CN101497590A - 13-alkoxy-3,15-dioxo-gibberellic acid ester and preparation thereof - Google Patents
13-alkoxy-3,15-dioxo-gibberellic acid ester and preparation thereof Download PDFInfo
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Abstract
The invention provides a compound with a structural general formula (A) which is a 13-oxoalkyl-3,15-dioxo gibberellic acid ester matter and a method for preparing the same. Tests on anti-cancer activity prove that the compound has strong in vitro anti-tumor activity, R<1> is equal to CH3; 2 to 5 alkyl groups of carbon, and PhCH2R<2> is equal to H; Ar; in ArCH2 and a formula of 1 to 5 alkyl groups of carbon, R<1> is methyl, 2 to 5 alkyl groups of carbon and benzyl; and R<2> is hydrogen, substituted benzyl and 1 to 5 alkyl groups of carbon.
Description
Technical field
The present invention relates to the medicinal compound of medical and health and chemical field, specifically is a kind of 13-alcoxyl generation-3,15-dioxo-gibberellic acid ester class material and preparation method thereof.
Background technology
Malignant tumour is a class disease of serious threat human health, and chemotherapy is the important means of control at present and treatment malignant tumour.Chemotherapeutic core is a high reactivity, the discovery and the application of the anticancer compound of highly selective, nontoxic or low toxic side effect.The chemotherapeutics of clinical application at present much all makes toxic side effect such as the patient feels sick, vomiting, leukopenia, bone marrow depression, has influenced patient body Health and Living quality, thereby has greatly limited the clinical application of chemotherapeutics.Therefore, seek the important topic that the high antineoplastic novel compound of therapeutic index becomes new drug research.
Plant hormones regulators,gibberellins is that a class extensively is present in plant and microbe is interior, have the plant-growth promotion or plant-growth suppresses bioactive tetracyclic diterpene compounds, with the Plant hormones regulators,gibberellins of commercialization fermentative production, as GA
3, GA
4, GA
7For raw material carries out structure of modification, there is important use to be worth such as new active Plant hormones regulators,gibberellins such as antibiotic, anticancer and derivative thereof in the hope of finding to have better plant-growth promotion or plant growth inhibiting activity and other.
In the present invention's research in early stage, the present inventor is with gibberic acid GA
3Synthetic 3 and 15 of obtaining are oxidized to the gibberic acid derivative of carbonyl simultaneously and find that this compounds has very strong antitumour activity for raw material, lower to normal cytotoxicity simultaneously, applied for patent in 2004 and obtained the authorization that the patent No. is ZL200410021939.In the recent period we find again 13 halogenated 3, the 15-dioxo-gibberellic acid ester has good antitumor activity.We have prepared a series of 13 oxyalkylated derivatives and have found that this compounds has the inhibition activity of remarkable vitro to the human tumor cell line growing multiplication in the present invention.
Summary of the invention
The present invention proposes a kind of compound with general structure (A): promptly the 13-alcoxyl is for-3,15-dioxo-gibberellic acid ester class material, the present invention also provides the preparation method of this compound, and this compounds experiment showed, to have stronger anti tumor activity in vitro through antitumour activity.
The object of the present invention is achieved like this:
R in the formula
1Alkyl, benzyl for methyl, 2 carbon to 5 carbon; R
2Be the benzyl of hydrogen, replacement and the alkyl of 1 carbon to 5 carbon.
The method that the present invention prepares above-claimed cpd is as follows: with 3,13,15-trihydroxy-gibberellic acid ester (2) is a starting raw material, and compound (2) prepares with reference to the method among the patent ZL200410021939.Compound (2) adds the oxalyl chloride of methyl-sulphoxide and suitable proportion or the oxygenant of methyl-sulphoxide and sulfur oxychloride formation under the low temperature in low polar solvent, 3 and 15 hydroxyls of oxidation are 3, in the time of the 15-dicarbapentaborane, 13 chlorination take place simultaneously generate the compound with general structure (1), be 13-halo-3, the 15-dioxo-gibberellic acid ester.
Reaction formula with compound (2) preparation compound (1) is as follows:
The R of (1) and (2) in the formula
1=CH
3The alkyl of 2-5 carbon and benzyl,
A) DMSO, ClCOCOCl or DMSO, SOCl
2, NEt
3/ CH
2Cl
2
Described low polar solvent is benzene, toluene, methylene dichloride, trichloromethane, normal hexane, cyclohexane, sherwood oil, and consumption is 10～100mL solvent/g substrate; Is oxygenant with methyl-sulphoxide and oxalyl chloride or methyl-sulphoxide and sulfur oxychloride at-70 ℃ to-40 ℃ compounds that form down, adds substrate afterreaction 5-30 minute of waiing upon oxidation and chloro, adds triethylamine again and reacts 5-30 minute.
Described compound amount is in molar ratio: substrate/methyl-sulphoxide/oxalyl chloride or sulfur oxychloride/triethylamine=1/2～50/2～6/4～100.Preferential each compound amount that adopts is in molar ratio: substrate/methyl-sulphoxide/oxalyl chloride/triethylamine=1/10/5/14.
13-halo-3,15-dioxo-gibberellic acid ester (1) is at methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, amylalcohol, primary isoamyl alcohol, hexanol, hexalin, benzylalcohol, p-methoxybenzyl alcohol, to hydroxy-benzyl alcohol, 3,4,5-trimethoxy benzylalcohol or 3, in 4-dimethoxy-benzyl alcohol etc. and its corresponding pure reagent of alcoxyl, at dehalogenate inorganic salt reagent such as salt of wormwood, yellow soda ash, sodium bicarbonate, silver carbonate, Quilonum Retard, cesium carbonate, Silver Trifluoroacetate, three fluosulfonic acid silver, Silver monoacetate, under the existence of Silver Nitrate etc., reaction obtains the 13-alcoxyl for-3 in polar solvent, 15-dioxo-gibberellic acid ester (A), the alcohol reagent dosage is 10～100mL solvent/g substrate, and the inorganic salt reagent dosage is: substrate/inorganic salt=1/1～50.Polar solvent is corresponding alcohol, acetonitrile, acetone or N, dinethylformamide.Temperature of reaction adopts room temperature or 60 ° of C to the coordinative solvent reflux temperature.
More preferably preparation has the 13-alcoxyl of general structure (A) for-3, the method of 15-dioxo-gibberellic acid ester, be with 13-halo-3,15-dioxo-gibberellic acid ester (1) is at corresponding alcoholic solvent or at acetonitrile or at N, add and the corresponding pure reagent of alkoxyl group in the dinethylformamide solvent, add salt of wormwood then, yellow soda ash, sodium bicarbonate, silver carbonate, Quilonum Retard, cesium carbonate, Silver Trifluoroacetate, three fluosulfonic acid silver, Silver monoacetate or Silver Nitrate inorganic salt reagent, spend prepared in reaction target compound to the reflux temperature heating in room temperature or Celsius 60, the consumption of each compound is in molar ratio in the reaction: substrate/alcohol/inorganic salt=1/10～500/1-5.
The preparation feedback formula of compound (A) is as follows,
(1) and R (A) in the formula
1=CH
3The alkyl of 2-5 carbon and benzyl,
(A) R
2=CH
3The benzyl of the alkyl of 2-5 carbon and benzyl and replacement,
B) alcohol/inorganic salt, heating.
Have the application of drug regimen aspect preparation treatment cancer drug that the compound of general structure (A) and at least a pharmaceutically acceptable vehicle or carrier make, can be used for treating cancer.
Embodiment
Enumerate typical compound of the present invention below in conjunction with embodiment, but the present invention is not limited in these embodiment or is limited by these embodiment.Compound 1 prepares referring to the method among the CN 200810058297.1.
General structure is compound 13-alcoxyl generation-3 of (A), and the general preparation method of 15-dioxo-gibberellic acid ester is as follows:
Compound 1 (300 milligrams, 0.77 mmole) is dissolved in the corresponding absolute alcohol of 5-15 milliliter, adds 212 milligrams of silver carbonates, back flow reaction 24 hours.After the thin-layer chromatography detection reaction finishes, the evaporated under reduced pressure solvent. add 20-25 milliliter ethyl acetate, wash with water 2 times, each 5 milliliters, 5 milliliters of washings of saturated aqueous common salt 1 time, organic phase anhydrous sodium sulfate drying, remove by filter siccative, decompression steams solvent to doing, and gets yellow powder powder solid, crude product 275mg.Silica gel column chromatography: n-hexane/ethyl acetate=5/1 → 2/1, purifying get white solid compound 75-310 milligram.Yield 20-80%.
13 β-acetoxy-3,15-dioxy Methyl gibberellate
(10ent-13β-acetoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.20(1H，d，J＝9.3Hz)，6.09(1H，s)，6.04(1H，d，J＝9.3Hz)，5.63(1H，s)，3.60(1H，d，J＝10.8Hz)，3.60(3H，s)，3.13(1H，d，J＝10.8Hz)，2.80(1H，d，J＝10.2Hz)，2.60(1H，dd，J＝7.2，12.6Hz)，2.47-2.00(3H，m)，2.09(3H，s)，1.95-1.79(2H，m)，1.30(3H，s).
13C?NMR(75MHz，CDCl
3)δ(ppm)：201.29，191.25，172.82，170.40，169.85，149.56，146.10，129.58，119.18，89.16，81.71，65.45，61.45，60.43，52.34，48.89，48.19，36.47，33.91，21.86，17.84，11.91.
13 β-methanoyl-3,15-dioxy Methyl gibberellate
(ent-13β-formyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：8.08(1H，s)，7.20(1H，d，J＝9.3Hz)，6.16(1H，s)，6.08(1H，d，J＝9.3Hz)，5.69(1H，s)，3.65(1H，d，J＝10.5Hz)，3.64(3H，s)，3.17(1H，d，J＝11.4Hz)，2.84(1H，d，J＝10.5Hz)，2.72-2.60(1H，m)，2.50-2.38(1H，m)，2.41(1H，d，J＝11.4Hz)，2.25(1H，dd，J＝5.0，12.6Hz)，2.04-1.86(2H，m)，1.34(3H，s).
13C?NMR(75MHz，CDCl
3)δ(ppm)：200.87，191.16，172.76，170.32，159.55，149.08，145.92，129.78，119.65，89.13，82.53，65.56，61.55，60.62，52.46，49.02，48.27，36.75，34.21，17.85，11.98.
13 'beta '-methoxies-3,15-dioxy Methyl gibberellate
(ent-13β-methoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.19(1H，d，J＝9.3Hz)，6.17(1H，s)，6.07(1H，d，J＝9.3Hz)，5.55(1H，s)，3.66(1H，d，J＝10.5Hz)，3.64(3H，s)，3.29(3H，s)，2.83(1H，d，J＝10.5Hz)，2.42-2.10(5H，m)，1.92-1.62(2H，m)，1.34(3H，s).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.54，191.26，173.01，170.59，149.48，146.08，129.73，119.30，89.37，80.89，65.62，61.63，60.65，52.44，50.84，49.29，48.56，34.67，33.96，17.77，11.99.EIMS?m/z(％)：387(M
++1，6％)，386(M
+，18％)，358(52)，355(12)，342(8)，331(7)，313(13)，310(5)，299(8)，282(30)，281(19)，255(37)，237(100)，223(40)，217(60)，205(18)，196(22)，185(9)，175(11)，165(20)，153(14)，141(19)，128(39)，115(50)，109(15).
13 β-oxyethyl group-3,15-dioxy Methyl gibberellate
(ent-13β-ethoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioicacid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.20(1H，d，J＝9.3Hz)，6.13(1H，s)，6.06(1H，d，J＝9.3Hz)，5.54(1H，s)，3.65(1H，d，J＝10.5Hz)，3.63(3H，s)，3.53-3.34(2H，m)，2.81(1H，d，J＝10.5Hz)，2.42-2.20(5H，m)，1.90-1.69(2H，m)，1.32(3H，s)，1.20(3H，t，J＝7.2Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.69，191.29，173.00，170.60，149.98，146.12，129.66，118.97，89.37，80.43，65.57，61.57，60.62，58.62，52.39，49.24，48.55，35.31，34.60，17.69，15.85，11.95.EIMS?m/z(％)：401(M
++1，2％)，400(M
+，11％)，372(35)，356(9)，345(68)，327(13)，313(8)，296(16)，269(27)，267(29)，251(100)，231(36)，223(32)，208(27)，196(32)，185(18)，178(15)，157(12)，149(15)，141(17)，128(32)，115(50)，109(17).
13 β-isopropoxy-3,15-dioxy Methyl gibberellate
(ent-13β-isoproxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.19(1H，d，J＝9.3Hz)，6.12(1H，s)，6.07(1H，d，J＝9.3Hz)，5.61(1H，s)，3.82-3.70(1H，m)，3.65(3H，s)，3.63(1H，d，J＝10.2Hz)，2.82(1H，d，J＝10.2Hz)，2.44(1H，d，J＝10.8Hz)，2.41-2.15(4H，m)，1.94-1.70(2H，m)，1.34(3H，s)，1.20(3H，d，J＝5.7Hz)，1.18(3H，d，J＝5.7Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.84，191.24，172.98，170.61，151.15，146.04，129.66，118.90，89.39，80.50，66.07，65.58，61.58，60.57，52.37，49.33，48.55，36.38，36.12，24.99，24.64，17.72，11.92.EIMS?m/z(％)：415(M
++1，9％)，414(M
+，35％)，386(35)，372(25)，370(16)，358(9)，344(64)，340(21)，327(25)，325(33)，312(38)，310(35)，299(34)，296(17)，269(33)，265(17)，251(28)，239(100)，223(70)，213(51)，211(42)，196(47)，189(92)，185(81)，171(69)，165(56)，157(42)，153(26)，141(68)，128(26)，115(17).
13 β-propoxy--3,15-dioxy Methyl gibberellate
(ent-13β-propoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioicacid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.19(1H，d，J＝9.3Hz)，6.11(1H，s)，6.04(1H，d，J＝9.3Hz)，5.53(1H，s)，3.62(3H，s)，3.62(1H，d，J＝10.5Hz)，3.52-3.22(2H，m)，2.80(1H，d，J＝10.5Hz)，2.40-2.10(5H，m)，1.92-1.67(2H，m)，1.65-1.52(2H，m)，1.31(3H，s)，0.93(3H，t，J＝7.2Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.76，191.33，173.02，170.64，150.05，146.19，129.61，119.00，89.40，80.24，65.55，64.74，61.54，60.60，52.39，49.22，48.51，35.15，34.61，23.54，17.69，11.95，10.79.EIMSm/z(％)：415(M
++1，7％)，414(M
+，16％)，386(29)，370(13)，355(8)，341(23)，327(14)，325(25)，311(51)，310(57)，299(22)，283(38)，269(24)，265(100)，251(31)，241(45)，239(49)，223(55)，213(46)，211(38)，196(50)，185(36)，171(22)，165(15)，157(10)，141(15)，128(32)，115(41).
13 Beta-Butoxies-3,15-dioxy Methyl gibberellate
(ent-13β-butoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioicacid?7-methyl?ester?19，10-lactone)
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.19(1H，d，J＝9.3Hz)，6.13(1H，s)，6.06(1H，d，J＝9.3Hz)，5.54(1H，s)，3.64(3H，s)，3.63(1H，d，J＝10.2Hz)，3.48-3.30(2H，m)，2.81(1H，d，J＝10.2Hz)，2.41-2.18(5H，m)，1.92-1.69(2H，m)，1.62-1.52(2H，m)，1.48-1.34(2H，m)，1.24(3H，s)，0.93(3H，t，J＝7.2Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.75，191.28，172.99，170.62，150.18，146.11，129.68，118.95，89.39，80.28，65.60，62.94，61.61，60.68，52.39，49.32，48.61，35.18，34.72，32.46，19.52，17.73，14.07，11.95.EIMS?m/z(％)：430(M
++2，6％)，428(M
+，18％)，402(5)，400(19)，384(20)，358(28)，355(29)，340(10)，325(59)，324(63)，311(41)，299(34)，285(31)，279(100)，267(49)，251(65)，239(69)，225(33)，223(92)，222(51)，213(45)，196(85)，185(43)，178(27)，171(27)，165(17)，158(15)，141(14)，128(30)，115(42)，97(17).
13 β-isobutoxy-3,15-dioxy Methyl gibberellate
(ent-13β-isobutoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.19(1H，d，J＝9.3Hz)，6.12(1H，s)，6.06(1H，d，J＝9.3Hz)，5.54(1H，s)，3.64(3H，s)，3.63(1H，d，J＝10.5Hz)，3.22-3.08(2H，m)，2.81(1H，d，J＝10.5Hz)，2.42-2.18(5H，m)，1.92-1.65(3H，m)，1.33(3H，s)，0.94(3H，d，J＝6.7Hz)，0.93(3H，d，J＝6.7Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.85，191.33，173.02，170.67，150.22，146.16，129.67，119.03，89.42，80.12，69.71，65.60，61.59，60.67，52.43，49.32，48.59，35.01，34.75，29.07，19.59，17.74，11.97.
13 β-pentyloxy-3,15-dioxy Methyl gibberellate
(ent-13β-pentyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.18(1H，d，J＝9.3Hz)，6.07(1H，s)，6.01(1H，d，J＝9.3Hz)，5.49(1H，s)，3.58(3H，s)，3.56(1H，d，J＝10.5Hz)，3.42-3.23(2H，m)，2.77(1H，d，J＝10.5Hz)，2.38-2.11(5H，m)，1.92-1.62(2H，m)，1.61-1.46(2H，m)，1.35-1.22(4H，m)，1.27(3H，s)，0.84(3H，t，J＝6.7Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.63，191.23，172.91，170.54，149.98，146.18，129.44，118.83，89.32，80.15，65.42，63.08，61.42，60.48，52.24，49.08，48.37，35.02，34.48，29.90，28.36，22.54，17.58，14.04，11.82.
13 β-isopentyloxy-3,15-dioxy Methyl gibberellate
(ent-13β-isopentyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.15(1H，d，J＝9.3Hz)，6.07(1H，s)，6.01(1H，d，J＝9.3Hz)，5.48(1H，s)，3.58(3H，s)，3.57(1H，d，J＝10.5Hz)，3.45-3.23(2H，m)，2.76(1H，d，J＝10.5Hz)，2.38-2.10(5H，m)，1.92-1.62(3H，m)，1.50-1.38(2H，m)，1.27(3H，s)，0.85(3H，d，J＝6.7Hz)，0.84(3H，d，J＝6.7Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.78，191.33，173.04，170.66，150.21，146.16，129.68，119.01，89.42，80.29，65.60，61.60，61.53，60.68，52.43，49.31，48.57，39.22，35.05，34.72，25.19，22.89，22.77，17.75，11.98.
1,13 β-dimethoxy-3,15-dioxy Methyl gibberellate
(ent-1，13β-dimethoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-16-ene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：6.16(1H，s)，5.52(1H，s)，3.79(1H，d，J＝5.1Hz)，3.65(3H，s)，3.61(1H，d，J＝10.5Hz)，3.35(3H，s)，3.28(3H，s)，2.98-2.51(4H，m)，2.40-2.12(4H，m)，1.80-1.56(2H，m)，1.22(3H，s).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.22，198.35，174.04，170.78，149.47，118.86，93.38，80.94，74.99，64.17，61.04，57.82，52.40，52.23，50.80，49.03，44.45，39.27，34.89，34.35，17.69，10.58.EIMS?m/z(％)：419(M
++1，5％)，418(M
+，10％)，390(76)，387(19)，359(39)，358(30)，345(11)，342(22)，331(32)，327(11)，315(20，313(27)，303(19)，283(49)，282(45)，255(86)，251(47)，237(56)，223(65)，217(45)，211(30)，196(51)，195(49)，173(24)，163(26)，149(31)，141(45)，128(57)，115(100)，105(31).
13 β-methanoyl-3,15-dioxy gibberic acid benzyl ester
(ent-13β-formyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.97(1H，s)，7.30-7.12(5H，m)，7.13(1H，d，J＝9.3Hz)，6.01(1H，s)，6.00(1H，d，J＝9.3Hz)，5.57(1H，s)，4.99(2H，s)，3.60(1H，d，J＝10.5Hz)，3.06(1H，d，J＝11.4Hz)，2.80(1H，d，J＝10.5Hz)，2.62-2.50(1H，m)，2.42-2.30(1H，m)，2.28(1H，d，J＝11.4Hz)，2.18(1H，dd，J＝5.1，12.6Hz)，1.94-1.78(2H，m)，1.26(3H，s).
13C?NMR(75MHz，CDCl
3)δ(ppm)：200.76，191.03，172.63，169.60，159.38，148.93，145.78，134.86，129.64，128.89，128.64，128.54，128.48，119.29，89.00，82.33，67.45，65.40，61.38，60.48，49.00，48.21，36.56，33.99，17.69，11.90.
13 'beta '-methoxies-3,15-dioxy gibberic acid benzyl ester
(ent-13β-methoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.32-7.21(5H，m)，7.19(1H，d，J＝9.3Hz)，6.14(1H，s)，6.07(1H，d，J＝9.3Hz)，5.49(1H，s)，5.08(1H，d，J＝12.0Hz)，5.00(1H，d，J＝12.0Hz)，3.66(1H，d，J＝10.5Hz)，3.09(3H，s)，2.87(1H，d，J＝10.5Hz)，2.37-2.20(4H，m)，1.92-1.68(2H，m)，1.35(3H，s).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.60，191.25，172.98，169.94，148.87，146.09，135.05，129.72，128.88，128.66，128.63，119.32，89.35，81.03，67.59，65.59，61.56，60.63，50.59，49.30，48.63，35.60，33.38，17.67，12.07.EIMS?m/z(％)：462(M
+，0.5％)，418(1％)，389(2)，371(15)，356(6)，343(19)，327(4)，312(4)，280(6)，269(13)，237(5)，221(15)，217(7)，195(5)，165(11)，149(10)，128(7)，115(12)，91(100).HRMSm/zFound：485.1561，Calcd.for?C
27H
26O
7Na(M+Na)
+：485.1576.
13 β-oxyethyl group-3,15-dioxy gibberic acid benzyl ester
(ent-13β-ethoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioicacid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.37-7.21(5H，m)，7.19(1H，d，J＝9.3Hz)，6.12(1H，s)，6.07(1H，d，J＝9.3Hz)，5.49(1H，s)，5.08(1H，d，J＝12.0Hz)，5.00(1H，d，J＝12.0Hz)，3.65(1H，d，J＝10.5Hz)，3.32-3.08(2H，m)，2.85(1H，d，J＝10.5Hz)，2.35-2.17(5H，m)，1.92-1.71(2H，m)，1.35(3H，s)，1.15(3H，t，J＝6.9Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.70，191.25，172.96，169.93，149.56，146.13，135.11，129.66，128.86，128.61，118.96，89.36，80.65，67.54，65.58，61.54，60.70，58.46，49.30，48.67，36.26，34.10，17.62，15.82，14.31，12.04.EIMS?m/z(％)：476(M
+，1％)，448(0.2)，432(0.8)，421(2)，385(8)，357(15)，341(6)，324(4)，311(5)，283(9)，267(10)，255(3)，231(5)，221(11)，213(4)，195(5)，179(7)，149(8)，128(6)，115(8)，107(5)，91(100).
13 β-isopropoxy-3,15-dioxy gibberic acid benzyl ester
(ent-13β-isoβroxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.27-7.13(5H，m)，7.12(1H，d，J＝9.3Hz)，6.03(1H，s)，5.99(1H，d，J＝9.3Hz)，5.49(1H，s)，5.00(1H，d，J＝11.7Hz)，4.90(1H，d，J＝11.7Hz)，3.56(1H，d，J＝10.5Hz)，3.33-3.23(1H，m)，2.79(1H，d，J＝10.5Hz)，2.30-2.10(5H，m)，1.81-1.63(2H，m)，1.28(3H，s)，1.01(3H，d，J＝6.3Hz)，0.98(3H，d，J＝6.3Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.83，191.27，172.98，169.91，150.69，146.18，135.02，129.63，128.93，128.58，119.14，89.38，80.76，67.56，65.96，65.55，61.45，60.56，49.21，48.49，37.01，35.76，24.85，24.49，17.63，12.06.EIMS?m/z(％)：490(M
+，4％)，462(1)，399(1)，384(2)，375(8)，357(17)，329(24)，313(22)，311(20)，295(7)，285(8)，267(15)，239(10)，221(9)，213(9)，211(7)，185(10)，171(13)，165(6)，149(12)，128(3)，91(100).
13 β-propoxy--3,15-dioxy gibberic acid benzyl ester
(ent-13β-propoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioicacid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.33-7.20(5H，m)，7.20(1H，d，J＝9.3Hz)，6.12(1H，s)，6.07(1H，d，J＝9.3Hz)，5.49(1H，s)，5.08(1H，d，J＝11.7Hz)，4.99(1H，d，J＝11.7Hz)，3.65(1H，d，J＝10.5Hz)，3.19-3.00(2H，m)，2.86(1H，d，J＝10.5Hz)，2.38-2.18(5H，m)，1.92-1.73(2H，m)，1.61-1.47(2H，m)，1.35(3H，s)，0.89(3H，d，J＝7.5Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.78，191.26，172.96，169.95，149.56，146.14，135.05，129.65，128.84，128.62，119.08，89.36，80.47，67.55，65.56，64.63，61.53，60.67，49.27，48.64，36.15，34.08，23.51，17.61，12.05，10.72.EIMS?m/z(％)：490(M
+，1％)，463(0.8)，446(1)，435(0.9)，399(2)，373(3)，371(4)，357(8)，339(4)，329(5)，313(3)，311(11)，297(9)，285(4)，267(13)，239(4)，221(10)，213(5)，193(5)，149(3)，128(3)，115(4)，107(5)，91(100).
13 Beta-Butoxies-3,15-dioxy gibberic acid benzyl ester
(ent-13β-butoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioicacid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.37-7.18(5H，m)，7.18(1H，d，J＝9.3Hz)，6.11(1H，s)，6.07(1H，d，J＝9.3Hz)，5.48(1H，s)，5.07(1H，d，J＝11.8Hz)，4.98(1H，d，J＝11.8Hz)，3.65(1H，d，J＝10.5Hz)，3.22-3.02(2H，m)，2.86(1H，d，J＝10.5Hz)，2.33-2.10(6H，m)，1.93-1.70(3H，m)，1.61-1.45(2H，m)，1.35(3H，s)，0.90(3H，d，J＝7.3Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.78，191.25，172.95，169.95，149.57，146.14，135.02，129.63，128.81，128.59，119.04，89.35，80.45，67.53，65.55，62.71，61.49，60.65，49.26，48.61，36.09，34.07，32.38，19.41，17.60，14.04，12.02.EIMS?m/z(％)：504(M
+，0.9％)，460(1)，449(2)，431(1.5)，385(4)，360(7)，357(10)，339(4)，329(6)，311(7)，280(3)，267(7)，255(6)，239(5)，221(5)，195(5)，171(4)，165(3)，128(3)，107(5)，91(100).
13 β-isobutoxy-3,15-dioxy gibberic acid benzyl ester
(ent-13β-isobutoxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.27-7.10(5H，m)，7.11(1H，d，J＝9.3Hz)，6.03(1H，s)，5.99(1H，d，J＝9.3Hz)，5.40(1H，s)，5.00(1H，d，J＝11.8Hz)，4.90(1H，d，J＝11.8Hz)，3.57(1H，d，J＝10.5Hz)，2.94-2.72(2H，m)，2.78(1H，d，J＝10.5Hz)，2.30-2.05(5H，m)，1.83-1.59(3H，m)，1.27(3H，s)，0.81(3H，d，J＝6.5Hz)，0.80(3H，d，J＝6.5Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.82，191.25，172.93，169.95，149.65，146.16，135.01，129.60，128.77，128.61，119.10，89.36，80.31，69.51，67.52，65.54，61.49，60.65，49.26，48.62，35.99，34.12，28.95，19.55，19.49，17.59.12.01.
13 β-pentyloxy-3,15-dioxy gibberic acid benzyl ester
(ent-13β-pentyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.27-7.08(5H，m)，7.11(1H，d，J＝9.3Hz)，6.03(1H，s)，5.98(1H，d，J＝9.3Hz)，5.40(1H，s)，4.99(1H，d，J＝11.7Hz)，4.90(1H，d，J＝11.7Hz)，3.57(1H，d，J＝10.5Hz)，3.14-2.96(2H，m)，2.79(1H，d，J＝10.5Hz)，2.30-2.05(6H，m)，1.83-1.61(2H，m)，1.51-1.38(2H，m)，1.30-1.14(3H，m)，1.26(3H，s)，0.83(3H，d，J＝6.3Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.72，191.22，172.91，169.91，149.56，146.15，135.01，129.56，128.77，128.56，128.50，118.96，89.32，80.44，67.47，65.50，62.98，61.46，60.61，49.22，48.58，36.09，34.03，29.93，28.37，22.57，17.56，14.09，11.98.
13 β-isopentyloxy-3,15-dioxy gibberic acid benzyl ester
(ent-13β-isopentyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-benzyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.25-7.05(5H，m)，7.12(1H，d，J＝9.3Hz)，6.03(1H，s)，5.98(1H，d，J＝9.3Hz)，5.40(1H，s)，4.99(1H，d，J＝11.8Hz)，4.90(1H，d，J＝11.8Hz)，3.56(1H，d，J＝10.5Hz)，3.20-2.96(2H，m)，2.79(1H，d，J＝10.5Hz)，2.30-2.05(5H，m)，1.83-1.51(3H，m)，1.41-1.28(2H，m)，1.26(3H，s)，0.81(3H，d，J＝6.5Hz)，0.79(3H，d，J＝6.5Hz).
13C?NMR(75MHz，CDCl
3)δ(ppm)：202.72，191.22，172.91，169.92，149.61，146.15，134.97，129.55，128.76，128.55，128.52，118.88，89.33，80.40，67.46，65.49，61.45，61.24，60.59，49.22，48.55，39.16，35.96，34.06，25.03，22.77，22.71，17.56，11.98.
13 β-benzyloxy-3,15-dioxy gibberic acid benzyl ester
(ent-13β-benzyloxy-3，15-dioxo-10β-hydroxy-20-norgibberella-1，16-diene-7，19-dioic?acid?7-methyl?ester?19，10-lactone)：
1H-NMR(300MHz，CDCl
3)，δ(ppm)：7.41-7.25(5H，m)，7.21(1H，d，J＝9.3Hz)，6.21(1H，s)，6.08(1H，d，J＝9.3Hz)，5.65(1H，s)，4.55(1H，d，J＝11.7Hz)，4.47(1H，d，J＝11.7Hz)，3.65(3H，s)，3.64(1H，d，J＝10.5Hz)，2.84(1H，d，J＝10.5Hz)，2.56-2.36(3H，m)，2.36-2.18(2H，m)，1.98-1.70(2H，m)，1.35(3H，s).
13CNMR(75MHz，CDCl
3)δ(ppm)：202.46，191.25，172.96，170.58，149.65，146.08，138.31，129.66，128.62，127.79，127.26，119.42，89.35，81.09，65.56，65.42，61.56，60.73，52.44，49.21，48.54，35.46，34.82，17.72，11.96.
General formula is the antitumour activity experiment of the compound of A
According to the half-inhibition concentration (IC of MTT method to K562 six kinds of tumor cell lines such as (human leukemia cell lines)
50) measurement result shows: 13-alcoxyl generation-3, the IC of 15-dioxo-gibberellic acid ester compd A
50=0.2～47.3 μ g/mL all have the stronger restraining effect to tumour cell.
Claims (7)
1, a kind of compound with following general structural formula (A), name is called: 13-alcoxyl generation-3, the 15-dioxo-gibberellic acid ester,
2, preparation method with compound of general structure (A) as claimed in claim 1, it is characterized in that with 13-halo-3,15-dioxo-gibberellic acid ester (1) is a starting raw material, at first with the corresponding pure reagent of alkoxyl group in add dehalogenate inorganic salt reagent, room temperature or Celsius 60 is spent to the reflux temperature reacting by heating in polar solvent then, 13-halo-3,13 of 15-dioxo-gibberellic acid ester (1) the alkoxyl group substitution reaction take place generate the compound with general structure (A): the 13-alcoxyl is for-3, the 15-dioxo-gibberellic acid ester, described raw material 13-halo-3, the structural formula of 15-dioxo-gibberellic acid ester (1) is as follows
R in the formula
1=CH
3, 2 carbon to 5 carbon alkyl and benzyl (PhCH
2), X=Cl, Br.
3, preparation method according to claim 2, it is characterized in that described and the corresponding pure reagent of alkoxyl group are methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, amylalcohol, primary isoamyl alcohol, hexanol, hexalin, benzylalcohol, p-methoxybenzyl alcohol or to hydroxy-benzyl alcohol, 3,4,5-trimethoxy benzylalcohol, 3,4-dimethoxy-benzyl alcohol, consumption are 10～100mL solvent/g substrate.
4, preparation method according to claim 2, it is characterized in that described inorganic salt reagent is salt of wormwood, yellow soda ash, sodium bicarbonate, silver carbonate, Quilonum Retard, cesium carbonate, Silver Trifluoroacetate, three fluosulfonic acid silver, Silver monoacetate or Silver Nitrate, consumption is in molar ratio: substrate/inorganic salt=1/1～50.
5, preparation method according to claim 2 is characterized in that described polar solvent is corresponding alcohol, acetonitrile, acetone or N, dinethylformamide.
6, preparation method according to claim 2, it is characterized in that preparation has the 13-alcoxyl of general structure (A) for-3, during the 15-dioxo-gibberellic acid ester, with 13-halo-3,15-dioxo-gibberellic acid ester (1) is at corresponding alcoholic solvent or at acetonitrile or at N, add and the corresponding pure reagent of alkoxyl group in the dinethylformamide solvent, add salt of wormwood then, yellow soda ash, sodium bicarbonate, silver carbonate, Quilonum Retard, cesium carbonate, Silver Trifluoroacetate, three fluosulfonic acid silver, Silver monoacetate, Silver Nitrate inorganic salt reagent, spend prepared in reaction target compound to the reflux temperature heating in room temperature or Celsius 60, the consumption of each compound is in molar ratio in the reaction: substrate/alcohol/inorganic salt=1/10～500/1-5.
7, the described application of compound aspect preparation treatment cancer drug of claim 1 with general structure (A).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276370A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | 17- alkylthio group gibberellic acid ester type compounds and preparation method thereof and anticancer usage |
| CN108276369A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | Mostly thio gibberellic acid ester type compound and preparation method thereof and anticancer usage |
-
2009
- 2009-03-11 CN CNA2009100941803A patent/CN101497590A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276370A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | 17- alkylthio group gibberellic acid ester type compounds and preparation method thereof and anticancer usage |
| CN108276369A (en) * | 2018-02-09 | 2018-07-13 | 云南大学 | Mostly thio gibberellic acid ester type compound and preparation method thereof and anticancer usage |
| CN108276370B (en) * | 2018-02-09 | 2022-02-15 | 云南大学 | 17-alkylthio gibberellin ester compound, preparation method and anti-tumor application thereof |
| CN108276369B (en) * | 2018-02-09 | 2022-04-01 | 云南大学 | Polythiagibberellic acid ester compound, preparation method and anti-tumor application thereof |
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