CN103483341A - 2, 4-pyrrolidine-diketone compounds and synthesis method thereof - Google Patents
2, 4-pyrrolidine-diketone compounds and synthesis method thereof Download PDFInfo
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Abstract
The invention discloses equisetin-derived 2, 4-pyrrolidine-diketone compounds. The diketone compounds have the structure shown in the specification, wherein R1 is hydrogen, alkyl, aryl or a heteroatom group containing O and N; R2 is hydrogen or alkyl; R3 is hydrogen or alkyl. A synthesis method of the diketone compounds comprises eight steps, wherein aldehyde II is prepared in the four steps; a polyene compound III is prepared through a Wittig reaction or Horner-Wadswort-Emmons reaction; a compound IV' is prepared through a Diels-Alder reaction; finally a compound V is prepared by ammonolysis and Dieckmann condensation. The compounds have relatively high biological activity and bring the foundation to the research and development of anti-cancer medicaments; the raw materials used in synthesis are simple and easy to obtain; the synthesis process is simple to carry out; the yield is relatively high.
Description
Technical field
The present invention relates to new compound and synthetic method thereof, especially novel organic compound and the synthetic route thereof of a class based on the equisetin structure.
Background technology
Tetramic acid contains typical 2 in a kind of skeleton, the compound of 4-pyrrolidine-2,4-diketo structural unit, the representative compound of this type of natural product comprises (-)-equisetin (1), fusarisetin A (2), diaporthichalasin (3), (-)-tirandamycin (4) etc.The compound that contains this element has biological activity widely, and its antitumor properties is particularly outstanding, therefore has good potential pharmaceutical use.Since the sixties in 20th century, Tetramic acid class natural product has caused the attention of vast synthetic chemistry man gradually, and at its configuration, determine, the aspect such as synthetic makes some progress, for follow-up development is laid a good foundation.
1974, fusarine (-)-equisetin (1) separates and obtains first from the one-level meta-bolites of sickle-like bacteria fusarium equiseti, shown biological activity preferably in relevant test, comprise germ resistance, the characteristic that suppresses HIV virus activity, cytotoxicity and be combined with DNA, therefore caused the extensive concern of synthetic chemistry man, total following synthetic route:
1) Danishefsky group is complete synthesis; 1989, Danishefsky group reported first (-)-equisetin complete synthesis, route is totally 15 steps, overall yield is 3.8%.（Turos,E.;Audia,J.E.;Danishefsky,S.J.J.Am.Chem.Soc.1989,111,8231.）
2) Rodr í guez group is complete synthesis; 2000, Rodr í guez group reported the second synthetic route of (-)-equisetin (1), and route is totally 13 steps, and total recovery is 10.1%, on synthetic, larger improvement has been arranged, but route was still longer.（Burke,L.T.;Dixon,D.J.;Ley,S.V.;Rodríguez,F.Org.Lett.2000,2,3611.）
3) Shishido group is complete synthesis; Calendar year 2001, Shishido group has reported the 3rd synthetic route of equisetin, and route is totally 24 steps, total recovery 6.7%.This route is especially too loaded down with trivial details compared to front two lines, has shared 8 steps in allylic introducing.（Kumiko,Y.K.;Shindo,M.;Shishido,K.Tetrahedron?Lett.2001,42,2517.）
4) the complete synthesis route of second of Rodr í guez group; 2005, Rodr í guez group has reported the synthetic route of the 4th (-)-equisetin (1), and route is totally 13 steps, total recovery 26.6%, this route and his article one route of report have larger similarity, but all improve on productive rate and stereoselectivity.(Burke,L.T.;Dixon,D.J.;Ley,S.V.;Rodríguez,F.Org.Biomol.Chem.2005,3,274.)
In sum, although the route of existing several synthetic (-)-equisetin (1), but every route all exists route long, total recovery is low, the problems such as stereoselectivity is poor, therefore develop an efficient synthetic route, and by the compound of the synthetic a series of classes (-) of this route-equisetin (1), therefrom find out activity better, the compound that toxicity is lower still has very high Research Significance.
Summary of the invention
The purpose of this invention is to provide a kind of 2,4-pyrrolidine-2,4-diketo class new compound and synthetic method, this compounds will be applied in cancer therapy drug, its synthesis material is simple and easy to get, building-up process is simple to operate, and productive rate is higher.
The object of the present invention is achieved like this:
A kind of derivative 2 based on equisetin, the 4-pyrrolidine-2,4-diketo compound, this compounds has the following formula structure:
In formula: R
1for hydrogen, alkyl, aryl or containing O, N heteroatom group; R
2for hydrogen or alkyl; R
3for hydrogen or alkyl; Its synthetic route is as follows:
Route 1:
The first step: set out by (-)-geranial, by four-step reaction, obtain Compound I I, detailed process is through the ethylene glycol protective reaction, ozone oxidation reaction, and Huo Naer-Wordsworth-Ai Mengsi reaction, de-ethylene glycol protective reaction obtains Compound I I;
Second step: by Compound I, I sets out, react to obtain compound III by Wittig reaction or Huo Naer-Wordsworth-Ai Mengsi, the tetrahydrofuran solution that concrete operations are Witting reagent or phosphoric acid ester reagent under-78 ℃ with alkali reaction 30min, again Compound I I is added, wherein Witting reagent or phosphoric acid ester reagent, alkali, between Compound I I three, the amount of substance ratio is: 3.0:3.3:1.0; Be warming up to 30 ℃, reaction 1-18h, after reaction finishes, in reaction, add phosphate buffer solution, stir 10min, tetrahydrofuran (THF) is spin-dried for, be extracted with ethyl acetate, organic phase is also washed with saturated ammonium chloride and saturated sodium-chlor, anhydrous sodium sulfate drying, be spin-dried for, the rapid column chromatography purifying obtains compound III;
The 3rd step: set out by compound III, by ammonolysis reaction, obtain compound IV; The tetrahydrofuran solution that concrete operations are compound III and amino acid methyl ester trifluoroacetic acid silver under alkaline condition is made catalyzer, compound III wherein, and amino acid methyl ester, alkali, between trifluoroacetic acid silver, the amount of substance ratio is: 1.0:1.2:4.0:1.5; React 15-30min under-5 ℃, reaction adds saturated sodium chloride solution after finishing wherein, under room temperature, stirs 5min, crosses diatomite and gets final product, and column chromatography purification obtains compound IV;
The 4th step: set out by compound IV, obtain compound V by Di Ersi – Alder reaction, concrete operations are under-78 ℃, the dichloromethane solution of compound IV reacts 1-4h under the katalysis of boron trifluoride diethyl etherate, compound IV wherein, boron trifluoride diethyl etherate amount of substance ratio between the two is: 1.0:3.0; Reaction adds saturated sodium chloride solution after finishing wherein, under room temperature, stirs 10min, methylene dichloride is spin-dried for, is extracted with ethyl acetate, and wash with saturated sodium hydrogen carbonate solution and saturated sodium-chloride, anhydrous sodium sulfate drying, be spin-dried for, and the rapid column chromatography purifying obtains compound V;
The 5th step: by compound, V sets out, and by diekmann condensation, reacts to obtain compound VI, and the methanol solution that concrete operations are compound V reacts 1-4h with sodium methylate under 0 ℃, compound V wherein, and sodium methylate amount of substance ratio between the two is: 1.0:3; Reaction adds hydrochloric acid soln after finishing wherein, under room temperature, stirs 5min, adds saturated sodium chloride solution, uses dichloromethane extraction, and organic phase is washed with saturated sodium chloride solution, and anhydrous sodium sulfate drying is spin-dried for, and the thin-layer chromatography purifying obtains compound VI;
Route 2:
The first step: set out by (-)-geranial, by four-step reaction, obtain Compound I I, detailed process is through the ethylene glycol protective reaction, ozone oxidation reaction, and Huo Naer-Wordsworth-Ai Mengsi reaction, de-ethylene glycol protective reaction obtains Compound I I;
Second step: by Compound I, I sets out, react to obtain compound III by Wittig reaction or Huo Naer-Wordsworth-Ai Mengsi, the tetrahydrofuran solution that concrete operations are Witting reagent or phosphoric acid ester reagent under-78 ℃ with alkali reaction 30min, again Compound I I is added, wherein Witting reagent or phosphoric acid ester reagent, alkali, between Compound I I three, the amount of substance ratio is: 3.0:3.3:1.0; Be warming up to 30 ℃, reaction 1-18h, after reaction finishes, in reaction, add phosphate buffer solution, stir 10min, tetrahydrofuran (THF) is spin-dried for, be extracted with ethyl acetate, organic phase is also washed with saturated ammonium chloride and saturated sodium-chlor, anhydrous sodium sulfate drying, be spin-dried for, the rapid column chromatography purifying obtains compound III;
The 3rd step: set out by compound III, by Di Ersi – Alder reaction obtain compound IV ', the dichloromethane solution that concrete operations are compound III reacts 1h under the katalysis of boron trifluoride diethyl etherate, compound III wherein, boron trifluoride diethyl etherate amount of substance ratio between the two is: 1.0:3.0; Reaction adds saturated sodium chloride solution after finishing wherein, under room temperature, stirs 10min, methylene dichloride is spin-dried for, is extracted with ethyl acetate, and wash with saturated sodium hydrogen carbonate solution and saturated sodium-chloride, anhydrous sodium sulfate drying, be spin-dried for, the rapid column chromatography purifying obtain compound IV ';
The 4th step: by compound IV ' set out, obtain compound V by ammonolysis reaction, concrete operations are that compound IV ' with the tetrahydrofuran solution of amino acid methyl ester is under alkaline condition, trifluoroacetic acid silver is made catalyzer, react 10-30min under 0 ℃, wherein compound IV ', amino acid methyl ester, alkali, between trifluoroacetic acid silver, the amount of substance ratio is: 1.0:1.2:4.0:1.5; React 15-30min under-5 ℃, reaction adds saturated sodium chloride solution after finishing wherein, under room temperature, stirs 5min, crosses diatomite and gets final product, and column chromatography purification obtains compound V;
The 5th step: by compound, V sets out, and by diekmann condensation, reacts to obtain compound VI, and the methanol solution that concrete operations are compound V reacts 1-4h with sodium methylate under 0 ℃, compound V wherein, and sodium methylate amount of substance ratio between the two is: 1.0:3.0; Reaction adds hydrochloric acid soln after finishing wherein, under room temperature, stirs 5min, adds saturated sodium chloride solution, uses dichloromethane extraction, and organic phase is washed with saturated sodium chloride solution, and anhydrous sodium sulfate drying is spin-dried for, and the thin-layer chromatography purifying obtains compound VI;
Described alkali is the silica-based Lithamide of hexamethyl two, the silica-based sodium amide of hexamethyl two, n-Butyl Lithium or triethylamine;
Described amino acid methyl ester is various amino acid methyl esters;
Described Lewis acid is boron trifluoride diethyl etherate, dimethylaluminum chloride or methyl aluminum chloride;
The Threonine methyl esters that described various amino acid methyl ester is proline methyl ester or methyl protection;
Described this compounds will be applied in cancer therapy drug.
Advantage of the present invention:
, all ingredients that uses in reaction involved in the present invention is all simple and easy to get, but business buy, and do not relate to the poisonous and harmful hazardous substance; The reaction conditions gentleness, route is brief, and productive rate is higher.
, the invention provides the compound of series of novel skeleton structure, and there is biological activity preferably, will be applied in cancer therapy drug.
(3), can attempt each seed amino acid in route, for medicament research and development lays the foundation.
Embodiment
The following examples will better illustrate the present invention, but what need emphasize is that the present invention never only limits to the represented content of these embodiment.
The data that following examples are given, comprise concrete operations and reaction conditions and product.Product purity is identified by nuclear-magnetism.
Provide following four examples:
Embodiment 1
Synthesizing of compound 5
Synthetic compound 11: take 10 (3.4g, 8.70mmol) in the reaction flask of 200mL drying, the tetrahydrofuran (THF) that adds 44mL (0.2M), drip n-Butyl Lithium (6mL under-78 ℃, 9.6mmol), add again the 5mL tetrahydrofuran solution of 9 (872mg, 2.90mmol) after reaction 10min under 0 ℃, rise to 0 ℃ after reaction 30min and react again 10min at this temperature under-78 ℃.Add wherein the ammonium chloride solution that 20mL is saturated after reacting completely, stir 10min under room temperature, tetrahydrofuran (THF) is spin-dried for, by (50mL * 2) ethyl acetate, extract, merge organic phase and wash (20mL * 1) with saturated ammonium chloride (20mL * 2) solution and saturated sodium-chloride, anhydrous sodium sulfate drying, be spin-dried for.The yellow liquid 812mg of rapid column chromatography (1% ethyl acetate/petroleum ether), productive rate is 83%.HRMS(EI):Exact?mass?calcd?for?C
20H
32SO
2[M]
+:336.2123;Found:336.2122,
1H?NMR(400MHz,CDCl
3)δ6.63(t,J=7.0Hz,1H),6.31(dd,J=25.9,11.2Hz,1H),6.01(p,J=10.2Hz,1H),5.63–5.44(m,2H),3.82(s,2H),2.42–2.13(m,2H),2.12–1.99(m,1H),2.01–1.87(m,1H),1.86–1.67(m,6H),1.62–1.38(m,11H),1.36–1.19(m,1H),1.00–0.80(m,3H).
13C?NMR(400MHz,CDCl
3)δ193.6,193.3,146.0,137.0,131.9,131.5,129.7,127.1,127.0,53.8,48.8,39.9,35.0,33.0,30.2,29.7,27.0,19.4,18.0,11.3。
Synthetic compound 12: take 11 (100mg, 0.30mmol) in the reaction flask of 50mL drying, the methylene dichloride that adds 15mL (0.02M), add a small amount of iodine (3mg, 5mmol%), under 11 ℃ after anti-4h, then add boron trifluoride diethyl etherate (34 μ L under-78 ℃, 0.27mmol), rise to 0 ℃ after reaction 30min and react again 15min at this temperature.After reacting completely, add wherein the sodium chloride solution that 5mL is saturated, stir 10min under room temperature, methylene dichloride is spin-dried for, by (10mL * 2) ethyl acetate, extract, and wash (5mL * 1) with saturated sodium bicarbonate (5mL * 2) solution and saturated sodium-chloride, anhydrous sodium sulfate drying, be spin-dried for.The yellow liquid 60mg of rapid column chromatography (1% ethyl acetate/petroleum ether), productive rate is 60%.MS(m/z)(%):EI[M](%)calcd?for?C
20H
32SO
2:336;found336(1),280(22),247(57),219(100),149(59).
1H?NMR(400MHz,CDCl
3)δ5.62–5.40(m,1H),5.40–5.19(m,1H),2.02–1.83(m,1H),1.70(ddd,J=26.8,23.5,12.6Hz,3H),1.60–1.46(m,9H),1.45(s,1H),1.43(d,J=3.0Hz,1H),1.33–1.22(m,2H),1.22–1.07(m,2H),1.06–0.98(m,3H),0.96(t,J=5.8Hz,2H),0.93–0.78(m,6H).
13C?NMR(400MHz,CDCl
3)δ205.9,193.1,129.8,129.2,54.5,53.1,48.8,41.9,39.5,38.7,38.5,35.5,33.3,30.2,29.6,27.0,22.4,18.7,17.7,17.2。
Synthetic compound 14: take 12 (80mg, 0.24mmol) in the reaction tubes of the drying of 20mL, the tetrahydrofuran (THF) and the 13 (61mg that add 3mL (0.1M), 0.48mmol), triethylamine (133 μ L, 0.96mmol) and the trifluoroacetic acid that adds fast under 0 ℃ silver (83mg, 0.36mmol), react 10min at this temperature.After reacting completely, add wherein the sodium chloride solution that 0.5mL is saturated, under room temperature, stir 5min, cross diatomite and get final product.Column chromatography purification (30% ethyl acetate/petroleum ether), obtain orange solid 77mg, and productive rate is 93%.HRMS(EI):Exact?mass?calcd?for?C
22H
33NO
4[M]
+:375.2410;Found:375.2412.
1H?NMR(400MHz,CDCl
3)δ5.49(s,1H),5.33(t,J=9.8Hz,1H),4.64–4.42(m,1H),3.85–3.26(m,6H),2.34–1.83(m,5H),1.71(s,4H),1.64–1.52(m,1H),1.47(s,2H),1.21(d,J=13.0Hz,2H),1.02(dd,J=18.4,6.2Hz,3H),0.95(d,J=6.8Hz,1H),0.89(d,J=3.2Hz,3H),0.82(d,J=6.7Hz,3H).
13C?NMR(400MHz,CDCl
3)δ207.3,172.4,166.1,129.8,129.2,58.7,53.0,52.1,47.6,46.1,45.0,41.9,39.3,38.4,35.6,33.3,29.3,27.2,24.7,22.4,18.7,17.4。
Synthetic compound 5: take 14 (77mg, 0.20mmol) in the spherical reaction tubes of the drying of 20mL, add 10mL (0.02M) methyl alcohol and sodium methylate (61mg, 1.00mmol), in 60 ℃ the reaction 2h.After reacting completely, add wherein hydrochloric acid soln (5mL, 1N), under room temperature, stir 5min, add the sodium chloride solution that 5mL is saturated, with methylene dichloride (15mL * 5), merge organic phase, wash (10mL * 1) with saturated sodium chloride solution, anhydrous sodium sulfate drying, be spin-dried for.Thin-layer chromatography purifying (20% ethyl acetate/petroleum ether), obtain red solid 63mg, and productive rate is 90%.HRMS(EI):Exact?mass?calcd?for?C
21H
29NO
3[M]
+:343.2147;Found:343.2145.
1H?NMR(400MHz,CDCl
3)δ5.67–5.40(m,1H),5.30(d,J=9.8Hz,1H),3.99–3.78(m,1H),3.78–3.53(m,1H),3.37–3.21(m,1H),2.81(s,1H),2.26–2.16(m,1H),2.14–1.93(m,2H),1.92–1.58(m,5H),1.53–1.35(m,5H),1.16–0.96(m,2H),0.96–0.81(m,5H),0.79(d,J=6.9Hz,3H).
13C?NMR(400MHz,CDCl
3)δ207.3,172.4,166.1,129.8,129.2,87.3,58.7,53.0,52.1,47.6,46.1,45.0,41.9,39.3,38.4,35.6,33.3,29.3,27.2,24.7,22.4,18.7,17.4。
Embodiment 2
Synthesizing of compound 6
Synthetic compound 16: take 15 (147mg, 0.41mmol) in the reaction flask of 50mL, the tetrahydrofuran (THF) and the 13 (105mg that add 20mL (0.02M), 0.82mmol), triethylamine (228 μ L, 1.64mmol) and the trifluoroacetic acid that adds fast under 0 ℃ silver (142mg, 0.62mmol), react 10min at this temperature.After reacting completely, add wherein the sodium chloride solution that 0.5mL is saturated, under room temperature, stir 5min, cross diatomite and get final product.Column chromatography purification (30% ethyl acetate/petroleum ether), obtain safran solid 150mg, 90% productive rate.HRMS(EI):Exact?mass?calcd?for?C
24H
35NO
4[M]
+:401.2566;Found:401.2567,
1H?NMR(400MHz,CDCl
3)δ5.47–5.27(m,3H),5.26–5.11(m,1H),4.52(dd,J=8.3,3.6Hz,1H),3.77–3.55(m,3H),3.49(t,J=6.4Hz,2H),3.31(d,J=15.8Hz,1H),2.54(dd,J=9.1,4.8Hz,1H),2.36(d,J=7.8Hz,2H),2.27–2.09(m,3H),2.09–1.83(m,3H),1.84–1.62(m,3H),1.59(dd,J=8.7,3.6Hz,2H),1.46(d,J=2.9Hz,3H),1.02(dt,J=21.9,11.3Hz,1H),0.93–0.77(m,6H).
13CNMR(400MHz,CDCl
3)δ206.9,172.6,166.2,131.3,130.4,126.3,125.9,58.6,53.1,52.0,49.4,47.7,46.4,41.8,39.7,38.3,35.4,33.3,29.3,27.1,24.8,22.3,17.7,17.3。
Synthetic compound 6: take 16 (120mg, 0.30mmol) in the spherical reaction tubes of the drying of 20mL, add 15mL (0.01M) methyl alcohol and sodium methylate (80mg, 1.50mmol), in 60 ℃ the reaction 4h.After reacting completely, add wherein hydrochloric acid soln (5mL, 1N), under room temperature, stir 5min, add the sodium chloride solution that 5mL is saturated, with methylene dichloride (15mL * 5), merge organic phase, wash (10mL * 1) with saturated sodium chloride solution, anhydrous sodium sulfate drying, be spin-dried for.Thin-layer chromatography purifying (20% ethyl acetate/petroleum ether), obtain red solid 79mg, 66% productive rate.HRMS(EI):Exact?mass?calcd?for?C
23H
31NO
3[M]
+:369.2304;Found:369.2303,
1H?NMR(400MHz,CDCl
3)δ5.57–5.32(m,2H),5.28–5.00(m,2H),3.90(dd,J=9.5,7.2Hz,1H),3.70(ddd,J=21.7,12.6,10.2Hz,1H),3.36(s,1H),3.32–3.11(m,1H),2.26–2.16(m,1H),2.18–2.00(m,2H),1.99–1.88(m,1H),1.63(d,J=29.2Hz,4H),1.54–1.35(m,6H),1.25(s,3H),1.20–0.96(m,2H),0.96–0.70(m,4H).
13C?NMR400MHz,CDCl
3)δ199.5,192.8,181.3,131.1,129.9,126.6,126.5,101.9,67.7,48.9,45.1,43.9,42.3,39.9,38.3,35.7,33.5,28.3,27.4,26.8,22.5,17.9,13.9。
Embodiment 3
Synthesizing of compound 7
Synthetic compound 18: take 15 (60mg, 0.17mmol) in the reaction tubes of the drying of 20mL, the tetrahydrofuran (THF) and the 17 (35mg that add 4mL (0.1M), 0.24mmol), triethylamine (100 μ L, 0.68mmol) and the trifluoroacetic acid that adds fast under 0 ℃ silver (70mg, 0.26mmol), react 10min at this temperature.After reacting completely, add wherein the sodium chloride solution that 0.5mL is saturated, under room temperature, stir 5min, cross diatomite and get final product.Column chromatography purification (5% ethyl acetate/petroleum ether), obtain white solid 52mg.75% productive rate.HRMS(EI):Exact?mass?calcd?for?C
25H
39NO
4[M]
+:417.2879;Found:417.2877,
1H?NMR(400MHz,CDCl
3)
1H?NMR(400MHz,CDCl
3)δ5.48–5.28(m,3H),5.19(dd,J=15.5,7.6Hz,1H),4.92(t,J=8.8Hz,1H),3.87–3.56(m,4H),3.53–3.30(m,1H),3.02–2.71(m,3H),2.54(dd,J=8.7,4.7Hz,1H),2.28–2.07(m,1H),1.70(ddd,J=22.5,18.8,9.6Hz,6H),1.60–1.53(m,3H),1.52–1.37(m,1H),1.25(d,J=15.6Hz,3H),1.14–1.04(m,1H),1.00(t,J=8.4Hz,3H),0.96–0.92(m,3H),0.91–0.81(m,4H),
13C?NMR(400MHz,CDCl
3)δ207.1,171.8,168.8,131.6,130.8,126.8,126.5,61.6,53.7,52.0,50.0,46.4,42.2,40.2,38.7,35.8,33.6,32.2,27.8,27.5,22.7,20.0,19.1,18.0,17.7。
Synthetic compound 7: take 18 (68mg, 0.16mmol) in the reaction tubes of 20mL, add 3mL (0.05M) methyl alcohol and sodium methylate (26mg, 0.48mmol), in 0 ℃ the reaction 5h.After reacting completely, add wherein hydrochloric acid soln (2mL, 1N), under room temperature, stir 5min, add the sodium chloride solution that 5mL is saturated, with methylene dichloride (5mL * 5), merge organic phase, wash (5mL * 1) with saturated sodium chloride solution, anhydrous sodium sulfate drying, be spin-dried for.Thin-layer chromatography purifying (5% ethyl acetate/petroleum ether), obtain orange solid 30mg, 49% productive rate.HRMS(EI):Exact?mass?calcd?for?C
24H
35NO
3[M]
+:385.2617;Found:385.2618,
1H?NMR(400MHz,CDCl
3)δ5.38(s,2H),5.26(dt,J=20.6,6.1Hz,1H),5.18(s,1H),3.48(s,1H),3.36(s,1H),2.99(s,3H),2.48–2.19(m,1H),2.00(d,J=26.4Hz,1H),1.90–1.57(m,5H),1.46(dd,J=32.2,22.3Hz,7H),1.19–0.99(m,5H),0.98–0.76(m,7H).
13C?NMR(400MHz,CDCl
3)δ198.0,191.1,176.8,130.9,129.7,126.9,126.7,100.9,70.2,48.4,45.0,42.3,40.1,38.6,35.7,33.5,29.1,28.4,27.9,22.5,17.7,17.5,17.0,14.0.
Embodiment 4
Synthesizing of compound 8
Synthetic compound 20: take 15 (86mg, 0.24mmol) in the reaction tubes of the drying of 20mL, the tetrahydrofuran (THF) and the 19 (42mg that add 3mL (0.1M), 0.29mmol), triethylamine (128 μ L, 0.92mmol) and the trifluoroacetic acid that adds fast under 0 ℃ silver (82mg, 0.36mmol), react 10min at this temperature.After reacting completely, add wherein the sodium chloride solution that 0.5mL is saturated, under room temperature, stir 5min, cross diatomite and get final product.Column chromatography purification (30% ethyl acetate/petroleum ether), obtain white solid 85mg.85% productive rate.HRMS(EI):Exact?mass?calcd?for?C
24H
37NO
5[M]
+:419.2672;Found:419.2676,
1H?NMR(400MHz,CDCl
3)δ5.51–5.24(m,3H),5.21–5.05(m,1H),4.73(t,J=13.7Hz,1H),4.54–4.37(m,1H),3.88–3.59(m,4H),3.58–3.42(m,1H),3.20–2.79(m,3H),2.54(dt,J=12.6,6.3Hz,1H),2.40(s,1H),1.70(ddd,J=35.1,24.4,11.0Hz,5H),1.57(d,J=6.4Hz,3H),1.47(s,1H),1.29(t,J=7.1Hz,2H),1.24(d,J=10.5Hz,3H),1.19(d,J=5.9Hz,1H),1.15–0.93(m,2H),0.94–0.80(m,4H).
13C?NMR(400MHz,CDCl
3)δ207.7,170.1,169.0,131.0,130.5,126.7,126.4,66.2,64.0,53.4,52.2,49.8,46.1,41.8,39.9,38.4,36.0,35.5,33.4,27.2,22.4,19.7,17.8,17.4。
Synthetic compound 8: take 20 (85mg, 0.22mmol) in the dry reaction pipe of 20mL, add 3mL (0.1M) methyl alcohol and sodium methylate (38mg, 0.70mmol), in 0 ℃ the reaction 2h.After reacting completely, add wherein hydrochloric acid soln (5mL, 1N), under room temperature, stir 5min, add the sodium chloride solution that 5mL is saturated, with methylene dichloride (15mL * 5), merge organic phase, wash (10mL * 1) with saturated sodium chloride solution, anhydrous sodium sulfate drying, be spin-dried for.Thin-layer chromatography purifying (30% ethyl acetate/petroleum ether), obtain red solid 59mg, 69% productive rate.HRMS(EI):Exact?mass?calcd?for?C
23H
33NO
4[M]
+:387.2410;Found:387.2411,
1H?NMR(400MHz,CDCl
3)δ5.38(s,2H),5.27(dt,J=20.6,6.1Hz,1H),5.17(d,J=7.7Hz,1H),4.18(s,1H),3.91(s,1H),3.78(s,1H),3.34(s,1H),2.96(s,3H),1.93(d,J=8.5Hz,1H),1.76(dt,J=20.3,14.2Hz,4H),1.50(d,J=5.4Hz,4H),1.44(s,3H),1.16–0.97(m,6H),0.88(dd,J=19.0,9.2Hz,4H).
13C?NMR(400MHz,CDCl
3)δ199.6,192.3,177.0,130.7,129.8,126.9,126.6,100.7,66.6,66.5,48.7,45.2,42.2,39.9,38.4,35.6,33.4,28.2,27.2,22.4,17.7,17.1,13.8。
Claims (4)
- One kind derivative 2 based on equisetin, the 4-pyrrolidine-2,4-diketo compound, this compounds has following structure:
Wherein, R 1for hydrogen, alkyl, aryl or containing O, N heteroatom group; R 2for hydrogen or alkyl; R 3for hydrogen or alkyl. - 2. the synthetic method of the described compounds of claim 1 is characterized in that the method has following two kinds of synthetic routes:Route 1:The first step: set out by (-)-geranial, by four-step reaction, obtain Compound I I, detailed process is through the ethylene glycol protective reaction, ozone oxidation reaction, and Huo Naer-Wordsworth-Ai Mengsi reaction, de-ethylene glycol protective reaction obtains Compound I I;Second step: by Compound I, I sets out, react to obtain compound III by Wittig reaction or Huo Naer-Wordsworth-Ai Mengsi, the tetrahydrofuran solution that concrete operations are Witting reagent or phosphoric acid ester reagent under-78 ℃ with alkali reaction 30min, again Compound I I is added, be warming up to 30 ℃, reaction 1-18h, after reaction finishes, add phosphate buffer solution in reaction, stir 10min, tetrahydrofuran (THF) is spin-dried for, be extracted with ethyl acetate, organic phase is also washed with saturated ammonium chloride and saturated sodium-chlor, anhydrous sodium sulfate drying, be spin-dried for, the rapid column chromatography purifying obtains compound III, wherein between Witting reagent or phosphoric acid ester reagent, alkali, Compound I I three, the amount of substance ratio is: 3.0:3.3:1.0,The 3rd step: set out by compound III, by ammonolysis reaction, obtain compound IV; The tetrahydrofuran solution that concrete operations are compound III and amino acid methyl ester trifluoroacetic acid silver under alkaline condition is made catalyzer, react 15-30min under-5 ℃, reaction adds saturated sodium chloride solution after finishing wherein, stir 5min under room temperature, cross diatomite, column chromatography purification obtains compound IV; Wherein between compound III, amino acid methyl ester, alkali, trifluoroacetic acid silver, the amount of substance ratio is: 1.0:1.2:4.0:1.5;The 4th step: set out by compound IV, by Di Ersi – Alder reaction, obtain compound V, concrete operations are under-78 ℃, the dichloromethane solution of compound IV reacts 1-4h under the katalysis of boron trifluoride diethyl etherate, reaction adds saturated sodium chloride solution after finishing wherein, under room temperature, stirs 10min, methylene dichloride is spin-dried for, be extracted with ethyl acetate, and wash anhydrous sodium sulfate drying with saturated sodium hydrogen carbonate solution and saturated sodium-chloride, be spin-dried for, the rapid column chromatography purifying obtains compound V; Wherein compound IV, boron trifluoride diethyl etherate between the two the amount of substance ratio be: 1.0:3.0;The 5th step: by compound, V sets out, react to obtain compound VI by diekmann condensation, the methanol solution that concrete operations are compound V reacts 1-4h with sodium methylate under 0 ℃, after reaction finishes, add wherein hydrochloric acid soln, stir 5min under room temperature, add saturated sodium chloride solution, use dichloromethane extraction, organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate drying, be spin-dried for, and the thin-layer chromatography purifying obtains compound VI; Wherein compound V, sodium methylate between the two the amount of substance ratio be: 1.0:3.0;Route 2:the first step: set out by (-)-geranial, by four-step reaction, obtain Compound I I, detailed process is through the ethylene glycol protective reaction, ozone oxidation reaction, and Huo Naer-Wordsworth-Ai Mengsi reaction, de-ethylene glycol protective reaction obtains Compound I I;
Second step: by Compound I, I sets out, react to obtain compound III by Wittig reaction or Huo Naer-Wordsworth-Ai Mengsi, the tetrahydrofuran solution that concrete operations are Witting reagent or phosphoric acid ester reagent under-78 ℃ with alkali reaction 30min, again Compound I I is added, be warming up to 30 ℃, reaction 1-18h, after reaction finishes, add phosphate buffer solution in reaction, stir 10min, tetrahydrofuran (THF) is spin-dried for, be extracted with ethyl acetate, organic phase is also washed with saturated ammonium chloride and saturated sodium-chlor, anhydrous sodium sulfate drying, be spin-dried for, the rapid column chromatography purifying obtains compound III, wherein between Witting reagent or phosphoric acid ester reagent, alkali, Compound I I three, the amount of substance ratio is: 3.0:3.3:1.0,The 3rd step: set out by compound III, by Di Ersi – Alder reaction obtain compound IV ', the dichloromethane solution that concrete operations are compound III reacts 1h under the katalysis of boron trifluoride diethyl etherate, after reaction finishes, add wherein saturated sodium chloride solution, stir 10min under room temperature, methylene dichloride is spin-dried for, be extracted with ethyl acetate, and wash with saturated sodium hydrogen carbonate solution and saturated sodium-chloride, anhydrous sodium sulfate drying, be spin-dried for, the rapid column chromatography purifying obtain compound IV '; Wherein compound III, boron trifluoride diethyl etherate between the two the amount of substance ratio be: 1.0:3.0;The 4th step: by compound IV ' set out, obtain compound V by ammonolysis reaction, concrete operations are that compound IV ' with the tetrahydrofuran solution of amino acid methyl ester is under alkaline condition, trifluoroacetic acid silver is made catalyzer, under 0 ℃, reacts 10-30min, under-5 ℃, reacts 15-30min, reaction adds saturated sodium chloride solution after finishing wherein, stir 5min under room temperature, cross diatomite, column chromatography purification obtains compound V; Wherein compound IV ', the amount of substance ratio is between amino acid methyl ester, alkali, trifluoroacetic acid silver: 1.0:1.2:4.0:1.5;The 5th step: by compound, V sets out, react to obtain compound VI by diekmann condensation, the methanol solution that concrete operations are compound V reacts 1-4h with sodium methylate under 0 ℃, after reaction finishes, add wherein hydrochloric acid soln, stir 5min under room temperature, add saturated sodium chloride solution, use dichloromethane extraction, organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate drying, be spin-dried for, and the thin-layer chromatography purifying obtains compound VI; Wherein compound V, sodium methylate between the two the amount of substance ratio be: 1.0:3.0;Described alkali is the silica-based Lithamide of hexamethyl two, the silica-based sodium amide of hexamethyl two, n-Butyl Lithium or triethylamine;Described amino acid methyl ester is various amino acid methyl esters;Described Lewis acid is boron trifluoride diethyl etherate, dimethylaluminum chloride or methyl aluminum chloride. - 3. synthetic method according to claim 2, is characterized in that the Threonine methyl esters that described various amino acid methyl ester is proline methyl ester or methyl protection.
- 4. the application of the described compounds of claim 1, is characterized in that the application of this compounds in preparing cancer therapy drug.
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| CN105012352A (en) * | 2014-04-28 | 2015-11-04 | 北京大学 | Application of Equisetin in preparation of medicine for preventing and treating metabolic syndrome |
| CN105384727A (en) * | 2015-10-10 | 2016-03-09 | 中国科学院南海海洋研究所 | Tetramic acid compound and preparation method thereof, and application of tetramic acid compound in preparing anti-tumor and anti-viral drugs |
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| CN105012352A (en) * | 2014-04-28 | 2015-11-04 | 北京大学 | Application of Equisetin in preparation of medicine for preventing and treating metabolic syndrome |
| CN105012352B (en) * | 2014-04-28 | 2017-05-24 | 北京大学 | Application of Equisetin in preparation of medicine for preventing and treating metabolic syndrome |
| CN105384727A (en) * | 2015-10-10 | 2016-03-09 | 中国科学院南海海洋研究所 | Tetramic acid compound and preparation method thereof, and application of tetramic acid compound in preparing anti-tumor and anti-viral drugs |
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