CN103524556A - Diacerhein aminophosphonate derivatives, and synthetic method and applications thereof - Google Patents
Diacerhein aminophosphonate derivatives, and synthetic method and applications thereof Download PDFInfo
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Abstract
The invention discloses a series of diacerhein aminophosphonate derivatives, and a synthetic method and applications thereof. The synthetic method of the diacerhein aminophosphonate derivatives comprises: taking diacerhein and an alpha-aminophosphonate as raw materials, dissolving in a polar solvent, in the presence of a catalyst HOBT and a condensing agent EDAC, reacting completely; and adding trichloromethane into the reaction liquid, washing with water, applying the organic layer to silica gel for column chromatography, eluting with a mixed solvent of ethyl acetate and petroleum ether with a volume ratio of 1:6-100 to obtain the corresponding derivative. The diacerhein aminophosphonate derivatives have the structural general formula (I) as shown in the description, wherein R is p-bromophenyl, o-bromophenyl, m-bromophenyl, p-fluorophenyl, o-fluorophenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, m-methoxyphenyl, o-methoxyphenyl, phenyl, naphthyl, p-methoxyphenyl, m-methylphenyl, p-methylphenyl, m-fluorophenyl or anthryl.
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; in rhubarb yellow anthraquinone ring 4,5 positions, added two ethanoyl, thus the complication of having avoided rhubarb yellow easily to suffer from diarrhoea when oral administration.Be mainly used to clinically treat osteoarthritis and drawing property sacroiliitis late.Recently study discovery, it has good curative effect to rheumatic arthritis, osteoporosis, adult's acute respiratory syndrome and pulmonary emphysema.
α-aminophosphonicacid ester is the midbody compound with biological activity and pharmaceutical activity, has been widely used at present the aspects such as microbiotic, sterilant, enzyme inhibitors and weedicide.But have not yet to see, in rhubarb yellow, introduce the derivative of this functional group of α-aminophosphonicacid ester and this analog derivative at the open report of 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 is 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-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-bromophenyl) methyl } diethyl phosphonate;
(b) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (2-bromophenyl) methyl } diethyl phosphonate;
(c) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (3-bromophenyl) methyl } diethyl phosphonate;
(d) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-fluorophenyl) methyl } diethyl phosphonate;
(e) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (2-fluorophenyl) methyl } diethyl phosphonate;
(f) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-chloro-phenyl-) methyl } diethyl phosphonate;
(g) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (3-chloro-phenyl-) methyl } diethyl phosphonate;
(h) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (2-chloro-phenyl-) methyl } diethyl phosphonate;
(i) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (3-p-methoxy-phenyl) methyl } diethyl phosphonate;
(j) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (2-p-methoxy-phenyl) methyl } diethyl phosphonate;
(k) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (phenyl) methyl } diethyl phosphonate;
(l) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (naphthyl) methyl } diethyl phosphonate;
(m) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-p-methoxy-phenyl) methyl } diethyl phosphonate;
(n) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (3-aminomethyl phenyl) methyl } diethyl phosphonate;
(o) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-tolyl) methyl } diethyl phosphonate;
(p) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (3-fluorophenyl) methyl } diethyl phosphonate;
(q) O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (anthryl) methyl } diethyl phosphonate.
The synthetic method of above-mentioned SF-277 aminophosphonate ester derivatives is: according to general formula (I), take diacetyl rhein and α-aminophosphonicacid ester is raw material, be dissolved in polar solvent, under the condition of catalyzer I-hydroxybenzotriazole and the existence of condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, reaction is to complete; In reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography, the mixed solvent wash-out that the ethyl acetate that to use by volume ratio be 1:6～100 and sherwood oil form, elutriant solvent evaporated, 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 synthetic of above-mentioned α-aminophosphonicacid ester can carry out with reference to existing document (B.Kaboudin, K.Moradi, Tetrahydron Lett.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 (aldehyde wherein, the mol ratio of ammonium acetate and diethyl phosphite is 2～3:1～1.5:1～1.5, , under 80～90 ℃ of conditions, stir 10～12h, again toward adding ether (add-on of ether is 1～1.5 times of amount of substance of aldehyde) in this flask, under ice bath, adding concentrated hydrochloric acid makes reaction system be acid (pH=5～6) and stir 2～3h, the extraction of system water, collect water layer and by extracted with diethyl ether, remove organic impurity again, regather water layer, and be 8～10 to adding sodium hydroxide solution to regulate its pH in the water layer of collecting, by ethyl acetate (or ether), extract, 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 of using in above-mentioned synthetic method can directly be bought from the market, also can be according to existing ordinary method or with reference to method (the MA Yan-ru reporting in existing document, ZHAO Xiao-yu, XU Zhen.Chinese Joumal of Synthetic Chemistry, 2 (2007): 244-246.) synthesize; Concrete synthetic method can be: the pyridine solution that adds rhubarb yellow in round-bottomed flask, under normal temperature, add diacetyl oxide (mol ratio of rhubarb yellow and diacetyl oxide is 1～2:1.5～3), stir 3～4h, add trichloromethane, washing, collected organic layer anhydrous sodium sulfate drying, obtains target product diacetyl rhein through purification by silica gel column chromatography (the mixed solvent wash-out that the ethyl acetate that is 1:4～10 by volume ratio and sherwood oil form).
In above-mentioned synthetic method, described polar solvent is a kind of or two or more combination being arbitrarily selected from dimethyl sulfoxide (DMSO), DMF, ethyl acetate, methyl alcohol, ethanol, propyl alcohol, butanols, methylene dichloride and trichloromethane.When the above-mentioned two or more combination of being chosen as of polar solvent, 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 after diacetyl rhein and α-aminophosphonicacid ester can being mixed, add again polar solvent to dissolve; After diacetyl rhein can also being dissolved with polar solvent, directly add α-aminophosphonicacid ester solid.The consumption of polar solvent can determine as required, and generally, with amount that can solubilizing reaction raw material, generally, the diacetyl rhein of 1mmol or 1mmol α-aminophosphonicacid ester dissolve with the polar solvent of 5～20mL.
In above-mentioned synthetic method, the metering ratio that the ratio of the amount of substance of diacetyl rhein and α-aminophosphonicacid ester is 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, more preferably 0.1～0.2 of diacetyl rhein amount of substance times.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 special being particular about not, but can obtain higher yield with following order of addition(of ingredients): after first diacetyl rhein being dissolved, add catalyzer, stir, and then add condensing agent, after stirring, add again α-aminophosphonicacid ester (now α-aminophosphonicacid ester can add with the form of solid, and the form with liquid after also it can being dissolved with polar solvent adds) to react.
In above-mentioned synthetic method, reaction is preferably carried out under the condition lower than 80 ℃, is more preferably under the condition of 20～40 ℃ and carries out.Whether reaction can adopt thin-layer chromatography to follow the tracks of is completely detected, and under above-mentioned preferred temperature of reaction condition, stirring reaction is to completely approximately needing the time of 3～5h.
In above-mentioned synthetic method, the described mixed solvent for wash-out, the volume ratio of ethyl acetate and sherwood oil is preferably 1:6～50,1:6～20 more preferably, 1:6～10 more preferably, then 1:7～9 more preferably.
The present invention also comprises the application of above-mentioned SF-277 aminophosphonate ester derivatives in preparing antitumor drug.
The present invention also comprises take the antitumor drug that above-mentioned SF-277 aminophosphonate ester derivatives prepared as effective constituent.
Compared with prior art, the invention provides the SF-277 aminophosphonate ester derivatives of a series of novel structures, and their its synthetic method and application.Applicant finds that the anti-tumor activity that most SF-277 aminophosphonate ester derivatives has is all much higher than rhubarb yellow, has good potential pharmaceutical use, is expected to the preparation for various antitumor drugs.
Embodiment
With specific embodiment, the invention will be further described below, but the present invention is not limited to these embodiment.
Embodiment 1:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (4-bromophenyl) methyl } diethyl phosphonate (a) synthetic
1) α-O, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester synthetic
In round-bottomed flask, add p-bromobenzaldehyde, ammonium acetate and diethyl phosphite (mol ratio is 2:1:1), stirring reaction 10h under 80 ℃ of conditions, toward adding ether add-on in this round-bottomed flask, be 1.2 times of amount of substance of p-bromobenzaldehyde again), under ice bath, adding concentrated hydrochloric acid makes reaction system be acid (pH=6) and stir 3h, the extraction of reaction system water, collect water layer and by extracted with diethyl ether, remove organic impurity again, regather water layer, and be that to regulate its pH be 9 for 10% sodium hydroxide solution to adding mass concentration in the water layer of collecting, 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) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL dimethyl sulfoxide (DMSO), under ice bath, drip 0.5mmol catalyzer I-hydroxybenzotriazole, stirring at room 10min, then add 1.1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 10min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (4-bromophenyl) methyl-phosphorous acid diethyl ester is (with 5mL dmso solution wiring solution-forming, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:8 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid a.
To gained orange solids, a analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield80%.paint?yellow?solid.m.p.218～220℃.
1H?NMR(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).
31P?NMR(202MHz,CDCl
3)δ(ppm):21.25.ESI-MS?m/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 is amino) kharophen] (4-bromophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 2:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (2-bromophenyl) methyl } diethyl phosphonate (b) synthetic
1) α-O, O' diethylamino (2-bromophenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with o-bromobenzaldehye, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in to 10mL N, in dinethylformamide, under ice bath, drip 0.05mmol catalyzer I-hydroxybenzotriazole, stirring at room 13min, then add 1.2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 13min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (2-bromophenyl) methyl-phosphorous acid diethyl ester, under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:10 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtains faint yellow solid b.
To gained faint yellow solid, b analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield79%.paint?yellow?solid.m.p.220～222℃.
1H?NMR(500MHz?CDCl
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-MS?m/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 is amino) kharophen] (2-bromophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 3:O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (3-bromophenyl) methyl } diethyl phosphonate (c) synthetic
1) α-O, O' diethylamino (3-bromophenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with 3-bromobenzaldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL methyl alcohol, under ice bath, drips 0.5mmol catalyzer I-hydroxybenzotriazole, stirring at room 10min, then add 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (3-bromophenyl) methyl-phosphorous acid diethyl ester is (with 20mL dissolve with ethanol wiring solution-forming, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:50 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid c.
To gained faint yellow solid, c analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield79%.paint?yellow?solid.m.p.218～220℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):21.14.ESI-MS?m/z:694.1(M+Na)
+.
Therefore, can determine that gained orange solids c is O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) 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 } diethyl phosphonate (d) synthetic
1) α-O, O' diethylamino (4-fluorophenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with p-Fluorobenzenecarboxaldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
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, under ice bath, drip 0.2mmol catalyzer I-hydroxybenzotriazole, stirring at room 8min, then add 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 3min, in this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (4-fluorophenyl) methyl-phosphorous acid diethyl ester (dissolves wiring solution-forming with 10mL trichloromethane, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 4.5h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:20 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid d.
To gained faint yellow solid, d analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield79%.paint?yellow?solid.m.p.222～224℃.1H?NMR(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),31P?NMR(202MHz,CDCl3)δ(ppm):20.6120.59.ESI-MS?m/z:634.1(M+Na)
+.
Therefore, can determine that gained faint yellow solid d is 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:
Embodiment 5:O, O' diethyl { [2-(4,5-diacetyl-9,10-dioxo-9,10-dihydroanthracene) kharophen] (2-fluorophenyl) methyl } diethyl phosphonate (e) synthetic
1) α-O, O' diethylamino (2-fluorophenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with o fluorobenzaldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in the mixing solutions of 5mL ethyl acetate, under ice bath, drip 0.08mmol catalyzer I-hydroxybenzotriazole, stirring at room 5min, then add 1.8mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 13min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (2-fluorophenyl) methyl-phosphorous acid diethyl ester is (with 10mL acetic acid ethyl dissolution wiring solution-forming, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:8 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid e.
To gained faint yellow solid, e analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield80%.paint?yellow?solid.m.p.162～164℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):20.97.ESI-MS?m/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:
Embodiment 6:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (4-chloro-phenyl-) methyl } diethyl phosphonate (f) synthetic
1) α-O, O' diethylamino (4-chloro-phenyl-) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with 4-chloro-benzaldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
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, under ice bath, drip 0.08mmol catalyzer I-hydroxybenzotriazole, stirring at room 5min, then add 1.8mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min, in this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (4-chloro-phenyl-) methyl-phosphorous acid diethyl ester is (with 4mL methyl alcohol and 1mL dissolve with ethanol wiring solution-forming, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 3.5h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:9 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid f.
To gained faint yellow solid, f analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield80%.paint?yellow?solid.m.p.219～221℃.1H?NMR(500MHz?CDCl3)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),31P?NMR(202MHz,CDCl3)δ(ppm):21.34.ESI-MS?m/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 is amino) kharophen] (4-chloro-phenyl-) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 7:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (2-chloro-phenyl-) methyl } diethyl phosphonate (h) synthetic
1) α-O, O' diethylamino (2-chloro-phenyl-) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with adjacent chlorobenzene phenyl aldehyde replacement p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in to 10mL N, in dinethylformamide, under ice bath, drip 0.5mmol catalyzer I-hydroxybenzotriazole, stirring at room 6min, then add 1mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (2-chloro-phenyl-) methyl-phosphorous acid diethyl ester is (with 5mL acetic acid ethyl dissolution wiring solution-forming, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:100 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid h.
To gained faint yellow solid, h analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield80%.paint?yellow?solid.m.p.227～229℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):21.92.ESI-MS?m/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 is amino) kharophen] (2-chloro-phenyl-) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 8:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (2 – p-methoxy-phenyl) methyl } diethyl phosphonate (j) synthetic
1) α-O, O' diethylamino (2-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with o-methoxybenzaldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL methyl alcohol, under ice bath, drips 0.1mmol catalyzer I-hydroxybenzotriazole, stirring at room 5min, then add 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min, in this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (2-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester (is used 5mL N, dinethylformamide dissolves wiring solution-forming, mode with solution adds), under 35 ℃ of conditions, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:80 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtain faint yellow solid j.
To gained faint yellow solid, j analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield82%.paint?yellow?solid.m.p.218～220℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):20.70.ESI-MS?m/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 is amino) kharophen] (2 – p-methoxy-phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 9:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (phenyl) methyl } diethyl phosphonate (k) synthetic
1) α-O, O' diethylamino (phenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with phenyl aldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL methyl alcohol, under ice bath, drip 0.2mmol catalyzer I-hydroxybenzotriazole, stirring at room 10min, then add 1.2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 5min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (phenyl) methyl-phosphorous acid diethyl ester, under room temperature condition, stirring reaction, to complete (about 4h), then adds trichloromethane in reaction solution, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:60 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtains faint yellow solid k.
To gained faint yellow solid, k analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield81%.paint?yellow?solid.m.p.213～215℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):21.04..ESI-MS?m/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 is amino) kharophen] (phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 10:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-4,5-diacetyl-9) kharophen] (naphthyl) methyl } diethyl phosphonate (l) synthetic
1) α-O, O' diethylamino (naphthyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with naphthaldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 15mL butanols, under ice bath, drip 0.5mmol catalyzer I-hydroxybenzotriazole, stirring at room 5min, then add 1.3mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, continue to stir 6min; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (naphthyl) methyl-phosphorous acid diethyl ester (dissolves wiring solution-forming with 5mL butanols, mode with solution adds), under 50 ℃ of conditions, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:10 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid l.
To gained faint yellow solid, l analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield82%.paint?yellow?solid.m.p.218～220℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):21.28.ESI-MS?m/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 is amino) kharophen] (naphthyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 11:O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-p-methoxy-phenyl) methyl } diethyl phosphonate (m) synthetic
1) α-O, O' diethylamino (4-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with aubepine, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL dimethyl sulfoxide (DMSO), under ice bath, drip 0.5mmol catalyzer I-hydroxybenzotriazole, stirring at room is even, then add 1.5mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (4-p-methoxy-phenyl) methyl-phosphorous acid diethyl ester, under 60 ℃ of conditions, stirring reaction is to complete (about 3h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:6 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, collect elutriant, elutriant solvent evaporated, obtains faint yellow solid m.
To gained faint yellow solid, m analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield80%.paint?yellow?solid.m.p.219～221℃.1H?NMR(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-MS?m/z:646.2(M+Na)
+.
Therefore, can determine that gained faint yellow solid m is O, O' diethyl { [2-(10-dihydroanthracene is amino for 4,5-diacetyl-9,10-dioxo-9) kharophen] (4-p-methoxy-phenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 12:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (4-aminomethyl phenyl) methyl } diethyl phosphonate (o) synthetic
1) α-O, O' diethylamino (4-tolyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with p-tolyl aldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL trichloromethane, drips 0.1mmol catalyzer I-hydroxybenzotriazole under ice bath, stirring at room is even, then add 2mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (4-tolyl) methyl-phosphorous acid diethyl ester is (with 10mL dimethyl sulfoxide (DMSO) wiring solution-forming, mode with solution adds), under 20 ℃ of conditions, stirring reaction is to complete (about 4h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:30 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid o.
To gained faint yellow solid, o analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield81%.paint?yellow?solid.m.p.218～220℃.1H?NMR(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).31P?NMR(202MHz,CDCl3)δ(ppm):21.56.ESI-MS?m/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 is 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) synthetic
1) α-O, O' diethylamino (3-fluorophenyl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with between fluorobenzaldehyde replace p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 10mL methyl alcohol, drips 0.3mmol catalyzer I-hydroxybenzotriazole under ice bath, stirring at room is even, then add 1.6mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (3-fluorophenyl) methyl-phosphorous acid diethyl ester is (with 5mL dimethyl sulfoxide (DMSO) wiring solution-forming, mode with solution adds), under 10 ℃ of conditions, stirring reaction is to complete (about 5h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:15 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid p.
To gained faint yellow solid, p analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield81%.paint?yellow?solid.m.p.219～221℃.1H?NMR(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-MS?m/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 is amino) kharophen] (3-fluorophenyl) methyl } diethyl phosphonate, its structural formula is shown below:
Embodiment 14:O, O' diethyl { [10-dioxo-9,10-dihydroanthracene is amino for 2-(4,5-diacetyl-9) kharophen] (anthryl) methyl } diethyl phosphonate (q) synthetic
1) α-O, O' diethylamino (anthryl) methyl-phosphorous acid diethyl ester synthetic
By step 1 in embodiment 1) described method and condition synthesize, different, with anthraldehyde, replaces p-bromobenzaldehyde.
2) target product is synthetic:
In round-bottomed flask, 1mmol diacetyl rhein is dissolved in 5mL methyl alcohol, drips 0.1mmol catalyzer I-hydroxybenzotriazole under ice bath, stirring at room is even, then add 1.5mmol condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, stir; In this round-bottomed flask, drip 1mmol α-O again, O' diethylamino (anthryl) methyl-phosphorous acid diethyl ester is (with 5mL dimethyl sulfoxide (DMSO) wiring solution-forming, mode with solution adds), under room temperature condition, stirring reaction is to complete (about 5h), then in reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography after anhydrous sodium sulfate drying for organic layer, the mixed solvent wash-out forming with ethyl acetate: sherwood oil=1:7 (volume ratio), thin-layer chromatography is followed the tracks of and is detected, and collects elutriant, elutriant solvent evaporated, obtains faint yellow solid q.
To gained faint yellow solid, q analyzes, and its physics and chemistry and spectral characteristic are as follows:
Yield80%.paint?yellow?solid.m.p.219～221℃.1H?NMR(500MHz?CDCl3)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-MS?m/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 is amino) kharophen] (anthryl) methyl } diethyl phosphonate, its structural formula is shown below:
For the purposes of SF-277 aminophosphonate ester derivatives of the present invention in pharmacy is described, the compound that applicant makes above-described embodiment 1～14 has carried out anti-tumor activity experiment.
The positive contrast medicine of anti-tumor medicine 5 FU 5 fluorouracil with clinical use, with coordinative solvent, make negative control, 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, compound has been carried out to anti tumor activity in vitro test.
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 (approximately 5 * 10
4～1 * 10
5individual/hole).
Cultivate 24h after cell attachment, add respectively the sample 10 μ L of series concentration, each sample is established 5 multiple holes, and wherein ethanol final concentration < 1%. separately establishes 4 of negative control holes, adds the blank matrix of 10 μ L.
Cell is in saturated humidity, 5%CO
2, under 37oC condition, hatch the every hole of 48h. and add 10 μ L MTT(5mg/ml), continue to cultivate 4h.
Suck supernatant liquor, add DMSO150 μ L/ hole, after fully dissolving, by microplate reader, at mensuration wavelength, be 570nm and measure OD value with reference to 630nm place, calculate each dosing holes cell proliferation inhibition rate, result as described in Table 1.
The IC of table 1 compound to different cell strains
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 most of SF-277 aminophosphonate ester derivatives of being 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 have shown good anti tumor activity in vitro, as compound o has good activity (IC to Hct-116 cell
50value is 9.83 μ M).In addition, as compound o has very high activity (IC to Spca-2 cell
50value is 11.38 μ M), over the medicine 5-Fluorouracil of clinical treatment human colon carcinoma.
In order further to verify the cytotoxicity of above-mentioned all compounds to human normal cell, we utilize mtt assay to human venous endothelial cell HUVEC(normal cell) carried out screening active ingredients, result shows the IC of all compounds
50value, all than the height of rhubarb yellow (as shown in table 1), that is to say that all derivatives are less than rhubarb yellow to the cytotoxicity of human normal cell line.
Claims (10)
1. SF-277 aminophosphonate ester derivatives, its general structure is as shown in the formula shown in (I):
Wherein, R is 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), take diacetyl rhein and α-aminophosphonicacid ester is raw material, be dissolved in polar solvent, under the condition of catalyzer I-hydroxybenzotriazole and the existence of condensing agent 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, reaction is to complete; In reaction solution, add trichloromethane, washing, collected organic layer, upper silica gel column chromatography, the mixed solvent wash-out that the ethyl acetate that to use by volume ratio be 1:6～100 and sherwood oil form, elutriant solvent evaporated, 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 combination being arbitrarily selected from dimethyl sulfoxide (DMSO), DMF, ethyl acetate, methyl alcohol, ethanol, propyl alcohol, butanols, methylene dichloride and trichloromethane.
5. according to the synthetic method of SF-277 aminophosphonate ester derivatives described in any one in claim 2～4, it 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. according to the synthetic method of SF-277 aminophosphonate ester derivatives described in any one in claim 2～4, it 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. according to the synthetic method of SF-277 aminophosphonate ester derivatives described in any one in claim 2～4, it is characterized in that: the temperature of described reaction is lower than 80 ℃.
8. according to the synthetic method of SF-277 aminophosphonate ester derivatives described in any one in claim 2～4, it is characterized in that: the described mixed solvent for wash-out, the volume ratio of ethyl acetate and sherwood oil is 1:6～10.
9. the application of SF-277 aminophosphonate ester derivatives claimed in claim 1 in preparing antitumor drug.
10. the antitumor drug that the SF-277 aminophosphonate ester derivatives claimed in claim 1 of take is prepared as effective constituent.
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| CN110066289A (en) * | 2018-01-23 | 2019-07-30 | 南京大学 | Based on anthryl [4+4] cycloaddition can backlight convert rare earth compounding |
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| WO1996030034A1 (en) * | 1995-03-29 | 1996-10-03 | Wisconsin Alumni Research Foundation | Production of rhein and rhein derivatives |
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| CN102225913A (en) * | 2011-04-07 | 2011-10-26 | 栗进才 | Rheinic acid derivatives and treatment application thereof |
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| WO1996030034A1 (en) * | 1995-03-29 | 1996-10-03 | Wisconsin Alumni Research Foundation | Production of rhein and rhein derivatives |
| 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 |
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| 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 |
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| CN110066289B (en) * | 2018-01-23 | 2021-07-30 | 南京大学 | Anthracene radical [4+4] cycloaddition-based reversible light conversion rare earth complex |
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