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CAS No. : | 31448-54-1 | MDL No. : | MFCD02682960 |
Formula : | C10H14N2O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NBKORJKMMVZAOZ-VPCXQMTMSA-N |
M.W : | 258.23 | Pubchem ID : | 500903 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With ammonia methyl alcohol; In methanol; at 90℃; for 18h; | 100 g of compound A4, 20 g of a 20% by mass ammonia methanol solution, and 400 mL of methanol were placed in an autoclave, and the mixture was reacted at a constant temperature of 90 C for 18 hours to the end. The methanol was concentrated, and ethyl acetate was added to be beaten, and the filtrate was dried. The compound A5 was obtained in a yield of 89% |
88% | With methanol; ammonia; at 0 - 20℃; for 48h; | A dried 50 mL round-bottomed flask was charged with 14 (3.00 g, 5.26 mmol) and 50 mL of a 7 N solution of NH3 in MeOH was then added at 0 C. The reaction was stirred at room temperature for 48 h. The solvent was then removed in vacuo and the residue was purified by column chromatography (ethyl acetate/MeOH 100:5?100:8) on silica gel to give product 15 (1.19 g) as a white solid in 88% yield. 1H NMR (300 MHz, DMSO-d6): delta 11.34 (s, 1H, 3-NH), 8.05 (d, 1H, J = 8.07 Hz, H-6), 5.80 (s, 1H, H-1'), 5.61 (d, 1H, J = 8.07 Hz, H-5),), 5.18 (d, 2H, J = 4.08 Hz, H-3', OH-3'), 5.10 (s, 1H, OH-2'), 4.06-3.59 (m, 4H, 2H-5', H-4', OH-5'), 1.01 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6): delta 163.1 (4-C), 150.8 (2-C), 140.5 (6-C), 101.5 (5-CH), 91.1 (1'-CH), 82.3 (4'-CH), 78.4 (2'-CH), 71.7 (3'-CH), 58.8 (5'-CH2), 19.93 (CH3); HRMS for C10H14N2O6 [M+H]+ calcd: 259.0924; found: 259.0929. |
With monomethanolamine; at 25 - 30℃; for 24h; | 6.8 g of compound IVb was added to the flask,Join20 mL of methanolic ammonia solution,25 ~ 30 reaction 24hAdd 0.7g activated carbon decolorization, filtration, Concentrated white solid,Add 20mL ethyl acetate slurry,Filtered and dried to give compound III, an off-white solid, 3.0 g in weight |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; at 0 - 20℃; for 16h; | To a stirred solution of 48-1 (30.0 g, 116 mmol) in anhydrous pyridine (240 mL) was added TIPDSCl (54.98 g, 174 mmol) in portions at 0 C. The mixture was stirred at RT for 16 h. The reaction was quenched with water, and concentrated to dryness at low pressure. The residue was diluted with EA, and washed with water and brine. The organic phase was dried over sodium sulfate, and concentrated at low pressure. The residue was purified on a silica gel column (50% EA in PE) to give 48-2 (58 g, 99%) |
99% | With pyridine; at 0 - 20℃; for 16h; | To a stirred solution of 48-1 (30.0 g, 116 mmol) in anhydrous pyridine (240 mE) was added TIPDSC1 (54.98 g, 174 mmol) in portions at 0 C. The mixture was stirred at RT for 16 h. The reaction was quenched with water, and concentrated to dryness at low pressure. The residue was diluted with EA, and washed with water and brine. The organic phase was dried over sodium sulfate, and concentrated at low pressure. The residue was purified on a silica gel colunm (50% EA in PE) to give 48-2 (58 g, 99%). |
99% | With pyridine; at 0 - 20℃; for 16h; | To a stirred solution of 48-1 (30.0 g, 116 mmol) in anhydrous pyridine (240 mL) was added TIPDSCl (54.98 g, 174 mmol) in portions at 0 C. The mixture was stirred at RT for 16 h. The reaction was quenched with water, and concentrated to dryness at low pressure. The residue was diluted with EA, and washed with water and brine. The organic phase was dried over sodium sulfate, and concentrated at low pressure. The residue was purified on a silica gel column (50% EA in PE) to give 48-2 (58 g, 99%). |
91.3% | With pyridine; at 0 - 20℃; | To a stirred solution of compound 7-1 (7.74 g, 11.6 mmol) in anhydrous pyridine (50 mL) was added TIPDSCl2 (9.45 g, 11.6 mmol) dropwise at 0 C. After addition, the mixture was warmed gradually to R.T. and stirred overnight. The reaction mixture was quenched with H2O, and the solvent was removed. The residue was dissolved in EA. The organic layer was washed by saturated aqueous NaHCO3 (50 mL) twice, dried over Na2SO4, and concentrated to give compound 7-2 (13.7 g, 91.3%) as a white foam. |
85% | With pyridine; at 20℃;Cooling with ice; Inert atmosphere; | To an ice-cold solution of <strong>[31448-54-1]2'-C-methyluridine</strong> (2.0 g, 7.6 mmol) in anhydrous pyridine (20 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) (2.40 g, 7.6 mmol) in small portions under N2. The reaction mixture was stirred at RT overnight. The solvent was removed under vacuum and the residue was taken up into EA (100 mL). The solution was washed with saturated NaHCO3 and brine. The organic layer was separated, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified on a silica gel column (DCM/MeOH=100/1 to 50/1) to give 4e-1 (3.2 g, 85%) as a white foam |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dmap; triethylamine; In ethyl acetate; at 50℃; for 3h; | In a 250 ml two-necked flask, add 100 ml of ethyl acetate,2.6g (10mmol) <strong>[31448-54-1]2'-C-methyluridine</strong> (this compound has been industrialized by our company), 2.0g (20mmol) triethylamine and 0.2g (2mmol) DMAP.Add 4.4 g (13 mmol) of 4,4'-bismethoxytrityl chloride as a solid,The reaction was then stirred at 50 C for 3 hours. After the TLC reaction is complete,Washed three times with water (50mlx3), dried over anhydrous sodium sulfate, spin-dried solvent, column chromatography (dichloromethane / methanol = 30: 1) to obtain 5.2g of 5'-O- (4,4-dimethoxytrityl)-<strong>[31448-54-1]2'-C-methyluridine</strong>, yield 93%. |
80% | With pyridine; at 20℃; for 5h; | Synthesis of compound 43; 42 43; To a solution of compound 42 (1.1 g, 4.26 mmol) in anhydrous pyridine (50 mL) was added DMTrCl (2.17 g, 6.39 mmol) at rt. The mixture was stirred for 5h, diluted with EtOAc (100 mL), washed with water (25 ml x 4), and dried over sodium sulfate. After filtration and concentration, the residue was co-evaporated with toluene (30 mL) and purified by flash column chromatography (MeOH in CH2Cl2 0 to 5%) to give 43 (1.9 g, 80%). 1H NMR (CDCl3) delta (ppm) 9.94 (s, IH, NH), 8.17 (d, IH, J= 8.0 Hz, H-6), 7.40-7.24 (m, 9H, aromatic), 6.84 (m, 4H, aromatic), 6.08 (s, IH, H- 1'), 5.28 (dd, IH, J= 2.0, 8.4 Hz, H-5), 4.80 (s, IH, HO), 4.11-4.01 (m, 2H, H-3' and 4'), 3.79 (s, 6H, (OCH3) x 2), 3.61 (dd, IH, J= 2.4, 11.6 Hz, H-5'), 3.55(dd, IH, J= 2.4, 11.2 Hz, H-5"), 2.87 (d, IH, J= 9.2 Hz, HO), 1.32 (s, 3H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 6; Synthesis of 1- Synthesis of 1-(2'-C-methyl-ss-D-ribofuranosyl)-4-thiophen- 3-yl-lH-pyrimidin-2-one (17); 9- (2'-C-methyl- (3-D-ribofuranosyl)-uracil (43) (1 mmol) is dissolved in dichloromethane (10 mL) under argon and 2,6-di-tert. butyl-4-methylpyridine (3 mmol) is added. The solution is cooled to 0 C and trifluoromethanesulfonic anhydride (3 mmol) is added and the reaction is allowed to warm to ambient temperature. After 12 hours the reaction is concentrated in vacuo and chromatographed on silica gel (ethyl acetate/dichoromethane). The product is dissolved in toluene (10 mL) and then K2CO3 (200 mg, 1.5 mmol), 3- thiopheneboronic acid (1.5 mmol) and Pd (PPh3) 4 (59 mg, 0.05 mmol) are added and the mixture is stirred under argon at 100 C for 8 h. After cooling to ambient temperature the mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. The residue is taken up into 10 mL NH3 saturated MeOH and is reacted at 55 C for 12 hours in a sealed tube. The reaction is cooled and concentrated in vacuo. The product is isolated by column chromatography on silica gel (chloroform/methanol/armmonia 9: 1: 0.5 v/v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 7; Synthesis of 1- (2'-C-methyl-ss-D-ribofuranosyl)-4-cyclopentyl- lH-pyrimidin-2-one (21); 9-(2'-C-methyl-ss-D-ribofuranosyl)-uracil (43) (1 mmol) is dissolved in dichloromethane (10 mL) under argon and 2,6-di-tert. butyl-4-methylpyridine (3 mmol) is added. The solution is cooled to 0 C and trifluoromethanesulfonic anhydride (3 mmol) is added and the reaction is allowed to wann to ambient temperature. After 12 hours the reaction is concentrated in vacuo and chromatographed on silica gel (ethyl acetate/dichoromethane). The product is dissolved in anhydrous THF (10 mL) and Pd (PPh3) 4 (59 mg, 0.05 mmol) is added under Ar atmosphere. Cyclopentylzinc bromide (1. 5 mmol, 0.5 M in THF) is then added and the reaction stirred at ambient temperature for 18 hours. The mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. The residue is taken up into 10 mL NH3 saturated MeOH and reacted at 55 C for 12 hours in a sealed tube. The reaction is cooled and concentrated in vacuo. The product is isolated by column chromatography on silica gel (chloroform/methanol/ammonia 9: 1 : 0. 5 v/v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.7% | With toluene-4-sulfonic acid; trimethyl orthoformate; In acetonitrile; at 40℃; | To a suspension of 2'-methyluridine (20 g, 77.52 mmol) in dry CH3CN (200 mL) were added cyclopentanone (20 mL) and trimethylorthoformate (20 mL) followed by p-toluenesulfonic acid monohydrate (7.4 g, 38.76 mmol). The reaction mixture was stirred at 40 C. overnight. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried and evaporated to give pure 3b-1 as a white solid (14.5 g, 57.7%). 1H NMR (CDCl3, 400 MHz) 8.86 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, J=8.0 Hz, 1H), 4.50 (d, J=4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m, 1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H). |
57.7% | With toluene-4-sulfonic acid; trimethyl orthoformate; at 40℃; | Compound 1 [000398] Step 1: Compound 3b-l - To a suspension of 2'-methyluridine (20 g, 77.52 mmol) in dry CH3CN (200 mL) were added cyclopentanone (20 mL) and trimethylorthoformate (20 mL) followed by p-toluenesulfonic acid monohydrate (7.4 g, 38.76 mmol). The reaction mixture was stirred at 40C overnight. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried and evaporated to give pure 3b-l as a white solid (14.5 g, 57.7%). NMR (CDC13, 400 MHz) 8.86 (s, 1H), 7.67 (d, J= 8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, J= 8.0 Hz, 1H), 4.50 (d, J= 4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m, 1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With toluene-4-sulfonic acid; In acetone; at 20℃; | To a solution of 38-1 (17 g, 65.9 mmol) and 2,2-dimethoxypropane (34.27 g, 329.5 mmol, 5 eq.) in acetone (200 mL) was added p-toluenesulfonic acid monohydrate (11.89 g, 62.6 mmol, 0.95 eq.). The =mixture was allowed to stir overnight at RT. The reaction was quenched with sat. aq. NaHCO3. The mixture was filtered, and dried over anhydrous Na2SO4. The filtrate was concentrated to give 38-2 (19 g, 97%) |
97% | With toluene-4-sulfonic acid; In acetone; at 20℃; | To a solution of 38-1 (17 g, 65.9 mmol) and 2,2- dimethoxypropane (34.27 g, 329.5 mmol, 5 eq.) in acetone (200 mE) was added p-toluenesulfonic acid monohydrate (11.89 g, 62.6 mmol, 0.95 eq.). The =mixture was allowed to stir overnight at RT. The reaction was quenched with sat. aq. NaHCO3. The mixture was filtered, and dried over anhydrous Na2SO4. The filtrate was concentrated to give 38-2 (19 g, 97%). |
97% | With toluene-4-sulfonic acid; In acetone; at 20℃; | To a solution of 38-1 (17 g, 65.9 mmol) and 2,2-dimethoxypropane (34.27 g, 329.5 mmol, 5 eq.) in acetone (200 mL) was added p-toluenesulfonic acid monohydrate (11.89 g, 62.6 mmol, 0.95 eq.). The =mixture was allowed to stir overnight at RT. The reaction was quenched with sat. aq. NaHCO3. The mixture was filtered, and dried over anhydrous Na2SO4. The filtrate was concentrated to give 38-2 (19 g, 97%). |
82% | With toluene-4-sulfonic acid; In acetone; at 20℃; for 16h; | To a suspension of <strong>[31448-54-1]2'-C-methyluridine</strong> (2.50 g, 7.6 mmol) in acetone (100 mL) were added p-Toluenesulfonic acid monohydrate (1.76 g, 9.2 mmol) and 2,2-dimethoxypropane (20 mL). The mixture was stirred at RT for 16 h. Then saturated NaHCO3 was added to adjust the pH to between approximately 6-7. The suspension was concentrated and the residue was purified on a silica gel column (5-7% MeOH in DCM) to give 3l-1 as a white solid (2.30 g, 82%). |
With toluene-4-sulfonic acid; In acetone; at 20℃; for 24h;Cooling with ice; | 2,2-Dimethylpropane (140 mL) is added to 2?-C-methyluridine 2 (100 g) in acetone (700 mL). The resulting mixture is cooled in an ice bath for 30 min, then p-toluenesulfonic acid (11 g) is added and the reaction mixture is stirred at rt for 24 h. After completion of the reaction (monitored by HPLC), the reaction mixture is cooled in an ice bath for 30 min and neutralized using cold potassium carbonate (12 g in 13 mL water, pH 7-8). The solvent is removed under reduced pressure until dryness. THF (500 mL) is added to the residue and the solids are removed by filtration. The filtrate is co-evaporated with silica gel and purified by chromatography over silica gel (5-15% MeOH in CHCl3) to give compound 3. 1H NMR (400 MHz, DMSO-d6, 300 K): delta 1.22 (s, 3H), 1.34 (s, 3H), 1.49 (s, 3H), 3.63 (dd, J=12.0 Hz, 2.8 Hz, 1H), 3.69 (dd, J=12.0 Hz, 3.1 Hz, 1H), 4.15 (m, 1H), 4.47 (d, J=2.8 Hz, 1H), 5.25 (br s, 1H), 5.63 (dd, J=8.2 Hz, 2.3 Hz), 6.01 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 11.37 (s, 1H); LC-MS: 299 amu (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-1H-imidazole; In acetonitrile; at 70℃; for 2h; | <strong>[31448-54-1]2'-C-methyluridine</strong> (77 mg, 0.3 mmol) was dissolved in 10 mL of anhydrous acetonitrile and 2 mL of N-methylimidazole. Compound 2d was added (0.3 g, 0.9 mmol) and the mixture was heated at 70 C. for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 30 mL of ethyl acetate, washed with 10% citric acid (2×10 mL), water, brine, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography on silica gel with methanol in dichloromethane (0 to 10%) to give 3f (224 mg) as light-tan solid. An analytical sample was obtained as a colorless solid by RP HPLC purification in gradient of methanol in water from 10% to 95% on a Synergy 4u Hydro-RP column (Phenominex). 1H NMR (CDCl3): delta 9.90 (bs, 1H), 7.62-7.58 (m, 1H), 7.32-7.28 (m, 2H), 7.20-7.16 (m, 2H), 5.97 & 5.94 (2s, 1H), 5.65 & 5.52 (2d, 1H), 4.54-4.46 (m, 1H), 4.39-4.24 (m, 1H), 4.20-4.04 (m, 3H), 3.85-3.79 (m, 1H), 3.73-3.65 (m, 2H), 1.39-1.32 (dd, 3H), 1.16-1.14 (d, 1H), 0.87-0.86 (m, 9H); 31P NMR: 667.85, 67.16 (1:1 mixture of diastereomers); ESI-LCMS: m/z 570.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.6% | With 1-methyl-1H-imidazole; In acetonitrile; at 20℃; for 72h; | To a solution of <strong>[31448-54-1]2'-C-methyluridine</strong> (150 mg, 0.581 mmol) in MeCN (1 mL) and N-methylimidazole (0.7 mL) was added 2h (651 mg, 1.86 mmol). The mixture was stirred at RT for 3 days. The solvent was removed and the residue was purified by RP HPLC (0.1% HCOOH in MeCN and water) to give 3n as a white solid (two isomers, 22 mg, 6.6%). 1H NMR (CD3OD, 400 MHz) delta 7.76, 7.78 (2d, J=9.2 Hz, 1H), 7.14-7.35 (m, 5H), 5.95, 5.97 (2s, 1H), 5.56, 5.63 (2d, J=8.4 Hz, 1H), 4.95-5.03 (m, 1H), 4.44-4.56 (m, 1H), 4.30-4.41 (M, 1H), 4.08-4.11 (m, 1H), 3.75-3.90 (m, 2H), 2.00-2.07 (m, 1H), 1.12-1.25 (m, 6H), 1.11, 1.15 (2s, 3H), 0.87-0.97 (m, 6H); 31P NMR (CD3OD, 162 MHz) delta 70.38, 69.13; ESI-LCMS: m/z 572 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 1h; | 1,2,4-Triazole (42 mg, 0.6 mmol) was suspended 1 mL of dry CH3CN. Triethylamine was added (0.088 mL, 0.63 mmol), and the mixture was vortexed to obtain a clear solution. After addition of PSCl3 (0.01 mL, 0.1 mmol), the mixture was vortexed and left for 20 minutes. The mixture was then centrifugated. The supernatant was added to the nucleoside (0.05 mmol), and the mixture was kept at ambient temperature for 1 hour. Tris(tetrabutylammonium) hydrogen pyrophosphate (180 mg, 0.2 mmol) was added. The mixture was then kept for 2 hours at RT. The reaction was cooled in an ice-water bath and quenched with water. The 5'-triphosphate, as mixture of diastereomers, was isolated by IE chromatography on an AKTA Explorer using column HiLoad 16/10 with Q Sepharose High Performance. The separation was done using a linear gradient of NaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). The fractions containing the nucleotide alpha-thiotriphosphate were combined, concentrated and desalted by RP HPLC on the same column as in Example 3. A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium buffer was used for elution over 20 minutes, flow 10 mL/min. Two separate compounds corresponding to individual diastereomers at the phosphorus chiral center were collected. Analytical RP HPLS was done in 50 mM triethylammonium acetate buffer, pH 7.5, containing linear gradient of acetonitrile from 0% to 25% in 7 minutes on a Synergy 4 micron Hydro-RP column (Phenominex). Retention time (R.T.) for the individual diastereomers is provided in Table 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1H-tetrazole; In acetonitrile; at 0 - 20℃; | Example 11; Preparation of 1-(7-Hydroxy-2-isopropoxy-7-methyl-2-thioxo-tetrahydro-2l5-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)-1H-pyrimidine-2,4-dione (11a); To a solution of P10-1 (155 mg, 0.60 mmol) in dry pyridine (4.0 mL) was added a solution of 0.45 M tetrazole in MeCN (3.33 mL) and P6-1 (190 mg, 0.72 mmol) at 0 C. The reaction mixture was stirred at room temperature overnight, and bis[3-(triethoxysilyl)propyl]tetrasulfide (388 mg, 0.72 mmol) was then added at 0 C. The mixture was stirred for another hour. The reaction mixture was concentrated and diluted with ethyl acetate, washed with saturated NaHCO3 and brine, and dried over anhydrous Na2SO4. The organic layer was concentrated, and the residue was purified by HPLC (MeCN and 0.1% HCOOH in water) to give compound 11a as a white solid (21 mg, 9.1%). 1H NMR (MeOD, 400 MHz) delta7.61-7.66 (m, 1H), 6.08 (s, 1H), 5.78-5.80 (m, 1H), 4.82-4.97 (m, 1H), 4.61-4.66 (m, 1H), 4.29-4.43 (m, 1H), 4.09-4.23 (m, 1H), 1.37-1.42 (m, 6H), 1.25 (s, 3H). 31P NMR (MeOD, 162 MHz) delta65.2, 61.3. ESI-LCMS m/z 379.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1H-tetrazole; In acetonitrile; at 0 - 20℃; | Example 10; Preparation of 1-(7-Hydroxy-2-methoxy-7-methyl-2-thioxo-tetrahydro-2l5-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl)-1H-pyrimidine-2,4-dione (10a); To a solution of P10-1 (320 mg, 1.24 mmol) in dry pyridine (9.0 mL) was added a solution of 0.45 M tetrazole in MeCN (9 mL) and P1-2 (390 mg, 1.49 mmol) at 0 C. The reaction mixture was stirred at room temperature overnight, and bis[3-(triethoxysilyl)propyl]tetrasulfide (803 mg, 1.49 mmol) was then added at 0 C. The mixture was stirred for another hour. The reaction mixture was concentrated and diluted with ethyl acetate, washed with saturated NaHCO3 and brine, and dried over anhydrous Na2SO4. The organic layer was concentrated, and the residue was purified by HPLC (MeCN and 0.1% HCOOH in water) to give compound 10a as a white solid (35 mg, 7.7%). 1H NMR (MeOD, 400 MHz) delta7.63-7.65 (d J=8.0 Hz, 1H), 6.07 (s, 1H), 5.75-5.79 (m, 1H), 4.60-4.70 (m, 1H), 4.21-4.46 (m, 1H), 4.10-4.12 (m, 1H), 3.81-3.90 (m, 3H), 1.26 (m, 3H). 31P NMR (MeOD, 162 MHz) delta64.3, 67.1. ESI-LCMS m/z 350.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; dmap; In dichloromethane; at 20 - 50℃; for 51h; | Example 49 Preparation of Compound 55 The preparation of Compound 55 is illustrated in Scheme 5, above. To a solution of <strong>[31448-54-1]2'-C-methyluridine</strong> (1 g) in pyridine (40 ml) were added acetic acid (3 ml) and DMAP. The mixture was stirred at 50 C. during 3 hours, followed by two days at room temperature. Then, the mixture was concentrated and co-evaporated with toluene and the residue purified by silica gel chromatography eluting with 0?10% methanol in dichloromethane to yield 2',3',5'-Tri-O-acetyl-<strong>[31448-54-1]2'-C-methyluridine</strong> (93%). MS (ESI, EI+) m/z=385.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With 1-methyl-1H-imidazole; at 0 - 2℃; for 21.5h; | Method C [0072] A solution of 2?-methyluridine (50 g, 0.193 mol, 1 eq.) and N-methylimidazole (NMI) (79.5 g, 0.968 mol, 5.0 eq) in methyl isobutyl ketone (MIBK) (300 mL) was stirred at 0 C. Compound 2 (99.7 g, 0.309 mol, 1.6 eq) was added dropwise into the solution over 0.5 hr. The mixture was stirred at 0 C. for 5 hr, warmed to 2 C. and stirred for 16 hr until an in process control showed 95% conversion and a diastereomeric ratio to be 2.1:1 of compound 3(ii)-Sp: compound 3(i)-Rp. [0073] The reaction was quenched by adding 2N HCl (300 mL) slowly and with stirring at 20 C. for 1 hr. The organic layer was separated and washed with 2N HCl (300 mL), 7% NaHCO3 (300 mL), and water (250 mL). [0074] The solution was concentrated to about 150 mL and charged with MTBE (500 mL). The mixture was warmed to 50 C., stirred for 1 hr, cooled to 0 C. over 1 hr and stirred for 4 hr. The solid was filtered to give the crude product with 95% purity and 4% diastereomer. The crude product was slurried in MTBE (500 mL) at 50 C. for 2 hr. The mixture was then cooled to 0 C., stirred for 2 hr and filtered to give the purified compound 3(ii)-Sp with 98% purity (compound 3(ii)-Rp: 2%). The solid was dried under vacuum at RT overnight to provide 40 g (38% yield) of 3(ii)-Sp. |
With 1-methyl-1H-imidazole; In acetonitrile; at -10 - 20℃; for 0.17h; | N-Methylimidazole (12 mL) was added to a solution of 2?-C-methyluridine 29 (6.34 g) in acetonitrile and cooled to -10 C. A solution of compound 28 (7.9 g) in acetonitrile was then added. The reaction mixture was stirred at 0 C. for 1 h and then at room temperature overnight (16 h). The solvent was evaporated and the residue purified by chromatography over silica gel (eluted with 0-2.5% methanol/DCM). The pure fractions were mixed and evaporated to dryness and the residue crystallized from MTBE. The solid obtained was suspended in MTBE and refluxed for 2 h cooled and filtered. The solid was washed with MTBE and dried to give 0.850 g of compound 30 (3b(ii)-Sp from application WO 2012/040127). About 3.5% of the other isomer Rp is present. [0301] 3b(ii)-Sp: 1H-NMR (CD3OD, 400 MHz): delta 7.76 (d, J=8.4 Hz, 1H), 7.34 (t, J=8.4 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.18 (t, J=7.6 Hz, 1H), 5.96 (s, 1H), 5.57 (d, J=8.4 Hz, 1H), 4.98 (m, 1H), 4.5 (m, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 3.81 (d, J=9.2 Hz, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.23, 1.22 (2d, J=6.8 Hz and 6 Hz, 6H), 1.15 (s, 3H); 31P-NMR (CD3OD, 162 MHz): delta 68.42 (96.5%) and 68.21 (3.5%); ESI-LCMS: m/z=544 [M+1]. | |
With silver trifluoromethanesulfonate; In acetonitrile; at 23℃; | (0418] The chemical reactions for coupling compound 3 with compound A-3 were performed using procedures discussed in Examples, 1-3, above and the reaction conditions specified in Table 1, below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; at 50℃; for 20h;Inert atmosphere; | 2-C-Methyluridine (0.79 g; 3.05 mmol) wasdissolved in dry pyridine (20 mL) under argon. 4-Methoxytrityl chloride (1.03 g; 3.36 mmol)was added and the mixture was stirred at 50 C for 20 hours. The reaction was quenched withsaturated aq NaHCO3 (50 mL) and subjected to DCM (3 × 100 mL) workup. The organic phasewas dried over Na2SO4 and evaporated to dryness. The residue was purified by Silica gelchromatography using DCM containing 5% MeOH as eluent. Compound 7 was obtained as solidin 92% yield (1.50 g). 1H-NMR (500 MHz, CDCl3) : 8.16 (d, 1H, J = 8.0 Hz, H6), 7.41 (m, 4H,MMTr), 7.26 (m, 6H, MMTr), 7.19 (m, 2H, MMTr), 6.86 (d, 2H, J = 9.0 Hz, MMTr), 6.09 (s,1H, H1), 5.23 (d, 1H, J = 8.0 Hz, H5), 4.05-4.17 (m, 2H, H3&H4), 3.81-3.84 (m, 4H, MeOMMTr& H5), 3.61 (br s, 2H, 2-&3-OH); 3.23 (d, 1H, J =12.5 Hz , H5), 1.36 (s, 3H, CH3).13C-NMR (100 MHz, CD3OD) : 164.64 (C4), 158.76 (MMTr), 151.02 (C2), 144.52 (MMTr),141.12 (C6), 135.35 (MMTr), 130.18, 128.10, 127.34, 126.46 and 112.64 (MMTr), 102.94 (C5),91.67 (C1), 87.66 (MMTr), 82.44 (C2), 78.66 (C4), 71.94 (C3), 59.05 (C5), 54.32 (OMe),18.80 (Me). HR-ESI-MS: [M+Na]+ obsd. 553.1921, calcd. 553.1945. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; iodine; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1.5h; | 1-((2R,3R,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (0.5 g, 1.9 mmol) was co-evaporated with 5 mL of pyridine and dried under vaccum. To a mixture of this residue, Ph3P (0.76 g, 2.9 mmol), and imidazole (0.2 g, 2.9 mmol) in THF (4 mL) was added a solution of I2 (0.59 g, 2.3 mmol) in THF (2 mL) at room temperature. After being stirred for 1 h, to this mixture was added Ph3P (250 mg, 0.95 mmol), imidazole (66 mg, 0.97 mmol), and a solution of I2 (200 mg, 0.79 mmol) in THF (1 mL). The reaction mixure was stirred at room temperature for 30 min, then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (711 mg, 1.93 mmol, 100 % yield). LC-MS: m/z 367.2 (M-H)-. |
78.9% | With pyridine; 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 10h; | Example 1 2'-C-Methyl-4'-Fluorouridine 1 To a stirred suspension of 1-1 (20 g, 77.5 mmol), PPh3 (30 g, 114.5 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF (300 mL) was added a solution of I2 (25 g, 98.4 mmol) in THF (100 mL) dropwise at 0 C. The mixture was warmed to room temperature (R.T.) and stirred at R.T. for 10 h. The reaction was quenched by MeOH (100 mL). The solvent was removed, and the residue was re-dissolved in a mixture ethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washed with saturated Na2S2O3 aq., and the aqueous phase was extracted with a mixture of EA and THF (2 L, 10:1). The organic layer was combined and concentrated to give a residue, which was purified on a silica gel column (0-10% MeOH in DCM) to give 1-2 (22.5 g, 78.9%) as a white solid. 1H NMR: (DMSO-d6, 400 MHz) delta 11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H). |
78.9% | With pyridine; 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | To a stirred suspension of 108-1 (20 g, 77.5 mmol), PPh3 (30 g, 114.5 mmol), imidazole (10 g, 147 mmol)and pyridine (90 mL) in anhydrous THF (300 mL) was added a solution of I2 (25 g, 98.4 mmol) in THF (100mL) dropwise at 0 C. The mixture was warmed to room temperature (RT) and stirred at RT for 10 h. Thereaction was quenched by MeOH (100 mL). The solvent was removed, and the residue was re-dissolved in amixture ethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washed with saturated Na2S2O3 aq.,and the aqueous phase was extracted with a mixture of EA and THF (2 L, 10:1). The organic layer wascombined and concentrated to give a residue, which was purified on a silica gel column (0-10% MeOH inDCM) to give 108-2 (22.5 g, 78.9%) as a white solid. 1H NMR: (DMSO-d6, 400 MHz) delta 11.42 (s, 1H), 7.59(d, J=8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H) |
78.9% | With pyridine; 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 10h; | To a stirred suspension of 108-1 (20 g, 77.5 mmol), PPh3 (30 g, 114.5 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mE) in anhydrous THF (300 mE) was added a solution of 12 (25 g, 98.4 mmol) in THF (100 mE) dropwise at 0C. The mixture was warmed to room temperature (RT) and stirred at RT for 10 h. The reaction was quenched by MeOH (100 mE). The solvent was removed, and the residue was re-dissolved in a mixture ethyl acetate (EA) and THF (2 E, 10:1). The organic phase was washed with saturated Na2S2O3 aq., and the aqueous phase was extracted with a mixture of EA and THF (2 E, 10:1). The organic layer was combined and concentrated to give a residue, which was purified on a silica gel colunm (0-10% MeOH in DCM) to give 108-2 (22.5 g, 78.9%) as a white solid. ?H NMR: (DMSO-d5, 400 MHz) oe11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H). |
78.9% | With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; pyridine; at 0 - 20℃; for 10h; | To a stirred suspension of 108-1 (20 g, 77.5 mmol), PPh3 (30 g, 114.5 mmol), imidazole (10 g, 147 mmol) and pyridine (90 mL) in anhydrous THF (300 mL) was added a solution of I2 (25 g, 98.4 mmol) in THF (100 mL) dropwise at 0 C. The mixture was warmed to room temperature (RT) and stirred at RT for 10 h. The reaction was quenched by MeOH (100 mL). The solvent was removed, and the residue was re-dissolved in a mixture ethyl acetate (EA) and THF (2 L, 10:1). The organic phase was washed with saturated Na2S2O3 aq., and the aqueous phase was extracted with a mixture of EA and THF (2 L, 10:1). The organic layer was combined and concentrated to give a residue, which was purified on a silica gel column (0-10% MeOH in DCM) to give 108-2 (22.5 g, 78.9%) as a white solid. 1H NMR: (DMSO-d6, 400 MHz) delta 11.42 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 5.82 (s, 1H), 5.63 (d, J=8.0 Hz, 1H), 5.50 (s, 1H), 5.23 (s, 1H), 3.77-3.79 (m, 1H), 3.40-3.62 (m, 3H), 0.97 (s, 3H). |
76% | With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃;Inert atmosphere; Large scale; | 3-Neck 3 L flask was charged with 2?-methyluridine (129 g, 500 mmol, 1.0 eq.), triphenylphosphine (196.5 g, 750 mmol, 1.5 eq.), imidazole (51 g, 750 mmol, 1.5 eq.) and anhydrous THF (750 mL). With stirring under an argon atmosphere, iodine (143.4 g, 565 mmol, 1.13 eq.) was added as a solution in THF (300 mL), while maintaining the temperature below 25 C. The mixture was stirred overnight at room temperature (RT). THF was replaced by MeOH under reduced pressure. Compound AA precipitated from methanol. The solid was aged overnight at 0 C., filtered off, washed with cold MeOH and dried under reduced pressure at 45-50 C. to yield compound AA (114.6 g, 62%) |
62% | With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 20 - 25℃;Inert atmosphere; | 10202] Compound 1 was prepared according to the scheme provide above. 3- Neck 3L flask was charged with 2?-methyluridine (129 g, 500 mmol, 1.0 eq.), triphenylphosphine (196.5 g, 750 mmol, 1.5 eq.), imidazole (51 g, 750 mmol, 1.5 eq.) and anhydrous THF (750 mL). With stirring under an argon atmosphere, iodine (143.4 g, 565 mmol, 1.13 eq.) was added as a solution in THF (3O0 mL), while maintaining the temperature below 25C. The mixture was stirred overnight at room temperature (RT). THF was replaced by MeOH under reduced pressure. Compound 1-1 precipitated from methanol. The solid was aged overnight at 0C, filtered off, washed with cold MeOH and dried under reduced pressure at 45-50C to yield 1-1 (114.6 g, 62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethyl phosphate; trichlorophosphate; at -20 - 0℃; for 0.666667h; | The nucleoside (B-N3, 0.8 g, 3.1 mmol) was stirred in triethylphosphate (PO(OEt)3, 15 mL) 1,8-bis(dimethylamino)naphthalene (0.8 g, 3.721 mmol, 1.2 eq) was added and the mixture was cooled to -20 C. Phosphorous oxychloride (POCl3, 0.96 g, 6.26 mmol, 1.3 eq) was added drop-wise and the mixture was stirred at -20 C. for 10 min. The mixture was allowed to warm to 0 C. and was stirred at this temperature for 30 min. This mixture was then cooled to -50 C. (dry ice/EtOH) B-2 (0.47 g, 2.79 mmol, 0.9 eq) was added followed by triethylamine (TEA, 0.99 mL, 0.713 mmol, 2.3 eq). After stirring at -50 C. for 30 minutes, B-4 (1.36 g, 0.93 mmol, 3 eq) was added to the mixture followed by 4-dimethylaminopyridine (DMAP, 0.94 g, 0.77 mmol, 2.5 eq). The mixture was allowed to warm to room temperature and was stirred overnight. Petroleum ether was added to the mixture and the precipitated material was isolated by vacuum filtration. This material was purified by column chromatography (silica gel, 200-300 mesh) using MeOH/DCM (0?7%) providing the crude product (570 mg). The crude product was purified by preparative column chromatography affording compound 4b, diastereomer 1 (30 mg, 1.7%) and compound 4b, diastereomer 2 (50 mg, 2.8%). | |
General procedure: 1-((2R,3R,4R,5R)-3-ethynyl-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (20 mg, 0.075 mmol) in a dry flask was co-evaporated with dry THF twice and then used for the reaction. To a dry flask under argon was added 1-((2R,3R,4R,5R)-3-ethynyl-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (20 mg, 0.075 mmol) and Proton sponge (63.9 mg, 0.298 mmol), then PO(OMe)3 (1.5 mL) was added. The mixture was sonicated and stirred at room temperature for 10 min to give a clear solution. Under stirring, POCl3 (0.031 mL, 0.336 mmol) was added dropwise via microsyringe. The reaction was stirred under room temperature for 1 h, an aliquot of the reaction solution was added to water (100 muL) and the resulting monophosphate was analyzed by analytical ion exchange (DIONEX column, 1N TEAB buffer and H2O). After 3h, monophosphate formed as the major peak. The reaction mixture was added to a premixed solution of Tributylammonium pyrophosphate (245 mg, 0.447 mmol) and tributylamine (0.177 mL, 0.746 mmol) in DMF (1.5 mL). The reaction was stirred at room temperature for 5 min, then quenched with 1N Triethylammonium bicarbonate (3.73 ml, 3.73 mmol) . The resulting solution was stirred at room temperature for 30 min and diluted with 3 mL of water. The crude was freeze dried to give a semisolid. The crude was dissolved in 5mL of water and purified by IEX column (DEAE FF16/10, HiPrep from GE lifescience) with a gradient of 0.5M TEAB buffer/H2O from 0% to 80% in 60 min. Desired fractions were collected and combined, some impurities were still present. The triphosphate from PREP-IEX purification was puirfied again by PREP-HPLC using Xbridge C18 column (5 uM, 19x100 mm) with a gradient of: 0% ACN for the first 5 min, followed by a gradient of ACN/0.1N TEAB Buffer from 0% to 20% in 30 mins, then flush with 50% ACN/0.1N TEAB buffer after triphosphate peak was eluted out. ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (5.8 mg, 3.74 mumol, 5.01 % yield) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 2?-chloro-2?-C-methyl-uridine (3.61 mmol) in triethyl phosphate (5 mL) at 0 C. under nitrogen was added POCl3 (5.42 mmol). The reaction mixture was allowed to warm to room temperature and stirred at this temperature during 12 hours. The reaction mixture was cooled down again to 0 C. and L-Alanine isopropyl ester hydrochloride (3.98 mmol) was added followed by addition of triethylamine (18.07 mmol). The reaction was stirred at room temperature during 20 minutes. The reaction mixture was cooled down to 0 C. and appropriate thiol (14.46 mmol) in CH3CN (4 mL) was added followed by addition of DBU (14.46 mmol). The reaction mixture was stirred at room temperature during 1 hour. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by chromatography on a Biotage column (eluent: CH2Cl2 to CH2Cl2/CH3OH 8/2) and by preparative HPLC to give the pure diastereoisomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
834 mg | With trifluorormethanesulfonic acid; In dichloromethane; at -2.9 - 10℃; for 20h;Large scale; | [04021 To a 50 L glass reactor equipped with a mechanical stirrer, reflux condenser, nitrogeninlet, temperature controller, and thermocouple coupled with reaction monitoring software, was charged compound A-3 (595 g, 1 eq.). A solution of compound B-4Bla (1.7 kg, 1.28 eq.) in dichioromethane (5.95 L) was prepared and added to the reaction vessel. The reaction was cooled to -2.9 C. To it, trifluoromethanesulfonic acid (548 mL, 932 g, 2.7 eq.) was added over 1 hr while maintaining the internal temperature 96.5% conversion of compound B-4Bla. The reaction mixture was cooled to 0 C. To it, water (5.95 L) was added over 42 minutes while maintaining the internal temperature below 10 C. Then, the reaction temperature was adjusted to 10 C, and the lower organic phase was removed to a flask. The pH of the aqueous layer was adjusted to 7.0 by adding 30 wt% ammonium hydroxide (32 mL). The aqueous phase was stirred two times with IPAc (5 and 4 L, respectively). The combined organic layer was concentrated to a final volume of 3-4 L and charged to the glass reactor. To it 5.75 L of IPAc was added, and the mixture was washed three times with 2N hydrochloric acid (3 x 5?95 L), followed by washing with 5 wt% aqueous sodium carbonate solution (5 L). The organic layer was concentrated, using rotary evaporator at33 C, to 6.75 L. The temperature was brought to room temperature and seeded with compound V, and the mixture was rotated for 30 minutes to ensure a slow crystallization. [04031 The solution was heated to 34 C and concentrated under vacuum to a final volume of 4.25 L. The solution was transferred from rotary evaporator to a clean 50 L glass reactor. The solution was further concentrated to 3 L. To it, toluene (5.95 L) was added over 1.5 hr at 50 - 52 C. The batch was heated to 60 C and held at that temperature for 45 minutes. Then the temperature was lowered to 10 C over 5 hrs and stirred at 10 C for 12 to 63 hrs. The solid was filtered, washed with a solvent mixture toluene/MTBE (80:20, 2 x 2.9 L), and dried at 45 - 50 C under vacuum with nitrogen sweep for 28 hrs to provide 834 g of white solid, compound Va.[0404] FIG. 4 is a 1H NMR spectrum of the product (compound Va). FIG. 5 is a 31P NMR spectrum of the product (compound Va). A HPLC chromatogram of the reaction is provided in FIG. 6. HPLC analysis of the compound Va resulting from the above reaction was found to be at least> 98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; triethylamine; In dichloromethane;Inert atmosphere; | 2?-C-methyl-2-thiouridine nucleoside analogs can be made by treating the parentnucleoside (1 equivalent) with tosyl chloride (1.2 equivalents) dissolved in pyridine:DCM (1:1) under an inert atmosphere. The resulting 5? -tosyl nucleoside analog can then be treated with sodium bicarbonate (5 equivalents) in reflux ethanol to obtain the 2-ethoxy nucleoside. Finally, the desired 2-thionucleoside analog can be obtained by treating the 2-ethoxyintermediate with sodium hydrosulfide (10 equivalents) in a polar solvent such as DMF. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95% | With dmap; triethylamine; at 20℃; | A suspension of 2?-Methyluridine (0.25 8 g, 0.999 mmol) in Ac20 (4.00 ml) in thepresence of DMAP (0.024 g, 0.200 mmol) and Et3N (0.139 ml, 0.999 mmol) was stirred at r.t.overnight. The reaction mixture became homogeneous and yellowish upon stirring. Thereaction was condensed on rotavap, and co-evaporated with EtOH (15 mL x 3). The product was purified via ISCO to give a white solid with a yield of >95%.Physical data: ?H NMR (400Hz, CDC13): oe 1.519 (s, 3H), 2.087 (s, 6H), 2.099 (s, 3H), 4.265 (m, 1), 4.369 (m, 2H), 5.220 (d, 1H, J= 6 Hz), 5.756 (d, 1H, J 8 Hz), 6.217 (s, 1H), 7.407(d, 1H, J= 8 Hz), 9.744 (s, 1H); ?3C NMR (100Hz, CDC13): oe 17.773, 20.520, 20.687,21.461, 62.649, 74.3 13, 79.284, 84.195, 89.409, 102.364, 140.530, 150.040, 163.071,169.643, 169.742, 170.3 18; MS: mlz 273.1 (M-uracil+H); LC-MS 99.6% purity; HRMS Calc. for C,6H2,09N2 (M+H): 385.12416, Found: 385.12420. |
> 95% | With dmap; triethylamine; at 20℃; | Example 71. A suspension of 2'-Methyluridine (0.258 g, 0.999 mmol) in Ac2O (4.00 ml) in the presence of DMAP (0.024 g, 0.200 mmol) and Et3N (0.139 ml, 0.999 mmol) was stirred at r.t. overnight. The reaction mixture became homogeneous and yellowish upon stirring. The reaction was condensed on rotavap, and co-evaporated with EtOH (15 mL x 3). The product was purified via ISCO to give a white solid with a yield of >95%. Physical data: 1H NMR (400Hz, CDCl3): delta 1.519 (s, 3H), 2.087 (s, 6H), 2.099 (s, 3H), 4.265 (m, 1), 4.369 (m, 2H), 5.220 (d, 1H, J = 6 Hz), 5.756 (d, 1H, J = 8 Hz), 6.217 (s, 1H), 7.407 (d, 1H, J = 8 Hz), 9.744 (s, 1H); 13C NMR (100Hz, CDCl3): delta 17.773, 20.520, 20.687, 21.461, 62.649, 74.313, 79.284, 84.195, 89.409, 102.364, 140.530, 150.040, 163.071, 169.643, 169.742, 170.318; MS: m/z 273.1 (M-uracil+H); LC-MS 99.6% purity; HRMS Calc. for C16H21O9N2 (M+H): 385.12416, Found: 385.12420 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.77 g | With toluene-4-sulfonic acid; In 1,2-dichloro-ethane; at 60℃; for 4h; | To a solution of cyclopentanone (6.0 g, 71 mmol) in MeOH (60 mL) was added TsOH.H2O (1.35 g, 7.1 mmol) and trimethoxymethane (8 mL) at RT. The solution was stirred at RT for 2 h. The reaction was quenched with NaOMe, and the mixture was extracted with hexane (30 mL). The organic layer was dried and concentrated to give crude 1,1-dimethoxycyclopentane (9.2 g), which was dissolved in 1,2-dichloroethane (50 mL). To the above solution was added 38-1 (5.0 g, 19.38 mmol) and TsOH.H2O (0.36 g, 1.9 mmol) at RT. The mixture was stirred at 60 C. for 4 h. The reaction was quenched with TEA and concentrated at low pressure. The residue was purified on silica gel column (1% MeOH in DCM) to give 39-1 (4.77 g, 76%) as a white solid |
4.77 g | With toluene-4-sulfonic acid; at 60℃; for 4h; | To a solution of cyclopentanone (6.0 g, 71 mmol) in MeOR (60 mE) was added TsOH.H20 (1.35 g, 7.1 mmol) and trimethoxymethane (8 mE) at RT. The solution was stirred at RT for 2 h. The reaction was quenched with NaOMe, and the mixture was extracted with hexane (30 mE). The organic layer was dried and concentrated to give crude 1,1 - dimethoxycyclopentane (9.2 g), which was dissolved in 1,2- dichloroethane (50 mE). To the above solution was added 38-1 (5.0 g, 19.38 mmol) and TsOH.H20 (0.36 g, 1.9 mmol) at RT. The mixture was stirred at 60 C. for 4 h. The reaction was quenched with TEA and concentrated at low pressure. The residue was purified on silica gel column (1% MeOR in DCM) to give 39-1 (4.77 g, 76%) as a white solid. |
4.77 g | With toluene-4-sulfonic acid; In 1,2-dichloro-ethane; at 60℃; for 4h; | To a solution of cyclopentanone (6.0 g, 71 mmol) in MeOH (60 mL) was added TsOH.H2O (1.35 g, 7.1 mmol) and trimethoxymethane (8 mL) at RT. The solution was stirred at RT for 2 h. The reaction was quenched with NaOMe, and the mixture was extracted with hexane (30 mL). The organic layer was dried and concentrated to give crude 1,1-dimethoxycyclopentane (9.2 g), which was dissolved in 1,2-dichloroethane (50 mL). To the above solution was added 38-1 (5.0 g, 19.38 mmol) and TsOH.H2O (0.36 g, 1.9 mmol) at RT. The mixture was stirred at 60 C. for 4 h. The reaction was quenched with TEA and concentrated at low pressure. The residue was purified on silica gel column (1% MeOH in DCM) to give 39-1 (4.77 g, 76%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Under the protection of N2, <strong>[31448-54-1]1-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione</strong> (260 mg, 1.01 mmol) and N,N-diisopropylethylamine (390 mg, 3.02 mmol) were dissolved into 10 mL anhydrous dichloromethane with 3 A molecular seives (2 g). After the mixture was cooled to 0 C., bis(diisopropylamino)chlorophosphine (322 mg, 1.21 mmol) was added. The reaction mixture was stirred at 0 C. for 30 min and was slowly warmed up to RT and stirred for 3 h. DMAP (61.5 mg, 0.50 mmol) was added to facilitate the cyclization. The reaction was stirred at RT for 16 h. The solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography using 25% acetone in hexane to obtain 163 mg (0.42 mmol, 42%) of the pure product. LCMS: for C16H26N3O6P calculated 387.2. found 388.0 [M+H]+. 1H NMR (500 MHz, CD3CN) delta: 9.29 (s, br, 1H), 7.40 (m, 1H), 5.94 (s, 1H), 5.68 (dd, J=4.0, 4.0 Hz, 1H), 4.42 (m, 1H), 4.17 (dd, J=10.0, 10.0 Hz, 1H), 3.88 (m, 1H), 3.75 (m, 2H), 3.56 (d, J=9.1 Hz, 1H), 3.47 (s, br, 1H), 1.22 (m, 12H), 1.17 (s, 3H). 13C NMR (500 MHz, CD3CN) delta: 140.16, 102.29, 93.10, 66.61, 44.44, 44.34, 24.20, 24.15, 19.71, -5.11. 31P NMR (500 MHz, CD3CN) delta: 150.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; | The compound 2?-C-methyluridine is treated with an acetal such as benzaldehyde dimethyl acetal, and an acid catalyst such as p-toluenesulfonic acid to generate acetal 3. Compound 3 is oxidized with an oxidizing agent such as pyridinium dichromate in the presence of an alcohol such as tert-butanol, an anhydride such as acetic anhydride and an organic solvent such as dichloromethane. The ester is reduced with a reducing agent such as sodium borodeuteride in a combination of protic solvents such as EtOD and D2O optionally at an elevated temperature. Compound 5 is treated with the phosphoramidate from Example 20, a Grignard reagent such as tert-butylmagnesium bromide in an organic solvent such as tetrahydrofuran optionally at a reduced temperature. The acetal is treated with an acid such as trifluoroacetic acid in an organic solvent such as dichloromethane to afford the product. The acetal can also be treated with a catalyst such as Pd(OH)2 in an organic solvent such as cyclohexene to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.3% | With 1,1'-carbonyldiimidazole; potassium hydroxide; In acetonitrile; at 20 - 80℃; for 20h; | To a flask containing 1.6 L acetonitrile was added Compound 1 (350 g, 1.36 mol, prepared according to the method described in International Patent Publication No. WO 2013/177219), 1,1 ' -carbonyldiimidazole (212 g, 1.78 mol), and potassium hydroxide (15.3 g, 0.27 mol). The internal reaction temperature was kept below 20 C during the addition reactants. The resulting reaction was then heated to 80 C over a 2 hour period, and allowed to stir at this temperature for an additional 18 hours. The reaction mixture was cooled to room temperature, and 700 mL acetonitrile was added. The resulting solution was filtered and the collected solid was dried at 60C for 4 hours, then slurried in 1.4 L ethanol for 30 minutes and filtered. The collected solid was dried for about 15 hours at 60C to provide the Compound 2 (267.5 g, 99.7% purity by HPLC, 75.3% yield). 1H NMR (DMSO-d6, 600.04 MHz): delta 1.59 (s, 3H), 4.01 (m, 1H), 4.24 (m, 1H), 5.03 (brs, 1H), 5.91-5.94 (m, 2H), 6.08 (brs, 1H), 7.86 (d, 1H, J= 7.2 Hz). |
1.5 g | With bis(phenyl) carbonate; sodium hydrogencarbonate; phosphoramide; at 150℃; | 2 g of compound III, diphenyl carbonate (1.5 eq),0.8 g of sodium bicarbonate,20mL phosphoric acid triamide heated to 150 C reaction,HPLC to control the reaction is complete,Cooled to room temperature, water was added, extracted with chloroform, the combined extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was distilled to give compound II as a white solid, 1.5 g in weight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 16.25h;Inert atmosphere; | S4: A round bottom flask was charged with 2'-methyluridine (0.850 g, 3.29 mmol), imidazole (0.896 g, 13.17 mmol), and DCM (6.5 mL), and the mixture was cooled to 0C under nitrogen with stirring. Trimethylsilyl triflate (2.24 mL, 12.34 mmol) was added dropwise via syringe over 15 min. The mixture was warmed to rt and stirred overnight. After 16 h stirring, the mixture was diluted with DCM (200 mL) and poured into ice-cold water (100 mL). The organic layer was removed, and the aqueous layer was extracted with DCM (1 x 100 mL). The combined organic layers were washed with ice-cold brine (1 x 100 mL), dried over Na2S04, filtered, and concentrated by rotary evaporation to give 1.8 g crude. The material was taken up in hexanes, and automated flash chromatography (40 g column, gradient of 5 to 20% EtOAc in hexanes) gave S4 (1.50 g, 96%) as a white flaky solid: 1H NMR (400 MHz, CDC13) delta 8.27 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 5.92 (s, 1H), 5.64 (dd, J = 8.2 Hz, 2.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.83 (d, J = 9.1 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 1.21 (s, 3H), 0.20 (s, 9H), 0.18 (s, 9H), 0.17 (s, 9H); LRMS mlz 475.2 [M+H]+. |
96% | With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 16.25h;Inert atmosphere; | S4: A round bottom flask was charged with 2'-methyluridine (0.850 g, 3.29 mmol), imidazole (0.896 g, 13.17 mmol), and DCM (6.5 mL), and the mixture was cooled to 0C under nitrogen with stirring. Trimethylsilyl triflate (2.24 mL, 12.34 mmol) was added dropwise via syringe over 15 min. The mixture was warmed to rt and stirred overnight. After 16 h stirring, the mixture was diluted with DCM (200 mL) and poured into ice-cold water (100 mL). The organic layer was removed, and the aqueous layer was extracted with DCM (1 x 100 mL). The combined organic layers were washed with ice-cold brine (1 x 100 mL), dried over Na2S04, filtered, and concentrated by rotary evaporation to give 1.8 g crude. The material was taken up in hexanes, and automated flash chromatography (40 g column, gradient of 5 to 20% EtOAc in hexanes) gave S4 (1.50 g, 96%) as a white flaky solid: 1H NMR (400 MHz, CDC13) delta 8.27 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 5.92 (s, 1H), 5.64 (dd, J = 8.2 Hz, 2.3 Hz, 1H), 4.05-3.95 (m, 2H), 3.83 (d, J = 9.1 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 1.21 (s, 3H), 0.20 (s, 9H), 0.18 (s, 9H), 0.17 (s, 9H); LRMS mlz 475.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of bis-(A/,A/-diisopropylamino)-chlorophosphine (0.27 g, 1 .0 mmol) in dry dichloromethane (0.5 mL) was added dropwise to a solution of 2-Me-2'-OH-uridine (0.26 g, 1 .0 mmol) and A/,A/-diisopropylethylamine (0.19 mL, 1 .1 mmol) in dry A/,A/-dimethylformamide (2.0 mL) at -78 C. The reaction mixture warmed to room temperature and was stirred for 1 hour. A solution of 4,5 dicyanoimidazole (0.1 1 g, 1 .0 mmol) in dry A/,A/-dimethylformamide (0.5 mL) was added and the resulting mixture was stirred for an additional 1 hour. The solution of the alcohol 1 (0.24 g, 1 .0 mmol) and 4,5-dicyanoimidazole (0.1 1 g, 1 .0 mmol) in dry A/,A/-dimethylformamide (1 .0 mL) was added and the resulting mixture was stirred overnight. A solution of f-butyl hydroperoxide (0.2 mL, 5-6 M in decane) was added and the mixture was stirred for 30 min. The volatiles were removed in vacuo to afford a residue, which was subjected to HPLC purification (acetonitrile/H20; 20% - 60%, 30 min) to give 0.023g of the more polar isomer 8A and 0.012g of the less polar isomer 8B as white powders (7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 12 (260 mg, 1 mmol) was dissolved in 20 mL of dry tetrahydrofuran,Tert-Butylmagnesium chloride Grignard reagent (1.0 M, 2 mL, 2 mmol) was added at 0 C,The reaction was stirred at room temperature for 30 minutes.A solution of compound 10a (1.0 g, 2 mmol) in tetrahydrofuran (4 mL) was slowly added dropwise,The reaction mixture was stirred at room temperature overnight,The reaction was quenched by addition of saturated ammonium chloride solution (20 mL)Ethyl acetate extraction (20 mL x 3),Organic combination,dry,concentrate,The residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give product 13 as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a suspension of uracil (3.09 g, 27.6 mmol) in CH3CN (60 mL) was added BSA (16.4 mL, 66.1 mmol), and the reaction mixture was heated at 80 C for 30 min. After the mixture was cooled to room temperature, (3R,4R,5R)-5-((benzoyloxy)methyl)-3-methyltetrahydrofuran-2,3,4-triyl tribenzoate (8 g, 13.8 mmol) and SnCl4 (5.7 mL, 48.2 mmol) were added. The reaction mixture was stirred at 80 C for 3 h. The reaction mixture was diluted with CH2Cl2. This solution was washed with water, sat. aq. NaHCO3 (x2), and water (resulting insoluble Sn residue was filtered through celite pad). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was was purified by silica gel column chromatography to give the product (7.595 g), which was treated with 33 % CH3NH2 in EtOH (60 mL) at room temperature for 7 h. After the mixture was concentrated, the redisue was purified by silica gel column chromatography to give the title compound (3.25 g, 91 % in 2 steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 20℃; for 12h; | 20 g of compound A5, 23.7 g of protecting group R2, 7.3 g of pyridine and 100 mL of dichloromethane were added to the reaction flask, and the protecting group R2 was selected to be a triphenylmethylalkyl group. The reaction was carried out at room temperature for 12 hours to the end, the aqueous phase was added, and the organic phase was concentrated and beaten. , dried to give compound A6, yield 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60%; 50 mg | To the redistilled trimethyl phosphate (5.421 g, 0.0387mmol,10 eq), POCl3 (0.653 g, 0.00425mol, 1.1 eq) was added at coolcondition in an ice bath and was further stirred for 2 h at 0 Cunder nitrogen atmosphere. Afterwards, 20-C-methyluridine (2-C-MU) (1.0 g, 0.00387mol, 1.0 eq), which was dried at 90 Covernight, was added in one portion under stirring and wasstirred for 4 h at 0 C under nitrogen atmosphere. The progressand completion of the reaction was monitored by TLCusing ammonium hydroxide: water: IPA (International DiabetesFederation. Diabetes Atlas, 315) as mobile phase. After thecompletion, the reaction mixture was poured into ice waterand adjusted to pH 7.0 with a 1N NaOH solution. This wasconcentrated completely under reduced pressure and washedwith 5mL of water several times. Reaction mass was adsorbedat amberlite IRA 68 column and eluted with 2N formic acid.The eluent was lyophilized to dryness, and the residue wasrecrystallized with ethanol to obtain 5-P-MU (0.7 g, 60% yield).White color solid; m/z338; 1HNMR (400 MHz, DMSO-d6):d 1.00 (s, 3 H, C2-CH3), 3.50-3.68 (m, 3H, C2-OH, C3-OH & C3-H), 3.78-3.81 (m, 2 H, C5), 5.12-5.19(m, 3 H, P-OH, C4), 5.60-5.62 (d, 1 H, C-5), 5.79(s, 1H, C1H), 8.04-8.06 (d, 1H, C-6),11,35 (s, 1 H, NH). |
Tags: 31448-54-1 synthesis path| 31448-54-1 SDS| 31448-54-1 COA| 31448-54-1 purity| 31448-54-1 application| 31448-54-1 NMR| 31448-54-1 COA| 31448-54-1 structure
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