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CAS No. : | 15397-15-6 | MDL No. : | MFCD07369658 |
Formula : | C34H28O9 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QJZSLTLDMBDKOU-VBHQRPIPSA-N |
M.W : | 580.58 | Pubchem ID : | 10875560 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
70% | With triethylamine In acetonitrile at 20 - 60℃; for 2 - 4 h; | 100 g (0.27 moles) of 3,5-di O-benzoyl-2-C-methyl-D-ribofuranose synthesized in example 6 is added by stirring to 300 ml of acetonitrile, then 280 ml (2 moles) of triethylamine is added. 78.3 ml (0.67 moles) of benzoyl chloride is dripped at room temperature. At the end of the addition the mixture is warmed for 2 hours at 60 C., then an HPLC test is carried out.The reaction mixture is cooled to room temperature and 150 ml of water is added. The solid is filtered, washed with a mixture acetonitrile/water=2/1 and dried under vacuum up to constant weight. 109 g of product 1,2,3,5-tetra-O-benzoyl-2-C-methyl-?-D-ribofuranose is obtained. Yield=70percent.The product 3,5-di-O-benzoyl-2-C-methyl-D-ribofuranose (8.25 Kg22.2 moles) synthesized in example 23 is dissolved in 21 Kg of acetonitrile and then loaded in a 100 l reactor. 16.8 Kg (166.5 moles) of triethylamine is added and 9.8 Kg (69.7 moles) of benzoyl chloride is dripped; the temperature grows spontaneously. Then the mixture is heated at 60° C. for 4 hours. Thereafter the reaction is cooled at room temperature and 13.7 l of water is dripped. The mixture is cooled at 0° C. and is kept under stirring 1 hour. The solid is filtered and washed with 8 l of a mixture 2/1 acetonitrile/water cooled at 0° C. and then with 4.7 Kg of cold methyl alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In acetonitrile at 60℃; for 2 - 4 h; | 100 g (0.27 moles) of 3,5-di O-BENZOYL-2-C-METHYL-D-RIBOFURANOSE synthesized in example 6 is added by stirring to 300 ml of acetonitrile, then 280 ml (2 moles) of triethylamine is added. 78.3 ml (0.67 moles) of benzoyl chloride is dripped at room temperature. At the end of the addition the mixture is warmed for 2 hours at 60 C, then an HPLC test is carried out. The reaction mixture is cooled to room temperature and 150 ml of water is added. The solid is filtered, washed with a mixture ACETONITRILE/WATER= 2/1 and dried under vacuum up to constant weight. 109 g of product 1, 2,3, 5-tetra-O-benzoyl-2-C-methyl-?-D-ribofuranose is obtained. Yield = 70percent. 1H-NMR (CDC13, 300 MHz): 8 ppm 7.07 (1H, s, H-1) ; 5.96 (1H, d, H-3); 4.79 (1H, m, H- 4); 4.62 (2H, system AB, CH2-5). 13C-NMR (CDC13, 300 MHz): 6 ppm 97. 97 (C-1) ; 86.82 (C-4); 78.71 (C-3); 76.31 (C-2), 64.01 (C-5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.1% | With triethylamine In dichloromethane at 15℃; for 3 h; Cooling with ice | A solution of the compound A2, 64 g of benzoyl chloride and 250 mL of dichloromethane were added to the reaction flask, and the mixture was cooled in an ice bath, stirred, and 48 g of triethylamine was slowly added dropwise. After the addition was completed, the reaction was stirred at 15 ° C for 3 hours. , washing with water, concentration, crystallization, to obtain compound A3, the total yield of step two and step three is 67.1percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Example 94; Synthesis of 2-(3, 4-Dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2 2H-[1 2, 41triazine-3. 5-dione (169); Step 1; Synthesis of 1, 2, 3, 5-Tetra-O-benzoyl-2'-C-methyl p-D-ribofuranose; The title intermediate was prepared as described herein above. <P>Step 2. Synthesis of 2- (3, 4-Dibenzoyl-5-benzoylinethyl-3-methyl-tetrahydro-furan- 2-yl)-2H- [1, 2, 4] triazine-3, 5-dione 2H- [1, 2,4] Triazine-3,5-dione (Aldrich) (194.5mg, 1.72mmol) was dissolved in anhydrous acetonitrile (6mL). BSA (0.85mL, 3. 44mmol) was added via syringe, and reaction was refluxed at 90C for 45 minutes. The reaction was then allowed to cool to room temperature. 1, 2,3, 5-Tetra-O-benzoyl-2'-C-methyl B-D-ribofuranose (500mg, 0. 861mmol) was dissolved in anhydrous acetonitrile (6mL) and added to the reaction mixture. TMSOTf (0. 625mL, 3. 44mmol) was then added to the reaction drop wise via syringe. The reaction mixture was then refluxed at 90C for 2 hours. The mixture was then diluted with EtOAc (200mL) and washed with 200 mL saturated NaHC03 solution. The organic layer was extracted 2x with 100 mL EtOAc and the combined organic fractions were washed with brine and dried over Magnesium sulfate. The reaction was purified via column chromatography on silica gel (2: 4: 4 EtOAc: DCM: hexane) to yield a white crystalline product (450mg, 0. 79mmol, 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | With N,O-bis-(trimethylsilyl)-acetamide; tin(IV) chloride; In acetonitrile; at 75℃; | 50 g of compound A3, 1 lg of uracil, 26 g of N,0-bis(trimethylsilyl)acetamide and a second organic solvent were added to the reaction flask, and the second organic solvent was acetonitrile, N,0-double (three The mass ratio of methylsilylacetamide to compound 3 is 1:1, the temperature is raised to 75 C, and 45 g of tin tetrachloride is slowly added dropwise. After the reaction, water and alkali are added to neutralize, and dichloromethane is added for extraction. The phases were separated, the organic phase was concentrated, beaten, and filtered to obtain Compound A4 in a yield of 90.3% |
80% | Example 51 Preparation of Compound 57 Compound 57 may be prepared according to Scheme 7, above. To a solution of uracil (4 g) in acetonitrile (120 ml) was added BSA (18 ml) and the mixture was stirred at 100 C. for 30 minutes. After cooling to room temperature, 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose (10 g) in acetonitrile (120 ml) and 5 nCl4 (7 ml) were added. The reaction mixture was stirred at 100 C. for 4 hours. The mixture was diluted with EtOAc and a saturated solution of NaHCO3 was added at 0 C. followed by filtration on celite. The filtrate was extracted with EtOAc and the organic layer was washed with a saturated solution of NaHCO3. After drying over Na2SO4 and filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0?20% EtOAc in dichloromethane to yield 2',3',5'-tri-O-benzoyl-2'-C-methyluridine (80%). 2',3',5'-tri-O-benzoyl-2'-C-methyluridine was characterized by the following spectroscopic data: MS (ESI, EI+) m/z=571.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 65℃; for 5.33h; | Step a: To beta-D-ribofuranose, 2-C-methyl-, 1,2,3,5-tetrabenzoate (4.0 g, 6.89 mmol, 1 equiv.) and 2,6-dichloropurine (1.43 g, 7.58 mmol, 1.1 equiv.) in acetonitrile (23 mL) at 0 C was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (2.58 mL, 17.23 mmol, 2.5 equiv.) followed by trimethylsilyl trifluoromethanesulfonate (5.11 mL, 28.25 mmol, 4.1 equiv.) dropwise over 5 minutes. The reaction mixture was stirred at 0 C for 15 minutes and heated at 65 C for 5 hours. After cooling to room temperature the reaction was diluted with dichloromethane, washed with sat. aq. sodium bicarbonate (x2), and brine (x1). The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The desired product was obtained following column chromatography (SiO2, 25% to 66% EtOAc/Hexane) as a white solid (1.30 g, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.7% | Compound 10-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0 C. The mixture was stirred at 0 C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0 C. The mixture was stirred at 0 C. for 30 mins. The mixture was heated to 70 C., and stirred overnight. The solution was cooled to RT and diluted with EA (100 mL). The solution was washed with sat. NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 10-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]+ | |
88.7% | Compound 10-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0 C. The mixture was stirred at 0 C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0 C. The mixture was stirred at 0 C. for 30 mins. The mixture was heated to 70 C., and stirred overnight. The solution was cooled to RT and diluted with EA (100 mL). The solution was washed with sat. NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 10-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]+. | |
With N,O-bis-(trimethylsilyl)-acetamide; trimethylsilyl trifluoromethanesulfonate; | Step 4 j0062j The chloro-nucleoside can be prepared readily from the tetrabenzoate and a chloro-purine derivative, as shown above. This chemistry is well described in theliterature (WO 2004/003 138; 1 Med. Chem., 47:2283 (2004); WO 2006/122207; Bioorg. Med. Chem. Leu., 17:2456 (2007); WO 2010/081082; Bioorg. Med. Chem. Lett., 20:4850 (2010); Bioorg. Med. Chem. Leu., 21:6007 (2011); WO 2011/123586; Bioorg. Med. Chem. Leu., 2 1:6788 (2011); WO 2012/048013). Methoxylation of the chloro-purinederivative with sodium methoxide has also been described in detail (Bioorg. Med. Chem.Lett., 21, 6007 (2011); WO 2011/123586; Bioorg. Med. Chem. Lett., 20:4850 (2010); WO2010/08 1082), the disclosures of which are herein incorporate by reference. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 83 percent / DBU, Me3SiOTf / acetonitrile / 4 h / 60 °C 2: 72 percent / methanolic NH3 / 7 h / Ambient temperature 3: 60 percent / ethanol / 5 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 - 76% | With triethylamine; In acetonitrile; at 20 - 60℃; for 2 - 4h; | 100 g (0.27 moles) of 3,5-di O-benzoyl-2-C-methyl-D-ribofuranose synthesized in example 6 is added by stirring to 300 ml of acetonitrile, then 280 ml (2 moles) of triethylamine is added. 78.3 ml (0.67 moles) of benzoyl chloride is dripped at room temperature. At the end of the addition the mixture is warmed for 2 hours at 60 C., then an HPLC test is carried out.The reaction mixture is cooled to room temperature and 150 ml of water is added. The solid is filtered, washed with a mixture acetonitrile/water=2/1 and dried under vacuum up to constant weight. 109 g of product 1,2,3,5-tetra-O-benzoyl-2-C-methyl-?-D-ribofuranose is obtained. Yield=70%.The product 3,5-di-O-benzoyl-2-C-methyl-D-ribofuranose (8.25 Kg22.2 moles) synthesized in example 23 is dissolved in 21 Kg of acetonitrile and then loaded in a 100 l reactor. 16.8 Kg (166.5 moles) of triethylamine is added and 9.8 Kg (69.7 moles) of benzoyl chloride is dripped; the temperature grows spontaneously. Then the mixture is heated at 60 C. for 4 hours. Thereafter the reaction is cooled at room temperature and 13.7 l of water is dripped. The mixture is cooled at 0 C. and is kept under stirring 1 hour. The solid is filtered and washed with 8 l of a mixture 2/1 acetonitrile/water cooled at 0 C. and then with 4.7 Kg of cold methyl alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 - 76% | With triethylamine; In acetonitrile; at 60℃; for 2 - 4h; | 100 g (0.27 moles) of 3,5-di O-BENZOYL-2-C-METHYL-D-RIBOFURANOSE synthesized in example 6 is added by stirring to 300 ml of acetonitrile, then 280 ml (2 moles) of triethylamine is added. 78.3 ml (0.67 moles) of benzoyl chloride is dripped at room temperature. At the end of the addition the mixture is warmed for 2 hours at 60 C, then an HPLC test is carried out. The reaction mixture is cooled to room temperature and 150 ml of water is added. The solid is filtered, washed with a mixture ACETONITRILE/WATER= 2/1 and dried under vacuum up to constant weight. 109 g of product 1, 2,3, 5-tetra-O-benzoyl-2-C-methyl-?-D-ribofuranose is obtained. Yield = 70%. 1H-NMR (CDC13, 300 MHz): 8 ppm 7.07 (1H, s, H-1) ; 5.96 (1H, d, H-3); 4.79 (1H, m, H- 4); 4.62 (2H, system AB, CH2-5). 13C-NMR (CDC13, 300 MHz): 6 ppm 97. 97 (C-1) ; 86.82 (C-4); 78.71 (C-3); 76.31 (C-2), 64.01 (C-5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With boron trifluoride diethyl etherate; In nitromethane; for 2h;Heating / reflux; | 1-O-Acetyl-2-C-methyl-2, 3, 5-tri-O-benzoyl-D-ribofuranose (1.0 g, 1.72 mmol) was dissolved in anhydrous nitromethane (10.0 mL) and to this solution compound 1.2 (312 mg, 1.21 mmol) was added. The resulting suspension was brought to reflux and borontrifluoride etherate (0.23 mL, 1.78 mmol) was added. The suspension became a clear solution, which was heated at reflux for 2 hr. The mixture was cooled, the solvents were evaporated and the off-white foamy residue was dissolved in ethyl acetate and then poured with stirring into aq. sat. NaHCO3. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried (NA2S04), filtered and evaporated to give an off-white solid. This material was purified by flash column chromatography on silica gel using CH2CL2 to 2-3% MeOH in dichoromethane as eluent to give the desired compound 1.4 (811 mg) as a yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium cyanide; In methanol; at 20℃; for 15h; | To a suspension OF 2-C-METHYL-1, 2,3, 5-TETRA-O-BENZOYL-ss-D-RIBOFURANOSE 1.3, (50 g) in anhydrous MeOH (1000 mL) was added KCN (150 mg) and the mixture was allowed to stir at room temperature under argon for 15 hr during which time all the material dissolved in the solvent and the solution became clear. The solvent was evaporated and the residue was dried under vacuum to deliver 14.9 g of product 7.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | To a suspension of heterocycle 4 (268 mg, 1.44 mmol) in anhydrous MeCN (8 mL) at rt was added BSA (971 uL, 3.93 mmol). The resultant mixture was heated to 80 C for 2.5 h whereupon 2-C-methyl-beta-D-ribofuranose 118 [prepared according to Wolfe et al. J. Org. Chem. 1997, 62, 1754-1759] (760 mg, 1.31 mmol) was added as a solution in MeCN (6 mL). To this mixture was added SnCl4 (276 uL, 2.35 mmol), and stirring at 80 C was continued for an additional 1.5 h. TLC analysis with 10% MeOH-CHCl3 indicated that the reaction was complete. The mixture was cooled to rt, diluted with EtOAc (150 mL), and partitioned with a 1:1 mixture (100 mL) of brine-NaHCO3. The aqueous phase was further extracted with EtOAc (50 mL), and the combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was submitted to HPLC (SiO2, 0-4% MeOH-DCM) to afford 353 mg (42%) of a white solid: 1H (400 MHz, DMSO-J6) delta 11.3 (br s, IH), 7.93-8.08 (br m, 3 H), 7.85-7.87 (m, 2 H), 7.33-7.66 (m, 10 H), 6.97 (br s, 2H), 6.64 (s, IH), 6.16-6.26 (br m, IH), 4.56-4.79 (br m, 3H), 1.79 (s, 3H); M+ m/z 642. |
Yield | Reaction Conditions | Operation in experiment |
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100% | Example 103; Synthesis of 4-Cyclopropylamino-1-(34-dihYdroxv-5-hydroxymethy1-3-methyl- tetrahydro-furan-2-el .-lH-parimidin-2-one (206); Step 1; Synthesis of 1-(3,4-Dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-y--IH-pyrimidne-2, 4-dione; 1H-Pyrimidne-2, 4-dione (Aldrich) is dissolved in anhydrous acetonitrile. BSA is added via syringe, and the reaction is refluxed at 90C for 45 minutes. The reaction is then allowed to cool to room temperature. 1, 2,3, 5-Tetra-O-benzoyl-2'-C- methyl p-D-ribofuranose is dissolved in anhydrous acetonitrile and added to the reaction mixture. TMSOTf is then added to the reaction drop wise via syringe. The reaction mixture is then refluxed at 90C for 2 hours. The mixture is then diluted with EtoAc and washed with saturated bicarbonate solution. The organic layer is extracted 2x with EtoAc and the combined organic fractions are washed with brine and dried over Magnesium sulfate. The reaction is purified via column chromatography on silica gel to yield the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2; Synthesis of 2',3',5'-Trisbenzoyl protected 5-Hydroxymethyl-3-methyl-2- (4-nitro-benzoimidazol-1-yl)-tetrahydro-furan-3, 4-diol; The product from Step 1 above (130. 5 mg, 0.8 mmol) was dissolved in 10 mL dry acetonitrile. 0.5 mL (2.0 mmol) of N, O-bis (trimethylsilyl) acetamide was added, and the solution was kept at reflux until clear-approximately 15 min. Next, 1, 2,3, 5-Tetra-0-benzoyl-2'-C-methyl P-D-ribofuranose (ribose X) (280.6 mg, 0.5 mmol) and trimethylsilyl trifluoromethanesulfonate (0.3 mL, 2.0 mmol) was added to solution. The reaction was kept at reflux for 1 h. After this time the reaction was allowed to cool to room temperature and was quenched by the addition of solid sodium bicarbonate (294 mg). The mixture was further diluted with 60 mL saturated sodium bicarbonate. The product was extracted with chloroform. The organic phase was washed with brine, dried with sodium sulfate and evaporated. The product was a greasy solid which was immediately taken to the next step in crude form. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step2; Synthesis of 2', 3', 5'-Trisbenzoyl protected 5-Hydroxymethyl-3-methyl-2- (7-nitro-imidazo [4, 5-b]-pyridin-3-yl-tetrahydro-furan-3, 4-diol; The product of Step 1 above (131. 1 mg, 0.8 mmol) was dissolved in 10 mL dry acetonitrile. 0.5 mL (2. 0 mmol) of N, O-bis (trimethylsilyl) acetamid was added, and the solution was kept at reflux until clear-approximately 15 min. Next, 1,2, 3,5- tetra-O-benzoyl-2'-C-methyl p-D-ribofuranose (ribose X) (290.3 mg, 0.5 mmol) and trimethylsilyl trifluoromethanesulfonate (0.3 mL, 2.0 mmol) was added to solution. The reaction was kept at reflux for 1 h. After this time the reaction was allowed to cool to room temperature and was quenched by the addition of solid sodium bicarbonate (294 mg). The mixture was further diluted with 60 mL saturated sodium bicarbonate. The product was extracted with chloroform. The organic phase was washed with brine, dried with sodium sulfate and evaporated. The product was a greasy, yellow solid which was taken immediately to the next step in crude form. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Example 95; Synthesis of 5-Hydroxymethyl-3-methyl-2-(6-thiophen-3-yl-purin tetrahydro-furan-3, 4-diol (1); Step 1; Synthesis of 2-(6-Bromo-purin-9-yl .-5-benzoyloxamethyl-3-methyl- tetrahydro-furan-3, 4-oxybenzoyl; 6-Bromo-9H-purine (Aldrich, 342.3mg, 1.72 mmol) was dissolved in anhydrous acetonitrile (6mL). BSA (0.85mL, 3. 44mmol) was added via syringe, and reaction was refluxed at 90C for 45 minutes. The reaction was then allowed to cool to room temperature. 1, 2,3, 5-Tetra-O-benzoyl-2'-C-methyl (3-D-ribofuranose (500mg, 0.861 mmol) was dissolved in anhydrous acetonitrile (6mL) and added to the reaction mixture. TMSOTf (0.625mL, 3.44 mmol) was then added to the reaction drop wise via syringe. The reaction mixture was then refluxed at 90C for 3.5 hours. The mixture was then diluted with EtOAc (lOOmL) and washed with 100mL saturated bicarbonate solution. The organic layer was extracted 2x with 100mL EtoAc and the combined organic fractions were washed with brine and dried over magnesium sulfate. This mixture was then concentrated in vacuo. The reaction was purified via column chromatography on silica gel (loaded on 5% EtoAc in DCM, eluted with 10% EtoAc in DCM) to yield an off white solid (500mg, 0.76mmol, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 110; Synthesis of 2- .-5-hydroxymethyl-3-meth tetrahydro-furan-3, 4-diol; Step 1; Synthesis of 2, 3n5 tribenzoyl protected-2- (6-Amino-8-methvl-purin-9-yl)-5- hydroxymethyl-3-methyl-tetrahydro-furan-3, 4-diol; To a solution of N, N-Dimethyl-N'- (8-methyl-9H-purin-6-yl)-formamidine (1.71 mmol) (the crude product of Step 2 in Example 109), in 1,2-dichloroethane (10 mL) was added BSA (l. OmL, 4.05 mmol) and heated to reflux for 1.5 hours under argon. The solution was allowed to cool slightly and 1, 2,3, 5-tetra-0-benzoyl-2'-C- methyl (3-D-ribofuranose (0.750g, 1. 29mmol) dissolved in 1,2-dichloroethane (lOmL) was added, followed immediately by TMSOTf (1. 5mL, 8. 3mmol). The reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature, diluted with methylene chloride, washed with saturated NaHC03 (1 x 75mL). The aqueous layer was back extracted with methylene chloride (2 x 50mL) and the combined organic layers were washed with H20 (1 x 75mL), brine (1 x 70mL), then dried over Na2S04 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 5% methanol in methylene chloride as the eluent. The appropriate fractions were pooled, concentrated in vacuo to give the title compound.. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 2; Synthesis of 8- (3, 4-Bis-benzoyloxy-5-benzoyloxymethyl-3-methyl- tetrahydro-furan-2-yl)-2-methylsulfanyl-4, 5-dioxo-3, 4, 5, 8-tetrahydro-pyrido [2, 3- d] pyrimidine-6-carboxylic acid ethyl ester; To a suspension of the product from Step 1 above (0.2g, 0.71mmol) in dry acetonitrile (3.5 mL), BSA (0.385 mL, 1.56 mmol) was added and the mixture refluxed under argon for 30min. The resulting solution was cooled to room temperature and 1, 2,3, 5-tetra-O-benzoyl-2'-C-methyl P-D-ribofuranose (0.32g, 0. 55mmol) in dry acetonitrile was added followed immediately by TMSOTf (0.513 mL, 2.84 mmol). The resulting reaction mixture was heated to reflux for 2 hours. The reaction was allowed to cool to room temperature then was concentrated in vacuo to an oily residue. The oily residue was taken up in EtOAc and washed 1X with saturated NaHC03 and the aqueous layer was re-extracted 2X with EtOAc. The organic fractions were combined, washed with H2O, brine, and dried over Na2S04 and concentrated in vacuo. The crude reaction was purified by column chromatography on silica gel using 10% methanol in methylene chloride for elution. The appropriate fractions were pooled, evaporated, and foamed from methylene chloride to get 0.406g (100%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Example 78; Synthesis of 2'-C-methyl-ss-D-ribofuranosyl-6-methylthio-purine (150); Step 1; Synthesis of 2'*3', 5'-Tri-O-benzoyl-2'-C-methvl-ss-D-ribofuranosyl-6- methylthio-purine; 6-Methylthio-purine (1.43 g, 8.6 mmolol) ) was suspended in 100 mL of dry CH3CN, bis-trimethylsilylacetamide (BSA) was added (5 mL, 20 mmolol) and the mixture was refluxed until the clear solution was formed (about 30 min). 1,2, 3,5- Tetra-O-benzoyl-2'-C-methyl p-D-ribofuranose (4g, 6.9 mmolol) was added followed by trimethylsilyl trifluoromethane sulfonate (TMSOTf) (5 mL). The mixture was refluxed for 4 hours, disappearance of the sugar was controlled by TLC in hexane-ethyl acetate (1: 1 v/v). Solution of 10% NaHC03 was added and the benzoylated nucleoside was extracted with ethyl acetate. Water fraction was extracted with organic (2 x 30 mL). Combined organic fractions were washed with water, dried over Na2S04 and evaporated. The titled nucleoside was isolated by column chromatography on silica gel using 5% ethyl acetate in toluene as eluent with 74% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Example 79; Synthesis of 2'-C-methyl-ss-D-ribofuranosyl-6-phenyladenine (155); 6-Phenyl-adenine (315 mg, 1.5 mmol) was suspended in 20 mL of dry CH3CN, BSA was added (0.4 mL) and the mixture was refluxed until the clear solution was formed (about 30 min). 1,2, 3, 5-Tetra-O-benzoyl-2'-C-methyl p-D- ribofuranose was added followed by trimethylsilyl trifluoromethane sulfonate (0.2 mL). The mixture was refluxed for 4 hours, disappearance of the sugar was controlled by TLC in hexane-ethyl acetate (1: 1 v/v). Solution of 10% NaHC03 was added and the benzoylated nucleoside was extracted with ethyl acetate. Water fraction was extracted with organic (2 x 30 mL). Combined organic fractions were washed with water, dried over Na2S04 and evaporated. The residue was dissolved in 20 mL of NH3/methanol and left overnight at ambient temperature. The reaction mixture was concentrated and purified by column chromatography on silica gel using ethyl acetate/iso-propanol/water (9: 1: 2, upper phase) as eluent. The title nucleoside was dissolved in methanol and precipitated with ether with 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 65℃; | To a pre-cooled (0 0C) solution of (2S,3tf ,4tf ,5tf )-5-(benzoyloxymethyl)-3- methyltetrahydrofuran-2,3,4-triyl tribenzoate (or 2,3,4,5-tetra-0-benzoyl-2-C- methyl-/?-D-ribofuranose) (CarboSynth Ltd, 10.0 g, 17.22 mmol), 2-amino-6- chloropurine (Aldrich, 3.2 g, 18.87 mmol), and l,8-diazabicycl[5.4.0]undec-7-ene (DBU) (7.7 mL, 51 mmol) in anhydrous acetonitrile (200 mL), was added trimethysilyl triflate (12.5 mL, 68.8 mmol) dropwise. The reaction mixture was then heated at 65 0C for 4 to 6 h, allowed to cool down to room temperature, poured into saturated aqueous sodium bicarbonate (300 mL), and extracted with dichloromethane (3x150 niL). The combined organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was precipitated from dichloromethane and methanol, filtrated, the solid was washed 2 times with methanol and dried to give the desired compound (8.5 g, 79 %) as a white solid (yields are from 65% (column) up to 90% (precipitation)).[00148] The following are the NMR results analyzing the synthesized compounds:1H NMR (500 MHz, CDCl3) delta 8.13 (dd, J = 1.2, 8.3, 2H), 8.02 - 7.94 (m, 5H), 7.65 - 7.60 (m, IH), 7.58 - 7.45 (m, 4H), 7.35 (q, J = 7.7, 4H), 6.65 (s, IH), 6.40 (d, J = 6.7, IH), 5.31 (s, 2H), 5.08 (dd, J = 4.2, 11.6, IH), 4.79 (dd, J = 6.4, 11.6, IH), 4.74 (td, J = 4.2, 6.5, IH), 1.60 (s, 3H).13C NMR (126 MHz, CDCl3) delta 166.31(C=O), 165.38(C=O), 165.32(C=O), 159.13(C2), 152.87(C6), 152.06(C4), 141.42(C8), 133.77(C-H Bn), 133.69 (C-H Bn), 133.28(C-H Bn), 129.90(C-H Bn), 129.82(C-H Bn), 129.78 (C Bn), 129.70(C-H Bn), 129.41(C Bn), 128.78(C Bn), 128.61(C-H Bn), 128.50(C-H Bn), 128.41(C-H Bn), 126.00(C5), 88.84(Cl'), 85.68(C2'), 79.43(C4'), 76.07(C3'), 63.57(C5'), 17.77(2'-Me). |
88.7% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 70℃; | Compound 16-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mL) was added DBU (39.5 g, 258.0 mmol) at 0 C. The mixture was stirred at 0 C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0 C. The mixture was stirred at 0 C. for 30 mins. The mixture was heated to 70 C., and stirred overnight. The solution was cooled to R.T. and diluted with EA (100 mL). The solution was washed with sat. NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 16-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS: m/z 628 [M+H]+. |
88.7% | Compound 10-1 (50 g, 86.0 mmol) and 6-Cl-guanine (16.1 g, 98.2 mmol) were co-evaporated with anhydrous toluene 3 times. To a solution of 10-1 in MeCN (200 mE) was added DRU (39.5 g, 258.0 mmol) at 0 C. The mixture was stirred at 0C. for 30 mins, and then TMSOTf (95.5 g, 430.0 mmol) was added dropwise at 0 C. The mixture was stirred at 0 C. for 30 mins. The mixture was heated to 70 C., and stirred overnight. The solution was cooled to RT and diluted with EA (100 mE). The solution was washed with sat. NaHCO3 solution and brine. The organic layer was dried overNa2504, and concentrated at low pressure. The residue was purified by column on silica gel (EA in PE from 10% to 40%) to give 10-2 (48.0 g, yield: 88.7%) as a yellow foam. ESI-MS:m/z 628 [M+H]. |
79% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 65℃; | To a pre-cooled (0 C) solution of (2S,3R,4R,5R)-5-(benzoyloxymethyl)-3- methyltetrahydrofuran-2,3,4-triyl tribenzoate (or 2,3,4,5-tetra-0-benzoyl-2-C-methyl-beta-D- ribofuranose) (CarboSynth Ltd, 10.0 g, 17.22 mmol), 2-amino-6-chloropurine (Aldrich, 3.2 g, 18.87 mmol), and l,8-diazabicycl[5.4.0]undec-7-ene (DBU) (7.7 mL, 51 mmol) in anhydrous acetonitrile (200 mL), was added trimethysilyl triflate (12.5 mL, 68.8 mmol) dropwise. The reaction mixture was then heated at 65 C for 4 to 6 h, allowed to cool down to room temperature, poured into saturated aqueous sodium bicarbonate (300 mL), and extracted with dichloromethane (3x150 mL). The combined organic phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was precipitated from dichloromethane and methanol, filtrated, the solid was washed 2 times with methanol and dried to give the desired compound (8.5 g, 79 %) as a white solid (yields are from 65% (column) up to 90% (precipitation)). LH NMR (500 MHz, CDC13) delta 8.13 (dd, J = 1.2, 8.3, 2H), 8.02 - 7.94 (m, 5H), 7.65 - 7.60 (m, 1H), 7.58 - 7.45 (m, 4H), 7.35 (q, J = 7.7, 4H), 6.65 (s, 1H), 6.40 (d, J = 6.7, 1H), 5.31 (s, 2H), 5.08 (dd, J = 4.2, 1 1.6, 1H), 4.79 (dd, J = 6.4, 1 1.6, 1H), 4.74 (td, J = 4.2, 6.5, 1H), 1.60 (s, 3H). 13C NMR (126 MHz, CDC13) delta 166.31(C=0), 165.38(C=0), 165.32(C=0), 159.13(C2), 152.87(C6), 152.06(C4), 141.42(C8), 133.77(C-H), 133.69 (C-H), 133.28(C-H), 129.90(C- H), 129.82(C-H), 129.78 (C), 129.70(C-H), 129.41(C), 128.78(C), 128.61(C-H), 128.50(C- H), 128.41(C-H), 126.00(C5), 88.84(C1 '), 85.68(C2'), 79.43(C4'), 76.07(C3 '), 63.57(C5'), 17.77(2'-Me). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 70℃; for 24h; | To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 3 (903 mg, 3.23 mmol), 2-C-methyl-1,2,3,5-tetra-O-benzoyl-beta-d-ribofuranose 4 (1.7 g, 2.93 mmol) and DBU (1.3 ml, 8.69 mmol) in MeCN (20 ml), TMSOTf (2.1 ml, 11.62 mmol) was added dropwise at 0 C and the mixture was then stirred at 70 C for 24 h. After cooling, the mixture was diluted with AcOEt (100 ml), washed with aq NaHCO3 (sat., 25 ml), H2O (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica (hexanes/toluene, 1:1; then hexanes/toluene/MeCN, 49:49:2?3:3:4) affording title compound 5 as a white foam (1.04 g, 48%). Product was recrystallized from EtOH. Mp 95-97 C. -69.3 (c 0.280, CHCl3). 1H NMR (500 MHz, CDCl3): 1.59 (s, 3H, CH3); 4.72 (td, 1H, J4?,3? = J4?,5?b = 5.8, J4?,5?a = 3.4, H-4?); 4.85 (dd, 1H, Jgem = 12.2, J5?b,4? = 5.8, H-5?b); 4.95 (dd, 1H, Jgem = 12.2, J5?a,4? = 3.4, H-5?a); 6.03 (d, 1H, J3?,4? = 5.8, H-3?); 6.95 (s, 1H, H-1?); 7.34, 7.46 and 7.47 (3 × m, 3 × 2H, H-m-Bz); 7.54, 7.59 and 7.61 (3 × m, 3 × 1H, H-p-Bz); 7.69 (s, 1H, H-6); 7.96, 8.10 and 8.11 (3 × m, 3 × 2H, H-o-Bz); 8.75 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 17.92 (CH3); 52.68 (C-5); 63.33 (CH2-5?); 75.55 (CH-3?); 80.04 (CH-4?); 84.93 (C-2?); 88.95 (CH-1?); 117.71 (C-4a); 128.49, 128.54 and 128.63 (CH-m-Bz); 128.65, 129.50 and 129.61 (C-i-Bz); 129.78, 129.83 and 129.92 (CH-o-Bz); 132.66 (CH-6); 133.38, 133.66, 133.72 (CH-p-Bz); 150.68 (C-7a); 151.17 (CH-2); 153.15 (C-4); 165.09, 165.33 and 166.32 (CO). MS (FAB): m/z 738 [M+H]. HRMS (FAB) for C33H26ClIN3O7 [M+H] Calcd: 738.0504. Found: 738.0491. Anal. Calcd for C33H25ClIN3O7: C, 53.71; H, 3.41; N, 5.69. Found: C 53.91; H 3.29; N 5.38. |
48% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 70℃; for 22.5h; | To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 8 (903 mg, 3.23 mmol), 2-C-methyl-l,2,3,5-tetra-O-benzoyl-/?-D-ribofuranose 9 (1.7 g, 2.93 mmol) and DBU (1.3 ml, 8.69 mmol) in MeCN (20 ml) was dropwise added TMSOTf (2.1 ml, 11.62 mmol) at 0 C and the mixture was then stirred at 70 C for 22.5 h. After cooling, the mixture was diluted with AcOEt (100 ml), washed with aq NaHCO3 (sat., 25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica (hexanes/toluene, 1 :1; then hexanes/toluene/MeCN, 49:49:2 ->; 3:3:4) affording title compound 10 as a white foam (1.04 g, 48%). Compound was recrystallized from EtOH. Mp 95 C. [alpha]20D -69.3 (c 0.280, CHCl3). 1H NMR (500 MHz, CDCl3): 1.59 (s, 3H, CH3); 4.72 (td, IH, J4-,3- = J4 ;5 b = 5.8, J4-,5 a = 3.4, H-4'); 4.85 (dd, IH, Jgem= 12.2, J5 M = 5.8, H-5'b); 4.95 (dd, IH, Jgem = 12.2, J5 a,4 = 3.4, H-5'a); 6.03 (d, lH, J3vr = 5.8, H-3'); 6.95 (s, IH, H-I '); 7.34, 7.46 and 7.47 (3 x m, 3 x 2H, H-m-Bz); 7.54, 7.59 and 7.61 (3 x m, 3 x IH, H-/?- Bz); 7.69 (s, IH, H-6); 7.96, 8.10 and 8.11 (3 x m, 3 x 2H, H-o-Bz); 8.75 (s, IH, H-2). 13C NMR (125.7 MHz, CDCl3): 17.92 (CH3); 52.68 (C-5); 63.33 (CH2-5'); 75.55 (CH-3'); 80.04 (CH-4'); 84.93 (C-2'); 88.95 (CH-I '); 117.71 (C-4a); 128.49, 128.54 and 128.63 (CH-w-Bz); 128.65, 129.50 and 129.61 (C-i-Bz); 129.78, 129.83 and 129.92 (CH-o-Bz); 132.66 (CH-6); 133.38, 133.66, 133.72 (CH-P-Bz); 150.68 (C-7a); 151.17 (CH-2); 153.15 (C-4); 165.09, 165.33 and 166.32 (CO). IR (CHCl3): 3092, 3066, 3034, 1727, 1602, 1587, 1577, 1538, 1504, 1493, 1451, 1444, 1339, 1316, 1269, 1248, 1178, 1162, 1141, 1116, 1070, 1027, 1002, 952, 943, 843, 822, 725, 712, 686, 617, 600. MS (FAB): m/z 738 (M+H). HRMS (FAB) for C33H26ClIN3O7 [M+H] calcd: 738.0504; found: 738.0491. Anal. Calcd for C33H25ClIN3O7: C, 53.71; H, 3.41; N, 5.69. Found: C 53.91; H 3.29; N 5.38. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a suspension of 4-amino-6-bromo-7H-pyrrolo[2,3-d]pyrimidine-5- carbonitrile, A (4.1 g, 0.017 mol) in acetonitrile (120 mL) at room temperature was added via syringe BSA (6.9 g, 0.034 mol) over a 20 min. period. The mixture was stirred at room temperature for 30 min. after which (2S,3R,4R,5R)-5-(benzoyloxymethyl)-3- methyltetrahydrofuran-2,3,4-triyl tribenzoate, B (10.0 g, 0.17 mol) was added in one portion followed by addition via syringe of TMS-OTf (11.3 g, 0.051 mol) over a 15 min. period. The mixture was stirred at room temperature for 15 min. and then heated to 65 C for 17 hr. The reaction mixture was diluted with ethyl acetate (120 mL) and the mixture was poured into saturated aqueous sodium bicarbonate solution (120 mL). After stirring for 20 min., the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. The mixture was filtered and the filtrate was evaporated in vacuo to give 15.8 g of crude product as a brown foam. The residue was dissolved in ethyl acetate, silica gel was added and the mixture was concentrated in vacuo. The residue was transferred to a pre-column and purified by silica gel chromatography using a stepwise gradient from hexanes to 40% ethyl acetate/hexanes to give 7.72 g (65%) of (2R,3R)-2-(4-amino-6-bromo-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5- (benzoyloxymethyl)-3-methyltetrahydrofuran-3,4-diyl dibenzoate, C as a yellow foam. 1H NMR indicated this was a mixture of anomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tin(IV) chloride; | Compound 1a (prepared according to J. Organic Chemistry, 1968, 2490) was subjected to the reaction conditions similar to those described in WO200512308, affording Compound 1b (Yield; 74%). Melting point; 101-103 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tin(IV) chloride; In 1,2-dichloro-ethane; at 20℃; for 6h;Inert atmosphere; | The freshly prepared persilylated 2-thiouracil 240 (4.22 g, 15.50 mmol) was dissolved in 1 ,2-dichloroethane (50 mL) under nitrogen with stirring at room temperature. A solution of 241 (4.50 g, 7.75 mmol) in 1,2-dichloroethane (50 mL) was added all at once to the stirredmixture.To this mixture was added SnC14 (1.36 mL, 3.03 g, 11.63 mmol) dropwise via syringe, and the mixture was stirred at room temperature 6 h until all starting material was consumed. The mixture was cooled to 0C and a sat. aq. NaHCO3 solution (125 mL) was added. The mixture was warmed to room temperature and stirred 30 mm. The mixture wasextracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with brine(1 x 100 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation to give 5.5g crude product. The crude material was taken up in dichloromethane, immobilized onCelite, and subjected to flash chromatography on the Combiflash (120 g column, 5 to 50%EtOAc in hexanes gradient) to give 242 (2.41 g, 53%) as a clear sticky solid in 90% purity.This material was used directly in the next step without further purification. ?H NMR (400MHz, CDC13) oe ppm 9.37 (br s, 1H), 8.10-8.05 (m, 4H), 7.82 (d, J 7.7 Hz, 2H), 7.70 (d, J8.3 Hz, 1H), 7.66-7.45 (m, 6H), 7.42 (t, J 7.8 Hz, 2H), 7.27-7.21 (m, 2H), 5.88 (d, J= 8.2,1H), 5.62 (d, J= 5.5 Hz, 1H), 4.91-4.83 (m, 2H), 4.77 (dd, J= 11.8 Hz, 4.7 Hz, 1H), 1.77 (s3H). |
2.41 g | With tin(IV) chloride; In 1,2-dichloro-ethane; at 20℃; for 6h; | Example 88. The freshly prepared persilylated 2-thiouracil 240 (4.22 g, 15.50 mmol) was dissolved in 1,2-dichloroethane (50 mL) under nitrogen with stirring at room temperature. A solution of 241 (4.50 g, 7.75 mmol) in 1,2-dichloroethane (50 mL) was added all at once to the stirred mixture. To this mixture was added SnCl4 (1.36 mL, 3.03 g, 11.63 mmol) dropwise via syringe, and the mixture was stirred at room temperature 6 h until all starting material was consumed. The mixture was cooled to 0C and a sat. aq. NaHCO3 solution (125 mL) was added. The mixture was warmed to room temperature and stirred 30 min. The mixture was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation to give 5.5 g crude product. The crude material was taken up in dichloromethane, immobilized on Celite, and subjected to flash chromatography on the Combiflash (120 g column, 5 to 50% EtOAc in hexanes gradient) to give 242 (2.41 g, 53%) as a clear sticky solid in ~90% purity. This material was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) ^ ppm 9.37 (br s, 1H), 8.10-8.05 (m, 4H), 7.82 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.3 Hz, 1H), 7.66-7.45 (m, 6H), 7.42 (t, J = 7.8 Hz, 2H), 7.27-7.21 (m, 2H), 5.88 (d, J = 8.2, 1H), 5.62 (d, J = 5.5 Hz, 1H), 4.91-4.83 (m, 2H), 4.77 (dd, J = 11.8 Hz, 4.7 Hz, 1H), 1.77 (s 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | To a solution of uracil 12 (250.0 mg, 2.20 mmol) in dry CH3CN (5 mL), was added N,O-bistrimethylsilylacetamide (1.18 mL, 7.00 mmol) and the mixture was stirred for 20 min at room temperature. To this mixture, a solution of 1,2,3,5-tetra-O-benzoyl-2'-methyl-beta-d-ribofuranosyl (1.16 g, 2.00 mmol) in dry CH3CN (10 mL) was added. After cooling to -20 C, TMSOTf (1.4 mL) was added and the reaction mixture was allowed to warm slowly to room temperature and then stirred at 70 C for 2 h. The mixture was then poured into ethyl acetate and washed with saturated aq NaHCO3. The water layer was again extracted with ethyl acetate. The organic extracts were combined, dried over Na2SO4 and filtered. After removal of all the volatiles in vacuo, the residue was purified by column chromatography (CH2Cl2/MeOH 49:1) on silica gel to give product 14 (983.0 mg) as an anomeric mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | To a solution of 6-methyluracil (302.0 mg, 2.40 mmol) in dry CH3CN (5 mL), was added N,O-bistrimethylsilylacetamide (1.18 mL, 7.00 mmol) and the mixture was stirred for 20 min at room temperature. To this mixture, a solution of 1,2,3,5-tetra-O-benzoyl-2'-methyl-beta-d-ribofuranose (1.16 g, 2.00 mmol) in dry CH3CN (10 mL) was added, followed by dropwise addition of TMSOTf (1.4 mL) at -20 C. The reaction mixture was then allowed to warm slowly to 10-15 C and stirred for 6 h. The mixture was then poured into CH2Cl2 and washed with saturated aq NaHCO3. The organic layer was combined, dried over Na2SO4 and filtered. After removal of all the volatiles, the residue was purified by column chromatography (hexane/ethyl acetate 3:1?3:2), to give product 2 (1.08 g) as an oil in 88.5% yield. The undesired N1,N3-bis-riboside (66.0 mg) was obtained as an oil in 5.7% yield. 1H NMR (300 MHz, DMSO-d6): delta 11.56 (s, 1H, 3-NH), 8.07-7.35 (m, 15H, aromatic), 6.34 (s, 1H, H-1'), 6.31 (d, 1H, J = 8.7 Hz, 3'- H), 5.66 (s, 1H, H-5), 4.73-4.66 (m, 1H, H-4'), 4.61-4.59 (m, 2H, H-5'), 2.39 (s, 3H, 6-CH3), 1.76 (s, 3H, 2'-CH3); 13C NMR (75 MHz, DMSO-d6): delta 165.6 (5"-C=O), 165.1 (2"-C=O), 164.9 (3"-C=O), 162.4 (4-C), 154.1 (2-C), 150.9 (6-C), 134.0-128.7 (15* C-aromatic), 102.9 (5-CH), 91.3 (1'-CH), 88.0 (4'-CH), 77.4 (2'-CH), 77.1 (3'-CH), 64.5 (5'-CH2), 19.7 (7-CH3), 18.1 (6'-CH3); HRMS for C32H28N2O9 [M+H]+ calcd: 585.1867; found: 585.1897. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.45 g | Step A: To a suspension of imidazo[4,5-d]pyridazine (3.48 g, 25.5 mmol) [for preparation see Journal of Heterocyclic Chemistry, 1969, Vol 6, 93] in dry acetonitrile (35 mL) was added 1,2,3,5-tetra-O-benzoyl-2-C-methyl-beta-D-ribofuranose (14.48 g, 25.0 mmol) at 20 C. and stirred for 15 mn. DBU (11.5 mL, 76.3 mmol) was added at 0 C. and the solution was stirred for 15 mn at 0 C. TMSOTf (24.7 mL, 127.8 mmol) was added at 0 C. and the mixture was heated at 80 C. for 20 hours. The reaction mixture was poured into an aqueous solution of sodium hydrogenocarbonate and extracted by ethyl acetate. The organic layer was evaporated to dryness to give a yellow powder. The crude product was purified on silica gel using dichloromethane/methanol (99.3/0.7) as eluant to give a slight yellow powder which was crystallized from isopropanol to give the title compound (2.45 g) as a white powder. 1H NMR (DMSO-d6) delta ppm: 1.48 (s, 3H, CH3), 4.75-4.96 (m, 3H, H4', 2H5'), 5.81 (d, 1H, J=5.5 Hz, H3'), 6.99 (s, 1H, H1'), 7.39-7.72 (m, 9H), 7.92-8.08 (m, 6H), 8.64 (s, 1H, H8), 8.71 (s, 1H, H3), 12.89 (br, 1H, NH). Mass spectrum: m/z (FAB>0) 1189 (2M+H)+, 585 (M+H)+, (FAB<0) 593 (M-H)- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With methanol; potassium cyanide; at 20℃; | To 2-C-methyl-1,2,3,5-tetra-O-benzoyl-beta-D-ribofuranose (4, 9.74 g, 16.75 mmol) in anhydrous MeOH (200 mL) was added KCN (30 mg, 0.45 mmol) and the mixture stirred at rt overnight. Concentration in vacuum and drying over P2O5 afforded 2-C-methyl-D-furanose in quantitative yield (2.82 g). The latter compound was dissolved in anhydrous acetone (200 mL) containing H2SO4 (200 L) and the mixture stirred overnight at rt before being neutralised with sat. NaHCO3 and concentrated in vacuum. The residue was dissolved in EtOAc (100 mL) and washed with water and sat. NaCl. The aqueous layer was extracted with EtOAc and the combined organiclayers dried over MgSO4, filtered and concentrated in vacuum affording 2,3-O-isopropylidene-2-C-methyl-D-furanose as a yellow oil (3 g, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With trimethylsilyl trifluoromethanesulfonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 65℃; for 5.33333h; | To f3-Dribofiiranose, 2-C-methyl-, i,2,3.5-tetrabenzoate (4.0 g, 689 mmoi, 1 equiv,) and 2,6-dichloropurine (1.43 g, 7.58 mmol, 1.1 equiv.) in acetonitrile (23 mL) at 0Cwas added 1,8-Diazabicycio[5.4.0]undec-7-ene (2.58 mL. 1723 mmoi, 2.5 equiv,) followed bytrimethylsilyl trifluoromethanesuifonate (5.11 mL, 2825 mmoi, 4.1 equiv,) dropwise over 5minutes. The reaction mixture was stirred at 0 C for 15 minutes and heated at 65 c? for 5 hours. After cooling to room temperature the reaction was diluted with dichioromethane, washed with sat. aq. sodium bicarbonate (x2), and brine (xi). The organics were dried over MgSO4. filtered and concentrated under reduced pressure. The desired product was obtained following columnchromatography (Si02, 25% to 66% EtOAc/1-Iexane) as a white solid (1.30 g. 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.1% | With triethylamine; In dichloromethane; at 15℃; for 3h;Cooling with ice; | A solution of the compound A2, 64 g of benzoyl chloride and 250 mL of dichloromethane were added to the reaction flask, and the mixture was cooled in an ice bath, stirred, and 48 g of triethylamine was slowly added dropwise. After the addition was completed, the reaction was stirred at 15 C for 3 hours. , washing with water, concentration, crystallization, to obtain compound A3, the total yield of step two and step three is 67.1% |
Yield | Reaction Conditions | Operation in experiment |
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72% | With trifluorormethanesulfonic acid In tetrahydrofuran at 50℃; for 2.66h; | 1.1 1) Condensation reaction Weigh 58 grams of 1,2,3,5-tetrabenzoyloxy-2-C-methyl-beta-D-ribofuranose and 18.3 grams of nicotinamide, dissolve them in 300ml of tetrahydrofuran, and dissolve them under stirring. Afterwards, transfer to a 1000ml three-necked flask with mechanical stirring for use. Transfer 30 grams of trifluoromethanesulfonic acid into the dropping funnel and slowly add it dropwise to the above system. The dropping time is 40 minutes. During the dropping, the temperature should not exceed 50°C. After the dropping, keep the temperature at 50°C. Reflux for 2 hours. After HPLC detects that the reaction is complete, it is cooled to room temperature. The reaction was quenched by adding 100ml of water; 200ml of dichloromethane was added with stirring to extract the product, the organic phase was washed three times with saturated brine and once with purified water, and concentrated to dryness under reduced pressure to obtain nicotinamide tribenzoyl nucleoside. Rate 72.0%, HPLC quantitative purity 87.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | Stage #1: 3-Methylmercapto-6-methyl-2H-1,2,4-triazinon-(5); 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose With BSA In 1,2-dichloro-ethane for 0.5h; Inert atmosphere; Stage #2: With anhydrous tin tetrachloride In 1,2-dichloro-ethane at 20℃; for 24h; Inert atmosphere; | 26 T117. A mixture of T108 (110 mg, 0.7 mmol) and T12 (435 mg, 0.84 mmol) was suspended in DCE (5 mL), then treated with BSA (0.21 mL, 0.84 mmol) and the mixture was stirred for 30 min, until complete dissolution. SnCl4 (0.246 mL, 2.1 mmol) added drop wise and the mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 and the white cake was filtrated on a Celite pad and was washed with DCM (50 mL). The separated organic layers were combined, dried over Na2SO4 and filtered. The filtrate was evaporated under vacuum to give compound T117 (0.4 g, 92.8% yield) as a colorless foam; UV- vis (MeOH) 234.99 nm IR 2698.40 cm-1 (νN-H), 1721.85 cm-1 (νC=O) and 1664.55 cm-1 (νC5=N) 1604.67 cm-1 (νC=S) ; 1H-NMR (CDCl3) δ 8.15-7.45 (15H, m, Ar), 6.88 (1H, s, Η-1’), 6.15 (1H, d, H-3', J = 8.4 Hz), 4.85-4.79 (2H, m, H-5a’, H-5b’), 4.76 (1H, d, H-3’, J = 4.4 Hz), 4.64 (1H, q, H-4’, J = 6.8,11.6 Hz), 2.64 (3H, s, CH3-S), 2.36 (3H, s, 5-CH3), 1.73 (3H, s, 2’- CH3); 13C-NMR (CDCl3) δ 166.57, 166.27, 165.61, 165.34, 159.93, 151.06, 133.99, 133.33, 130.05, 129.98, 129.84, 129.56, 128.96, 128.81, 128.46, 92.08, 87.79, 78.96, 76.74, 64.87, 17.46, 17.20, 14.93. |
92.8% | Stage #1: 3-Methylmercapto-6-methyl-2H-1,2,4-triazinon-(5); 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose With BSA In 1,2-dichloro-ethane for 0.5h; Inert atmosphere; Stage #2: With anhydrous tin tetrachloride In 1,2-dichloro-ethane at 20℃; for 24h; Inert atmosphere; | 26 T117. A mixture of T108 (110 mg, 0.7 mmol) and T12 (435 mg, 0.84 mmol) was suspended in DCE (5 mL), then treated with BSA (0.21 mL, 0.84 mmol) and the mixture was stirred for 30 min, until complete dissolution. SnCl4 (0.246 mL, 2.1 mmol) added drop wise and the mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 and the white cake was filtrated on a Celite pad and was washed with DCM (50 mL). The separated organic layers were combined, dried over Na2SO4 and filtered. The filtrate was evaporated under vacuum to give compound T117 (0.4 g, 92.8% yield) as a colorless foam; UV- vis (MeOH) 234.99 nm IR 2698.40 cm-1 (νN-H), 1721.85 cm-1 (νC=O) and 1664.55 cm-1 (νC5=N) 1604.67 cm-1 (νC=S) ; 1H-NMR (CDCl3) δ 8.15-7.45 (15H, m, Ar), 6.88 (1H, s, Η-1’), 6.15 (1H, d, H-3', J = 8.4 Hz), 4.85-4.79 (2H, m, H-5a’, H-5b’), 4.76 (1H, d, H-3’, J = 4.4 Hz), 4.64 (1H, q, H-4’, J = 6.8,11.6 Hz), 2.64 (3H, s, CH3-S), 2.36 (3H, s, 5-CH3), 1.73 (3H, s, 2’- CH3); 13C-NMR (CDCl3) δ 166.57, 166.27, 165.61, 165.34, 159.93, 151.06, 133.99, 133.33, 130.05, 129.98, 129.84, 129.56, 128.96, 128.81, 128.46, 92.08, 87.79, 78.96, 76.74, 64.87, 17.46, 17.20, 14.93. |
92.8% | Stage #1: 3-Methylmercapto-6-methyl-2H-1,2,4-triazinon-(5); 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose With N,O-bis-(trimethylsilyl)-acetamide In 1,2-dichloro-ethane for 0.5h; Inert atmosphere; Stage #2: With anhydrous tin tetrachloride In 1,2-dichloro-ethane at 20℃; for 24h; Inert atmosphere; | 26 T117. A mixture of T108 (110 mg, 0.7 mmol) and T12 (435 mg, 0.84 mmol) was suspended in DCE (5 mL), then treated with BSA (0.21 mL, 0.84 mmol) and the mixture was stirred for 30 min, until complete dissolution. SnCl4 (0.246 mL, 2.1 mmol) added drop wise and the mixture was stirred for 24 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 and the white cake was filtrated on a Celite pad and was washed with DCM (50 mL). The separated organic layers were combined, dried over Na2SO4 and filtered. The filtrate was evaporated under vacuum to give compound T117 (0.4 g, 92.8% yield) as a colorless foam; UV- vis (MeOH) 234.99 nm IR 2698.40 cm-1 (νN-H), 1721.85 cm-1 (νC=O) and 1664.55 cm-1 (νC5=N) 1604.67 cm-1 (νC=S) ; 1H-NMR (CDCl3) δ 8.15-7.45 (15H, m, Ar), 6.88 (1H, s, Η-1’), 6.15 (1H, d, H-3', J = 8.4 Hz), 4.85-4.79 (2H, m, H-5a’, H-5b’), 4.76 (1H, d, H-3’, J = 4.4 Hz), 4.64 (1H, q, H-4’, J = 6.8,11.6 Hz), 2.64 (3H, s, CH3-S), 2.36 (3H, s, 5-CH3), 1.73 (3H, s, 2’- CH3); 13C-NMR (CDCl3) δ 166.57, 166.27, 165.61, 165.34, 159.93, 151.06, 133.99, 133.33, 130.05, 129.98, 129.84, 129.56, 128.96, 128.81, 128.46, 92.08, 87.79, 78.96, 76.74, 64.87, 17.46, 17.20, 14.93. |
Tags: 15397-15-6 synthesis path| 15397-15-6 SDS| 15397-15-6 COA| 15397-15-6 purity| 15397-15-6 application| 15397-15-6 NMR| 15397-15-6 COA| 15397-15-6 structure
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