CN1290707A - Nucleoside 5'-thiophosphoryl amino-acid ester compound - Google Patents
Nucleoside 5'-thiophosphoryl amino-acid ester compound Download PDFInfo
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- CN1290707A CN1290707A CN 00129555 CN00129555A CN1290707A CN 1290707 A CN1290707 A CN 1290707A CN 00129555 CN00129555 CN 00129555 CN 00129555 A CN00129555 A CN 00129555A CN 1290707 A CN1290707 A CN 1290707A
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Abstract
Nucleoside 5'-thiiophosphoryl amino acid ester compound is prepared through the processes of dissolving thiophosphoryl trichloride in dried tetrahydrofuran, addition of carbamate hydrochloride through stirring, dripping acid binding agent to react, filtering, rotating distillation to eliminate solvent and other low boiling point matters, hydrolysis in ammonia water and final silica gel chromatography. The compound of the present invention may be used in developing medicine with antiviral, antitumor and HIV resisting activity.
Description
The present invention relates to the novel nucleoside 5 '-thiophosphoryl amino-acid ester compound of a class, this compounds has pharmaceutical activitys such as good biological activity and antiviral, antitumor, anti-HIV, can develop into antiviral, antitumor, the anti-HIV prodrug of a kind of ucleosides (prodrugs) in clinical application.
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.
The objective of the invention is to develop a class nucleosides-thiophosphoryl amino acid ester compound, by synthetic thiophosphoric acid compounds with opposing nuclease, synthetic dna oligo is to be used to develop antiviral, antitumor, HIV (human immunodeficiency virus)-resistant activity medicine.
Total following four kinds of the nucleoside 5 '-thiophosphoryl amino-acid ester compound of the present invention's preparation,
Wherein first kind is adenosine 5 '-thiophosphoryl amino acid ester compound, and its structural formula is:
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: 1) under nitrogen protection, room temperature (25 ℃) is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.2) the amino acid methyl ester hydrochloride of adding same substance amount in above-mentioned solution slowly drips acid binding agent (as triethylamine, the N-Methylimidazole) 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 adenosine that is dissolved in the dry pyridine is slowly splashed in the above-mentioned system, acid binding agent 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.5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product with silicagel column.
Second kind of compound wherein is guanosine 5 '-thiophosphoryl amino acid ester compound, and its structural formula is:
R is H in the said structure formula, CH
3, C
6H
5CH
2, (CH
3)
2CH
2, (CH
3)
2CHCH
3
The synthesis step of above-claimed cpd:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) the amino acid methyl ester hydrochloride of the amount of adding same substance in above-mentioned solution slowly drips acid binding agent (as triethylamine, the N-Methylimidazole) 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 guanosine that is dissolved in the dry pyridine is slowly splashed in the above-mentioned system, acid binding agent 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.
5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product with silicagel column.
The third compound wherein is cytidine 5 '-thiophosphoryl amino acid ester compound, and its structural formula is:
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:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) the amino acid methyl ester hydrochloride of the amount of adding same substance in above-mentioned solution slowly drips acid binding agent (as triethylamine, the N-Methylimidazole) 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 cytidine that is dissolved in the dry pyridine is slowly splashed in the above-mentioned system, acid binding agent 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.
5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product with silicagel column.
The 4th kind of compound wherein is uridine 5 '-thiophosphoryl amino acid ester compound, and its structural formula is:
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:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing (THF), is mixed with the solution of 1mol/L.
2) the amino acid methyl ester hydrochloride of the amount of adding same substance in above-mentioned solution slowly drips acid binding agent (as three second peace, N-Methylimidazole) 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 uridine that is dissolved in the dry THF is slowly splashed in the above-mentioned system, acid binding agent 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.
5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product with silicagel column.
The anti-HIV-1 activity experiment of above-mentioned synthetic series compound in cem cell and MT-4 cell finds all to have activity in various degree, can be used to develop antiviral, antitumor, HIV (human immunodeficiency virus)-resistant activity medicine.
Below be embodiments of the invention:
Embodiment 1: the preparation of adenosine 5 '-thiophosphoryl glycine methyl ester compound, wherein R is H.
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 adenosine that 1mmol (0.267g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product adenosine 5 '-thiophosphoryl glycine methyl ester at 16.5: 1: 1, productive rate is 68.4%.Spectral data is as follows:
31P NMR (DMSO-d
6, δ: ppm, J:Hz): δ 59.38,58.62;
1H NMR (500MHz, DMSO-d
6): δ 9.26,9.22 (bs, 1H, NH), 8.43 (1H, s, H-2), 8.23 (1H, s, H-8), 7.40 (2H, s, NH
2), 6.44 (1H, m, H-1 '), 4,50 (2H, m, H-2 ', 3 '), 3.97 (1H, m, H-4 '), 3.88 (3H, s,
OCH
3),3.64(2H,m,H-5′),3.57(2H,m,H-α);
13C?NMR(500MHz,DMSO-d
6):δ173.24(COOMe),163.70(C-2),150.43(C-4),140.76(C-6),101.76(C-1′),87.74(C-5),84.83(C-2′),73.54(C-3′),69.80(C-4′),60.87(C-5′),54.78(OCH
3),45.86(C-α);ESI-MS(pos.):m/z?435(M+H)
+;ESI-MS(neg.):m/z?433(M-H)
-。The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
HIV=Human?immunodeficiency?virus
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
-4M (CD
50?7×10
-6M)
CEM-SS 4×10
-3M (CD
50?9×10
-5M)
MT?4 2×10
-1M (CD
50 8×10
-6M)
Embodiment 2: the preparation of adenosine 5 '-thiophosphoryl alanine methyl ester compound, wherein R is CH3.The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 adenosine that 1mmol (0.267g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product adenosine 5 '-thiophosphoryl alanine methyl ester at 16.5: 1: 1, productive rate is 66.4%.Spectral data is as follows:
31P NMR (DMSO-d
6, δ: ppm, J:Hz): δ 59.86,58.53;
1H NMR (500MHz, DMSO-d
6): δ 9.44,9.40 (bs, 1H, NH), 8.89 (1H, s, H-2), 8.67 (1H, s, H-8), 7.67 (2H, s, NH
2), 6.59 (1H, m, H-1 '), 4,78 (2H, m, H-2 ', 3 '), 4.22 (1H, m, H-4 '), 3.98 (3H, s, OCH
3), 3.85 (2H, m, H-5 '), 3.67 (2H, m, H-α), 1.31,1.30 (3H, d,
3J=6, β-CH
3);
13C NMR (500MHz, DMSO-d
6): δ 180.24 (COOMe), 170.70 (C-2), 156.43 (C-4), l49.76 (C-6), (108.23 C-1 '), 89.66 (C-5), 85.87 (C-2 '), 76.23 (C-3 '), (69.66 C-4 '), 61.23 (C-5 '), 54.78 (OCH
3), 50.73 (C-α), 48.66 (C-β); ESI-MS (pos.): m/z 449 (M+H)
+ESI-MS (neg.): m/z 447 (M-H)
-The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-3M (CD
50 3×10
-6M)
CEM-SS 6×10
-3M (CD
50 9×10
-5M)
MT?4 8×10
-4M (CD
50 6×10
-6M)
Embodiment 3: the preparation of adenosine 5 '-thiophosphoryl phenylalanine methyl ester compound, wherein R is C
6H
5CH
2The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.22g), 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 adenosine that 1mmol (0.267g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product adenosine 5 '-thiophosphoryl phenylalanine methyl ester at 16.5: 1: 1, productive rate is 69.7%.Spectral data is as follows:
31P NMR (DMSO-d
6, δ: ppm, J:Hz): δ 60.64,60.33;
1H NMR (500MHz, DMSO-d
6): δ 9.21,9.15 (bs, 1H, NH), 8.67 (1H, s, H-2), 8.58 (1H, s, H-8), 7.88 (2H, s, NH
2), 7.15-7.35 (5H, m, Ph), 6.59 (1H, m, H-1 '), 4,55 (2H, m, H-2 ', 3 '), 4.37 (1H, m, H-4 '), 3.79 (3H, s, OCH
3), 3.66 (2H, m, H-5 '), 3.48 (2H, m, H-α), 2.32 (2H, m, H-β);
13C NMR (500MHz, DMSO-d
6): δ 174.24 (COOMe), 170.60 (C-2), 159.43 (C-4), 148.36 (Ph-Jpso), 136.11 (C-6), 135.12 (Ph-para), 130.42 (Ph-ortho), 119.91 (Ph-meta), 108.23 (C-1 '), 89.65 (C-5), 87.87 (C-2 '), 76.23 (C-3 '), (72.66 C-4 '), (61.23 C-5 '), 56.82 (C-β), 56.78 (OCH
3), 52.73 (C-α); ESI-MS (pos.): m/z 527 (M+H)
+ESI-MS (neg.): m/z 525 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-2M (CD
50 4×10
-5M)
CEM-SS 9×10
-3M (CD
50 4×10
-6M)
MT?4 6×10
-5M (CD
50 5×10
-6M)
Embodiment 4: the preparation of adenosine 5 '-thiophosphoryl valine methyl ester compound, wherein R is (CH
3)
2CHCH.
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 adenosine that 1mmol (0.267g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product adenosine 5 '-thiophosphoryl valine methyl ester at 16.5: 1: 1, productive rate is 59.2%.Spectral data is as follows:
31P NMR (DMSO-d
6, δ: ppm, J:Hz): δ 56.32,56.14;
1H NMR (500MHz, DMSO-d
6): δ 9.44,9.40 (bs, 1H, NH), 8.67 (1H, s, H-2), 8.58 (1H, s, H-8), 7.54 (2H, s, NH
2), 6.59 (1H, m, H-1 '), 4,78 (2H, m, H-2 ', 3 '), 4.22 (1H, m, H-4 '), 3.98 (3H, s, OCH
3), 3.85 (2H, m, H-5 '), 3.67 (1H, m, H-α), 3.45 (1H, m, H-β), 1.61 (3H, s, CH
3), 1.42 (3H, s, CH
3);
13C NMR (500MHz, DMSO-d
6): δ 172.24 (COOMe), 165.70 (C-2), 159.43 (C-4), 145.76 (C-6), (108.23 C-1 '), 89.66 (C-5), 85.87 (C-2 '), 76.23 (C-3 '), (69.66 C-4 '), 61.23 (C-5 '), 54.78 (OCH
3), 50.73 (C-α), 48.66 (C-β), 26.40 (CH
3), 26.86 (CH
3); ESI-MS (pos.): m/z 518 (M+H)
+ESI-MS (neg.): m/z 516 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 7×10
-3M (CD
50 8×l0
-6M)
CEM-SS 6×10
-3M (CD
50 5×10
-6M)
MT?4 8×10
-4M (CD
50 6×10
-5M)
Embodiment 5: the preparation of adenosine 5 '-thiophosphoryl leucine methyl compound, wherein R is (CH
3)
2CHCH
2
The structural formula of compound:
The synthesis step of compound
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.18g), 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 adenosine that 1mmol (0.267g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product adenosine 5 '-thiophosphoryl leucine methyl esters at 16.5: 1: 1, productive rate is 65.2%.Spectral data is as follows:
31P NMR (DMSO-d
6, δ: ppm, J:Hz): δ 58.32,57.68;
1H NMR (500MHz, DMSO-d
6): δ 9.31,9.27 (bs, 1H, NH), 8.67 (1H, s, H-2), 8.58 (1H, s, H-8), 7.54 (2H, s, NH
2), 6.59 (1H, m, H-1 '), 4,78 (2H, m, H-2 ', 3 '), 4.22 (1H, m, H-4 '), 3.98 (3H, s, OCH
3), 3.85 (2H, m, H-5 '), 3.67 (1H, m, H-α), 3.45 (1H, m, H-β), 3.21 (1H, m, H-γ), 1.61 (3H, s, CH
3), 1.42 (3H, s, CH
3);
13C NMR (500MHz, DMSO-d
6): δ 172.24 (COOMe), 165.70 (C-2), 159.43 (C-4), 145.76 (C-6), (109.23 C-1 '), 89.66 (C-5), 85.87 (C-2 '), 76.23 (C-3 '), (69.66 C-4 '), 61.23 (C-5 '), 54.78 (OCH
3), 50.73 (C-α), 48.66 (C-β), 46.35 (C-γ); ESI-MS (pos.): m/z 492 (M+H)
+ESI-MS (neg.): m/z 490 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-4M (CD
50 2×10
-6M)
CEM-SS 2×10
-4M (CD
50 5×10
-5M)
MT?4 5×10
-3M (CD
50 8×10
-6M)
Embodiment 6: the preparation of guanosine 5 '-thiophosphoryl glycine methyl ester compound, wherein R is H.
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 guanosine that 1mmol (0.283g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product guanosine 5 '-thiophosphoryl glycine methyl ester at 16.5: 1: 1, productive rate is 63.4%.
Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 57.68,57.39;
1H NMR (500MHz, D
2O): δ 8.18 (1H, s, H-8), 5.82,5.81 (1H, d,
3J=6.0, H-1 '), 4,89 (1H, m, H-2 '), 4.23 (1H, m, H-3 '), 3.23 (1H, m, H-4 '), 3.54 (3H, s, OCH
3), 3.65 (2H, m, H-5 '), 3.54 (2H, m, H-α), 1.66,1.65 (3H, d,
3J=6.0, β-CH
3);
13C NMR (500MHz, D
2O): δ 172.31 (COOMe), 165.81 (C-2), 158.67 (C-6), 152.34 (C-4), 139.66 (C-8), 118.71 (C-5), 89.42 (C-4 '), 86.25 (C-1 '), (73.55 C-3 '), 70.82 (C-2 '), 61.45 (C-5 '), 54.62 (OCH
3), 50.62 (C-β), 45.89 (C-α); ESI-MS (pos.): m/z 451 (M+H)
+ESI-MS (neg.): m/z 449 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-4M (CD
50 6×10
-5M)
CEM-SS 3×10
-4M (CD
50 4×10
-6M)
MT?4 6×10
-4M (CD
50 3×10
-5M)
Embodiment 7: the preparation of guanosine 5 '-thiophosphoryl alanine methyl ester compound, wherein R is CH
3
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.140g), slowly drip 2mmol (0.2g) triethylamine after stirring.
4) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the guanosine that 1mmol (0.283g) has been dissolved in the dry pyridine slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
5) 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.
6) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product guanosine 5 '-thiophosphoryl alanine methyl ester at 16.5: 1: 1, productive rate is 65.3%.
Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 58.88,58.37;
1H NMR (500MHz, D
2O): δ 8.07 (1H, s, H-8), 5.82,5.81 (1H, d,
1J=6.0, H-1 '), 4,51 (1H, m, H-2 '), 4.18 (1H, m, H-3 '), 3.94 (1H, m, H-4 '), 3.86 (3H, s, OCH
3), 3.68 (2H, m, H-5 '), 3.57 (2H, m, H-α);
13C NMR (500MHz, D
2O): δ 178.31 (COOMe), 156.81 (C-2), 153.67 (C-6), 151.34 (C-4), 135.66 (C-8), 116.71 (C-5), 86.42 (C-4 '), 85.25 (C-1 '), (73.74 C-3 '), 70.42 (C-2 '), 61.45 (C-5 '), 54.62 (OCH
3), 45.89 (C-α); ESI-MS (pos.): m/z 466 (M+H)
+ESI-MS (neg.): m/z 464 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 6×10
-4M (CD
50 7×10
-5M)
CEM-SS 9×10
-3M (CD
50 6×10
-5M)
MT?4 2×10
-4M (CD
50 8×10
-5M)
Embodiment 8: the preparation of guanosine 5 '-thiophosphoryl phenylalanine methyl ester compound, wherein R is C
6H
5CH
2
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.21g), 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 guanosine that 1mmol (0.283g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product guanosine 5 '-thiophosphoryl phenylalanine methyl ester at 16.5: 1: 1, productive rate is 70.3%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm.J:Hz): δ 57.18,56.89;
1H NMR (500MHz, D
2O): δ 8.07 (1H, s, H-8), 7.25-7.41 (5H, m, Ph), 5.79,5.78 (1H, d,
3J=6.0, H-1 '), 4,41 (1H, m, H-2 '), 4.18 (1H, m, H-3 '), 3.94 (1H, m, H-4 '), 3.86 (3H, s, OCH
3), 3.68 (2H, m, H-5 '), 3.57 (2H, m, H-α), 2.27 (2H, m, H-β);
13C NMR (500MHz, D
2O): δ 180.31 (COOMe), 166.81 (C-2), 161.67 (C-6), 158.34 (C-4), 151.26 (Ph-jpso), 135.66 (C-8), 130.07 (Ph-para), 128.23 (Ph-ortho), 118.45 (Ph-meta), 96.71 (C-5), 86.42 (C-4 '), 85.25 (C-1 '), (73.74 C-3 '), 70.42 (C-2 '), 61.45 (C-5 '), (57.22 C-β), 54.62 (OCH
3), 45.89 (C-α); ESI-MS (pos.): m/z 541 (M+H)
+ESI-MS (neg.): m/z 539 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-3M (CD
50 6×10
-5M)
CEM-SS 6×10
-4M (CD
50 5×10
-5M)
MT?4 2×10
-4M (CD
50 8×10
-5M)
Embodiment 9: the preparation of guanosine 5 '-thiophosphoryl valine methyl ester compound, wherein R is (CH
3)
2CH.
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.170g), 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 guanosine that 1mmol (0.283g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product guanosine 5 '-thiophosphoryl valine methyl ester at 16.5: 1: 1, productive rate is 66.2%.
Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 59.86,59.27;
1H NMR (500MHz, D
2O): δ 9.07 (1H, s, H-8), 6.82,6.81 (1H, d,
3J=6.0, H-1 '), 5,48 (1H, m, H-2 '), 4.95 (1H, m, H-3 '), 4.36 (1H, m, H-4 '), 3.86 (3H, s, OCH
3), 3.68 (2H, m, H-5 '), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 1.16,1.15 (3H, d,
3J=6.0, CH
3), 1.06,1.05 (3H, d,
3J=6.0, CH
3);
13C NMR (500MHz, D
2O): δ 178.31 (COOMe), 156.81 (C-2), 153.67 (C-6), 151.34 (C-4), 135.66 (C-8), 116.71 (C-5), 86.42 (C-4 '), 85.25 (C-1 '), (73.74 C-3 '), 70.42 (C-2 '), 61.45 (C-5 '), 54.62 (OCH
3), 45.89 (C-α), 44.24 (C-β), 23.66 (CH
3), 23.15 (CH
3); ESI-MS (pos.): m/z 493 (M+H)
+ESI-MS (neg.): m/z 491 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-3M (CD
50 3×10
-5M)
CEM-SS 5×10
-3M (CD
50 8×10
-5M)
MT?4 4×10
-3M (CD
50 6×10
-5M)
Embodiment 10: the preparation of guanosine 5 '-thiophosphoryl leucine methyl compound, wherein R is (CH
3)
2CHCH
2
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.180g), 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 guanosine that 1mmol (0.283g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product guanosine 5 '-thiophosphoryl leucine methyl esters at 16.5: 1: 1, productive rate is 62.2%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 58.86,58.27;
1H NMR (500MHz, D
2O): δ 9.07 (1H, s, H-8), 6.82,6.81 (1H, d,
3J=6.0, H-1 '), 5,48 (1H, m, H-2 '), 4.95 (1H, m, H-3 '), 4.36 (1H, m, H-4 '), 3.86 (3H, s, OCH
3), 3.68 (2H, m, H-5 '), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 3.22 (1H, m, H-γ), 1.16,1.15 (3H, d,
3J=6.0, CH
3), 1.06,1.05 (3H, d,
3J=6.0, CH
3);
13C NMR (500MHz, D
2O): δ 178.31 (COOMe), 166.81 (C-2), 159.67 (C-6), 156.34 (C-4), 134.66 (C-8), 116.71 (C-5), 86.42 (C-4 '), 85.25 (C-1 '), (73.74 C-3 '), 70.42 (C-2 '), 61.45 (C-5 '), 54.62 (OCH
3), 45.89 (C-α), 44.24 (C-β), 41.24 (C-γ); ESI-MS (pos.): m/z 508 (M+H)
+ESI-MS (neg.): m/z 506 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 6×10
-4M (CD
50 6×10
-5M)
CEM-SS 6×10
-4M (CD
50 5×10
-5M)
MT?4 8×10
-4M (CD
50 7×10
-5M)
Embodiment 11: the preparation of cytidine 5 '-thiophosphoryl glycine methyl ester compound, wherein R is H.
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 cytidine that 1mmol (0.242g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product cytidine 5 '-thiophosphoryl glycine methyl ester at 16.5: 1: 1, productive rate is 61.4%.
Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 57.88,56.16;
1H NMR (500MHz, D
2O): δ 7.90,7.89 (1H, d,
3J=5.5, H-6), 6.24 (1H, m, H-1 '), 5.84,5.83 (1H, d,
3J=6, H-5), 4.28 (1H, m, H-3 '), 3.88 (1H, m, H-4 '), 3.71 (3H, s, OCH
3), 3.65 (2H, m, H-5 '), 2.69 (2H, m, H-α), 2.15 (1H, H-2 ');
13C NMR (500MHz, D
2O): δ 177.63 (COOMe), 165.82 (C-4), 158.13 (C-2), 140.34 (C-6), 93.71 (C-5), 87.25 (C-1 '), 84.42 (C-4 '), 70.42 (C-3 '), 61.45 (C-5 '), 54.62 (OCH
3), 45.89 (C-α), 39.82 (C-2 '); ESI-MS (pos.): m/z 411 (M+H)
+ESI-MS (neg.): m/z 409 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-4M (CD
50 6×10
-5M)
CEM-SS 6×10
-3M (CD
50 4×10
-5M)
MT?4 6×10
-4M (CD
50 3×10
-6M)
Embodiment 12: the preparation of cytidine 5 '-thiophosphoryl alanine methyl ester compound, wherein R is CH
3
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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.
4) follow the tracks of reaction process with nuclear magnetic resonance analyser (NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the cytidine that 1mmol (0.242g) has been dissolved in the dry pyridine slowly splashes in the above-mentioned system, 1mmol (0.1g) triethylamine is continued to drip in the back that stirs.
5) 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.
6) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product cytidine 5 '-thiophosphoryl alanine methyl ester at 16.5: 1: 1, productive rate is 68.4%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 57.66,57.31;
1H NMR (500MHz, D
2O): δ 7.90,7.89 (1H, d,
3J=5.5, H-6), 6.88 (1H, m, H-1 '), 5.84,5.83 (1H, d,
3J=6, H-5), 4.68 (1H, m, H-3 '), 3.88 (1H, m, H-4 '), 3.71 (3H, s, OCH
3), 3.65 (2H, m, H-5 '), 2.89 (2H, m, H-α), 2.66 (1H, H-2 '), 1.45 (3H, d,
3J=6, H-β);
13C NMR (500MHz, D
2O): δ 185.63 (COOMe), 165.82 (C-4), 158.13 (C-2), 145.34 (C-6), 93.71 (C-5), 87.25 (C-1 '), 84.42 (C-4 '), 70.42 (C-3 '), 61.45 (C-5 '), 54.62 (OCH
3), 50.86 (C-β), 45.89 (C-α), 39.82 (C-2 '); ESI-MS (pos.): m/z 424 (M+H)
+ESI-MS (neg.): m/z 422 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-3M (CD
50 5×10
-5M)
CEM-SS 5×10
-3M (CD
50 8×10
-6M)
MT?4 7×10
-4M (CD
50 3×10
-6M)
Embodiment 13: the system of cytidine 5 '-thiophosphoryl phenylalanine methyl ester compound is put forth energy, and wherein R is C
6H
5CH
2
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.22g), 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 cytidine that 1mmol (0.242g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product cytidine 5 '-thiophosphoryl phenylalanine methyl ester at 16.5: 1: 1, productive rate is 66.7%.
Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 58.71,58.13;
1H NMR (500MHz, D
2O): δ 8.22,8.21 (1H, d,
3J=5.5, H-6), 7.29-7.41 (5H, m, Ph), 7.03 (1H, m, H-1 '), 5.84,5.83 (1H, d,
3J=6, H-5), 4.66 (1H, m, H-3 '), 3.82 (1H, m, H-4 '), 3.58 (3H, s, OCH
3), 3.44 (2H, m, H-5 '), 2.89 (2H, m, H-α), 2.66 (1H, H-2 '), 2.27 (1H, m, H-β);
13C NMR (500MHz, D
2O): δ 180.63 (COOMe), 165.82 (C-4), 158.13 (C-2), 146.36 (Ph-jpso), 117.02,136.11 (C-6), 137.12 (Ph-para), 136.42 (Ph-ortho), 122.91 (Ph-meta), 93.71 (C-5), (87.25 C-1 '), 84.42 (C-4 '), 70.42 (C-3 '), (61.45 C-5 '), 54.62 (OCH
3), 50.86 (C-β), 45.89 (C-α), 39.82 (C-2 '); ESI-MS (pos.): m/z 500 (M+H)
+ESI-MS (neg.): m/z 498 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-4M (CD
50 8×10
-5M)
CEM-SS 6×10
-4M (CD
50 8×10
-5M)
MT?4 8×10
-4M (CD
50 7×10
-5M)
Embodiment 14: the preparation of cytidine 5 '-thiophosphoryl valine methyl ester compound, wherein R is (CH
3)
2CH.
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 cytidine that 1mmol (0.242g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product cytidine 5 '-thiophosphoryl valine methyl ester at 16.5: 1: 1, productive rate is 63.4%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 59.98,59.21;
1H NMR (500MHz, D
2O): δ 7.90,7.89 (1H, d,
3J=5.5, H-6), 6.63 (1H, m, H-1 '), 5.84,5.83 (1H, d,
3J=6, H-5), 4.61 (1H, m, H-3 '), 3.69 (1H, m, H-4 '), 3.76 (3H, s, OCH
3), 3.65 (2H, m, H-5 '), 2.89 (2H, m, H-α), 2.66 (1H, H-2 '), 2.14 (1H, m, H-β);
13C NMR (500MHz, D
2O): δ 185.63 (COOMe), 165.82 (C-4), 158.13 (C-2), 145.34 (C-6), 93.71 (C-5), 87.25 (C-1 '), 84.42 (C-4 '), 70.42 (C-3 '), 61.45 (C-5 '), 54.62 (OCH
3), 50.86 (C-β), 49.89 (C-α), 46.21 (C-β), 39.82 (C-2), ESI-MS (pos.): m/z 466 (M+H)
+ESI-MS (neg.): m/z 464 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-4M (CD
50 5×10
-5M)
CEM-SS 5×10
-4M (CD
50 9×10
-5M)
MT?4 8×10
-3M (CD
50 3×10
-5M)
Embodiment 15: the preparation of cytidine 5 '-thiophosphoryl leucine methyl compound, wherein R is (CH
3)
2CHCH
2
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.18g), 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 cytidine that 1mmol (0.242g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product cytidine 5 '-thiophosphoryl leucine methyl esters at 16.5: 1: 1, productive rate is 65.4%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 56.36,56.56;
1H NMR (500MHz, D
2O): δ 7.96,7.95 (1H, d,
3J=6, H-6), 6.36 (1H, m, H-1 '), 5.84,5.83 (1H, d,
3J=6, H-5), 4.78 (1H, m, H-3 '), 3.88 (1H, m, H-4 '), 3.76 (3H, s, OCH
3), 3.65 (2H, m, H-5 '), 3.22 (2H, m, H-α), 2.96 (1H, H-2 '), 2.77 (1H, m, H-β), 2.39 (1H, m, H-γ);
13C NMR (500MHz, D
2O): δ 185.63 (COOMe), 165.82 (C-4), 158.13 (C-2), 145.34 (C-6), 93.71 (C-5), 88.25 (C-1 '), 85.42 (C-4 '), 70.42 (C-3 '), 61.45 (C-5 '), 54.88 (OCH
3), 50.86 (C-β), 48.89 (C-α), 46.21 (C-γ), 39.82 (C-2 '); ESI-MS (pos.): m/z 468 (M+H)
+ESI-MS (neg.): m/z 466 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-3M (CD
50 6×10
-6M)
CEM-SS 8×10
-3M (CD
50 9×10
-6M)
MT?4 7×10
-3M (CD
50 8×10
-6M)
Embodiment 16: the preparation of uridine 5 '-thiophosphoryl glycine methyl ester compound, wherein R is H.
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 uridine that 1mmol (0.244g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product uridine 5 '-thiophosphoryl glycine methyl ester at 16.5: 1: 1, productive rate is 68.4%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 57.68,56.89;
1H NMR (500MHz, D
2O): δ 7.79,7.78 (1H, dd,
3J=4.5, H-6), 5.82 (2H, m, H-1 ', 5), 4.93 (2H, m, H-2 ', 3 '), 4.52 (1H, m, H-4 '), 4.00 (2H, m, H-5 '), 3.63 (3H, s, OCH
3), 3.57 (2H, m, H-α);
13C NMR (500MHz, D
2O): δ 177.08 (COOMe), 169.02 (C-4), 153.99 (C-2), 145.39,145.36 (C-6), 104.33,104.22 (C-5), 95.83,95.16 (C-1 '), (87.97 C-4 '), 87.20,87.13 (C-2 '), 83.64, (83.51 C-3 '), 67.24 (C-5 '), 55.09 (OCH
3), 45.80,45.73 (C-α); ESI-MS (pos.): m/z 413 (M+H)
+ESI-MS (neg.): m/z 411 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-3M (CD
50 9×10
-5M)
CEM-SS 9×10
-3M (CD
50 8×10
-5M)
MT?4 8×10
-4M (CD
50 5×10
-6M)
Embodiment 17: the preparation of uridine 5 '-thiophosphoryl alanine methyl ester compound, wherein R is CH
3
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 uridine that 1mmol (0.244g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product uridine 5 '-thiophosphoryl alanine methyl ester at 16.5: 1: 1, productive rate is 71.4%.Spectral data is as follows: 31P NMR (D
2O, δ: ppm, J:Hz): δ 58.32,57.68;
1H NMR (500MHz, D
2O): δ 7.88,7.87 (1H, dd,
3J=5, H-6), 5.89 (2H, m, H-1 ', 5), 4.98 (2H, m, H-2 ', 3 '), 4.61 (1H, m, H-4 '), 4.04 (2H, m, H-5 '), 3.73 (3H, s, OCH
3), 3.57 (2H, m, H-α), 1.31,1.30 (3H, d,
3J=6, β-CH
3);
13C NMR (500MHz, D
2O): δ 175.04 (COOMe), 166.73 (C-4), 149.28 (C-2), 144.36,144.32 (C-6), 107.62,107.43 (C-5), 98.76,98.41 (C-1 '), (86.23 C-4 '), 85.71,85.63 (C-2 '), 82.70, (82.58 C-3 '), 65.44 (C-5 '), 56.87 (OCH
3), 50.73 (C-α), 48.66 (C-β); ESI-MS (pos.): m/z 426 (M+H)
+ESI-MS (neg.): m/z 424 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-4M (CD
50 6×10
-5M)
CEM-SS 7×10
-4M (CD
50 6×10
-5M)
MT?4 8×10
-4M (CD
50 5×10
-5M)
Embodiment 18: the preparation of uridine 5 '-thiophosphoryl phenylalanine methyl ester compound, wherein R is C
6H
5CH
2
The structural formula of compound:
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.21g), slowly drip 2mmol (0.2g) triethylamine after stirring.
3) follow the tracks of reaction process with nuclear magnetic resonance analyser (1NMR), treat that the phosphorus thiochloride total overall reaction finishes after, the uridine that 1mmol (0.244g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product uridine 5 '-thiophosphoryl phenylalanine methyl ester at 16.5: 1: 1, productive rate is 72.4%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 60.32,59.68;
1H NMR (500MHz, D
2O): δ 7.88,7.87 (1H, dd,
3J=5, H-6), 7.22-7.46 (5H, m, Ph), 6.08 (2H, m, H-1 ', 5), 5.15 (2H, m, H-2 ', 3 '), 4.71 (1H, m, H-4 '), 4.34 (2H, m, H-5 '), 3.93 (3H, s, OCH
3), 3.57 (2H, m, H-α), 2.37 (2H, m, H-β);
13C NMR (500MHz, D
2O): δ 178.04 (COOMe), 166.73 (C-4), 149.28 (C-2), 148.39 (Ph-jpso), 148.36,148.32 (C-6), 139.12 (Ph-para), 129.42 (Ph-ortho), 122.91 (Ph-meta), 110.62,110.43 (C-5), 98.76,98.41 (C-1 '), 88.23 (C-4 '), 85.71,85.63 (C-2 '), 83.27, (82.58 C-3 '), 65.44 (C-5 '), 56.87 (OCH
3), 50.73 (C-α), 48.66 (C-β); ESI-MS (pos.): m/z 522 (M+H)
+ESI-MS (neg.): m/z 520 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 8×10
-4M (CD
50 7×10
-5M)
CEM-SS 7×10
-4M (CD
50 6×10
-5M)
MT?4 6×10
-4M (CD
50 6×10
-5M)
Embodiment 19: the preparation of uridine 5 '-thiophosphoryl valine methyl ester compound, wherein R is (CH
3)
2CH.
The synthesis step of compound
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.14g), 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 uridine that 1mmol (0.244g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product uridine 5 '-thiophosphoryl valine methyl ester at 16.5: 1: 1, productive rate is 65.4%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 58.32,57.55;
1H NMR (500MHz, D
2O): δ 7.89,7.88 (1H, dd,
3J=5, H-6), 5.99 (2H, m, H-1 ', 5), 4.96 (2H, m, H-2 ', 3 '), 4.61 (1H, m, H-4 '), 4.04 (2H, m, H-5 '), 3.73 (3H, s, OCH
3), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 1.31,1.30 (2H, d, 2CH
3);
13C NMR (500MHz, D
2O): δ 178.04 (COOMe), 167.55 (C-4), 146.28 (C-2), 144.36,144.32 (C-6), 107.62,107.43 (C-5), 98.76,98.41 (C-1 '), (86.23 C-4 '), 85.71,85.63 (C-2 '), 82.70, (82.58 C-3 '), 65.44 (C-5 '), 56.87 (OCH
3), 50.73 (C-α), 48.66 (C-β), 22.45 (CH
3), 22.55 (CH
3); ESI-MS (pos.): m/z 454 (M+H)
+ESI-MS (neg.): m/z 452 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 9×10
-3M (CD
50 8×10
-5M)
CEM-SS 6×10
-3M (CD
50 8×10
-5M)
MT?4 8×10
-4M (CD
50 2×10
-5M)
Embodiment 20: the preparation of uridine 5 '-thiophosphoryl leucine methyl compound, wherein R is (CH
3)
2CHCH
2
The synthesis step of compound:
1) under nitrogen protection, room temperature (25 ℃) is dissolved in the phosphorus thiochloride of 1mmol (0.17g) 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 (0.18g), 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 uridine that 1mmol (0.244g) has been dissolved in the dry pyridine 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.
5) after the hydrolysis fully, carry out column chromatography for separation with silicagel column, eluent is a Virahol: ammoniacal liquor: water=can obtain product uridine 5 '-thiophosphoryl leucine methyl esters at 16.5: 1: 1, productive rate is 67.5%.Spectral data is as follows:
31P NMR (D
2O, δ: ppm, J:Hz): δ 59.66,59.10;
1H NMR (500MHz, D2O): δ 7.89,7.88 (1H, dd,
3J=5, H-6), 5.82 (2H, m, H-1 ', 5), 4.86 (2H, m, H-2 ', 3 '), 4.41 (1H, m, H-4 '), 4.04 (2H, m, H-5 '), 3.73 (3H, s, OCH
3), 3.57 (2H, m, H-α), 3.45 (1H, m, H-β), 3.21 (2H, m, H-γ), 1.31,1.30 (2H, d, 2CH
3);
13C NMR (500MHz, D
2O): δ 178.04 (COOMe), 167.55 (C-4), 152.28 (C-2), 146.36,146.32 (C-6), 107.62,107.43 (C-5), 98.76,98.41 (C-1 '), (88.23 C-4 '), 85.71,85.63 (C-2 '), 82.70, (82.58 C-3 '), 67.44 (C-5 '), 58.54 (OCH
3), 50.73 (C-α), 48.66 (C-β), 35.68 (C-γ), 22.45 (CH
3), 22.55 (CH
3); ESI-MS (pos.): m/z 468 (M+H)
+ESI-MS (neg.): m/z 466 (M-H)
-
The anti-HIV-1 activity experiment of this compound in cem cell and MT-4 cell
ED
50 CEM-TK- 5×10
-5M (CD
50 6×10
-4M)
CEM-SS 6×10
-5M (CD
50 4×10
-5M)
MT?4 7×10
-5M (CD
50 7×10
-5M)
Nucleoside 5 '-thiophosphoryl amino acid methyl ester be a class brand-new have an active compound of inverase, by synthetic different types of nucleosides-amino acid conjugate, and carry out activity experiment, tentatively obtain satisfied result, be further development and the development of new inverase achievement in research that provides the foundation.
Claims (4)
1, a kind of adenosine 5 '-thiophosphoryl amino acid ester compound is characterized in that, the structural formula of this compound is:
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, room temperature is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing, and is mixed with the solution of 1mol/L;
(2) the amino acid methyl ester hydrochloride of adding same substance amount in above-mentioned solution slowly drips acid binding agent after stirring;
(3) follow the tracks of reaction process with nuclear magnetic resonance analyser, treat that the phosphorus thiochloride total overall reaction finishes after, the adenosine that is dissolved in the dry pyridine is slowly splashed in the above-mentioned system, the back that stirs continue to drip acid binding agent;
(4) after reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last;
(5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product of the present invention with silicagel column.
2, a kind of guanosine 5 '-thiophosphoryl amino acid ester compound is characterized in that, the structural formula of this compound is:
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:
(1) under nitrogen protection, room temperature is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing, and is mixed with the solution of 1mol/L;
(2) the amino acid methyl ester hydrochloride of the amount of adding same substance in above-mentioned solution slowly drips acid binding agent after stirring;
(3) use nuclear magnetic resonance analyser; Follow the tracks of reaction process, treat that the phosphorus thiochloride total overall reaction finishes after, the guanosine that is dissolved in the dry pyridine is slowly splashed in the above-mentioned system, acid binding agent is continued to drip in the back that stirs;
(4); After reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last;
(5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product of the present invention with silicagel column.
3, a kind of cytidine 5 '-thiophosphoryl amino acid ester compound is characterized in that, the structural formula of this compound is:
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:
(1) under nitrogen protection, room temperature is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing, and is mixed with the solution of 1mol/L;
(2) the amino acid methyl ester hydrochloride of the amount of adding same substance in above-mentioned solution slowly drips acid binding agent after stirring;
(3) follow the tracks of reaction process with nuclear magnetic resonance analyser, treat that the phosphorus thiochloride total overall reaction finishes after, the cytidine that is dissolved in the dry pyridine is slowly splashed in the above-mentioned system, the back that stirs continue to drip acid binding agent;
(4) after reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last;
(5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product of the present invention with silicagel column.
4, a kind of uridine 5 '-thiophosphoryl amino acid ester compound is characterized in that, the structural formula of this compound is:
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:
(1) under nitrogen protection, room temperature is dissolved in phosphorus thiochloride in the dry tetrahydrofuran (THF) of crossing, and is mixed with the solution of 1mol/L;
(2) the amino acid methyl ester hydrochloride of the amount of adding same substance in above-mentioned solution slowly drips acid binding agent after stirring;
(3) follow the tracks of reaction process with nuclear magnetic resonance analyser, treat that the phosphorus thiochloride total overall reaction finishes after, the uridine that is dissolved in the dry THF is slowly splashed in the above-mentioned system, the back that stirs continue to drip acid binding agent;
(4) after reaction is finished, filter, rotary distillation removes and desolvates and other low-boiling point materials, is hydrolyzed with ammoniacal liquor at last;
(5) after the hydrolysis fully, carry out column chromatography for separation, can obtain product with silicagel column;
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