* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 6, p. 695 - 698
2
[ 5987-73-5 ]
[ 16645-06-0 ]
[ 31199-61-8 ]
[ 3181-38-2 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 9, p. 1887 - 1894
3
[ 3181-38-2 ]
[ 5987-73-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-benzyl-N,N,N-triethylammonium chloride; <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile at 70℃; for 2 h;
2,3,5-Tri-O-acetylinosine [4] (5.00g, 12.68 mmol, 1.00 equiv), benzyltriethylammonium chloride (5.77 g, 25.36 mmol, 2.00 equiv) andN,N-dimethylaniline (1.8 mL, 13.94 mmol, 1.10 equiv) were dissolved in 50 mL dry acetonitrile. Theflask was placed on a preheated oil bath (70 °C), POCl3 (5.9 mL, 63.40 mmol, 5.00 equiv) was addedslowly and the reaction mixture was stirred for 2 h at the same temperature. After that, the solvent andexcess POCl3 were removed under reduced pressure (high vacuum, 70 °C). The residue was pouredon a CHCl3/ice-mixture and the solution was stirred for 20 min. The organic phase was separated andthe aqueous phase was extracted 3 times with CHCl3. The organic phases were combined and washedwith a 5 percent NaHCO3 solution until the aqueous layer showed a slightly basic reaction. Subsequentlythe organic phase was separated, dried with MgSO4 and the solvent was removed under reducedpressure. Purification by silica gel chromatography (EtOAc) gave compound 17 as a yellow oil (5.23g, quant.)
Reference：
[1] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1563 - 1569
[2] Russian Journal of Bioorganic Chemistry, 1999, vol. 25, # 9, p. 603 - 611
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6736 - 6739
[4] Patent: WO2005/84653, 2005, A2, . Location in patent: Page/Page column 42
[5] British Journal of Pharmacology, 2017, vol. 174, # 14, p. 2287 - 2301
[6] Patent: WO2005/84653, 2005, A2, . Location in patent: Page/Page column 42
4
[ 3181-38-2 ]
[ 5987-73-5 ]
Yield
Reaction Conditions
Operation in experiment
96%
With thionyl chloride; N,N-dimethyl-formamide In chloroform
To a solution of triacetoxy inosine (3. 00g, 7. 63mol) in CHC13 (25mL) was added DMF (1. 80mL, 22.9mmol) and thionyl chloride (1. 68mL, 22. 9mmol) and the resulting solution was refluxed overnight before removal of the solvents in vacuo. The residue was then partitioned between DCM and aq. NaHCO3 and the separated organic phase was washed with brine and dried over MgS04 to afford triacetoxy 6-chloroadenosine as apale yellow oil (3.03g, 96percent).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 11, p. 2937 - 2942
[2] Tetrahedron Letters, 2000, vol. 41, # 11, p. 1695 - 1697
[3] Organic and Biomolecular Chemistry, 2005, vol. 3, # 3, p. 462 - 470
[4] Patent: WO2005/54269, 2005, A1, . Location in patent: Page/Page column 14
[5] Monatshefte fur Chemie, 2003, vol. 134, # 6, p. 851 - 873
[6] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 6, p. 695 - 698
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 782 - 793
[8] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. 20, # 7, p. 534 - 537
[9] Journal of Organic Chemistry, 1985, vol. 50, # 15, p. 2664 - 2667
[10] Journal of Medicinal Chemistry, 1985, vol. 28, # 11, p. 1636 - 1643
[11] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 1, p. 11 - 28
[12] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 5, p. 859 - 866
[13] Patent: EP2407474, 2012, A1, . Location in patent: Page/Page column 5
[14] Journal of Medicinal Chemistry, 2012, vol. 55, # 18, p. 8066 - 8074,9
[15] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6248 - 6263
5
[ 87-42-3 ]
[ 13035-61-5 ]
[ 5987-73-5 ]
Yield
Reaction Conditions
Operation in experiment
69%
With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 0 - 60℃; Molecular sieve; Inert atmosphere
10145] Compound LCDO6 was synthesized under standard glycosylation conditions. Briefly, 3-D-ribofuranose 1,2,3,5- tetraacetate (5.5 g, 17.3 mmol) and 6-chloropurine (2.7 g, 17.3 mmol) were dissolved in anhydrous MeCN (50 mL) containing molecular sieves (MS 4 A), followed by the addition ofTMSOTf (300 pL) at 0°C. under argon protection. The reaction mixture was heated at 60°C. overnight and quenched by addition of triethylamine to pH 7. The solvents were then removed and column chromatography (methanol :dichloromethane, 1:20) gave the product as a yellowish solid (4.9 g, 69percent). ‘H NMR (400 MHz, CDC13) ö 8.77 (s, 1H, H-8), 8.24 (s, 1H, H-2), 6.23 (d, 1H, J=5.4 Hz, H-i’), 5.94 (dd, 1H, J=5.4, 5.0 Hz, H-2’), 5.63 (dd, 1H, J=5.0, 4.5 Hz, H-3’), 4.35 (m, 3H, H-4’, H-5’), 2.26 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.01 (s, 3H, CH3).
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1439 - 1442
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3058 - 3065
[3] Patent: US2016/185805, 2016, A1, . Location in patent: Paragraph 0144; 0145
[4] Nucleosides, nucleotides and nucleic acids, 2002, vol. 21, # 1, p. 73 - 78
6
[ 7387-57-7 ]
[ 5987-73-5 ]
Reference：
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 1993, vol. 74, # 1-4, p. 249 - 260
[2] Journal of Organic Chemistry, 1980, vol. 45, # 20, p. 3969 - 3974
[3] Journal of Organic Chemistry, 2003, vol. 68, # 2, p. 666 - 669
[4] Journal of Organic Chemistry, 2002, vol. 67, # 19, p. 6788 - 6796
7
[ 108-24-7 ]
[ 58-63-9 ]
[ 5987-73-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 18, p. 8066 - 8074,9
8
[ 16321-99-6 ]
[ 5987-73-5 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 19, p. 6788 - 6796
[2] Synthesis, 1982, # 8, p. 670 - 672
9
[ 16321-99-6 ]
[ 5987-73-5 ]
[ 5987-76-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 241 - 252
10
[ 108-24-7 ]
[ 2004-06-0 ]
[ 5987-73-5 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 59, p. 14702 - 14706
[2] Organic Letters, 2015, vol. 17, # 6, p. 1513 - 1516
11
[ 87-42-3 ]
[ 13035-61-5 ]
[ 5987-73-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1478 - 1489
12
[ 58-63-9 ]
[ 5987-73-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 782 - 793
[2] Organic and Biomolecular Chemistry, 2005, vol. 3, # 3, p. 462 - 470
[3] Monatshefte fur Chemie, 2003, vol. 134, # 6, p. 851 - 873
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 1, p. 11 - 28
[5] Journal of Organic Chemistry, 1985, vol. 50, # 15, p. 2664 - 2667
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 11, p. 2937 - 2942
[7] Patent: EP2407474, 2012, A1,
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6248 - 6263
EXAMPLE 8 6-chloro-9-beta-D-ribofuranosyl-9H-purine STR15 532 g of the product of Example 7 are dissolved in 2.43 L of dry methanol. The solution is cooled at about -11 C. and 13.2 g of sodium methoxide are added under stirring. When the addition is complete the stirring is continued for minimum 1 hour. The temperature is raised to 20 C.-25 C. for minimum 2 hours. The precipitate is filtered and rinsed with methanol to afford 304.6 g of crude product. Yield: 86.4%.
Example 1 6-Chloropurineriboside 2',3',5'-Triacetyl-6-chloropurineriboside (oil, 6.0 g) was dissolved in methanol (30 ml). The mixture was cooled to 5C and 1N sodium hydroxide-methanol solution (0.6 ml) was added. The mixture was stirred for 5 hr. Acetic acid (0.04 ml) and ethyl acetate (30 ml) was added to the reaction mixture and the mixture was stirred under ice-cooling for 1 hr. The precipitate was collected by filtration, washed with ethyl acetate, and vacuum dried at 40C to give the title compound (3.08 g). 1H-NMR(DMSO-d6, ppm) delta: 3.59-3.74 (2H, m), 4.00-4.01(1H, s), 4.19-4.21(1H, m), 4.59-4.62(1H, m), 5.10-5.12(1H, m), 5.27(1H, d, J=5.1Hz), 5.59(1H, d, J=5.8Hz), 6.06(1H, d, J=5.3Hz), 8.83(1H, s), 9.06(1H, s).
With ammonium hydroxide; In methanol; water; at 0 - 20℃; for 24h;
10146] To a solution of LCDO6 (1.0 g, 2.42 mmol) inmethanol (10 mE) at 0 C. was added ammonium hydroxide (30% in water, 400 pL). The reaction mixture was then stirred for 24 hours at r.t. and the reaction was quenched by addition of DOWEX-5x8-200. The reaction mixture was then filtered and solvents were removed to give a yellowish solid (ECDO7), which was then dissolved/suspended in acetonitrile(5 mE), followed by the addition of propargyl amine (1.5 mE, 24.2 mmol) and potassium carbonate (1.0 g, 7.26 mmol). The suspension was stirred at r.t. for 2 days, and solvents were removed. The compound was purified by column chromatography (methanol:dichloromethane, 1:20) to give the product as a yellowish white solid (517mg, 70%, two steps). ?H NMR (500 MHz, DMSO-d6): oe 8.42 (s, 1H, H-8), 8.30 (s, 1H, H-2), 5.92 (d, 1H, J=6.4 Hz, H-i?), 5.50 (d, iH, J=6.7 Hz, NH), 5.37 (dd, iH, J=4.5, 1.5 Hz), 5.17 (d, iH, J=4.5 Hz, OH), 4.60 (dd, iH, J=6.0, 5.5 Hz, H-2?), 4.20 (br, 2H, NHCH2), 4.16 (dd, iH, J=4.0, 3.5 Hz, H-4?), 4.00 (dd, iH, J=5.5, 3.0 Hz, H-3?), 3.70 (m, iH, H-5a?), 3.57 (m, iH, H-Sb?), 3.04 (s, iH, propargylCH). ?3C NMR (125 MHz, DMSO-d6): 155.1 (Ar), 152.6 (Ar), 148.0 (Ar), 139.8 (Ar), 121.0 (Ar), 88.2 (C-i?), 85.8, 82.1, 73.5, 72.4, 70.1, 61.3, 28.8 (NHCH2). HRMS (ESI) calcd for C,3H,6N504 (M+H) 306.1201. found: 306.1258.
With thionyl chloride; N,N-dimethyl-formamide; In chloroform;
To a solution of triacetoxy inosine (3. 00g, 7. 63mol) in CHC13 (25mL) was added DMF (1. 80mL, 22.9mmol) and thionyl chloride (1. 68mL, 22. 9mmol) and the resulting solution was refluxed overnight before removal of the solvents in vacuo. The residue was then partitioned between DCM and aq. NaHCO3 and the separated organic phase was washed with brine and dried over MgS04 to afford triacetoxy 6-chloroadenosine as apale yellow oil (3.03g, 96%).
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 40℃; for 6h;Reflux;
O 2', O 3', O 5' -tri-acetylinosine was dissolved in dry CH2Cl(50mL) and dry DMF(1ml) and heated to 40C. A solution of SOCl2(3.3g) in CH2Cl2 (2.5mL) was added dropwised . The reaction mixture was gently refluxed for an additional 6h. The reaction mixture was cooled to room temperature and diluted with CH2Cl2. The organic layer was washed with saturated NaHCO3 solution (2 × 50mL) and brine (2 × 50mL) and (dried anhydrous sodium sulfate). The organic phase was concentrated in vacuo and used for the subsequent reaction without any further purification.
With tetrabutylammonium nitrate; trifluoroacetic anhydride; In dichloromethane; at 0℃; for 5.33333h;
Tetrabutylammonium nitrate (10.1g, 33.0mmol) was dissolved in dry dichloromethane (50 mL), cooled to 0 deg.] C, was added trifluoroacetic anhydride (4.6mL, 33.0mmol), stirred for 20 minutes, was added freshly prepared 6-chlorotriacetylpurine nucleoside (3, 9.1g, 22mmol), kept at 0 deg.] C, reacted for 5 hours, saturated sodium bicarbonate solution (100 mL), stirred, the organic phase was separated, the aqueous phase was dried over anhydrous dichloro methane (20 mL) and extracted twice, the organic phase was collected, dried and the solvent was removed under reduced pressure to give a pale yellow oil, 4 is the target product, yield 81%.
58%
With tetrabutylammonium nitrate; trifluoroacetic acid; In dichloromethane; at 0℃; for 2.5h;
To a solution of TBAN (4. 43 g, 14. 5mmol) in DCM (15mL) at 0 C was added TFAA (2. 05mL, 14. 5mmol) and the resulting solution was stirred for 5mins, before the addition of triacetoxy 6-chloroadenosine (4g, 9.7mmol) in DCM (20mL). The resulting brown solution was stirred for 2. 5h before being quenched with aq. NaHCO3, extracted into DCM and dried over MgSO4. Purification via trituration from EtOH yielded triacetoxy 2- nitro, 6-chloroadenosine as a pale yellow solid which was washed with 1: 1 EtOH/water to afford 2.57g, 58%.
With tetramethylammonium nitrate; trifluoroacetic anhydride; In dichloromethane; at 0 - 20℃; for 2.5h;
The mixture was cooled to 0C and a solution of triacetoxy-6-chloro-adenosine (leq) in DCM was added. The resulting solution was allowed to warm to rt over 2. 5h. The solution was then washed with aq. NaHC03, brine and water (x3) and the organic phase dried over MgS04. Crystallisation from DCM/EtOH afforded triacetoxy-6- chloro-2-nitro-adenosine as a pale yellow solid which was washed with water and EtOH.
With N-benzyl-N,N,N-triethylammonium chloride; N,N-dimethyl-aniline; trichlorophosphate; In acetonitrile; at 70℃; for 2h;
2,3,5-Tri-O-acetylinosine [4] (5.00g, 12.68 mmol, 1.00 equiv), benzyltriethylammonium chloride (5.77 g, 25.36 mmol, 2.00 equiv) andN,N-dimethylaniline (1.8 mL, 13.94 mmol, 1.10 equiv) were dissolved in 50 mL dry acetonitrile. Theflask was placed on a preheated oil bath (70 C), POCl3 (5.9 mL, 63.40 mmol, 5.00 equiv) was addedslowly and the reaction mixture was stirred for 2 h at the same temperature. After that, the solvent andexcess POCl3 were removed under reduced pressure (high vacuum, 70 C). The residue was pouredon a CHCl3/ice-mixture and the solution was stirred for 20 min. The organic phase was separated andthe aqueous phase was extracted 3 times with CHCl3. The organic phases were combined and washedwith a 5 % NaHCO3 solution until the aqueous layer showed a slightly basic reaction. Subsequentlythe organic phase was separated, dried with MgSO4 and the solvent was removed under reducedpressure. Purification by silica gel chromatography (EtOAc) gave compound 17 as a yellow oil (5.23g, quant.)
With thionyl chloride; N,N-dimethyl-formamide; In chloroform; for 16h;Heating / reflux;
To a solution of triacetoxy inosine (leq) in CHC13 was added DMF (3eq) and thionyl chloride (3 eq) and the resulting solution was refluxed for 16h. The solvents were then removed in vacuo and the residue dissolved in DCM and washed with aq. NaHC03 and brine and the organic phase dried over MgS04 to afford triacetoxy-6-chloro- adenosine.
Preparation Example 1 2',3',5'-Triacetyl-6-chloropurineriboside 2',3',5'-Triacetylinosine (20 g) was added to chloroform (160 ml) and N,N-dimethylformamide (2.7 g), thionyl chloride (19.9 g) was added dropwise thereto, and the mixture was stirred under reflux for 3 hr. Water (200 ml) was added under cooling in an ice bath. The mixture was stirred for 1 hr and partitioned. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and concentrated to dryness to give 2',3',5'-triacetyl-6-chloropurineriboside (24.4 g) as an oil. 1H-NMR(CDCl3, ppm) delta: 2.10 (3H, s), 2.12(3H, s), 2.17 (3H, s), 4.37-4.51(3H, m), 5.64-5.67(1H, m), 5.94-5.97(1H, m), 6.24-6.25(1H, d, J=5.2Hz), 8.30(1H, s), 8.79(1H, s).
A mixture of magnesium turnings (466 mg, 19.2 mmol) and 2-thienyl bromide (1.8 mL, 19.2 mmol) in anhydrous THF (5 mL) was stirred under argon for 3 h at 37 C. The resulting red color solution was cooled to 0 C and treated with a 1 M THF solution of ZnBr2 (19.2 mL) and the thick suspension was stirred further for 1 h at room temperature. (Ph3P)4Pd (277 mg, 0.24 mmol) in THF (5 mL) was added followed by the addition of a solution of 6 (2 g, 4.85 mmol) in THF (20 mL) and the mixture was heated for 2 h at 45 C. The mixture was then cooled down to room temperature and quenched with saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (20 mL) and kept overnight at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 5% MeOH in CHCl3) to give (1.3 g, 89%) as a yellow solid
(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-cyclopropyl-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of magnesium turnings (74 mg, 3.0 mmol) and cyclopropyl bromide (0.24 mL, 3.02 mmol) in anhydrous THF (6 mL) was heated for 1 h at 60 C until complete dissolution of the magnesium. The solution was cooled to room temperature and was treated with a 1.13 M solution of ZnBr2 (2.7 mL, 3.0 mmol) and the resulting white suspension was stirred for 1 h at room temperature. (Ph3P)4Pd (50 mg, 0.04 mmol) in THF (1 mL) was added to the mixture, followed by the addition of 6 (0.22 g, 0.53 mmol) in THF (2 mL) and the mixture was heated for 4 h at 45 C. The mixture was then cooled down to room temperature and quenched with saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (10 mL) and kept for 2 h at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 7% EtOH in CHCl3 to give (0.148 g, 92%) as a pale yellow solid which was crystallized from MeOH-heptane
A mixture of magnesium turnings (45 mg, 1.8 mmol) and cyclobutyl bromide (0.25 mg, 1.85 mmol) in anhydrous THF (5 mL) was heated for 3 h at 60 C until complete dissolution of the magnesium. The solution was cooled to -78 C and treated with ZnBr2 (1.13 M, 1.6 mL, 1.8 mmol) in THF and the resulting white suspension was warmed gradually to room temperature and was stirred further for 1 h at room temperature. (Ph3P)4Pd (27 mg) in THF (1 mL) was added, followed by addition of 3 (0.15 g, 0.36 mmol) in THF (2 mL) and the mixture was heated for 4 h at 55 C. The mixture was then cooled down to room temperature and quenched with a saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (10 mL) and kept overnight at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 5% MeOH in CHCl3) to give (88 mg, 78%) as a pale yellow solid which was crystallized from EtOH in hexanes
A solution of EtZnBr (1.2 mmoL) was generated by dropwise addition of ZnBr2 (1.13 M, 1.1 mL, 1.2 mmol) in THF to 2 M solution of EtMgBr (1.1 mmol, 0.3 mL) in THF (6 mL) for 1 h at -78 C. The solution was allowed to warm gradually to room temperature and then (Ph3P)4Pd (27 mg, 0.02 mmol) in THF (2 mL) was added to the mixture. A solution of compound 6 (0.197 g, 0.477 mmol) in dry THF (4 mL) was added and the mixture was heated under argon for 1 h at 55 C. The mixture was then cooled down to room temperature and quenched with saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (15 mL) and kept overnight at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 5% EtOH in CHCl3) to give (0.11 g, 82%) 8 as a white solid
A solution of (Ph3P)4Pd (23 mg, 0.02 mmol) in THF (1 mL) was added to a solution of n-BuZnCl [generated as above from a 2 M solution n-BuMgCl (0.5 mL) and 1.13 M solution ZnBr2 (1 mL) at -78 C to r.t., for 1 h] in THF (5 mL) at room temperature. A solution of 6 (0.166 g, 0.4 mmol) in THF (2 mL) was added and the mixture was heated for 2 h at 55 C. The mixture was then cooled down to room temperature and quenched with a saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (10 mL) and kept for 3 h at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 5% EtOH in CHCl3) to give (0.11 g, 89%) 10 as a pale yellow waxy solid, which was recrystallized from H2O-EtOH
(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-propyl-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of (Ph3P)4Pd (25 mg, 0.02 mmol) in THF (1 mL) was added to a solution of n-PrZnCl [generated as above from a 2 M solution n-PrMgCl (0.53 mL) and a 1.13 M solution of ZnBr2 (1 mL) at -78 C to r.t., for 1 h] in THF (5 mL) at room temperature. A solution of 6 (0.175 g, 0.424 mmol) in THF (2 mL) was added and the mixture was heated for 5 h at 55 C. The mixture was then cooled down to room temperature and quenched with a saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (10 mL) and stirred for 2 h at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 5% EtOH in CHCl3) to give (0.107 g, 86%) 9 as a pale yellow waxy solid, which was recrystallized from EtOH
(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-cyclopentyl-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of (Ph3P)4Pd (46 mg, 0.04 mmol) in THF (1.5 mL) was added to a solution of cyclopentylZnCl [generated as above from a 2 M Et2O solution cyclopentylMgCl (0.5 mL) and a 1.13 M THF solution of ZnBr2 (1 mL) at -78 C to r.t., for 1 h] in THF (5 mL) at room temperature. A solution of 3 (0.224 g, 0.543 mmol) in THF (3 mL) was added and the mixture was heated for 45 min at 55 C. The mixture was then cooled down to room temperature and quenched with saturated solution of NH4Cl. The solvent was concentrated under reduced pressure and the residue was partitioned between CHCl3 and H2O. The residue obtained by evaporation of the dried organic phase was dissolved in MeOH saturated with NH3 (10 mL) and kept overnight at room temperature. The solvent was evaporated and the residue was purified by a flash silica gel chromatography (elution with 7% EtOH in CHCl3) to give (0.1 g, 60%) 14 as a pale yellow foam
With triethylamine; In tetrahydrofuran; at 60℃;Sealed tube;
Step 1 (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (2.00 g, 4.85 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489] was dissolved in THF (15 mL), and dimethylamine hydrochloride (1.19 g, 14.5 mmol) and triethylamine (2.70 mL, 19.38 mL) were added thereto, and the mixture was stirred overnight at 60 C. in a sealed tube. To the reaction solution, dimethylamine hydrochloride (1.19 g, 14.5 mmol) and triethylamine (2.70 mL, 19.39 mL) were added, and the mixture was further stirred overnight at 60 C. To the mixture, water was added, and the mixture was extracted with chloroform and concentrated under reduced pressure to obtain (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-(dimethylamino)-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (2.2 g, yield: 1.08%). ESI-MS (m/z): 422 (M+1)
2.2 g
With triethylamine; In tetrahydrofuran; at 60℃;Sealed tube;
Step 1 (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (2.00 g, 4.85 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489] was dissolved in THF (15 mL), and dimethylamine hydrochloride (1.19 g, 14.5 mmol) and triethylamine (2.70 mL, 19.38 mL) were added thereto, and the mixture was stirred overnight at 60 C. in a sealed tube. To the reaction solution, dimethylamine hydrochloride (1.19 g, 14.5 mmol) and triethylamine (2.70 mL, 19.38 mL) were added, and the mixture was further stirred overnight at 60 C. To the mixture, water was added, and the mixture was extracted with chloroform and concentrated under reduced pressure to obtain (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-(dimethylamino)-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (2.2 g, yield: 108%). ESI-MS (m/z): 422 (M+1)
N6-phenyl-2',3'5'-tri-O-acetyl-adenosine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 80℃; for 14h;
A mixture of 18 [24, 38] (193 mg, 0.467 mmol) and aniline hydrochloride (70 mg, 0.540 mmol) was solved in n-BuOH (5 ml) and then DIPEA (0.185 ml, 1.08 mmol) was added in one portion. The solution was stirred at 80 C. The reaction was monitored by TLC (ethyl acetate:hexane - 2:1). After 14 h, the reaction mixture was evaporated in vacuum and the residue was diluted with methylene chloride (30 ml) and washed with water (2 * 15 ml). The organic layer was separated, dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by column chromatography on silica gel. The product was eluted with CH2Cl2-EtOH (97:3) mixture. Yield of N6-phenyl-2',3'5'-tri-O-acetyl-adenosine was 219 mg (93%) as foam. Rf 0.42 (ethyl acetate-hexane, 2:1 v/v). 1H NMR (400 MHz, CDCl3): delta = 2.09 (s, 3H, Ac), 2.13 (s, 3H, Ac), 2.15 (s, 3H, Ac), 4.37-4.49 (m, 3H, H4', H5'a, H5'b), 5.64 (dd, 1H, J3',2' = 5.3 Hz, J3',4' = 4.5 Hz, H3'), 5.91 (dd, 1H, J2',1' = 5.2 Hz, J2',3' = 5.3 Hz, H2'), 6.22 (d, 1H, J1',2' = 5.2 Hz, H1'), 7.15-722 (m, 1H, Hp-Ph), 7.37-7.44 (m, 2H, Hm-Ph), 7.72-7.78 (m, 2H, Ho-Ph), 8.05 (s, 1H, H8), 8.51 (s, 1H, H2).
O<SUP>6</SUP>-(3-phenylpropan-1-yl)inosine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium tert-butylate; at 20℃; for 24h;
General procedure: To the mixture of 18 [28, 30] (300 mg, 0.727 mmol) and 2-phenylethanol (7.5 ml, 61.8 mmol), t-BuOK (816 mg, 7.27 mmol) was gradually added. The mixture was stirred at room temperature for 24 h. After neutralization with AcOH (0.42 ml, 61.8 mmol), the solution was directly subjected to column chromatography. Elution with a gradient of EtOH in CH2Cl2 (1:100 ? 1:8) gave 21 (252 mg, 93%) as a white powder.
9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-(4-oxopyridin-1-yl)purine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Step a (Method 2): A mixture of <strong>[626-64-2]4-hydroxypyridine</strong> (0.21 g, 2.2 mmol) and sodium hydride (60% dispersion in mineral oils, 107 mg, 2.66 mmol) in DMF (5 mL) was stirred at rt under nitrogen for 17 min. The resulting mixture was added to cold 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-chloropurine (0.82 g, 2.0 mmol) in DMF (5 mL) stirred at 0 C. under nitrogen. The reaction was stirred at 0 C. for 2 h, TLC analysis showed complete reaction). After removal of volatiles, the residue was chromatographed (CH2Cl2 then MeOH/CH2Cl2, 1:13) to give 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-6-(4-pyridin-1-yl)purine (0.766 g, 82%).
2,2,6,6-tetramethyl-1-((2-nitrobenzyloxy)methoxy)piperidin-4-amine[ No CAS ]
9-(2',3',5'-tri-O-acetylribofuranosyl)-6-(2,2,6,6-tetramethyl-1-((2-nitrobenzyloxy)methoxy)-piperidin-4-ylamino)purine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 20 - 75℃;
A solution of 17 (0.55 g, 1.33 mmol, 1.00 equiv),diisopropylethylamine (0.5 mL, 2.93 mmol, 2.20 equiv) and 10 [2] (0.59 g, 1.74 mmol, 1.30 equiv) in1-propanol was stirred for 7 h at 75 C. The solution was cooled down to ambient temperature, stirredfor another 14 h and the solvent was removed under reduced pressure. Purification by silica gelchromatography (EtOAc) gave the title compound 18 as a light yellow foam (0.74 g, 78%)
Chemistry
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