CN1133640C - 3'-azido-deoxythymidine-5'-thiopyhosphamino acid ester compound and its preparing process - Google Patents

3'-azido-deoxythymidine-5'-thiopyhosphamino acid ester compound and its preparing process Download PDF

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CN1133640C
CN1133640C CNB011307854A CN01130785A CN1133640C CN 1133640 C CN1133640 C CN 1133640C CN B011307854 A CNB011307854 A CN B011307854A CN 01130785 A CN01130785 A CN 01130785A CN 1133640 C CN1133640 C CN 1133640C
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compound
raw material
zidovodine
solution
methyl ester
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CN1343672A (en
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赵玉芬
苗志伟
付华
成昌梅
韩波
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Tsinghua University
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Abstract

The present invention relates to a 3'-azido-deoxythymidine-5'-thiopyhosphamino acid ester compound and a preparation method thereof. The compound has a structural formula disclosed in the specification, and the preparation method comprises the following steps: first, thiophosphoryl chloride as a raw material is dissolved in tetrahydrofuran; second, amino acid methyl ester hydrochloride is added, the mixture is uniformly stirred, and an acid-binding agent is added for reaction; third, after the reaction, a 3'-azido-deoxythymidine solution dissolved in the tetrahydrofuran is added to the solution; finally, after the reaction, a 3'-azido-deoxythymidine-5'-thiopyhosphamino acid ester compound is prepared by the processes of filtration, distillation, hydrolysis and column chromatography separation. The compound has the anti-AIDS pharmic activity.

Description

A kind of 3 ' Zidovodine-5 '-thiophosphoryl amino acid ester compound and preparation method thereof
The present invention relates to a kind of 3 ' Zidovodine-5 '-thiophosphoryl amino acid ester compound and preparation method thereof, this compounds has good biological activity and antiviral, antitumor, anti-ly likes now pharmaceutical activity such as virus, can develop in clinical application that a kind of ucleosides is antiviral, antitumor, anti-likes viral now prodrug (prodrugs).
Thiophosphoric acid contains the structure that a sulphur replaces oxygen on phosphorus atom, though this structure is still keeping original electric charge, the character that is keeping highly water-soluble, but other physicochemical properties of the dna oligo of thiophosphoric acid (S-oligos) and biology attribute all have very big difference with natural phosphodiester prototype.One of marked difference is that thiophosphoric acid has resistivity to nuclease.Because the phosphodiester class antisense oligonucleotide that adds has been fallen in the existence of exonuclease in the cell, very fast digestion, make its forfeiture action function.By synthetic thiophosphoric acid compounds with opposing nuclease, be used for the treatment of purpose for using the synthetic dna oligo from now on, opened up the road of a hope beyond doubt.
The objective of the invention is to propose a kind of 3 ' Zidovodine-5 '-thiophosphoryl amino acid ester compound and preparation method thereof, this compounds can be developed and be used for antiviral, antitumor, the anti-virus activity medicine now of liking.
3 ' the Zidovodine-5 that the present invention proposes '-thiophosphoryl amino acid methyl ester compound, the structural formula of compound is:
Figure C0113078500031
R is H in the said structure formula, CH 3, C 6H 5CH 2, (CH 3) 2CH 2, (CH 3) 2CHCH 2
The synthesis step of above-claimed cpd is as follows:
1) under nitrogen protection, cryosel is bathed under the condition that is cooled to-4～-8 ℃, and the raw material phosphorus thiochloride is dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution that concentration is 0.8～1.0mol/L.
2) add amino acid methyl ester hydrochloride with the amount of raw material same substance in above-mentioned solution, slowly drip acid binding agent after stirring, acid binding agent is a triethylamine, and the add-on of acid binding agent is 2 times of amount of raw material.
3) follow the tracks of above-mentioned reaction process, after treating that the raw material total overall reaction finishes, to slowly splash in the solution in second step with 3 ' the Zidovodine solution that is dissolved in the tetrahydrofuran (THF) of the amount of raw material same substance, the acid binding agent with the amount of raw material same substance is continued to drip in the back that stirs.
4) after monitoring reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last.After hydrolysis is finished, carry out column chromatography for separation with silicagel column, promptly get 3 ' Zidovodine-5 '-thiophosphoryl amino acid methyl ester compound.
Use the above-mentioned synthetic series compound of method preparation of the present invention, 3 ' Zidovodine-5 '-the thiophosphoryl amino acid methyl ester be a class brand-new have an anti-active compound of virus drugs now of liking, by synthetic different types of nucleosides-amino acid conjugate, and carry out activity experiment, tentatively obtained satisfied result, liked now the virus drugs achievement in research that provides the foundation for further development and development of new resist.
Below introduce embodiments of the invention:
Embodiment 1: preparation 3 ' Zidovodine-5 '-thiophosphoryl glycine methyl ester compound, wherein R is H.
The structural formula of compound is:
Figure C0113078500041
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and the phosphorus thiochloride of 1mmol (0.17g) is dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the glycine methyl ester hydrochloride of 1mmol (0.125g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the 3 ' Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last.After hydrolysis is finished, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=33: 1: 1 can obtain product 3 ' Zidovodine-5 '-the thiophosphoryl glycine methyl ester, productive rate is 88.9%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 61.70,62.10; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH), 7.41 (1H, s, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6): δ 173.24 ( COOMe), 163.70 (C-2), 150.43 (C-4), 140.76 (C-6), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), 65.87 (C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 435 (M+H) +ESI-MS (neg.): m/z 433 (M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 5×10 -3μM (CD 50?182μM)
CEM-SS 4×10 -2μM (CD 50?49μM)
MT4 2 * 10 -2μ M (CD 5060 μ M) embodiment 2: preparation 3 ' Zidovodine-5 '-thiophosphoryl alanine methyl ester compound, wherein R is CH 3The structural formula of compound is:
Figure C0113078500051
The synthesis step of compound:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and the phosphorus thiochloride of 1mmol (0.17g) is dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the alanine methyl ester hydrochloride of 1mmol (0.14g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the 3 ' Zidovodine that 1mmol (0.267g) has been dissolved among the THF slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last.After hydrolysis is finished, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=33: 1: 1 can obtain product 3 ' Zidovodine-5 '-the thiophosphoryl alanine methyl ester, productive rate is 82.3%.
Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 60.20,61.70; 1H NMR (500MHz, DMSO-d 6): δ 9.81 (1H, sb, NH), 7.51 (1H, s, H-6), and 6.34 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.56 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.40 (3H, d, Ala-Me); 13C NMR (500MHz, DMSO-d 6): δ 178.24 ( COOMe), 163.70 (C-2), 150.43 (C-4), 140.76 (C-6), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), 65.87 (C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 20.86 (d, Ala-Me, J=5Hz), 12.60 (5-Me); ESI-MS (pos.): m/z 449 (M+H) +ESI-MS (neg.): m/z 447 (M-H) -. the anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 5×10 -3μM (CD 50?288μM)
CEM-SS 4×10 -2μM (CD 50?49μM)
MT4 8 * 10 -2μ M (CD 5069 μ M) embodiment 3: preparation 3 ' Zidovodine-5 '-thiophosphoryl phenylalanine methyl ester compound, wherein R is C 6H 5CH 2The structural formula of compound is:
The synthesis step of compound is as follows:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and the phosphorus thiochloride of 1mmol (0.17g) is dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the phenylalanine methyl ester hydrochloride of 1mmol (0.215g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the 3 ' Zidovodine that 1mmol (0.266g) has been dissolved among the THF slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last.After hydrolysis is finished, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=33: 1: 1 can obtain product 3 ' Zidovodine-5 '-the thiophosphoryl phenylalanine methyl ester, productive rate is 80.6%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 60.70,61.30; 1H NMR (500MHz, DMSO-d 6): δ 9.88 (1H, sb, NH), 7.46 (1H, s, H-6), 7.15-7.35 (5H, m, Ph), and 6.32 (1H, m, H-1 '), 4.20-4.44 (4H, H-3 ', H4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-α), 2,50 (1H, m, H-2 '), 2.32 (2H, m, H-β), 2.02 (3H, s, 5-Me); 13C NMR (500MHz, DMSO-d 6): δ 174.39 ( COOMe), 163.66 (C-2), 151.24 (C-4), 148.36 (Ph-jpso), 140.93 (C-6), 135.12 (Ph-para), 130.42 (Ph-ortho), 119.91 (Ph-meta), 111.52 (C-5), (84.94 C-1 '), (82.40 C-4 '), 65.87 (C-5 '), 60.54 (C-3 '), (56.82 C-β), 54.78 (OCH 3), 50.41 (C-α), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 449 (M+H) +ESI-MS (neg.): m/z 447 (M-H) -The anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 8×10 -3μM (CD 50?112μM)
CEM-SS 3×10 -2μM (CD 50?29μM)
MT4 6 * 10 -2μ M (CD 5044 μ M) embodiment 4: preparation 3 ' Zidovodine-5 '-thiophosphoryl valine methyl ester compound, wherein R is (CH 3) 2CH 2The structural formula of compound is:
The synthesis step of compound:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and the phosphorus thiochloride of 1mmol (0.17g) is dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the valine methyl ester hydrochloride of 1mmol (0.17g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the 3 ' Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last.After hydrolysis is finished, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=33: 1: 1 can obtain product 3 ' Zidovodine-5 '-the thiophosphoryl valine methyl ester, productive rate is 87.3%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 61.70,62.40; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH), 7.41 (1H, s, H-6), and 6.32 (1H, m, H-1 '), 4.20-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.67 (1H, m, H-α), 3.45 (1H, m, H-β), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.61 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 174.24 ( COOMe), 165.70 (C-2), 150.63 (C-4), 141.26 (C-6), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), 65.87 (C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 26.86 (CH 3), 26.40 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 477 (M+H) +ESI-MS (neg.): m/z 475 (M-H) -. the anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK - 6×10 -3μM (CD 50?77μM)
CEM-SS 1×10 -2μM (CD 50?48μM)
MT4 2×10 -2μM (CD 50?62μM)
Embodiment 5: preparation 3 ' Zidovodine-5 '-thiophosphoryl leucine methyl compound, wherein R is (CH 3) 2CHCH 2
The structural formula of compound is:
The synthesis step of compound:
1) under nitrogen protection, cryosel is bathed and to be cooled to-4～-8 ℃, and the phosphorus thiochloride of 1mmol (0.17g) is dissolved in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) in above-mentioned solution, add the leucine methyl ester hydrochloride of 1mmol (0.184g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the 3 ' Zidovodine that 1mmol (0.31g) has been dissolved among the THF slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
4) finish with the NMR monitoring reaction after, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last.After hydrolysis is finished, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=33: 1: 1 can obtain product 3 ' Zidovodine-5 '-thiophosphoryl leucine methyl esters, productive rate is 88.3%.Spectral data is as follows: 31P NMR (DMSO-d 6, δ: ppm, J:Hz): δ 60.6,61.8; 1H NMR (500MHz, DMSO-d 6): δ 9.80 (1H, sb, NH), 7.41 (1H, s, H-6), and 6.32 (1H, m, H-1 '), 4.20.-4.41 (4H, H-3 ', H-4 ', H-5 '), 4.01 (1H, m, Ala-NH), 3.88 (3H, s, OCH 3), 3.57 (2H, m, H-o), and 3.45 (1H, m, H-β), 3.21 (1H, m, H-γ), 2,50 (1H, m, H-2 '), 2.02 (3H, s, 5-Me), 1.61 (3H, s, CH 3), 1.42 (3H, s, CH 3); 13C NMR (500MHz, DMSO-d 6): δ 173.24 ( COOMe), 163.70 (C-2), 150.43 (C-4), 140.76 (C-6), 111.52 (C-5), 84.94 (C-1 '), 82.40 (C-4 '), 65.87 (C-5 '), 60.54 (C-3 '), 54.78 (OCH 3), 50.41 (C-α), 48.66 (C-β), 46.35 (C-γ), 23.40 (CH 3), 22.86 (CH 3), 37.46 (C-2 '), 12.60 (5-Me); ESI-MS (pos.): m/z 491 (M+H) +ESI-MS (neg.): m/z 489 (M-H) -. the anti-love of this compound in cem cell and MT-4 cell is virus-1 activity experiment now
Like virus=Human immunodeficiency virus now
MT-4＝Human?leukenia?T?cell
CEM＝Human?lymphoblastoid?T?cell
ED 50=antiviral activity index
CD 50=cytotoxicity index
ED 50 CEM-TK- 8×10 -3μM (CD 50 79μM)
CEM-SS 9×10 -2μM (CD 50 78μM)
MT4 5×10 -2μM (CD 50 23μM)

Claims (2)

1, a kind of 3 ' Zidovodine-5 '-thiophosphoryl amino acid methyl ester compound, it is characterized in that the structural formula of this compound is:
Figure C0113078500021
R is H, CH in the said structure formula 3, C 6H 5CH 2, (CH 3) 2CH 2Or (CH 3) 2CHCH 2In any.
2, a kind of preparation method of compound as claimed in claim 1 is characterized in that this method comprises following each step:
1) under nitrogen protection, cryosel is bathed under the condition that is cooled to-4～-8 ℃, and the raw material phosphorus thiochloride is dissolved in the dry tetrahydrofuran (THF) of crossing, and is mixed with the solution that concentration is 0.8～1.0mol/L;
2) add amino acid methyl ester hydrochloride with the amount of raw material same substance in above-mentioned solution, slowly drip the acid binding agent triethylamine after stirring, the add-on of acid binding agent is 2 times of amount of raw material;
3) follow the tracks of above-mentioned reaction process, after treating that the raw material total overall reaction finishes, to slowly splash in the solution in second step with 3 ' the Zidovodine solution that is dissolved in the tetrahydrofuran (THF) of the amount of raw material same substance, the acid binding agent with the amount of raw material same substance is continued to drip in the back that stirs
4) after monitoring reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last, carries out column chromatography for separation with silicagel column, promptly get 3 ' Zidovodine-5 '-thiophosphoryl amino acid methyl ester compound.
CNB011307854A 2001-08-24 2001-08-24 3'-azido-deoxythymidine-5'-thiopyhosphamino acid ester compound and its preparing process Expired - Fee Related CN1133640C (en)

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