CN1304408C - Derivative of vibothymidine and its preparation process and application - Google Patents
Derivative of vibothymidine and its preparation process and application Download PDFInfo
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- CN1304408C CN1304408C CNB2004100061641A CN200410006164A CN1304408C CN 1304408 C CN1304408 C CN 1304408C CN B2004100061641 A CNB2004100061641 A CN B2004100061641A CN 200410006164 A CN200410006164 A CN 200410006164A CN 1304408 C CN1304408 C CN 1304408C
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- cyclohexyl
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Abstract
The present invention discloses a thymidine derivative, a preparation method thereof and an application thereof. A thymidine derivative provided by the present invention is a compound with a general formula (I), wherein n is 0, 1, 2 or 4; the compound with the general formula (I) can be 3'-azidothymidine-5'-phosphorylated(N-methyl imidazole-2-formyl alkyl diamine) cyclohexyl ester and 2', 3'-dehydrogenated deoxythymidine-5'-phosphorylated(N-methyl imidazole-2-formyl alkyl diamine)isopropyl ester. The present invention also provides a method for preparing a compound with a general formula. The thymidine derivative of the present invention is a candidate premedical compound with the effects of anti-virus, anti-tumor and anti-AIDS virus.
Description
Technical field
The present invention relates to a kind of compound and preparation method thereof and application, particularly a kind of thymidine derivative and preparation method thereof and application.
Background technology
(Azidodeoxythymidine AZT) is the analogue of synthetic thymidine to Zidovodine, and it is synthetic to block proviral DNA, is a kind of reverse transcriptase inhibitors, can suppress duplicating of virus such as HIV.Zidovodine U.S. food and FAD is at first ratified to be used for clinical.It can improve the cd4 cell number, slows down the process of disease, prolongs patient's survival, reduces conditionality and infects, and reduces mortality ratio.Main side effect is bone marrow depression, pancytopenia and cause secondary infection and increase the weight of, and can also cause drug fever, fash etc. in addition.2 ', 3 '-dehydrogenation deoxythymidine also is the thymidine derivative with AIDS resisting virus activity.
The innovation and creation content
The purpose of this invention is to provide a kind of thymidine derivative.
Thymidine derivative provided by the present invention has the structure of general formula (I):
Wherein, n is 0,1,2 or 4; Work as R
1During for cyclohexyl, R
2Be the group that formula II represents, this moment, general formula (I) compound was 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) cyclohexyl; Work as R
1During for sec.-propyl, R
2Be the group that formula III is represented, this moment, general formula (I) compound was 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) isopropyl ester.
Second purpose of the present invention provides a kind of method for preparing general formula (I) compound.
The method for preparing general formula (I) compound provided by the present invention may further comprise the steps:
1) 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester are dissolved in the methylene dichloride;
2) dichloromethane solution of adding and 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl or the equimolar N-Methylimidazole of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester-2-formyl alkyl diamine in the solution of step 1);
3) to step 2) mixed solution in drip and 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl or the equimolar chloro Diisopropylamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester and 0.3mL three amine, phosphorus spectrum monitoring reaction fully till;
4) be spin-dried for solvent, carry out chromatographic separation, promptly obtain 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) isopropyl ester.
In aforesaid method, the concentration of the dichloromethane solution of 3 '-Zidovodine-5 ' described in the step 1)-hydrogen phosphorous acid cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester is 0.025M; The concentration of the dichloromethane solution of the Methylimidazole of N-step 2)-2-formyl alkyl diamine is 0.03M.Being reflected under the condition of ice bath in the step 3) carried out, and for adding fast response, can stir in the reaction process; The amount of trihexylamine described in the step 3) is 0.3mL; Chromatography described in the step 4) is a silica gel column chromatography, and used eluent is methylene dichloride and methanol mixed solvent, and wherein, the ratio of methylene dichloride and methyl alcohol is 20: 1.
Thymidine derivative of the present invention is to have 3 '-Zidovodine of AIDS resisting virus, anti-tumor activity and have 2 ' of AIDS resisting virus activity, the derivative of 3 '-dehydrogenation deoxythymidine, thereby may have better AIDS resisting virus, anti-tumor activity, be have antiviral, antitumor, drug compound before the candidate of AIDS resisting virus.
Embodiment
The preparation of embodiment 1,3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) cyclohexyl
The structural formula of 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) cyclohexyl is as follows:
The synthesis step of 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) cyclohexyl is as follows:
1) 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl is dissolved in the methylene dichloride of 10mL.
2) add the dichloromethane solution that contains with the equimolar N-Methylimidazole of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl-2-formyl hexanediamine in above-mentioned solution, the concentration of this solution is 0.025M.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with equimolar chloro Diisopropylamine of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl and 0.3mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) cyclohexyl with 20: 1 mixed solvents of methylene dichloride and methyl alcohol.Productive rate is 97%.
The spectral data of 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) cyclohexyl is as follows:
31P NMR (200MHz CDCl
3) δ 9.11ppm;
1H NMR (400MHz CDCl
3) δ 10.68,10.37 (br, 1H, 3-H), 7.86 (br, 1H, CO-NH), 7.47,7.39 (s, s, 1H, 6-H), 7.09 (s, 1H, H
Imidozole), 6.96 (s, 1H, H
Imidozole), 6.17 (m, 1H, 1 '-H), 4.38 (m, 2H, 3 '-H, CH
Cyclohexyl), 4.18 (m, 2H, 5 '-H), 4.06 (s, 4H, N-CH
3, 4 '-H), 3.38 (m, 2H, CH
2), 2.86 (m, 3H, CH
2, P-NH), 2.50,2.35 (m, 2H, 2 '-H), 1.95 (s, 5H, 5-CH
3, CH
2cyclohexyl), 1.72 (m, 2H, CH
2cyclohexyl), 1.32-1.59 (m, 14H, 3 * CH2
Cyclohexyl, 4 * CH
2) ppm;
13C NMR (400MHz CDCl
3) δ 164.26,164.10 (C
4), 159.09 (C
CO), 150.56 (C
2), 139.08 (C
Imidozale), 135.57 (C
6), 127.08 (C
Imidozale), 125.31 (C
Imidozale), 111.25,111.10 (C
5), 85.57,85.24 (C
1 '), 82.96,82.73 (C
4 '), 76.60 (C
Cyclohexyl), 65.23,64.88 (C
5 '), 60.78 (C
3 '), 41.38 (C
CH2), 38.95 (C
CH2), 37.63,37.57 (C
2 '), 35.76 (C
Me), 33.66,33.59 (C
Cyclohexyl), 31.84,31.67 (C
CH2), 29.44,29.35 (C
CH2), 26.53 (C
CH2), 26.39,26.33 (C
CH2), 25.10 (C
Cyclohexyl), 23.69 (C
Cyclohexyl), 12.58 (C
Me) ppm; ESI-MS:636 (M+H)
+, 658 (M+Na)
+.
The preparation of embodiment 2,3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl butanediamine) cyclohexyl
The structural formula of 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl butanediamine) cyclohexyl is as follows:
The synthesis step of 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl butanediamine) cyclohexyl is as follows:
1) 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl is dissolved in the methylene dichloride of 15mL.
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl butanediamine of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl same substance amount and 0.5mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates with methylene dichloride and methyl alcohol (30: 1) mixed solvent, promptly obtains 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl butanediamine) cyclohexyl.Productive rate is 91%.
The spectral data of this compound is as follows:
31P NMR (200MHz CDCl
3) δ ppm;
1H NMR (400MHzCDCl
3) δ 10.70 (br, 1H, 3-H), 7.94 (br, 1H, CO-NH), 7.38,7.32 (s, s, 1H, 6-H), 7.15 (d, 1H, J 6.03Hz, H
Imidozole), 6.96 (s, 1H, H
Imidozole), 6.05 (m, 1H, 1 '-H), 4.45 (m, 1H, CH
Cyclohexyl), 4.30 (m, 1H, 3 '-H), 4.19 (m, 2H, 5 '-H), 4.05 (s, 4H, N-CH
3, 4 '-H), 3.44 (m, 2H, CH
2), 2.96 (m, 3H, CH
2, P-NH), 2.45 (m, 2H, 2 '-H), 1.93 (s, 5H, 5-CH
3, CH
2cyclohexyl), 1.74-1.26 (m, 12,4 * CH
2cyclohexyl, 2 * CH
2) ppm;
13C NMR (400MHz CDCl
3) δ 164.17,164.07 (C
4), 159.29 (C
CO), 150.71,150.24 (C
2), 138.94,138.91 (C
Imidozale), 136.25 (C
6), 127.51,127.48 (C
Imidozale), 125.39 (C
Imidozale), 111.37,111.22 (C
5), 86.55,86.24 (C
1 '), 82.77,82.63 (C
4 '), 76.54,76.52 (C
Cyclohexyl), 64.78 (C
5 '), 61.09,60.67 (C
3 '), 41.14 (C
CH2), 38.64,38.62 (C
CH2), 37.14,36.96 (C
2 '), 35.75 (C
Me), 33.59,33.53 (C
Cyclohexyl), 28.99,28.97 (C
CH2), 26.72,26.68 (C
CH2), 25.09 (C
Cyclohexyl), 23.66 (C
Cyclohexyl), 12.51 (C
Me) ppm; ESI-MS:608 (M+H)
+, 630 (M+Na)
+.
The preparation of embodiment 3,3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl propylene diamine) cyclohexyl
The structural formula of this compound is:
The synthesis step of this compound is as follows:
1) 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl is dissolved in the methylene dichloride of 15mL.
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl propylene diamine of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl same substance amount and 0.3mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl propylene diamine) cyclohexyl with methylene dichloride and methyl alcohol (28: 1) mixed solvent.Productive rate is 88%.
The spectral data of this compound is as follows:
31P NMR (200MHz CDCl
3) δ 9.44,9.24ppm;
1H NMR (CDCl
3) δ 10.59,10.50 (br, 1H, 3-H), 8.12 (br, 1H, CO-NH), 7.35,7.41 (s, s, 1H, 6-H), 7.19 (s, 1H, H
Imidozole), 6.98 (s, 1H, H
Imidozole), 6.04 (m, 1H, 1 '-H), 4.45 (m, 1H, CH
Cyclohexyl), 4.35 (m, 1H, 3 '-H), 4.20 (m, 2H, 5 '-H), 4.04 (s, 4H, N-CH
3, 4 '-H), 3.65 (m, 1H, P-NH), 3.50 (m, 2H, CH
2), 3.02 (m, 2H, CH
2), 2.40 (m, 2H, 2 '-H), 1.93 (s, 5H, 5-CH
3, CH
2cyclohexyl), 1.31-1.80 (m, 10H, CH
2, 4 * CH
2cyclohexyl) ppm;
13C NMR (400MHz CDCl
3) δ 164.06 (C
4), 159.37 (C
CO), 150.67,150.63 (C
2), 138.59 (C
Imidozale), 136.37 (C
6), 127.26 (C
Imidozale), 125.48 (C
Imidozale), 111.41,111.33 (C
5), 86.62,86.26 (C
1 '), 82.78,82.62 (C
4 '), 76.56 (C
Cyclohexyl), 64.99,64.82 (C
5 '), 60.85,60.59 (C
3 '), 38.46,38.43 (C
CH2), 37.20 (C
CH2), 36.96 (C
2 '), 35.85 (C
Me), 33.62 (C
Cyclohexyl), 31.54,31.45 (C
CH2), 25.12 (C
Cyclohexyl), 23.68 (C
Cyclohexyl), 12.46 (C
Me) ppm; ESI-MS:594 (M+H)
+, 616 (M+Na)
+.
The preparation of embodiment 4,3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl quadrol) cyclohexyl
The structural formula of compound is:
The synthesis step of this compound is as follows:
1) 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl is dissolved in the methylene dichloride of 10mL.
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl quadrol of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl same substance amount and 0.5mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl quadrol) cyclohexyl with methylene dichloride and methyl alcohol (25: 1) mixed solvent.Productive rate is 90%.
The spectral data of this compound is as follows:
31P NMR (200MHz CDCl
3) δ 8.99ppm;
1H NMR (400MHz CDCl
3) δ 11.24,11.07 (s, s, 1H, 3-H), 8.41 (br, 1H, CO-NH), 7.35,7.23 (s, s, 1H, 6-H), 7.26 (s, 1H, H
Imidozole), 6.98 (s, 1H, H
Imidozole), 5.89,5.98 (m, 1H, 1 '-H), 4.49 (m, 1H, CH
Cyclohexyl), 4.22 (m, 3H, 3 '-H, 5 '-H), 4.05 (s, 3H, N-CH
3), 3.95 (m, 1H, 4 '-H), 3.57 (m, 3H, P-NH, CH
2), 3.15 (m, 2H, CH
2), 2.38 (m, 2H, 2 '-H), 1.90 (s, 5H, 5-CH
3, CH
2cyclohexyl), 1.73 (m, 2H, CH
2cyclohexyl), 1.51-1.25 (m, 6H, 3 * CH
2cyclohexyl) ppm;
13C NMR (400MHz CDCl
3) δ 164.18 (C
4), 159.51,159.45 (C
CO), 150.83 (C
2), 138.52 (C
Imidozale), 137.14,136.80 (C
6), 127.46 (C
Imidozale), 125.53 (C
Imidozale), 111.36,111.31 (C
5), 87.56,86.68 (C
1 '), 82.69,82.55 (C
4 '), 76.55 (C
Cyclohexyl), 64.44,64.28 (C
5 '), 60.13,60.04 (C
3 '), 41.36,41.29 (C
CH2), 40.96,40.61 (C
CH2), 37.17,36.84 (C
2 '), 35.86 (C
Me), 33.63,33.48 (C
Cyclohexyl), 25.10 (C
Cyclohexyl), 23.68 (C
Cyclohexyl), 12.39 (C
Me) ppm; ESI-MS:580 (M+H)
+, 602 (M+Na)
+.
Embodiment 5:2 ', the preparation of 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) isopropyl ester
The structural formula of this compound is:
The synthesis step of this compound is as follows:
1) 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester is dissolved in right amount in the methylene dichloride of (concrete amount please be provided).
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl hexanediamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount and 0.5mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl hexanediamine) isopropyl ester with methylene dichloride and methyl alcohol (30: 1) mixed solvent.Productive rate is 93%.
The spectral data of this compound is as follows:
31P NMR (200MHz CDCl
3) δ 9.75,8.89ppm;
1H NMR (400MHz CDCl
3) δ 10.10,10.74 (br, 1H, 3-H), 8.11,8.02 (br, 1H, CO-NH), 7.36,7.28 (s, s, 1H, 6-H), 7.12 (s, 1H, H
Imidozole), 7.03 (s, 1H, 1 '-H), 6.97 (s, 1H, H
Imidozole), 6.35 (m, 1H, 3 '-H), 5.91 (m, 1H, 2 '-H), 5.01 (s, 1H, 4 '-H), 4.65 (m, 1H, CH (CH
3)
2), 4.17 (m, 2H, 5 '-H), 4.07 (s, 3H, N-CH
3), 3.39 (m, 2H, CH
2), 2.80 (m, 2H, CH
2), 2.65 (m, 1H, P-NH), 1.95 (s, 3H, 5-CH
3), 1.57 (m, 2H, CH
2), 1.35 (m, 2H, CH
2), 1.32 (m, 10H, 2 * CH
2, CH (CH
3)
2) ppm;
13C NMR (400MHz CDCl
3) δ 164.59,164.34 (C
4), 158.95 (C
CO), 151.33 (C
2), 139.06 (C
Imidozale), 136.19,135.97 (C
6), 133.67,133.39 (C
3 '), 127.15,126.97 (C
2 '), 126.74 (C
Imidozale), 125.24 (C
Imidozale), 111.24,110.95 (C
5), 89.90,89.58 (C
1 '), 85.17,84.98 (C
4 '), 71.45 (C
CH), 66.77,65.72 (C
5 '), 41.33,41.24 (C
CH2), 39.03 (C
CH2), 35.83 (C
Me), 31.95,31.76 (C
CH2), 29.40,29.32 (C
CH2), 26.65 (C
CH2), 26.52 (C
CH2), 23.96,23.81 (C
Me), 12.57,12.50 (C
Me) ppm; ESI-MS:553 (M+H)
+, 575 (M+Na)
+.
Embodiment 6:2 ', the preparation of 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl butanediamine) isopropyl ester
The structural formula of this compound is:
The synthesis step of this compound is as follows:
1) 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester is dissolved in the methylene dichloride of 15ml.
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl butanediamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount and 0.5mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl butanediamine) isopropyl ester with methylene dichloride and methyl alcohol (25: 1) mixed solvent.Productive rate is 92%.
The spectral data of this compound is as follows:
31P NMR (200MHzCDCl
3) δ ppm;
1H NMR (400MHzCDCl
3) δ 10.91,10.63 (s, s, 1H, H-3), 7.95,7.93 (br, 1H, CO-NH), 7.35,7.26 (s, s, 1H, H-6), 7.10 (s, 1H, H
Imidozole), 6.99 (s, 1H, 1 '-H), 6.96 (s, 1H, H
Imidozole), 6.35 (m, 1H, 3 '-H), 5.90 (m, 1H, 2 '-H), 4.99 (s, 1H, 4 '-H), 4.62 (m, 1H, CH (CH
3)
2), 4.13 (m, 2H, 5 '-H), 4.05 (s, 3H, N-CH
3), 3.40 (m, 2H, CH
2), 2.87-3.05 (m, 3H, P-NH, CH
2), 1.92 (s, 3H, 5-CH
3), 1.58 (m, 4H, 2 * CH
2), 1.31 (t, 6H, J 6.6Hz, CH (CH
3)
2) ppm;
13C NMR (400MHz CDCl
3) δ 164.53,164.32 (C
4), 159.29 (C
CO), 151.37,151.34 (C
2), 139.04 (C
Imidozale), 136.05,135.87 (C
6), 133.59,133.48 (C
3 '), 127.38,127.35 (C
2 '), 127.00 (C
Imidozale), 125.34, (C
Imidozale), 111.36,111.14 (C
5), 89.97,89.70 (C
1 '), 85.04,84.88 (C
4 '), 71.50,70.48 (C
CH), 65.88,66.98 (C
5 '), 41.10,41.03 (C
CH2), 38.64,38.57 (C
CH2), 35.69 (C
Me), 29.10,28.88 (C
CH2), 26.72,26.62 (C
CH2), 23.89,23.76 (C
Me), 12.50 (C
Me) ppm; ESI-MS:(M+H)
+, (M+Na)
+.
Embodiment 7:2 ', the preparation of 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl propylene diamine) isopropyl ester
The structural formula of compound is:
The synthesis step of this compound is as follows:
1) 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester is dissolved in the methylene dichloride of 10mL.
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl propylene diamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount and 0.3mL, and continue to stir 10 hours, phosphorus Spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl propylene diamine) isopropyl ester with methylene dichloride and methyl alcohol (20: 1) mixed solvent.Productive rate is 83%.
The spectral data of this compound is as follows:
31P NMR (200MHz CDCl
3) δ 9.63,9.44ppm;
1H NMR (400MHz CDCl
3) δ 10.55 (br, 1H, 3-H), 8.10 (br, 1H, CO-NH), 7.39,7.30 (s, s, 1H, 6-H), 7.15 (s, 1H, H
Imidozole), 6.99 (m, 2H, 1 '-H,, H
Imidozole), 6.37 (d, J 5.6Hz, 1H, 3 '-H), 5.89 (m, 1H, 2 '-H), 4.99 (s, 1H, 4 '-H), 4.63 (m, 1H, CH (CH
3)
2), 4.14 (m, 2H, 5 '-H), 4.04 (s, 3H, N-CH
3), 3.70 (m, 1H, P-NH), 3.48 (m, 2H, CH
2), 2.97 (m, 2H, CH
2), 1.91 (s, 3H, 5-CH
3), 1.75 (m, 2H, CH
2), 1.31 (m, 6H, CH (CH
3)
2) ppm;
13C NMR (400MHz CDCl
3) δ 164.35 (C
4), 159.49 (C
CO), 151.31 (C
2), 138.68 (C
Imidozale), 136.12,135.99 (C
6), 133.56,133.49 (C
3 '), 127.33 (C
2 '), 127.08 (C
Imidozale), 125.47 (C
Imidozale), 111.28,111.18 (C
5), 89.96,89.64 (C
1 '), 85.11,84.93 (C
4 '), 71.46 (C
CH), 66.61,66.01 (C
5 '), 47.35 (C
CH2), 38.20 (C
CH2), 35.79,35.69 (C
Me), 31.36 (C
CH2), 23.88,23.82 (C
Me), 12.44 (C
Me) ppm; ESI-MS:511 (M+H)
+, 533 (M+Na)
+.
Embodiment 8:2 ', the preparation of 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl quadrol) isopropyl ester
The structural formula of this compound is:
The synthesis step of this compound is as follows:
1) 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester is dissolved in the methylene dichloride of 15mL.
2) in above-mentioned solution, add the dichloromethane solution contain with the N-Methylimidazole-2-formyl quadrol of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount.
3) under the condition of ice bath, in above-mentioned mixed solution, slowly drip three amine with the chloro Diisopropylamine of 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester same substance amount and 0.5mL, and continue to stir 10 hours, phosphorus spectrum monitoring reaction fully till.
4) being spin-dried for solvent, is that eluent carries out silica gel column chromatography and separates and promptly obtain 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl quadrol) isopropyl ester with methylene dichloride and methyl alcohol (23: 1) mixed solvent.Productive rate is 87%.
The spectral data of this compound is as follows:
31P NMR (200MHz CDCl
3) δ 9.37,9.11ppm;
1H NMR (400MHz CDCl
3) δ 10.70 (br, 1H, 3-H), 8.27 (br, 1H, CO-NH), 7.36,7.27 (s, s, 1H, 6-H), 7.18 (s, 1H, H
Imidozole), 6.93 (m, 2H, 1 '-H, H
Imidozole), 6.33 (m, 1H, 3 '-H), 5.88 (m, 1H, 2 '-H), 4.96 (m, 1H, 4 '-H), 4.64 (m, 1H, CH (CH
3)
2), 4.17 (m, 2H, 5 '-H), 4.05 (s, 3H, N-CH
3), 3.65 (m, 1H, P-NH), 3.52 (m, 2H, CH
2), 3.16 (m, 2H, CH
2), 1.89 (d, 3H, J 4.6Hz, 5-CH
3), 1.31 (m, 6H, CH (CH
3)
2) ppm;
13C NMR (400MHz CDCl
3) δ 164.32 (C
4), 159.62,159.55 (C
CO), 151.29 (C
2), 138.56 (C
Imidozale), 136.05 (C
Imidozale), 133.45,133.20 (C
3 '), 127.51,127.44 (C
2 '), 127.25,127.19 (C
Imidozale), 125.49 (C
Imidozale), 111.35,111.28 (C
5), 90.23,89.69 (C1 '), 84.94,84.87 (C
4 '), 71.62,70.59 (C
CH), 66.59,65.99 (C
5 '), 41.35 (C
CH2), 40.62,40.44 (C
CH2), 35.83 (C
Me), 23.89,23.77 (C
Me), 12.40 (C
Me) ppm; ESI-MS:497 (M+H)
+, 519 (M+Na)
+.
Claims (10)
1, general formula (I) compound:
(formula I)
Wherein, n is 0,1,2 or 4; Work as R
1During for cyclohexyl, R
2Be the group that formula II represents, this moment, general formula (I) compound was 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) cyclohexyl; Work as R
1During for sec.-propyl, R
2Be the group that formula III is represented, this moment, general formula (I) compound was 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) isopropyl ester.
(formula II) (formula III)
2, a kind of method for preparing the described general formula of claim 1 (I) compound may further comprise the steps:
1) 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester are dissolved in the methylene dichloride;
2) dichloromethane solution of the N-Methylimidazole-2-formyl alkyl diamine of adding and 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-identical mole number of hydrogen phosphorous acid isopropyl ester in the solution of step 1);
3) to step 2) mixed solution in drip and 3 '-Zidovodine-5 '-hydrogen phosphorous acid cyclohexyl or 2 ', the chloro Diisopropylamine and the 0.3-0.5mL trihexylamine of 3 '-dehydrogenation deoxythymidine-5 '-identical mole number of hydrogen phosphorous acid isopropyl ester are till phosphorus spectrum monitoring reaction is complete;
4) be spin-dried for solvent, carry out chromatographic separation, promptly obtain 3 '-Zidovodine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-phosphorylated (N-Methylimidazole-2-formyl alkyl diamine) isopropyl ester.
3, method according to claim 2, it is characterized in that: the concentration of the dichloromethane solution of 3 '-Zidovodine-5 ' described in the step 1)-hydrogen phosphorous acid cyclohexyl or 2 ', 3 '-dehydrogenation deoxythymidine-5 '-hydrogen phosphorous acid isopropyl ester is 0.02-0.025M; The concentration of the dichloromethane solution of the Methylimidazole of N-step 2)-2-formyl alkyl diamine is 0.02-0.03M.
4, according to claim 2 or 3 described methods, it is characterized in that: being reflected under ice bath, the agitation condition in the step 3) carried out.
5, according to claim 2 or 3 described methods, it is characterized in that: the amount of trihexylamine described in the step 3) is 0.3mL.
6, according to claim 2 or 3 described methods, it is characterized in that: the monitoring of phosphorus spectrum is adopted in the reaction of described step 3).
7, according to claim 2 or 3 described methods, it is characterized in that: chromatography described in the step 4) is a silica gel column chromatography.
8, according to claim 2 or 3 described methods, it is characterized in that: the used eluent of chromatography described in the step 4) is methylene dichloride and methanol mixed solvent, and wherein, the ratio of methylene dichloride and methyl alcohol is 20: 1.
9, the application of the described general formula of claim 1 (I) compound in the preparation azidothymidine.
10, the application of the described general formula of claim 1 (I) compound in preparation medicine for treating tumor thing.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0284405A2 (en) * | 1987-03-27 | 1988-09-28 | Baker Norton Pharmaceuticals, Inc. | Anti-viral compounds, dosage forms and methods |
| JPH02262588A (en) * | 1989-04-03 | 1990-10-25 | Mitsubishi Kasei Corp | Mew phosphonic acid derivative |
| WO1993016093A1 (en) * | 1992-02-13 | 1993-08-19 | Herbert Schott | Amphiphilic nucleoside phosphate analogs |
| CN1343673A (en) * | 2001-08-24 | 2002-04-10 | 清华大学 | Thiophosphamino acid ester compound containing 3'-azido-deoxythymidine and its preparing process |
-
2004
- 2004-03-04 CN CNB2004100061641A patent/CN1304408C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0284405A2 (en) * | 1987-03-27 | 1988-09-28 | Baker Norton Pharmaceuticals, Inc. | Anti-viral compounds, dosage forms and methods |
| JPH02262588A (en) * | 1989-04-03 | 1990-10-25 | Mitsubishi Kasei Corp | Mew phosphonic acid derivative |
| WO1993016093A1 (en) * | 1992-02-13 | 1993-08-19 | Herbert Schott | Amphiphilic nucleoside phosphate analogs |
| CN1343673A (en) * | 2001-08-24 | 2002-04-10 | 清华大学 | Thiophosphamino acid ester compound containing 3'-azido-deoxythymidine and its preparing process |
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