CN103524556B - SF-277 aminophosphonate ester derivatives and synthetic method thereof and application - Google Patents
SF-277 aminophosphonate ester derivatives and synthetic method thereof and application Download PDFInfo
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Abstract
The invention discloses a series of SF-277 aminophosphonate ester derivatives and their synthetic method and application.The synthetic method of described rhubarb yellow aminophosphonate ester derivatives is: with diacetyl rhein and α-aminophosphonicacid ester for raw material, be dissolved in polar solvent, react under catalyzer HOBT and condensing agent EDAC existent condition; In reaction solution, adding trichloromethane, washing, silicagel column on organic layer, with being the mixed solvent wash-out that the ethyl acetate of 1:6 ~ 100 and sherwood oil form by volume ratio, namely obtaining corresponding derivative.The general structure of described SF-277 aminophosphonate ester derivatives is as shown in the formula shown in (I):
Description
Technical field
The present invention relates to Rhein derivatives, be specifically related to SF-277 aminophosphonate ester derivatives and synthetic method thereof and application.
Background technology
Diacetyl rhein (Diacerhein; chemical name is 4; 5-diacetyl-9; 10-dihydro-9,10-dioxy-2-anthracene carboxylic acid), have another name called diacerein; it is the derivative of rhubarb yellow; with the addition of two ethanoyl in rhubarb yellow anthraquinone ring 4,5 position, thus avoid the complication that rhubarb yellow easily suffers from diarrhoea when oral administration.Be mainly used to treatment osteoarthritis and drawing property sacroiliitis late clinically.Recently study discovery, it has good curative effect to rheumatic arthritis, osteoporosis, adult acute's respiratory syndrome and pulmonary emphysema.
α-aminophosphonicacid ester is the midbody compound with biological activity and pharmaceutical activity, has been widely used in the aspects such as microbiotic, sterilant, enzyme inhibitors and weedicide at present.But have not yet to see the derivative of introducing this functional group of α-aminophosphonicacid ester in rhubarb yellow and this analog derivative open report at anti-tumor aspect.
Summary of the invention
The technical problem to be solved in the present invention is to provide the SF-277 aminophosphonate ester derivatives of a class formation novelty, and their its synthetic method and application.
SF-277 aminophosphonate ester derivatives of the present invention, its general structure is as shown in the formula shown in (I):
Wherein, R be to bromobenzene, adjacent bromobenzene, a bromobenzene, to fluorobenzene, adjacent fluorobenzene, to chlorobenzene, a chlorobenzene, adjacent chlorobenzene, meta-methoxy benzene, O-methoxy benzene, benzene, naphthalene, to anisole, a methylbenzene, to methylbenzene, a fluorobenzene or anthracene.
Corresponding to the selection of above-mentioned R, general formula (I) compound is:
(a) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-bromophenyl) methyl } diethyl phosphonate;
(b) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (2-bromophenyl) methyl } diethyl phosphonate;
(c) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-bromophenyl) methyl } diethyl phosphonate;
(d) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-fluorophenyl) methyl } diethyl phosphonate;
(e) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (2-fluorophenyl) methyl } diethyl phosphonate;
(f) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-chloro-phenyl-) methyl } diethyl phosphonate;
(g) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-chloro-phenyl-) methyl } diethyl phosphonate;
(h) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (2-chloro-phenyl-) methyl } diethyl phosphonate;
(i) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-p-methoxy-phenyl) methyl } diethyl phosphonate;
(j) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (2-p-methoxy-phenyl) methyl } diethyl phosphonate;
(k) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (phenyl) methyl } diethyl phosphonate;
(l) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (naphthyl) methyl } diethyl phosphonate;
(m) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-p-methoxy-phenyl) methyl } diethyl phosphonate;
(n) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-aminomethyl phenyl) methyl } diethyl phosphonate;
(o) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-tolyl) methyl } diethyl phosphonate;
(p) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-fluorophenyl) methyl } diethyl phosphonate;
(q) O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (anthryl) methyl } diethyl phosphonate.
The synthetic method of above-mentioned SF-277 aminophosphonate ester derivatives is: according to general formula (I), with diacetyl rhein and α-aminophosphonicacid ester for raw material, be dissolved in polar solvent, under catalyzer I-hydroxybenzotriazole and condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride existent condition, reaction is to complete; Trichloromethane is added, washing, collected organic layer in reaction solution, upper silica gel column chromatography, with being the mixed solvent wash-out that the ethyl acetate of 1:6 ~ 100 and sherwood oil form by volume ratio, elutriant solvent evaporated, namely obtains corresponding SF-277 aminophosphonate ester derivatives.
In above-mentioned synthetic method, corresponding to SF-277 aminophosphonate ester derivatives, being chosen as of described α-aminophosphonicacid ester:
α-O, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-bromophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-bromophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-fluorophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-fluorophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-chloro-phenyl-) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-chloro-phenyl-) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-chloro-phenyl-) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (naphthyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-aminomethyl phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-tolyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-fluorophenyl) methyl-phosphorous acid diethyl ester; Or
α-O, O' diethylamino (anthryl) methyl-phosphorous acid diethyl ester.
The synthesis of above-mentioned α-aminophosphonicacid ester can be carried out with reference to existing document (B.Kaboudin, K.Moradi, TetrahydronLett.46 (2005) 2989-2991).Concrete synthetic method can be: in flask, add aldehyde (selecting different aldehyde according to different α-aminophosphonicacid esters), ammonium acetate and diethyl phosphite (wherein aldehyde, the mol ratio of ammonium acetate and diethyl phosphite is 2 ~ 3:1 ~ 1.5:1 ~ 1.5, , 10 ~ 12h is stirred under 80 ~ 90 DEG C of conditions, ether (add-on of ether is 1 ~ 1.5 times of the amount of substance of aldehyde) is added again in this flask, adding concentrated hydrochloric acid under ice bath makes reaction system be acid (pH=5 ~ 6) and stir 2 ~ 3h, system water extracts, collect water layer and remove organic impurity by extracted with diethyl ether again, regather water layer, and add sodium hydroxide solution and regulate its pH to be 8 ~ 10 in the water layer collected, extract by ethyl acetate (or ether), collected organic layer, organic layer is through anhydrous sodium sulfate drying, obtain corresponding α-aminophosphonicacid ester, all α-aminophosphonicacid esters are pale yellow oily liquid body.In this synthetic method, being chosen as of aldehyde: p-bromobenzaldehyde, o-bromobenzaldehye, 3-bromobenzaldehyde, p-Fluorobenzenecarboxaldehyde, o fluorobenzaldehyde, 4-chloro-benzaldehyde, m chlorobenzaldehyde, o-chlorobenzaldehyde, NSC 43794, o-methoxybenzaldehyde, phenyl aldehyde, naphthaldehyde, aubepine, a tolyl aldehyde, p-tolyl aldehyde, a fluorobenzaldehyde or anthraldehyde.
The raw material diacetyl rhein used in above-mentioned synthetic method can directly be bought from the market, also can according to existing ordinary method or with reference to the method (MAYan-ru reported in existing document, ZHAOXiao-yu, XUZhen.ChineseJoumalofSyntheticChemistry, 2 (2007): 244-246.) synthesize; Concrete synthetic method can be: the pyridine solution adding rhubarb yellow in round-bottomed flask, diacetyl oxide (mol ratio of rhubarb yellow and diacetyl oxide is 1 ~ 2:1.5 ~ 3) is added under normal temperature, stir 3 ~ 4h, add trichloromethane, washing, collected organic layer anhydrous sodium sulfate drying, namely obtains target product diacetyl rhein through purification by silica gel column chromatography (be the mixed solvent wash-out that the ethyl acetate of 1:4 ~ 10 and sherwood oil form by volume ratio).
In above-mentioned synthetic method, described polar solvent is a kind of or two or more arbitrarily combination be selected from dimethyl sulfoxide (DMSO), DMF, ethyl acetate, methyl alcohol, ethanol, propyl alcohol, butanols, methylene dichloride and trichloromethane.When polar solvent be chosen as above-mentioned two or more combination time, the proportioning between them can be any proportioning.Specifically when dissolving, diacetyl rhein and α-aminophosphonicacid ester can be dissolved with polar solvent respectively, remix together; Also add polar solvent after diacetyl rhein and α-aminophosphonicacid ester can being mixed again to dissolve; After diacetyl rhein polar solvent can also being dissolved, directly add α-aminophosphonicacid ester solid.The consumption of polar solvent can be determined as required, and generally with can the amount of solubilizing reaction raw material, under normal circumstances, diacetyl rhein or the 1mmol α-aminophosphonicacid ester polar solvent of 5 ~ 20mL of 1mmol dissolve.
In above-mentioned synthetic method, the ratio of the amount of substance of diacetyl rhein and α-aminophosphonicacid ester is the metering ratio of chemical equation, is 1:1.
In above-mentioned synthetic method, the add-on of described catalyzer I-hydroxybenzotriazole (HOBT) is 0.05 ~ 0.5 times of diacetyl rhein amount of substance, be preferably 0.05 ~ 0.2 times of diacetyl rhein amount of substance, be more preferably 0.1 ~ 0.2 times of diacetyl rhein amount of substance.Because the membership that adds of catalyzer produces thermopositive reaction, therefore described catalyzer preferably adds under condition of ice bath.
In above-mentioned synthetic method, the add-on of described condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDAC) is 1 ~ 2 times of diacetyl rhein amount of substance, is preferably 1 ~ 1.5 times of diacetyl rhein amount of substance.
In the synthetic method described in the application, the order of addition(of ingredients) of diacetyl rhein, α-aminophosphonicacid ester, catalyzer and condensing agent is not exquisite especially, but higher yield can be obtained with following order of addition(of ingredients): after first being dissolved by diacetyl rhein, add catalyzer, stir, and then add condensing agent, add α-aminophosphonicacid ester (now α-aminophosphonicacid ester can add in solid form, adds in fluid form after also it can being dissolved with polar solvent) after stirring again to react.
In above-mentioned synthetic method, reaction is preferably carried out under lower than the condition of 80 DEG C, is more preferably and carries out under the condition of 20 ~ 40 DEG C.Whether reaction can adopt thin-layer chromatography tracing detection completely, and under above-mentioned preferred temperature of reaction condition, stirring reaction is to the time completely approximately needing 3 ~ 5h.
In above-mentioned synthetic method, described in the mixed solvent of wash-out, the volume ratio of ethyl acetate and sherwood oil is preferably 1:6 ~ 50, is more preferably 1:6 ~ 20, more preferably 1:6 ~ 10, more more preferably 1:7 ~ 9.
The present invention also comprises above-mentioned SF-277 aminophosphonate ester derivatives and is preparing the application in antitumor drug.
The present invention also comprises the antitumor drug prepared for effective constituent with above-mentioned SF-277 aminophosphonate ester derivatives.
Compared with prior art, the invention provides the SF-277 aminophosphonate ester derivatives of a series of novel structure, and their its synthetic method and application.Applicant finds that the anti-tumor activity that most SF-277 aminophosphonate ester derivatives has all is much higher than rhubarb yellow, has good potential pharmaceutical use, is expected to the preparation for various antitumor drug.
Embodiment
With specific embodiment, the invention will be further described below, but the present invention is not limited to these embodiments.
The synthesis of embodiment 1:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (4-bromophenyl) methyl } diethyl phosphonate (a)
1) synthesis of α-O, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester
P-bromobenzaldehyde is added in round-bottomed flask, ammonium acetate and diethyl phosphite (mol ratio is 2:1:1), stirring reaction 10h under 80 DEG C of conditions, 1.2 times that ether add-on is the amount of substance of p-bromobenzaldehyde are added again) in this round-bottomed flask, adding concentrated hydrochloric acid under ice bath makes reaction system be acid (pH=6) and stir 3h, reaction system water extracts, collect water layer and remove organic impurity by extracted with diethyl ether again, regather water layer, and to collect water layer in add mass concentration be 10% sodium hydroxide solution regulate its pH to be 9, be extracted with ethyl acetate, collected organic layer, organic layer is through anhydrous sodium sulfate drying, obtain α-O, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL dimethyl sulfoxide (DMSO), 0.5mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 10min, then add 1.1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 10min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester is (with 5mL dmso solution wiring solution-forming, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:8 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid a.
Gained orange solids a is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield80%.paintyellowsolid.m.p.218～220℃.
1HNMR(500MHz,CDCl
3)δ8.62(d,J=1.6Hz,1H),8.23(d,J=7.7Hz,1H),7.91(d,J=1.6Hz,2H),7.79(t,J=7.8Hz,1H),7.51(d,J=8.4Hz,2H),7.44(dd,J=7.6,2.9Hz,3H),5.67(dd,J=21.4,9.3Hz,1H),4.19-4.14(m,2H),4.05–3.97(m,1H),3.85–3.77(m,1H),2.45(s,3H),2.45(s,3H),1.32(t,J=7.1Hz,3H),1.15(t,J=7.0Hz,3H).
31PNMR(202MHz,CDCl
3)δ(ppm):21.25.ESI-MSm/z:694.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid a is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (4-bromophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 2:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (2-bromophenyl) methyl } diethyl phosphonate (b)
1) synthesis of α-O, O' diethylamino (2-bromophenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with o-bromobenzaldehye.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mLN, in dinethylformamide, 0.05mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 13min, then add 1.2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 13min; 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (2-bromophenyl) methyl-phosphorous acid diethyl ester, under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:10 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains faint yellow solid b.
Gained faint yellow solid b is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield79%.paintyellowsolid.m.p.220～222℃.
1HNMR(500MHzCDCl
3)δ(ppm):1.09(t,J=7.1Hz,3H,CH
3),1.35(t,J=7.2Hz,3H,CH
3),2.43(s,3H),2.45(s,3H),3.72-4.26(m,4H,OCH
2),6.31(dd,J=9.0,21.4Hz1H,PCH),7.17-8.22(m,9H,Ar-H,1H,NH).
31PNMR(202MHz,CDCl
3)δ(ppm):21.33.ESI-MSm/z:694.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid b is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (2-bromophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 3:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-bromophenyl) methyl } diethyl phosphonate (c)
1) synthesis of α-O, O' diethylamino (3-bromophenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with 3-bromobenzaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL methyl alcohol, 0.5mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 10min, then add 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (3-bromophenyl) methyl-phosphorous acid diethyl ester is (with 20mL dissolve with ethanol wiring solution-forming, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:50 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid c.
Gained faint yellow solid c is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield79%.paintyellowsolid.m.p.218～220℃.1HNMR(500MHz,CDCl3)δ9.11(dd,J=9.3,3.6Hz,1H),8.67(d,J=1.8Hz,1H),8.13(dd,J=7.8,1.3Hz,1H),7.95(d,J=1.8Hz,1H),7.76(d,J=1.8Hz,1H),7.73(t,J=7.9Hz,1H),7.53(d,J=7.5Hz,1H),7.40(d,J=1.3Hz,1H),7.37(d,J=0.9Hz,1H),7.14(t,J=7.9Hz,1H),5.81(dd,J=22.0,9.4Hz,1H),4.22–4.13(m,2H),4.03–3.98(m,1H),3.86-3.81(m,1H),2.42(s,3H),2.40(s,3H),1.27(t,J=7.1Hz,3H),1.13(t,J=7.1Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):21.14.ESI-MSm/z:694.1(M+Na)
+.
Therefore, can determine that gained orange solids c is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-bromophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 4:O, O' diethyl [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene) kharophen) (4-fluorophenyl) methyl } synthesis of diethyl phosphonate (d)
1) synthesis of α-O, O' diethylamino (4-fluorophenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with p-Fluorobenzenecarboxaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in the mixing solutions (volume ratio of methylene dichloride and trichloromethane is 1:1) of 10mL methylene dichloride and trichloromethane, 0.2mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 8min, then add 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 3min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (4-fluorophenyl) methyl-phosphorous acid diethyl ester (dissolves wiring solution-forming with 10mL trichloromethane, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 4.5h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:20 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid d.
Gained faint yellow solid d is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield79%.paintyellowsolid.m.p.222～224℃.1HNMR(500MHz,CDCl3)δ1.11(t,J=7.1Hz,3H),1.29(t,J=7.1Hz,3H),2.42(s,3H),2.43(s,3H),3.82–3.73(m,1H),4.00–3.93(m,1H),4.19–4.10(m,2H),5.76(dd,J=21.3,9.3Hz,1H),7.03(t,J=8.6Hz,2H),7.41(dd,J=8.1,1.0Hz,1H),7.64–7.49(m,2H),7.76(t,J=7.9Hz,1H),7.91(d,J=1.7Hz,1H),8.18(dd,J=7.7,1.0Hz,1H),8.41(d,J=6.1Hz,1H),8.62(d,J=1.7Hz,1H),31PNMR(202MHz,CDCl3)δ(ppm):20.6120.59.ESI-MSm/z:634.1(M+Na)
+.
Therefore, can determine gained faint yellow solid d be O, O' diethyl [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene) kharophen) (4-fluorophenyl) methyl diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 5:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene) kharophen] (2-fluorophenyl) methyl } diethyl phosphonate (e)
1) synthesis of α-O, O' diethylamino (2-fluorophenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with o fluorobenzaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in the mixing solutions of 5mL ethyl acetate, 0.08mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 5min, then add 1.8mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 13min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (2-fluorophenyl) methyl-phosphorous acid diethyl ester is (with 10mL acetic acid ethyl dissolution wiring solution-forming, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:8 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid e.
Gained faint yellow solid e is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield80%.paintyellowsolid.m.p.162～164℃.1HNMR(500MHz,CDCl3)δ8.66(d,J=1.8Hz,1H),8.43(dd,J=9.4,4.3Hz,1H),8.20(dd,J=7.8,1.3Hz,1H),7.94(d,J=1.8Hz,1H),7.77(t,J=7.9Hz,1H),7.57(ddd,J=8.7,5.1,1.9Hz,2H),7.42(dd,J=8.0,1.3Hz,1H),7.05(d,J=8.5Hz,2H),5.75(dd,J=21.4,9.3Hz,1H),4.20–4.11(m,2H),3.98–3.94(m,1H),3.80–3.74(m,1H),2.44(s,3H),2.43(s,3H),1.31(t,J=7.1Hz,3H),1.12(t,J=7.0Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):20.97.ESI-MSm/z:634.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid e is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene) kharophen] (2-fluorophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 6:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (4-chloro-phenyl-) methyl } diethyl phosphonate (f)
1) synthesis of α-O, O' diethylamino (4-chloro-phenyl-) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with 4-chloro-benzaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in the mixing solutions (volume ratio of ethyl acetate and methyl alcohol is 2:1) of 8mL ethyl acetate and methyl alcohol, 0.08mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 5min, then add 1.8mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (4-chloro-phenyl-) methyl-phosphorous acid diethyl ester is (with 4mL methyl alcohol and 1mL dissolve with ethanol wiring solution-forming, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 3.5h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:9 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid f.
Gained faint yellow solid f is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield80%.paintyellowsolid.m.p.219～221℃.1HNMR(500MHzCDCl3)δ(ppm):1.16(t,J=7.0Hz,3H,CH3),1.32(t,J=7.1Hz,3H,CH3),2.43(s,3H),2.45(s,3H),3.82-4.21(m,4H,OCH2),5.76(dd,J=9.3,22.4Hz1H,PCH),7.28-8.40(m,9H,Ar-H,1H,NH),31PNMR(202MHz,CDCl3)δ(ppm):21.34.ESI-MSm/z:640.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid f is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (4-chloro-phenyl-) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 7:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (2-chloro-phenyl-) methyl } diethyl phosphonate (h)
1) synthesis of α-O, O' diethylamino (2-chloro-phenyl-) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with adjacent chlorobenzene phenyl aldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mLN, in dinethylformamide, 0.5mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 6min, then add 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (2-chloro-phenyl-) methyl-phosphorous acid diethyl ester is (with 5mL acetic acid ethyl dissolution wiring solution-forming, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:100 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid h.
Gained faint yellow solid h is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield80%.paintyellowsolid.m.p.227～229℃.1HNMR(500MHz,CDCl3)δ8.64(d,J=1.8Hz,1H),8.23(dd,J=7.8,1.2Hz,1H),7.92(d,J=1.8Hz,2H),7.79(t,J=7.9Hz,1H),7.71(d,J=7.6Hz,1H),7.46–7.39(m,2H),7.32–7.26(m,3H),6.29(dd,J=21.5,8.9Hz,1H),4.27–4.18(m,2H),3.98-3.93(m,1H),3.77–3.70(m,1H),2.45(s,6H),1.36(t,J=7.1Hz,3H),1.10(t,J=7.1Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):21.92.ESI-MSm/z:640.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid h is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (2-chloro-phenyl-) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 8:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (2 – p-methoxy-phenyl) methyl } diethyl phosphonate (j)
1) synthesis of α-O, O' diethylamino (2-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with o-methoxybenzaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL methyl alcohol, 0.1mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 5min, then add 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (2-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester is (with 5mLN, dinethylformamide dissolves wiring solution-forming, add in the mode of solution), under 35 DEG C of conditions, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:80 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid j.
Gained faint yellow solid j is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield82%.paintyellowsolid.m.p.218～220℃.1HNMR(500MHz,CDCl3)δ8.57(d,J=1.8Hz,1H),8.22(dd,J=7.8,1.2Hz,1H),8.03(d,J=9.1Hz,1H),7.92(d,J=1.8Hz,1H),7.77(t,J=7.9Hz,1H),7.49(d,J=7.6Hz,1H),7.42(dd,J=8.0,1.2Hz,1H),7.30(t,J=7.9Hz,1H),7.00–6.94(m,2H),6.12(dd,J=21.0,9.5Hz,1H),4.19–4.13(m,2H),4.01–3.94(m,1H),3.97(s,3H)3.83–3.75(m,1H),2.44(s,6H),1.31(t,J=7.1Hz,3H),1.10(t,J=7.0Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):20.70.ESI-MSm/z:646.2(M+Na)
+.
Therefore, can determine that gained faint yellow solid j is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (2 – p-methoxy-phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 9:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (phenyl) methyl } diethyl phosphonate (k)
1) synthesis of α-O, O' diethylamino (phenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with phenyl aldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL methyl alcohol, 0.2mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 10min, then add 1.2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min; 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (phenyl) methyl-phosphorous acid diethyl ester, under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:60 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains faint yellow solid k.
Gained faint yellow solid k is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield81%.paintyellowsolid.m.p.213～215℃.1HNMR(500MHz,CDCl3)δ8.64(s,1H),8.47(d,J=8.6Hz,1H),8.17(dd,J=7.5,2.7Hz,1H),7.93(s,1H),7.75(td,J=7.9,3.5Hz,1H),7.58(s,2H),7.40(dd,J=7.8,2.8Hz,1H),7.32(d,J=7.7Hz,3H),5.78(dd,J=19.9,7.9Hz,1H),4.21–4.10(m,2H),3.94-3.93(m,1H),3.76–3.67(m,1H),2.43(s,3H),2.42(s,3H),1.29(t,J=8.6Hz,3H),1.08(t,J=8.5Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):21.04..ESI-MSm/z:616.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid k is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 10:O, O' diethyl { [2-4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (naphthyl) methyl } diethyl phosphonate (l)
1) synthesis of α-O, O' diethylamino (naphthyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with naphthaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 15mL butanols, 0.5mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature 5min, then add 1.3mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 6min, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (naphthyl) methyl-phosphorous acid diethyl ester (dissolves wiring solution-forming with 5mL butanols, add in the mode of solution), under 50 DEG C of conditions, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:10 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid l.
Gained faint yellow solid l is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield82%.paintyellowsolid.m.p.218～220℃.1HNMR(500MHz,CDCl3)δ8.68(d,J=1.8Hz,1H),8.25(dd,J=7.8,1.3Hz,1H),8.05(s,2H),7.96(d,J=1.8Hz,1H),7.84(dd,J=15.8,5.9Hz,3H),7.80(d,J=7.8Hz)7.70(d,J=8.4Hz,1H),7.48(ddd,J=20.0,6.9,2.0Hz,3H),5.93(dd,J=21.2,9.2Hz,1H),4.27-4.18(m,2H),4.02-3.97(m,1H),3.77-3.72(m,1H),2.47(s,3H),2.46(s,3H),1.36(t,J=7.1Hz,3H),1.10(t,J=7.1Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):21.28.ESI-MSm/z:666.2(M+Na)
+.
Therefore, can determine that gained faint yellow solid l is O, O' diethyl { [2-4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (naphthyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 11:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-p-methoxy-phenyl) methyl } diethyl phosphonate (m)
1) synthesis of α-O, O' diethylamino (4-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with aubepine.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL dimethyl sulfoxide (DMSO), 0.5mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature is even, then add 1.5mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir; 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (4-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester, under 60 DEG C of conditions, stirring reaction is to complete (about 3h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:6 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtains faint yellow solid m.
Gained faint yellow solid m is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield80%.paintyellowsolid.m.p.219～221℃.1HNMR(500MHzCDCl3)δ(ppm):1.13(t,J=6.6Hz,3H,CH3),1.31(t,J=6.6Hz,3H,CH3),3.76(s,3H,OCH3),2.46(s,3H),2.47(s,3H),3.80-4.18(m,4H,OCH2),5.75(dd,J=7.6,21.7Hz1H,PCH),6.83-8.26(m,9H,Ar-H,1H,NH),.31PNMR(202MHz,CDCl3)δ(ppm):20.92.ESI-MSm/z:646.2(M+Na)
+.
Therefore, can determine that gained faint yellow solid m is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (4-p-methoxy-phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 12:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (4-aminomethyl phenyl) methyl } diethyl phosphonate (o)
1) synthesis of α-O, O' diethylamino (4-tolyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with p-tolyl aldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL trichloromethane, 0.1mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature is even, then add 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (4-tolyl) methyl-phosphorous acid diethyl ester is (with 10mL dimethyl sulfoxide (DMSO) wiring solution-forming, add in the mode of solution), under 20 DEG C of conditions, stirring reaction is to complete (about 4h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:30 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid o.
Gained faint yellow solid o is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield81%.paintyellowsolid.m.p.218～220℃.1HNMR(500MHz,CDCl3)δ8.65(d,J=1.8Hz,1H),8.24(dd,J=7.8,1.2Hz,1H),7.92(d,J=1.8Hz,1H),7.87(dd,J=9.1,4.4Hz,1H),7.79(t,J=7.9Hz,1H),7.43(dd,J=8.0,1.1Hz,3H),7.18(d,J=8.1Hz,2H),5.69(dd,J=20.8,9.3Hz,1H),4.21–4.11(m,2H),3.99–3.93(m,1H),3.75-3.70(m,1H),2.45(s,3H),2.45(s,3H),2.34(s,3H),1.32(t,J=7.1Hz,3H),1.12(t,J=7.1Hz,3H).31PNMR(202MHz,CDCl3)δ(ppm):21.56.ESI-MSm/z:630.2(M+Na)
+.
Therefore, can determine that gained faint yellow solid o is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (4-aminomethyl phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 13:O, O' diethyl [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene is amino) kharophen] (3-fluorophenyl) methyl } diethyl phosphonate (
p) synthesis
1) synthesis of α-O, O' diethylamino (3-fluorophenyl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, with between fluorobenzaldehyde replace p-bromobenzaldehyde.
2) synthesis of target product:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL methyl alcohol, 0.3mmol catalyzer I-hydroxybenzotriazole is dripped under ice bath, stirring at room temperature is even, then add 1.6mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (3-fluorophenyl) methyl-phosphorous acid diethyl ester is (with 5mL dimethyl sulfoxide (DMSO) wiring solution-forming, add in the mode of solution), under 10 DEG C of conditions, stirring reaction is to complete (about 5h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:15 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid p.
Gained faint yellow solid p is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield81%.paintyellowsolid.m.p.219～221℃.1HNMR(500MHzCDCl3)δ(ppm):1.15(t,J=7.0Hz,3H,CH3),1.31(t,J=7.1Hz,3H,CH3),2.43(s,3H),2.44(s,3H),3.85-4.22(m,4H,OCH2),5.81(dd,J=9.4,22.0Hz1H,PCH),6.95-8.60(m,10H,Ar-H,1H,NH).31PNMR(202MHz,CDCl3)δ(ppm):20.24.ESI-MSm/z:634.1(M+Na)
+.
Therefore, can determine that gained orange solids p is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (3-fluorophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
The synthesis of embodiment 14:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (anthryl) methyl } diethyl phosphonate (q)
1) synthesis of α-O, O' diethylamino (anthryl) methyl-phosphorous acid diethyl ester
By step 1 in embodiment 1) described in method and condition synthesize, unlike, replace p-bromobenzaldehyde with anthraldehyde.
2) synthesis of target product:
In round-bottomed flask, be dissolved in by 1mmol diacetyl rhein in 5mL methyl alcohol, under ice bath, drip 0.1mmol catalyzer I-hydroxybenzotriazole, stirring at room temperature is even, then add 1.5mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir, 1mmol α-O is dripped again in this round-bottomed flask, O' diethylamino (anthryl) methyl-phosphorous acid diethyl ester is (with 5mL dimethyl sulfoxide (DMSO) wiring solution-forming, add in the mode of solution), under room temperature condition, stirring reaction is to complete (about 5h), then in reaction solution, trichloromethane is added, washing, collected organic layer, upper silica gel column chromatography after organic over anhydrous dried over sodium sulfate, with ethyl acetate: the mixed solvent wash-out that sherwood oil=1:7 (volume ratio) forms, thin-layer chromatography tracing detection, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid q.
Gained faint yellow solid q is analyzed, its physics and chemistry and spectral characteristic as follows:
Yield80%.paintyellowsolid.m.p.219～221℃.1HNMR(500MHzCDCl3)δ(ppm):0.63(t,J=7.1Hz,3H,CH3),1.42(t,J=7.1Hz,3H,CH3),2.47(s,3H),2.49(s,3H),3.31-4.35(m,4H,OCH2),7.24-7.28(m,2H,Ar-H),7.31(dd,J=8.5,25.7Hz1H,PCH),7.38-8.79(m,12H,Ar-H,1H,NH).31PNMR(202MHz,CDCl3)δ(ppm):22.34.ESI-MSm/z:716.2(M+Na)
+.
Therefore, can determine that gained faint yellow solid q is O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene amino) kharophen] (anthryl) methyl } diethyl phosphonate, its structural formula is shown below:
In order to the purposes of SF-277 aminophosphonate ester derivatives of the present invention in pharmacy is described, applicant has carried out anti-tumor activity experiment to the compound that above-described embodiment 1 ~ 14 obtains.
With the anti-tumor medicine 5 FU 5 fluorouracil of Clinical practice for positive control drug, negative control is made with coordinative solvent, with HCT-116(human colon cancer cell), Spca-2 (lung carcinoma cell), CNE(nasopharyngeal carcinoma cell), Hela (cervical cancer cell), HepG-2 (liver cancer cell), HUVEC(Human umbilical vein endothelial cells) be subject cell strain; With mtt assay, anti tumor activity in vitro test is carried out to compound.
By medicine and co-culture of cells 48h, according to the result of preliminary experiment cell growth rate, inoculate the cell 190 μ L of certain density in 96 well culture plates (about 5 × 10
4~ 1 × 10
5individual/hole).
Cultivate 24h after cell attachment, add the sample 10 μ L of series concentration respectively, 5 multiple holes established by each sample, and wherein ethanol final concentration < 1%. separately establishes negative control hole 4, adds 10 μ L bare substrate.
Cell is in saturated humidity, 5%CO
2, hatch the every hole of 48h. under 37oC condition and add 10 μ LMTT(5mg/ml), continue to cultivate 4h.
Suck supernatant liquor, add DMSO150 μ L/ hole, fully dissolving rear microplate reader at mensuration wavelength is that 570nm and reference 630nm place measure OD value, and calculate each dosing holes cell proliferation inhibition rate, result as described in Table 1.
Table 1 compound is to the IC of different cell strain
50value
As can be seen from the table, the anti tumor activity in vitro of rhubarb yellow (Rhein) itself is not high, and the cytotoxicity of the most of SF-277 aminophosphonate ester derivatives prepared by the present invention is all higher than the activity of rhubarb yellow.For people's colon cell cancer Hct-116 cell, some derivatives show good anti tumor activity in vitro, as compound o has good activity (IC to Hct-116 cell
50value is 9.83 μMs).In addition, as compound o has very high activity (IC to Spca-2 cell
50value is 11.38 μMs), exceed the medicine 5-Fluorouracil of clinical treatment human colon carcinoma.
In order to verify that above-mentioned all compounds are to the cytotoxicity of human normal cell further, we utilize mtt assay to human venous endothelial cell HUVEC(normal cell) carry out screening active ingredients, result shows the IC of all compounds
50value is all than the height (as shown in table 1) of rhubarb yellow, and that is the cytotoxicity of all derivatives to human normal cell line is less than rhubarb yellow.
Claims (10)
1. SF-277 aminophosphonate ester derivatives, its general structure is as shown in the formula shown in (I):
Wherein, R be to bromobenzene, adjacent bromobenzene, a bromobenzene, to fluorobenzene, adjacent fluorobenzene, to chlorobenzene, a chlorobenzene, adjacent chlorobenzene, meta-methoxy benzene, O-methoxy benzene, benzene, naphthalene, to anisole, a methylbenzene, to methylbenzene, a fluorobenzene or anthracene.
2. the synthetic method of SF-277 aminophosphonate ester derivatives described in claim 1, it is characterized in that: according to general formula (I), with diacetyl rhein and α-aminophosphonicacid ester for raw material, be dissolved in polar solvent, under catalyzer I-hydroxybenzotriazole and condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride existent condition, reaction is to complete; Trichloromethane is added, washing, collected organic layer in reaction solution, upper silica gel column chromatography, with being the mixed solvent wash-out that the ethyl acetate of 1:6 ~ 100 and sherwood oil form by volume ratio, elutriant solvent evaporated, namely obtains corresponding SF-277 aminophosphonate ester derivatives.
3. the synthetic method of SF-277 aminophosphonate ester derivatives according to claim 2, is characterized in that: described α-aminophosphonicacid ester is:
α-O, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-bromophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-bromophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-fluorophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-fluorophenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-chloro-phenyl-) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-chloro-phenyl-) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-chloro-phenyl-) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (2-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (naphthyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-aminomethyl phenyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (4-tolyl) methyl-phosphorous acid diethyl ester;
α-O, O' diethylamino (3-fluorophenyl) methyl-phosphorous acid diethyl ester; Or
α-O, O' diethylamino (anthryl) methyl-phosphorous acid diethyl ester.
4. the synthetic method of SF-277 aminophosphonate ester derivatives according to claim 2, it is characterized in that: described polar solvent is a kind of or two or more arbitrarily combination be selected from dimethyl sulfoxide (DMSO), DMF, ethyl acetate, methyl alcohol, ethanol, propyl alcohol, butanols, methylene dichloride and trichloromethane.
5. the synthetic method of SF-277 aminophosphonate ester derivatives according to any one of claim 2 ~ 4, is characterized in that: the add-on of described catalyzer I-hydroxybenzotriazole is 0.05 ~ 0.5 times of diacetyl rhein amount of substance.
6. the synthetic method of SF-277 aminophosphonate ester derivatives according to any one of claim 2 ~ 4, is characterized in that: the add-on of described condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride is 1 ~ 2 times of diacetyl rhein amount of substance.
7. the synthetic method of SF-277 aminophosphonate ester derivatives according to any one of claim 2 ~ 4, is characterized in that: the temperature of described reaction is for lower than 80 DEG C.
8. the synthetic method of SF-277 aminophosphonate ester derivatives according to any one of claim 2 ~ 4, it is characterized in that: described in the mixed solvent of wash-out, the volume ratio of ethyl acetate and sherwood oil is 1:6 ~ 10.
9. SF-277 aminophosphonate ester derivatives according to claim 1 is preparing the application in antitumor drug.
10. with the antitumor drug that SF-277 aminophosphonate ester derivatives according to claim 1 is prepared for effective constituent.
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| CN101003548A (en) * | 2006-12-12 | 2007-07-25 | 中国林业科学研究院林产化学工业研究所 | Rosinyl diterpene modified alpha - phosphoramidate, preparation method, and application for anti tumors |
| CN101255121A (en) * | 2008-04-15 | 2008-09-03 | 中国医学科学院医药生物技术研究所 | Preparation technique of lysine rhein and use thereof in tumour therapy |
| CN101822660A (en) * | 2010-05-13 | 2010-09-08 | 中国人民解放军肾脏病研究所 | Rhein compound or application of salt thereof in preparing drugs preventing and curing hypofunction of islet beta cell |
| CN102225913A (en) * | 2011-04-07 | 2011-10-26 | 栗进才 | Rheinic acid derivatives and treatment application thereof |
| CN102321120A (en) * | 2011-07-18 | 2012-01-18 | 盐城师范学院 | Method for synthesizing alpha-aminophosphonate through water phase cleaning |
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| CN101003548A (en) * | 2006-12-12 | 2007-07-25 | 中国林业科学研究院林产化学工业研究所 | Rosinyl diterpene modified alpha - phosphoramidate, preparation method, and application for anti tumors |
| CN101255121A (en) * | 2008-04-15 | 2008-09-03 | 中国医学科学院医药生物技术研究所 | Preparation technique of lysine rhein and use thereof in tumour therapy |
| CN101822660A (en) * | 2010-05-13 | 2010-09-08 | 中国人民解放军肾脏病研究所 | Rhein compound or application of salt thereof in preparing drugs preventing and curing hypofunction of islet beta cell |
| CN102225913A (en) * | 2011-04-07 | 2011-10-26 | 栗进才 | Rheinic acid derivatives and treatment application thereof |
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