CN1263890A - Chiral anonace-lactone compounds,and its synthesizing process and application - Google Patents

Chiral anonace-lactone compounds,and its synthesizing process and application Download PDF

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CN1263890A
CN1263890A CN 99125750 CN99125750A CN1263890A CN 1263890 A CN1263890 A CN 1263890A CN 99125750 CN99125750 CN 99125750 CN 99125750 A CN99125750 A CN 99125750A CN 1263890 A CN1263890 A CN 1263890A
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lactone compounds
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吴毓林
曾步兵
伍贻康
姚祝军
俞干
陈晓光
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

A chiral sirikaya lectone kind compound is prepared from chiral haloakane and chiral dihydroxylalkyl carboxylate through synthesis. It features higher anticancer activity.

Description

Chiral anonace-lactone compounds, preparation method and use
The present invention relates to a kind of lactone compound, specifically a kind of chiral anonace-lactone compounds, preparation method and use.
Annona lactone (Annonaceous aectogenins) is a class natural product of finding from the annonaceae plant, because having antitumour activity, it is paid attention to (A.Cave etc. by people, Progress in the Chemistry ofOrganic natural Products:Acetogenins from Annonaceae.New York, Springer-Verlag, 1997,70,81-288), people such as Wu Yulin had once reported a kind of Annona lactone analogue (CN97106368.0) with antitumour activity, had following molecular formula: R wherein 1, R 2, R 3, R 4Be H or chirality OH; I=1-6; M=8-12; N=0-5; O=3-12.This series of compounds is the synthetic epoxy intermediate that contains the gamma-butyrolactone that is substituted or resets of raw material by chiral hydroxy acid, with polyoxyethylene glycol compounds and epoxy intermediate through coupling, catalytic hydrogenation, elimination react the product Annona lactone analogue, but this method does not obtain chiral product, and this analogue is to cancer cells Lethal Dose 50 LC 50Be 3-6E-05, people expect new synthetic method and approach, and expectation obtains chiral anonace-lactone compounds, so that further improve its antitumour activity, finally is developed to the new cancer therapy drug of a class.
The object of the invention provides a kind of chiral anonace-lactone compounds, is to have optically active compound.
The object of the invention also provides a kind of preparation method of above-claimed cpd.
Another purpose of the present invention provides the purposes of above-claimed cpd.
Chiral anonace-lactone compounds of the present invention is the optically active compound with following molecular formula:
Figure A9912575000052
In other words, this compound is
Figure A9912575000061
Figure A9912575000062
Or Refer in particular to
Figure A9912575000064
Figure A9912575000065
Or
Figure A9912575000066
Deng compound, Y=C wherein 6-20Alkyl, n=1-3, m=7-19.
Above-mentioned chiral anonace-lactone compounds of the present invention can be with molecular formula
Figure A9912575000067
Or Chirality haloalkane and molecular formula be Or Chirality dihydroxyl base alkyl carboxylic acid ester be starting raw material.
Above-mentioned chirality alkyl halide and chirality dihydroxyl alkyl carboxylic acid ester, at dialkyltin R 2There are generation linked reaction down in SnO and monovalence metal fluoride, again with behind the methoxychlor methane protection hydroxyl, make the alpha-position of terminal ester group form negative ion with the diisopropylamine lithium reaction, with molecular formula are then
Figure A99125750000611
Chiral aldehydes reaction obtain the aldol condensation product, obtain α, β-unsaturated lactone with organic amine compound, acid treatment that lone-pair electron are arranged on trifluoroacetic anhydride (TFAA) or the aceticanhydride/nitrogen-atoms successively, obtain final product with mineral acid catalysis deprotection group.Available following reaction formula is represented:
Figure A9912575000071
N=1-3 wherein, m=7-19, Y=C 6-20Alkyl, P=MOM, THP or TBS, the MOM=methoxymethyl, the THP=tetrahydrofuran base, the TBS=dimethyl tertiary butyl is silica-based.
Preparation method of the present invention can further describe: above-mentioned chirality haloalkane 6, chirality dihydroxyl alkyl carboxylic acid ester 7, monovalence metal fluoride and R 1 2The SnO mol ratio is 1: 0.5-2: 1-5: 1-2, react 1-24h generation chipal compounds 5 with room temperature to reflux temperature in one or more polar solvents.Described monovalence metal fluoride is LiF, NaF, KF, CsF etc., is good with CsF wherein.In the described dialkyltin, R 1=C 1-6Alkyl, with dibutyl oxygen tin for well.
Chipal compounds 5, diisopropyl ethylenediamine and methoxychlor methane mol ratio are 1: 1-5: during 1-5, in polar solvent, to room temperature, react 1-10h, obtain chipal compounds 4 with 0 ℃,
Chipal compounds 4,
Figure A9912575000081
Chiral aldehydes, diisopropylamine lithium (LDA) and HMPA mol ratio are 1: 1-2: 1-5: 0-5, recommending mol ratio is 1: 1-2: 1-3: 1-3, in polar solvent and room temperature to-78 ℃ the reaction 0.5-5h after, in room temperature and polar solvent, react 5-10h with mineral acid again, add organic amine compound and trifluoroacetic anhydride (TFAA) or aceticanhydride that lone-pair electron are arranged on the nitrogen-atoms, to room temperature, react 1-10h at 0 ℃, obtain chipal compounds 1.Described mineral acid can be H 2SO 4, HNO 3, HCl etc., the organic amine compound that lone-pair electron are arranged on the described nitrogen-atoms can be lauryl amine, dimethylamine, Trimethylamine 99, triethylamine, trioctylamine, methylbenzylamine, 1.8-phenodiazine-dicyclo [5,4,0] undecane-7-alkene (DBU) etc., but is good with triethylamine.
In one or more polar solvents and under the room temperature, above-mentioned chipal compounds 1 usefulness mineral acid catalysis deprotection base becomes final product 8.
Described polar solvent can be CH 2Cl 2, CCl 3H, CH 3OH, C 2H 5OH, ether, toluene, N, dinethylformamide (DMF) etc.
Compound of the present invention has high antitumour activity, as the EC to colorectal carcinoma HCT-8 50(μ g/ml) reaches 0.032-0.097.Can be used for cancer therapy drug.And the preparation method is simple and easy, is a kind of method that is suitable for suitability for industrialized production.
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited.
Embodiment 1
Synthesizing of target compound basic framework is example with following reaction and compound.
(10: 0-10) reflux 1-2h gets a settled solution with chloroform/methanol with compound 103.23mmol, dibutyl oxygen tin 3-5mmol.Concentrate and dry 6h under vacuum.After adding Potassium monofluoride or cesium fluoride 3-6mmol continuation vacuum-drying 2h, add 20mlDMF.Add iodide 9.3-10mmol behind 45 ℃ of heating 2h.React 18h under the room temperature.Pressure reducing and steaming DMF, add 30ml ethyl acetate and 10ml saturated nacl aqueous solution in the residuum, stir half an hour, remove solid shape insolubles by the sand core funnel that is covered with silica gel, organic layer in the separating filtrate, water layer merges organic layer, anhydrous sodium sulfate drying with ethyl acetate extraction three times (20ml * 3), concentrate, column chromatography gets product 1.02g, yield 55% (50-72%).
Embodiment 2
The hydroxyl protection of embodiment 1 product is an example with following reaction and compound.
Figure A9912575000091
When compound 111.6mmol is dissolved in the new methylene dichloride that steams of 20ml, add the 1.3ml diisopropyl ethylenediamine, 0 ℃ is cooled off half an hour down, adds 0.8-1.5ml methoxychlor methane.React 8h under the room temperature.TLC follows the tracks of reaction raw materials and disappears.Reaction solution extracts with methylene dichloride (30ml * 3), and extraction liquid washs with saturated sodium-chloride, and anhydrous sodium sulfate drying concentrates, and column chromatography gets product 12 (919mg, 93%).
Figure A9912575000092
1.5-5mmol the 10ml THF of diisopropylamine lithium and the hexane solution of 10ml be cooled to-78 ℃ with acetone, add the 0.5ml HMPA.Stirred 30 minutes.Compound 12 (1.5mmol) is dissolved among the new anhydrous THF of steaming of 10ml, slowly is added drop-wise in the reaction solution, stirs 30 minutes, slowly be added dropwise to above-mentioned aldehyde (760mg is dissolved in 10ml THF) under-78 ℃, behind the stirring 2h, be raised to room temperature then gradually, tell water and organic phase, water merges organic phase with extracted with diethyl ether twice, the saturated sodium-chloride washed twice, anhydrous sodium sulfate drying concentrates, and adds 30ml THF and 10% dilute sulphuric acid in the residuum.Stirring reaction 18h adds 3g sodium-chlor and stirred 30 minutes, reaction solution ethyl acetate extraction three times (40ml * 3), the organic layer anhydrous sodium sulfate drying concentrates, and adds 10ml and newly steams anhydrous methylene chloride and 2.5ml anhydrous triethylamine, 0 ℃ was cooled off 30 minutes, add the 1.6ml trifluoroacetic anhydride (TFAA), react 8h under the room temperature, reaction solution concentrates, dry, column chromatography gets product 13 (430mg, two step 40-52%).
Embodiment 3
Mineral acid catalysis is taken off the MOM reaction and is obtained final product, is example with the following formula.
Figure A9912575000101
Compound 13 (0.29mmol) adds 0.5-10ml THF MeOH: 6N HCl (1: 1: 2), reacts 14h under the room temperature, the reaction solution extracted with diethyl ether, and anhydrous sodium sulfate drying concentrates, and column chromatography gets product 9 (146mg, 91%). 1H?NMR(CDCl 3，600MHz)：δ6.98(br?S，1H)，4.99(br?g，J＝6.6Hz，1H)，3.82-3.74(br?m，
2H)，3.72-3.60(br?m.4H)，3.54(br?d，J＝9.6Hz，2H)，3.32(br?t，
J＝9.0Hz，2H)，2.26(br?t，J＝7.5Hz，2H)，1.54(q，J＝7.2Hz，2H)，
1.40(d，J＝6.6Hz，3H)，1.48-1.16(br?m，40H)，0.88(t，J＝7.2Hz，
3H) .IR (film, KBr), cm -1: 3443,2992,2982,1752,1130, EIMS:291,325,555
Embodiment 4
The employing molecular formula is
Figure A9912575000102
With Chirality halogenide, with molecular formula be respectively
Figure A9912575000104
And
Figure A9912575000106
Chirality dihydroxyl alkyl carboxylic acid ester reaction, operation is with implementing 1,2 and 3, the result obtains respectively (compound 12,15R, 24R), (compound 10,15S 24S) reach (compound 11,15R, 24S) product.Compound 12
1H?NMR(CDCl 3，600MHz)，δ：6.98(d，J＝1.2Hz，1H)，4.99(dq，J＝7.2，1.2Hz，1H)，3.83-3.74(m，2H)，3.72-3.60(m，4H)，3.53(dd，J＝9.6，10.2Hz，2H)，3.32(dd，J＝9.6，8.4Hz，2H)，2.26(br?t，J＝7.8Hz，2H)，1.55(q，J＝6.6Hz，2H)，1.40(d，J＝7.2Hz，3H)，1.50-1.20(m，40H)，0.88(t，J＝6.9Hz，3H).
IR (film, KBr), cm -1: 3442,2994,2986,1756,1123
EIMS:291,326,555 compounds 10
1H?NMR(CDCl 3，600MHz)，δ：6.97(d，J＝1.2Hz，1H)，4.98(dq，J＝7.2，1.2Hz，1H)，3.81-3.75(m，2H)，3.71-3.61(m，4H)，3.52(dd，J＝9.6，10.2Hz，2H)，3.31(dd，J＝9.6，8.4Hz，2H)，2.50(br?s，2H，OH)，2.26(t，J＝7.8Hz，2H)，1.53(q，J＝7.8Hz，2H)，1.40(d，J＝6.6Hz，3H)，1.48-1.20(m，40H)，0.87(t，J＝7.2Hz，3H).
IR (film, KBr), cm -1: 3445,2993,2984,1750,1138
EIMS：290，325，555
1H?NMR(CDCl 3，600MHz)，δ：6.98(d，J＝1.2Hz，1H)，4.99(dq，J＝1.2，6.6Hz，1H)，3.78(m，2H)，3.72-3.62(m，4H)，3.53(dd，J＝2.4，9.6Hz，2H)，3.32(dd，J＝9.6，8.4Hz，2H)，2.26(br?t，J＝7.8Hz，2H)，2.15(br?S，2H，OH)，1.55(q，J＝7.2Hz，2H)，1.40(d，J＝6.6Hz，3H)，1.48-1.20(m，40H)，0.88(t，J＝6.9Hz，3H)
The IR film, KBr), cm -1: 3440,2987,1752,1130
EIMS：290，325，555
Embodiment 5
The employing molecular formula is
Figure A9912575000122
With Chirality halogenide, with molecular formula be respectively
Figure A9912575000124
And
Figure A9912575000125
Chirality dihydroxyl alkyl carboxylic acid ester reaction, operation is as embodiment 1,2 and 3.The result obtains respectively Compound 13, Compound 14, Compound 15 Hes Compound 16.Compound 13
1H?NMR(300MHz，CDCl 3，)，δ：0.87(t，3H)，1.2～1.6(m，35H)，2.30(t，2H)，3.30(q，2H)，
3.40(t，2H)，3.58(m，4H)，4.12(m，2H)，4.98(m，1H)，6.93(s，1H).
13C?NMR(75Mhz，CDCl 3)，δ：168.84，117.68，78.43，77.32，76.29，75.63，73.38，
39.63，37.62，27.34，26.53，21.09。
IR (Kbr, film), cm -1: 3418,2993,2982,1758,1480,1440,1220,920.
EIMS:499 (M+1), 480 (M-H 2O), 429,357,353,309,295,267,111,95,69,55 compounds 14
1H?NMR(300MHz，CDCl 3)，δ：0.89(t，3H)，1.2～1.72(m，49H)，2.32(t，2H)，3.33(q，2H)，
3.34(m，2H)，3.42(t，2H)，3.62(m，4H)，4.13(t，2H)，4.92(m，1H)，6.98(s，1H).
13C?NMR(75MHz，CDCl 3)，δ：168.38，118.78，77.62，76.68，76.38，75.38，74.29，
39.39，38.03，28.89，22.64，21.38。
IR (KBr, film), cm -1: 3423,2995,2984,2982,1753,1486,1438,1198,920.
EIMS:611 (M+1), 593 (M-18+1), 483,375,357,309,295 compounds 15
1H?NMR(300MHz，CDCl 3)，δ：0.87(t，3H)，1.2～1.8(m，61H)，2.30(t，2H)，3.34(q，2H)，
3.34(q，2H)，3.38(t，2H)，3.58(q，4H)，4.22(m，2H)，4.96(m，1H)，6.95(s，1H).
13C?NMR(75MHz，CDCl 3)，δ：169.73，120.60，78.52，77.60，76.32，75.48，74.38，
73.21，38.29，28.83，27.86，21.38。
IR (KBr, film), cm -1: 3446,2994,2983,2882, l756,1483,1160.
EIMS:68 (M+1), 663 (M-H 2O), 611,585,465,375,309,295. compounds 16
1H?NMR(300MHz，CDCl 3)，δ：0.88(t，3H)，1.25～1.7(m，67H)，2.34(t，2H)，3.33(q，2H)，
3.36(t，2H)，3.56(q，2H)，4.24(m，2H)，4.89(m，1H)，6.97(s，1H).
13C?NMR(75MHz，CDCl 3)，δ：168.74，119.50，77.53，77.10，76.68，75.46，75.41，
38.41，38.16，27.89，21.69。
IR (KBr, film), cm -1: 3440,2992,2986,2890,1754.
FAB：723(M+1)，1295.
Embodiment 6 embodiment biological activity tests
Compound 9,10,11 and 12 is measured the Lethal Dose 50 of the cancerous cell line of KB, A2780, HCT-8 and HT-29 according to the MTT method and is listed in the table below
EC 50(μg/ml)
Compound
KB A2780 HCT-8 HT-29
9 ＞1 ＞1 0.066 0.272
10 ＞1 ＞1 0.097 1.12
11 ＞1 ＞1 0.032 0.11
12 ＞1 ＞1 0.065 7.83

Claims (10)

1. chiral anonace-lactone compounds, the optically active compound that it is characterized in that having following molecular formula: Y=C wherein 6-20Alkyl, n=1-3, m=7-19.
2. chiral anonace-lactone compounds as claimed in claim 1, the optically active compound that it is characterized in that having following molecular formula:
Figure A9912575000023
Or
Figure A9912575000024
Wherein Y, n, m are the same.
3. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:
Figure A9912575000025
4. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:
Figure A9912575000026
5. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:
Figure A9912575000027
6. chiral anonace-lactone compounds as claimed in claim 1 is characterized in that molecular formula is:
Figure A9912575000031
7. the preparation method of a chiral anonace-lactone compounds as claimed in claim 1 is characterized in that by molecular formula being
Figure A9912575000032
Or
Figure A9912575000033
Chirality haloalkane and molecular formula be Or
Figure A9912575000035
Chirality dihydroxyl alkyl carboxylic acid ester, linked reaction takes place in the presence of tin alkyl and monovalence metal fluoride; Again with methoxychlor methane protection hydroxyl; Make the alpha-position of terminal ester group form negative ion with the diisopropylamine lithium reaction, with molecular formula be then Chiral aldehydes reaction obtain the aldol condensation product, obtain α, β-unsaturated lactone with organic amine compound, acid treatment that lone-pair electron are arranged on trifluoroacetic anhydride (TFAA) or the aceticanhydride/nitrogen-atoms successively; Acid catalysis deprotection group, wherein X=Cl, Br, I, n=1-3, Y=C 6-20Alkyl, P=THP, MOM or TBS, the MOM=methoxymethyl, the THP=THP trtrahydropyranyl, the TBS=dimethyl tertiary butyl is silica-based.
8. the method for the preparation of chiral anonace-lactone compounds as claimed in claim 7 is characterized in that making by following method:
(1) described chirality haloalkane, described chirality dihydroxyl alkyl carboxylic acid ester, monovalence metal fluoride and molecular formula are R 2The tin alkyl mol ratio of SnO is 1: 0.5-2: 1-5: 1-2, in one or more polar solvents and room temperature reaction 1-24h to the reflux temperature make
Figure A9912575000037
(2) product of above-mentioned (1), diisopropyl ethylenediamine and methoxychlor methane mol ratio are 1: 1-5: during 1-5, react 1-10h with 0 ℃ to room temperature in polar solvent, obtain
(3) product of above-mentioned (2), molecular formula are
Figure A9912575000041
Chiral aldehydes, diisopropylamine lithium and HMPA mol ratio be 1: 1-2: 1-5: 0-5, in polar solvent, under-78 ℃, react 0.5-5h with room temperature, after in room temperature and polar solvent, reacting 5-20h with mineral acid again, adding relative mol ratio is respectively on the nitrogen-atoms of 1-10 the organic amine compound of lone-pair electron and trifluoroacetic anhydride (TFAA) or the aceticanhydride of 1-3 is arranged, to room temperature, react 1-10h at 0 ℃, obtain
Figure A9912575000042
(4) in one or more polar solvent and under the room temperature, the product of above-mentioned (3) mineral acid catalytic reactions 10-20h,
Y=C in the above-mentioned molecular formula 6-20Alkyl, n=1-3, m=7-19, P=MOM, THP or TBS, the MOM=methoxymethyl, THP=tetrachloro pyranyl, the TBS=dimethyl tertiary butyl is silica-based, R 1=C 1-6Alkyl.
9. the preparation method of chiral anonace-lactone compounds as claimed in claim 8, the organic amine compound that it is characterized in that containing on the described nitrogen-atoms lone-pair electron is a triethylamine, described dialkyl tin is a tetrabutyl oxygen tin.
10. the purposes of a chiral anonace-lactone compounds as claimed in claim 1 is characterized in that cancer therapy drug.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101982464A (en) * 2010-09-17 2011-03-02 中国科学院广州生物医药与健康研究院 Annonaceous acetogenin compound and synthesis method and application thereof

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US5536848A (en) * 1994-06-14 1996-07-16 Purdue Research Foundation Bioactive acetogenins and derivatives
US5677467A (en) * 1996-10-03 1997-10-14 Regents Of The University Of Minnesota Synthesis of acetogenins
CN1109678C (en) * 1997-04-09 2003-05-28 中国科学院上海有机化学研究所 Annona lactone analogue and its use

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101982464A (en) * 2010-09-17 2011-03-02 中国科学院广州生物医药与健康研究院 Annonaceous acetogenin compound and synthesis method and application thereof
CN101982464B (en) * 2010-09-17 2013-08-28 中国科学院广州生物医药与健康研究院 Annonaceous acetogenin compound and synthesis method and application thereof

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