Hz)，2.25-2.55(6H，m)，3.31(2H，m)，3.53(2H，dd，J＝2.75，9.89Hz)，3.59-3.70(4H，m)，3.75-3.80(3H，m)，5.05(1H，q，J＝6.9Hz)，7.18(1H，s)ppm.
13C NMR(100MHz，CDCl
3)：174.5，151.8，131.1，77.9，75.9，70.5，70.2，69.8，37.4，33.3，33.0，31.9，31.2，29.6，29.5，29.3，25.5，22.6，19.0，14.1ppm.
IR(film)：3439，2919，2850，1759，1465，1324，1120，1096，1033，917cm
-1.
MS(ESI，m/z)：588(M
++H
2O)，593(M
++Na).
HRMS(ESI)calcd for C
33H
63O
7[M
++Na]593.4388，Found 593.4362.
Embodiment 6
Compound 3,4,5 and 6 is measured the Lethal Dose 50 of the cancerous cell line of KB, HCT-8, HT-29 and Bel7402 according to the MTT method and is listed in the table 1.
Table 1 compound 3,4,5 and 6 activity data
| Sample | IC 50(μg/ml) | |||
| KB | HT-29 | HCT-8 | Bel7402 | |
| SIOC-AA-3(10R) | ＞10 | ＞10 | 5.26 | 7.03 |
| SIOC-AA-4(10S) | ＞10 | ＞10 | 1.67 | 8.21 |
| SIOC-AA-5(10R) | ＞10 | ＞10 | 5.22 | 7.24 |
| SIOC-AA-6(10S) | ＞10 | ＞10 | 5.35 | 6.21 |
Compound 7,8,9 and 10 is measured the Lethal Dose 50 of the cancerous cell line of KB, HCT-8, HT-29 and Bel7402 according to the MTT method and is listed in the table 2.
Table 2 compounds 7,8,9 and 10 activity data
| Sample | IC 50(μg/ml) | |||
| KB | HT-29 | HCT-8 | Bel7402 | |
| 7 | ＞10 | ＞10 | 1.41 | 1.02 |
| 8 | ＞10 | ＞10 | 3.06 | 0.73 |
| 9 | 6.57 | 2.05 | 0.73 | 0.42 |
| 10 | 7.01 | ＞10 | 3.42 | 1.83 |
Compound 11 and 12 is measured the Lethal Dose 50 of the cancerous cell line of KB, HCT-8, HT-29 and Bel7402 according to the MTT method and is listed in the table 3.
Table 3 compounds 11 and 12 activity data
| Sample | IC 50(μg/ml) | |||
| HT-29 | HCT-8 | KB | Bel7402 | |
| 12(10S) | 4.70 | 1.70 | ＞10 | 1.59 |
| 11(10R) | 4.03 | 0.57 | ＞10 | 1.20 |
Compound 13 and adriamycin measure the Lethal Dose 50 of the cancerous cell line of KB, HCT-8, HT-29 and HELF according to the MTT method and list in the table 4.
The activity data of Table 4 compounds 13 and Zorubicin
| Sample | IC 50(μg/ml) | |||
| HT-29 | HCT-8 | KB | HELF | |
| 13 | 1.6×10 -3(1) | 8.0×10 -2 | ＞10 | ＞10 |
| adriamycin | 6.0×10 -2(37.5) | 3.6×10 -2 | 7.6×10 -2 | 1.92 |
Compound 14 is measured the Lethal Dose 50 of the cancerous cell line of KB, HCT-8, HT-29 and Bel7402 according to the MTT method and is listed in the table 5.
The activity data of Table 5 compounds 7, SIOC-AA-005 and Zorubicin
| Sample | IC 50(μg/ml) | |||
| KB | HT-29 | HCT-8 | Bel7402 | |
| 14 | ＞10 | ＞10 | 5.07 | 0.80 |
Claims (8)
1. the chiral anonace-lactone compounds modified of an ehter bond, the optically active compound that it is characterized in that having following molecular formula:
X=C wherein
6-C
20Alkyl, n=0-3, m=0-5, k=3-13, j=0-10.
2. the chiral anonace-lactone compounds that ehter bond as claimed in claim 1 is modified, the optically active compound that it is characterized in that having following molecular formula:
Wherein the definition of X, n, m, k, j is with claim 1.
3. the chiral anonace-lactone compounds that ehter bond as claimed in claim 1 is modified is characterized by the molecular formula with following structure:
4. the preparation method of the chiral anonace-lactone compounds of an ehter bond modification as claimed in claim 1 is characterized in that by molecular formula being that 18,19 chirality alkynes and molecular formula are that 15 chiral epoxy lactone fragments are starting raw material,
P is that methoxymethyl, THP trtrahydropyranyl, the dimethyl tertiary butyl are silica-based or trimethyl silicon based in the formula, and the definition of X, n, m, j is with claim 1,1=0-8.Linked reaction takes place in above-mentioned chirality alkynes and chiral epoxy lactone compound in the presence of lithium alkylide and borane reagent, be singly-bound with p-toluene sulfonyl hydrazide reduction triple bond, obtains final product with mineral acid deprotection group.
5. the preparation method of the chiral anonace-lactone compounds that ehter bond as claimed in claim 4 is modified is characterized in that making by following method:
(1) above-mentioned chirality alkynes (18,19) chiral epoxy lactone (15), n-BuLi, and BF
3Et
2The O mol ratio is 1: 1.1-1.5: 1-1.2: 1-1.2, and under-100 ℃-0 ℃ of one or more polar solvent neutralization, reaction 1-7h generates chipal compounds (20,21);
(2) product of above-mentioned (1), p-toluene sulfonyl hydrazide, sodium-acetate mol ratio are 1: 2-10: during 2-10, react 1-10h in polar solvent He under the reflux temperature, obtain chipal compounds 22;
(3) product of above-mentioned (2) is in one or more polar solvents, and under the acid catalysis, 0 ℃ is reacted optically active compound 2 that 30min-5h gets deprotection to room temperature;
X=C in the above-mentioned molecule
6-C
20Alkyl, n=0-3, m=0-5, k=3-13, j=0-10,1=0-8; P=MOM, THP, TBS or TMS, the MOM=methoxymethyl, the THP=THP trtrahydropyranyl, the TBS=dimethyl tertiary butyl is silica-based, and TMS=is trimethyl silicon based.
6. the preparation method of the chiral anonace-lactone compounds that ehter bond as claimed in claim 5 is modified is characterized in that described polar solvent is CH
2Cl
2, CHCl
3, CH
3OH, C
2H
5OH, ether, toluene, dimethyl sulphide, N, dinethylformamide.
7. the preparation method of the chiral anonace-lactone compounds that ehter bond as claimed in claim 5 is modified is characterized in that described acid can be H
2SO
4, HCl, BF
3Et
2O.
8. the purposes of the chiral anonace-lactone compounds of an ehter bond modification as claimed in claim 1 is characterized in that being used to prepare cancer therapy drug.
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|---|---|---|---|
| CNB031416330A CN1221540C (en) | 2003-07-16 | 2003-07-16 | Chird sugarapple lactone compound modified by ether bond, its synthesis method and application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031416330A CN1221540C (en) | 2003-07-16 | 2003-07-16 | Chird sugarapple lactone compound modified by ether bond, its synthesis method and application |
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| Publication Number | Publication Date |
|---|---|
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| CN1221540C true CN1221540C (en) | 2005-10-05 |
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ID=34155386
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|---|---|---|---|
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| Country | Link |
|---|---|
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2003
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