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CAS No. : | 2004-06-0 | MDL No. : | MFCD26142246 |
Formula : | C10H11ClN4O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 286.67 | Pubchem ID : | - |
Synonyms : |
6-Chloropurine riboside
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 63.28 |
TPSA : | 113.52 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.86 cm/s |
Log Po/w (iLOGP) : | 1.31 |
Log Po/w (XLOGP3) : | 0.26 |
Log Po/w (WLOGP) : | -1.23 |
Log Po/w (MLOGP) : | -2.06 |
Log Po/w (SILICOS-IT) : | -1.01 |
Consensus Log Po/w : | -0.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.0 |
Solubility : | 2.87 mg/ml ; 0.01 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.2 |
Solubility : | 1.79 mg/ml ; 0.00624 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.56 |
Solubility : | 79.0 mg/ml ; 0.275 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.71 |
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 |
---|---|---|
87% | With toluene-4-sulfonic acid In water | ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)methanol-Toluenesulfonic acid monohydrate (19.8 g, 104 mmol) was added to a stirred suspension of (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol (3.0 g, 10.5 mmol) in dried acetone (300 mL). The solid dissolved 15 min later. 2 h later, the solution was poured into stirred aqueous NaHC03 (0.5 N, 300 mL) slowly. After removed acetone in vacuo, the mixture was extracted with DCM (100 mL x 5). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2S04, filtered and concentrated to afford the target (3.0 g, yield: 87percent, purity >96percent) as a pale solid. 1H NMR (500 MHz, CD3OD) δ 8.71 (d, J = 1.0 Hz, 1H), 8.65 (d, J = 1.5 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.29 (dd, J = 2.0, 6.0 Hz, 1H), 4.96 (dd, J = 2.0, 6.0 Hz, 1H), 4.31 (d, J = 2.0 Hz, 1H), 3.68-3.59 (m, 2H), 1.51 (s, 3H), 1.29 (s, 3H) ppm; LCMS (m/z): 327.1 [M+l]+. |
86% | Stage #1: With toluene-4-sulfonic acid In water at 25℃; for 6 h; Stage #2: With sodium hydrogencarbonate In water |
Compound 356l-(4-(tert-butyl)phenyl)-3-(3-((((2R,3S,4R,5R)-5-(6-(dimethylamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yI)methyl)(isopropyl)amino)propyl)ureaStep 1. Preparation of ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanolp-Toluenesulfonic acid monohydrate (134 g, 700 mmol) was added to a stirred suspension of (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol (20 g, 70 mmol) in acetone (100 mL). After stirred at 25° C for 6 h, the reaction mixture was poured into stirred aqueous NaHC03 (0.5 N, 2000 mL) slowly. After removed acetone in vacuo, the mixture was extracted with DCM (800 mL x 3). The combined organic layers were washed with water (500 mL) and brine (500 mL), then dried over Na2S04 and concentrated to afford the title compound (19.5 g, yield: 86 percent) as a white solid. NMR(500 MHz, CDC13): δ 8.75 (s, 1H), 8.30 (s, 1H), 6.01 (d, J = 4.5 Hz, 1H), 5.19-5.17 (m, 1H), 5.10-5.09 (m, 1H), 4.54 (s, 1H), 3.96 (dd, J = 1.0, 12.5 Hz, 1H), 3.82 (dd, J = 2.0, 12.5 Hz, 1H), 1.64 (s, 3H), 1.37 (s, 3H) ppm; ESI (m/z): 327.1 [M+l]+. |
74.1% | at 20℃; for 3 h; | 200 mg (0.7 mmol) of the commercial precursor 6-chloropurine riboside and acetone (10 mL)were mixed under agitation at room temperature for 30 min. This was followed by the slowaddition of p-toluensulfonic acid (5.57 mmol). The solution was kept under stirring conditionsat room temperature for 3 h. The progress of the reaction was monitored by TLC. Sodiumbicarbonate (1.5 g) was added and maintained under agitation. Once the reaction was finished,the solid phase was removed and washed with ethyl acetate (2). The product was thenpurified by column chromatography with mixtures of CH2Cl2-MeOH, obtaining the compound[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (A); Yellow solid,74.1percent yield; m.p. 155–158 °C 1H–NMR (CDCl3, 400.1 MHz) δ 8.72 (s, 1H, CH-Ar purine); 8.31 (s, 1H,CH-Ar purine); 6.01 (d, J = 8.0 Hz, 1H, CH-1'); 5.16 (m, 1H, CH-2'); 4.97 (d, J = 7.83 Hz, 1H, CH-3');4.52 (d, J = 1.22 Hz, 1H, CH-4'); 3.83 (m, 2H, CH2-5'); 5.06 (m, 1 OH); 1.62 (s, 3H, ketal); 1.35 (s, 3H,ketal). 13C–NMR (CDCl3, 100.6 MHz) δ 151.6, 151.4, 148.8, 144.4, 132.5, 114.0, 93.4, 86.2, 83.2, 81.1,62.7, 27.1, 24.8. IR (KBr) λ/cm1 3320, 2906, 2863, 959, 733. Anal. Cal. C13H15ClN4O4: C = 47.75percent,H = 4.59percent, Cl = 10.85percent, N = 17.14percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: With toluene-4-sulfonic acid In acetone at 20℃; for 16 h; Stage #2: With water; sodium hydrogencarbonate In acetone |
Example 1: ((2R/3S/4R/5R)-5-{6-[(lS)-2/3-dihydro-lH-inden-l-ylamino]9H-purin-9-yl}- 3,4-dmydroxytetrahydrofuran-2-yl)methyl sulfamate (1-2)Step a: [('3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2>2-dimethyltetrahydrofuro- r3,4-diri,31dioxol-4-yllmethanol; [0162] 6-Chloro-β-D-ribofuranosylpurine (8.17g, 28.5mmol), p-toluenesulfonic acid monohydrate (5.42g, 28.5mmol) and 2,2~dimethoxypropane(17.5mL, 142.5mmol) were mixed in acetone(500mL). The reaction mixture was stirred at room temperature for lβhours. Saturated aqueous NaHCO3 solution (40OmL) was then added and the mixture was evaporated under reduced pressure to remove most of the acetone. The remaining aqueous residue was then extracted with chloroform(4 x 20OmL). The combined organics were dried- 78 - EPO <DP n="79"/>over Na2SO4, and then evaporated to yield the product as a white amorphous solid (9.22g, 99percent).[0163] LCMS: R.t. 1.22 min ES+ 327 (formic acid). |
97% | With toluene-4-sulfonic acid In acetone at 20℃; | To a stirred solution of chloropurine 23 (15.0 g, 52.2 mmol) in 175 mL of acetone was 2,2-dimethoxypropane (63.0mL, 538 mmol) followed by p-toluenesulfonic acid (10.9 g, 60 mmol). The resulting heterogeneous mixture wasstirred for 2.5 h at rt during which time the solution become homogenous and bright yellow. The volatiles were removed in vacuo to give a thick yellow oil. The oil was dissolved in 150 mL of EtOAc followed by the addition of 150 mL of saturated NaHCO3 over a period of 5 minutes during which time the yellow color disappeared. The resulting layers were separated and the aqueous layer was extracted with 2 × 150 mL of EtOAc. The combined organic layers were washed with 200 mL of brine, dried (Na2SO4) and concentrated in vacuo to give the acetonide S12 |
97% | With toluene-4-sulfonic acid In acetone at 20℃; for 2 h; | Next, electrophilic AMP analogs with two significantly different substituents at N6-position (i.e. a propargyl and phenyl alkyne) were synthesized following Scheme 2 and Scheme 3. Compound 2 that has a small hydrophobic group (propargyl alkyne) at the N6-position was prepared by coupling 2-chloroethanesulfonyl chloride with the 5-amino adenine moiety, followed by the deprotection of the acid labile acetonide (Scheme 2). The synthesis of compound 3, which has a large hydrophobic group (phenyl alkyne) at the N6-position, required tert-butyldimethylsilane (TI3DMS) protection and deprotection steps on the 5’ alcohol and Hoc protection on the N6-amine due to the instability of the reaction intermediates during the Mitsunobu reaction. Subsequent treatment with 2-chloroethanesulfonyl chloride and global deprotection of the acid labile protecting groups led to the formation of compound 3. |
89.03% | With toluene-4-sulfonic acid In acetone at 20℃; for 4 h; Inert atmosphere | (2R, 5R) -2- (6- chloro -9H- purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran-3,4-diol (4.8 g, 16.74 mmol) and 2,2 - dimethoxy-propane (10.26 mL, 83.71 mmol) toIn a nitrogen stream, and then p- toluene sulfonic acid monohydrate (3.18 g, 16.74 mmol) was dissolved in anhydrous acetone (120 mL) to It was added dropwise then stirred at room temperature for 4 hours.The completion of the reactionA check after the reaction with saturated aqueous sodium hydrogen carbonate solutionIt concludes.The reaction solutionThe organic layer was concentrated under reduced pressure with chloroform (4 X 20 mL) Extracted and washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate.Intermediate compound by separating the resulting residue was then concentrated under reduced pressure, by column chromatography ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)methanol (4.87 g, 89.03percent a)Obtained. |
83% | With toluene-4-sulfonic acid In acetone at 20℃; for 2 h; | Step 1 (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.47 g, yield: 72percent) was obtained according to the process described in the known method (Journal of Organic Chemistry (J. Org. Chem.), 2002, vol. 67, pp. 6708-67963 using (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (10.9 g, 26.4 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489]. (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.48 g, 19.1 mmol) was suspended in acetone (200 mL), and 2,2-dimethoxypropane (11.7 mL, 95.5 mmol) and 4-toluenesulfonic acid monohydrate (9.09 g, 47.8 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure until the amount of the solvent was decreased to about half. Chloroform was added thereto, and the mixture was extracted with chloroform and dried over sodium sulfate. Then, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1.3]dioxol-4-yl)methanol (5.17 g, yield: 83percent). ESI-MS (m/z): 327 (M+1) |
83% | With toluene-4-sulfonic acid In acetone at 20℃; for 2 h; | (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.47 g, yield: 72percent) was obtained according to the process described in the known method [Journal of Organic Chemistry (J. Org. Chem.), 2002, vol. 67, pp. 6788-6796] using (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (10.9 g, 26.4 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489]. (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.48 g, 19.1 mmol) was suspended in acetone (200 mL), and 2,2-dimethoxypropane (11.7 mL, 95.5 mmol) and 4-toluenesulfonic acid monohydrate (9.09 g, 47.8 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure until the amount of the solvent was decreased to about half. Chloroform was added thereto, and the mixture was extracted with chloroform and dried over sodium sulfate. Then, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (5.17 g, yield: 83percent). ESI-MS (m/z): 327 (M+1) |
79% | Stage #1: With toluene-4-sulfonic acid In acetone at 20℃; for 45 h; Stage #2: With sodium hydroxide In water for 0.0333333 h; |
To a 200-L reactor with moderate stirring were charged acetone (115 L, 23 vol) and 6-chloropurine-9-riboside (5.0 kg, 17.4 mol, 1.0 wt/1.0 vol). Subsequently, p- TsOH"H2O (166 g, 0.88 mol, 0.05 equiv, 0.033 wt) and 2,2-dimethoxypropane (7.6 L, 62 mol, 3.54 equiv, 1.52 vol) were added and the resulting yellow suspension stirred at ambient temperature. After 45 h, a sample of the resulting yellow-green solution was taken and analysis by HPLC revealed the starting material to be present at 0.42percent by conversion (overall purity 96.9 area percent). The batch was neutralized by the addition of IN NaOH (900 rnL, 0.90 mol, 0.05 equiv, 0.18 vol). This addition took approximately 2 min; the final pH was pH 7. The batch was allowed to stir for 1 h. The resulting cloudy yellow mixture was concentrated under reduced pressure at 35 + 5 0C on the rotary evaporator over a period of 8 h, until a volume of 45 L (9.0 vol) was achieved. The concentrate was stored under N2 at 2-8 °C.The concentrate was transferred to a 200-L reactor and stirring commenced. Water (45 L, 9.0 vol) was added and the resulting dilute suspension was stirred for 55 min. The batch was transferred portionwise to a 72-L reactor assembled in a heating mantle equipped for vacuum distillation. Distillation at 35 +/- 5 °C commenced and proceeded until a batch volume of 62 L (12.4 vol) was achieved (The distillation was conducted over a period of two days, and included 15 hours of aging at <30 0C once complete). The batch was transferred to a 72-L reactor assembled in a cooling bath. The batch was chilled over a period of A1A h until the temperature reached <5 0C and was stirred for an additional 1 h. The solids were filtered employing Sharkskin filter paper and the cake was rinsed with chilled 2:1 water/acetone (7.5 L, 1.5 vol) (The total filtration time was approximately 1 hour 40 minutes and included pulling N2 through the cake in order to help it dry). The damp solids (5.99 kg) were transferred into six glass <n="32"/>drying trays and dried under vacuum, in an oven at 40 +/- 5 0C. After drying for 47 h, the batch was packaged in 4-mil LDPE (double bags) under N2 and stored in a fiber drum. This afforded 6-chloropurine-9-riboside acetonide (4505 g, 79percent). |
76% | With toluene-4-sulfonic acid In acetone at 20℃; for 4 h; Inert atmosphere | A mixture of 6-chloropurine riboside (1) (1.0 g, 3.5 mmol), p-toluenesulfonic acid monohydrate (1.0 g, 5.3 mmol) and 2,2-dimethoxypropane (10 mL) in acetone (20 mL) was stirred at room temperature under N2 for 3 h. Another portion of 2,2-dimethoxypropane (10 mL) was added, and the mixture was stirred for another 1 h. The mixture was concentrated by rotary evaporation under reduced pressure. The residue was diluted with CH2C12, and extracted with water. The aqueous phase was washed with CH2C12, and the combined organic layers were washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered, concentrated by rotatory evaporation under reduced pressure, and purified by column chromatography (silica gel, EtOAc/hexane gradients from 3:7 to 1:0) to give compound 23 (870 mg, 76percent yield). C,3H,5C1N404; [cx]D25 = —112.6 (CHC13, c = 2); JR Vx (neat) 1592, 1563, 1490, 1438, 1419, 1400, 1384, 1337, 1259, 1202, 1154, 1136, 1108, 1080 cm-’; ‘H NMR (CDC13, 600 MHz) ö 8.79 (1 H, s), 8.25 (1 H, s), 6.00 (1 H, d, J= 4.6 Hz), 5.24—5.21 (1 H, m), 5.14 (1 H, dd, J 5.6, 1.5 Hz), 4.93 (1 H, dd, J 10.6, 2.0 Hz), 4.57 (1 H, d, J= 1.5 Hz), 4.00 (1 H, dt, J 12.7, 2.0 Hz), 3.84 (1 H, ddd, J 12.7, 10.6, 2.3 Hz), 1.68 (3 H, s), 1.41 (3 H, s); ‘3C NMR (CDC13, 150 MHz) ö 152.4, 151.7, 150.4, 144.7, 133.4, 114.5,94.1, 86.3, 83.2, 81.5, 63.2, 27.6, 25.2; ESJ—HRMS calcd. for C13H1635C1N404: 327.0855, found: m/z327.0868 [M + Hj. |
2.24 g | With (R)-10-camphorsulfonic acid In acetone at 20℃; for 11 h; | First step, 6-chloropurine riboside (2.0 g) and 2,2-dimethoxypropane (5.80 g) in dry acetone (100 ml), (1S)-(+)-camphor-10-sulfonic acid (1.60 g) was added as a catalyst. The reaction mixture was stirred at room temperature for 11 h. After evaporating the solvent, the mixture was dissolved in chloroform (200 ml), and a NaHCO3 solution (3*30 ml) was added. The water layer was extracted with chloroform (30 ml), then the chloroform layer was dried by anhydrous sodium sulfate and filtered. After evaporation of the solvent, the mixture was separated by column chromatography over silica gel eluting with CHCl3-CH3OH (100:1) to yield 2',3'-O-isopropylidene-6-chloropurine riboside (2.24 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With toluene-4-sulfonic acid; In water; | ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)methanol-Toluenesulfonic acid monohydrate (19.8 g, 104 mmol) was added to a stirred suspension of (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol (3.0 g, 10.5 mmol) in dried acetone (300 mL). The solid dissolved 15 min later. 2 h later, the solution was poured into stirred aqueous NaHC03 (0.5 N, 300 mL) slowly. After removed acetone in vacuo, the mixture was extracted with DCM (100 mL x 5). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2S04, filtered and concentrated to afford the target (3.0 g, yield: 87%, purity >96%) as a pale solid. 1H NMR (500 MHz, CD3OD) delta 8.71 (d, J = 1.0 Hz, 1H), 8.65 (d, J = 1.5 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.29 (dd, J = 2.0, 6.0 Hz, 1H), 4.96 (dd, J = 2.0, 6.0 Hz, 1H), 4.31 (d, J = 2.0 Hz, 1H), 3.68-3.59 (m, 2H), 1.51 (s, 3H), 1.29 (s, 3H) ppm; LCMS (m/z): 327.1 [M+l]+. |
86% | Compound 356l-(4-(tert-butyl)phenyl)-3-(3-((((2R,3S,4R,5R)-5-(6-(dimethylamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yI)methyl)(isopropyl)amino)propyl)ureaStep 1. Preparation of ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)methanolp-Toluenesulfonic acid monohydrate (134 g, 700 mmol) was added to a stirred suspension of (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol (20 g, 70 mmol) in acetone (100 mL). After stirred at 25 C for 6 h, the reaction mixture was poured into stirred aqueous NaHC03 (0.5 N, 2000 mL) slowly. After removed acetone in vacuo, the mixture was extracted with DCM (800 mL x 3). The combined organic layers were washed with water (500 mL) and brine (500 mL), then dried over Na2S04 and concentrated to afford the title compound (19.5 g, yield: 86 %) as a white solid. NMR(500 MHz, CDC13): delta 8.75 (s, 1H), 8.30 (s, 1H), 6.01 (d, J = 4.5 Hz, 1H), 5.19-5.17 (m, 1H), 5.10-5.09 (m, 1H), 4.54 (s, 1H), 3.96 (dd, J = 1.0, 12.5 Hz, 1H), 3.82 (dd, J = 2.0, 12.5 Hz, 1H), 1.64 (s, 3H), 1.37 (s, 3H) ppm; ESI (m/z): 327.1 [M+l]+. | |
74.1% | With toluene-4-sulfonic acid; at 20℃; for 3h; | 200 mg (0.7 mmol) of the commercial precursor 6-chloropurine riboside and acetone (10 mL)were mixed under agitation at room temperature for 30 min. This was followed by the slowaddition of p-toluensulfonic acid (5.57 mmol). The solution was kept under stirring conditionsat room temperature for 3 h. The progress of the reaction was monitored by TLC. Sodiumbicarbonate (1.5 g) was added and maintained under agitation. Once the reaction was finished,the solid phase was removed and washed with ethyl acetate (2). The product was thenpurified by column chromatography with mixtures of CH2Cl2-MeOH, obtaining the compound[6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-methanol (A); Yellow solid,74.1% yield; m.p. 155-158 C 1H-NMR (CDCl3, 400.1 MHz) delta 8.72 (s, 1H, CH-Ar purine); 8.31 (s, 1H,CH-Ar purine); 6.01 (d, J = 8.0 Hz, 1H, CH-1'); 5.16 (m, 1H, CH-2'); 4.97 (d, J = 7.83 Hz, 1H, CH-3');4.52 (d, J = 1.22 Hz, 1H, CH-4'); 3.83 (m, 2H, CH2-5'); 5.06 (m, 1 OH); 1.62 (s, 3H, ketal); 1.35 (s, 3H,ketal). 13C-NMR (CDCl3, 100.6 MHz) delta 151.6, 151.4, 148.8, 144.4, 132.5, 114.0, 93.4, 86.2, 83.2, 81.1,62.7, 27.1, 24.8. IR (KBr) lambda/cm1 3320, 2906, 2863, 959, 733. Anal. Cal. C13H15ClN4O4: C = 47.75%,H = 4.59%, Cl = 10.85%, N = 17.14%. |
With perchloric acid; at 0℃; for 2h; | To a suspension of 6-chloro-adenosine in acetone at 0C was added HC104 and stirring continued for 2h. Aq. NH3 was then added and the solution concentrated in vacuo. The solution was cooled to-20C and the resulting white precipitate of 2'3'-O- isopropylidene-6-chloro-adenosine was collected and washed with acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | With sodium methylate; In methanol; | 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. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With bis(isopropyl)ethylamine; In propan-1-ol; at 80℃; for 6h; | A mixture of <strong>[27757-86-4]3-(aminomethyl)thiophene</strong> (0.25 mL, 2.5 mmol), 6-chloropurine ribofuranoside (143 mg, 0.5 mmol), and diisopropylethylamine (2 mL, 12 mmol) in 1-propanol (25 mL) was heated at 80 C for 6 h. The mixture was concentrated by rotary evaporation, and recrystallized from MeOH to yield the desired product JMF3461 (136 mg, 75% yield). The purity of product was 99% as shown by HPLC on an HC-C18 column (Agilent, 4.6 chi 250 mm, 5 mutaueta) with elution of gradients of 50% aqueous MeOH. C15Hi7504S; yellow powder; mp 134.3-135.1 C; [a]2D= -58.6 (DMSO, c = 1.0); TLC (2-propanol/hexane, (2:3)) R = 0.33; 1H NMR (DMS0-4s, 400 MHz) 6 8.36 (2 H, br s), 8.22 (1 H, s), 7.43 (1 H, dd, J= 3, 5 Hz), 7.28 (1 H, d, J= 1.6 Hz), 7.09 (1 H, d, J= 4.8 Hz), 5.88 (1 H, d, J = 6.4 Hz), 5.43 (1 H, d, J= 6.0 Hz), 5.38 (1 H, q, J= 4.6 Hz), 5.17 (1 H, d, J= 4.4 Hz), 4.69 (2 H, s), 4.63^1.16 (1 H, m), 4.14-4.13 (1 H, m), 3.97-3.95 (1 H, m), 3.69-3.64 (1 H, m), 3.57-3.52 (1 H, m),13C NMR (DMSO-i/<s, 100 MHz) delta 154.4, 152.3, 148.5, 140.8, 139.9, 127.9, 125.1, 120.0, 1 19.8, 87.9, 85.9, 73.5, 70.7, 61.7, 42.9; ESI-MS calcd for CuH^NjC^S: 364.1080, found: m/z 364.1079 [M + H]+. |
75% | With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 80℃; for 6h; | <strong>[27757-86-4]3-(aminomethyl)thiophene</strong> (0.25 mL, 2.5 mmol) '6-chloropurine nucleofuranoside (143 mg, 0.5 mmol), and diisopropylethylamine (2 mL, 12 mmol) The 1-propanol (25 mL) mixture was heated at 80 C for 6 hours. The mixture was concentrated by rotary evaporation and recrystallized from EtOAc to give the desired product JMF 3461 ( 136 mg, 75% yield). The purity of the product is 99%, |
With triethylamine; In propan-1-ol; at 70℃; for 8h; | First step, hydroxyamine hydrochloride (874 mg) and NaOAc (1.18 g) were added to a solution of 3-thiophenecarbaldehyde (800 mg) in EtOH (50 ml). The reaction mixture was stirred at room temperature for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 3-thiophenecarbaldehyde oxime (722 mg) as a pale yellowish solid. Second step, 3-thiophenecarbaldehyde oxime (722 mg) and zinc dust (2.23 g) in HOAc (5 ml) was stirred at room temperature for 6 h. The reaction solution was filtered to remove the excess zinc dust and ZnOAc residue, and the filtrate was concentrated to yield 3-thiopheneylmethanamine (323 mg) as a yellowish oil. Third step, a mixture of 3-thiopheneylmethanamine (158 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(3-thiopheneylmethyl)-adenosine(150 mg) as a white solid: positive ESIMS m/z 364[M + H]+, 386[M + Na]+ and 402 [M + K]+; negative ESIMS m/z 362[M - H]-; 1H NMR (300MHz, DMSO-d6): the adenosine moiety delta 8.36 (2H, s, -NH, H-2), 8.22 (1H, s, H-8), 5.88 (1H, d, 6.0Hz, H-1), 5.43 (1H, d, 6.0Hz, -OH), 5.38 (1H, m, -OH), 5.17 (1H, d, 4.5Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.70-3.64 (1H, m, H-5a'), 3.58 (1H, m, H-5b'); the 3-thiopheneylmethyl moiety delta 7.43 (1H, dd, 4.8Hz, 3.0Hz, H-5"), 7.28 (1H, brs, H-2"), 7.08 (1H, dd, 4.8Hz, 0.9Hz, H-4"), 4.68 (2H, brs, H-7"); 13C NMR (75MHz, DMSO-d6): the adenosine moiety delta 154.4 (s, C-6), 152.5 (d, C-2), 148.6 (s, C-4), 140.9 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the 3-thiopheneylmethyl moiety delta 140.1 (s, C-3"), 127.7 (d, C-4"), 126.2 (d, C-5"), 121.8 (d, C-2"), 39.5 (t, C-6)omicron |
150 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Third step, a mixture of 3-thiopheneylmethanamine (158 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(3-thiopheneylmethyl)-adenosine (150 mg) as a white solid: positive ESIMS m/z 364[M+H]+, 386[M+Na]+ and 402 [M+K]+; negative ESIMS m/z 362[M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (2H, s, -NH, H-2), 8.22 (1H, s, H-8), 5.88 (1H, d, 6.0 Hz, H-1'), 5.43 (1H, d, 6.0 Hz, -OH), 5.38 (1H, m, -OH), 5.17 (1H, d, 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.70-3.64 (1H, m, H-5a'), 3.58 (1H, m, H-5b'); the 3-thiopheneylmethyl moiety delta 7.43 (1H, dd, 4.8 Hz, 3.0 Hz, H-5"), 7.28 (1H, brs, H-2"), 7.08 (1H, dd, 4.8 Hz, 0.9 Hz, H-4"), 4.68 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.4 (s, C-6), 152.5 (d, C-2), 148.6 (s, C-4), 140.9 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the 3-thiopheneylmethyl moiety delta 140.1 (s, C-3"), 127.7 (d, C-4"), 126.2 (d, C-5"), 121.8 (d, C-2"), 39.5 (t, C-6). |
150 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 158 mg of 3-thiophene methylamine was taken and dissolved in propanol (60 mL). To a solution of 6-chloropurine nucleoside (200 mg) and triethylamine (3 mL)The mixture was heated to 70 C., reacted for 8 hours, and the solvent was recovered with a reaction solution. Chloroform-methanol (20: 1) separated by silica gel column chromatography, To obtain 150 mg of N6-(3-thiophenemethyl)adenosine as a white solid |
Yield | Reaction Conditions | Operation in experiment |
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99% | Example 1: ((2R/3S/4R/5R)-5-{6-[(lS)-2/3-dihydro-lH-inden-l-ylamino]9H-purin-9-yl}- 3,4-dmydroxytetrahydrofuran-2-yl)methyl sulfamate (1-2)Step a: [('3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2>2-dimethyltetrahydrofuro- r3,4-diri,31dioxol-4-yllmethanol; [0162] 6-Chloro-beta-D-ribofuranosylpurine (8.17g, 28.5mmol), p-toluenesulfonic acid monohydrate (5.42g, 28.5mmol) and 2,2~dimethoxypropane(17.5mL, 142.5mmol) were mixed in acetone(500mL). The reaction mixture was stirred at room temperature for lbetahours. Saturated aqueous NaHCO3 solution (40OmL) was then added and the mixture was evaporated under reduced pressure to remove most of the acetone. The remaining aqueous residue was then extracted with chloroform(4 x 20OmL). The combined organics were dried- 78 - EPO <DP n="79"/>over Na2SO4, and then evaporated to yield the product as a white amorphous solid (9.22g, 99%).[0163] LCMS: R.t. 1.22 min ES+ 327 (formic acid). | |
97% | With toluene-4-sulfonic acid; In acetone; at 20℃; | To a stirred solution of chloropurine 23 (15.0 g, 52.2 mmol) in 175 mL of acetone was 2,2-dimethoxypropane (63.0mL, 538 mmol) followed by p-toluenesulfonic acid (10.9 g, 60 mmol). The resulting heterogeneous mixture wasstirred for 2.5 h at rt during which time the solution become homogenous and bright yellow. The volatiles were removed in vacuo to give a thick yellow oil. The oil was dissolved in 150 mL of EtOAc followed by the addition of 150 mL of saturated NaHCO3 over a period of 5 minutes during which time the yellow color disappeared. The resulting layers were separated and the aqueous layer was extracted with 2 × 150 mL of EtOAc. The combined organic layers were washed with 200 mL of brine, dried (Na2SO4) and concentrated in vacuo to give the acetonide S12 |
97% | With toluene-4-sulfonic acid; In acetone; at 20℃; for 2h; | Next, electrophilic AMP analogs with two significantly different substituents at N6-position (i.e. a propargyl and phenyl alkyne) were synthesized following Scheme 2 and Scheme 3. Compound 2 that has a small hydrophobic group (propargyl alkyne) at the N6-position was prepared by coupling 2-chloroethanesulfonyl chloride with the 5-amino adenine moiety, followed by the deprotection of the acid labile acetonide (Scheme 2). The synthesis of compound 3, which has a large hydrophobic group (phenyl alkyne) at the N6-position, required tert-butyldimethylsilane (TI3DMS) protection and deprotection steps on the 5? alcohol and Hoc protection on the N6-amine due to the instability of the reaction intermediates during the Mitsunobu reaction. Subsequent treatment with 2-chloroethanesulfonyl chloride and global deprotection of the acid labile protecting groups led to the formation of compound 3. |
89.03% | With toluene-4-sulfonic acid; In acetone; at 20℃; for 4h;Inert atmosphere; | (2R, 5R) -2- (6- chloro -9H- purin-9-yl) -5- (hydroxymethyl) tetrahydrofuran-3,4-diol (4.8 g, 16.74 mmol) and 2,2 - dimethoxy-propane (10.26 mL, 83.71 mmol) toIn a nitrogen stream, and then p- toluene sulfonic acid monohydrate (3.18 g, 16.74 mmol) was dissolved in anhydrous acetone (120 mL) to It was added dropwise then stirred at room temperature for 4 hours.The completion of the reactionA check after the reaction with saturated aqueous sodium hydrogen carbonate solutionIt concludes.The reaction solutionThe organic layer was concentrated under reduced pressure with chloroform (4 X 20 mL) Extracted and washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate.Intermediate compound by separating the resulting residue was then concentrated under reduced pressure, by column chromatography ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)methanol (4.87 g, 89.03% a)Obtained. |
83% | With toluene-4-sulfonic acid; In acetone; at 20℃; for 2h; | Step 1 (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.47 g, yield: 72%) was obtained according to the process described in the known method (Journal of Organic Chemistry (J. Org. Chem.), 2002, vol. 67, pp. 6708-67963 using (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (10.9 g, 26.4 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489]. (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.48 g, 19.1 mmol) was suspended in acetone (200 mL), and 2,2-dimethoxypropane (11.7 mL, 95.5 mmol) and 4-toluenesulfonic acid monohydrate (9.09 g, 47.8 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure until the amount of the solvent was decreased to about half. Chloroform was added thereto, and the mixture was extracted with chloroform and dried over sodium sulfate. Then, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1.3]dioxol-4-yl)methanol (5.17 g, yield: 83%). ESI-MS (m/z): 327 (M+1) |
83% | With toluene-4-sulfonic acid; In acetone; at 20℃; for 2h; | (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.47 g, yield: 72%) was obtained according to the process described in the known method [Journal of Organic Chemistry (J. Org. Chem.), 2002, vol. 67, pp. 6788-6796] using (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (10.9 g, 26.4 mmol) synthesized by the method described in the known method [Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, pp. 1478-1489]. (2R,3R,4S,5R)-2-(6-Chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (5.48 g, 19.1 mmol) was suspended in acetone (200 mL), and 2,2-dimethoxypropane (11.7 mL, 95.5 mmol) and 4-toluenesulfonic acid monohydrate (9.09 g, 47.8 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, and the solvent was evaporated under reduced pressure until the amount of the solvent was decreased to about half. Chloroform was added thereto, and the mixture was extracted with chloroform and dried over sodium sulfate. Then, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (heptane/ethyl acetate) to obtain ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (5.17 g, yield: 83%). ESI-MS (m/z): 327 (M+1) |
79% | To a 200-L reactor with moderate stirring were charged acetone (115 L, 23 vol) and 6-chloropurine-9-riboside (5.0 kg, 17.4 mol, 1.0 wt/1.0 vol). Subsequently, p- TsOH«H2O (166 g, 0.88 mol, 0.05 equiv, 0.033 wt) and 2,2-dimethoxypropane (7.6 L, 62 mol, 3.54 equiv, 1.52 vol) were added and the resulting yellow suspension stirred at ambient temperature. After 45 h, a sample of the resulting yellow-green solution was taken and analysis by HPLC revealed the starting material to be present at 0.42% by conversion (overall purity 96.9 area %). The batch was neutralized by the addition of IN NaOH (900 rnL, 0.90 mol, 0.05 equiv, 0.18 vol). This addition took approximately 2 min; the final pH was pH 7. The batch was allowed to stir for 1 h. The resulting cloudy yellow mixture was concentrated under reduced pressure at 35 + 5 0C on the rotary evaporator over a period of 8 h, until a volume of 45 L (9.0 vol) was achieved. The concentrate was stored under N2 at 2-8 C.The concentrate was transferred to a 200-L reactor and stirring commenced. Water (45 L, 9.0 vol) was added and the resulting dilute suspension was stirred for 55 min. The batch was transferred portionwise to a 72-L reactor assembled in a heating mantle equipped for vacuum distillation. Distillation at 35 +/- 5 C commenced and proceeded until a batch volume of 62 L (12.4 vol) was achieved (The distillation was conducted over a period of two days, and included 15 hours of aging at <30 0C once complete). The batch was transferred to a 72-L reactor assembled in a cooling bath. The batch was chilled over a period of A1A h until the temperature reached <5 0C and was stirred for an additional 1 h. The solids were filtered employing Sharkskin filter paper and the cake was rinsed with chilled 2:1 water/acetone (7.5 L, 1.5 vol) (The total filtration time was approximately 1 hour 40 minutes and included pulling N2 through the cake in order to help it dry). The damp solids (5.99 kg) were transferred into six glass <n="32"/>drying trays and dried under vacuum, in an oven at 40 +/- 5 0C. After drying for 47 h, the batch was packaged in 4-mil LDPE (double bags) under N2 and stored in a fiber drum. This afforded 6-chloropurine-9-riboside acetonide (4505 g, 79%). | |
76% | With toluene-4-sulfonic acid; In acetone; at 20℃; for 4h;Inert atmosphere; | A mixture of 6-chloropurine riboside (1) (1.0 g, 3.5 mmol), p-toluenesulfonic acid monohydrate (1.0 g, 5.3 mmol) and 2,2-dimethoxypropane (10 mL) in acetone (20 mL) was stirred at room temperature under N2 for 3 h. Another portion of 2,2-dimethoxypropane (10 mL) was added, and the mixture was stirred for another 1 h. The mixture was concentrated by rotary evaporation under reduced pressure. The residue was diluted with CH2C12, and extracted with water. The aqueous phase was washed with CH2C12, and the combined organic layers were washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered, concentrated by rotatory evaporation under reduced pressure, and purified by column chromatography (silica gel, EtOAc/hexane gradients from 3:7 to 1:0) to give compound 23 (870 mg, 76% yield). C,3H,5C1N404; [cx]D25 = -112.6 (CHC13, c = 2); JR Vx (neat) 1592, 1563, 1490, 1438, 1419, 1400, 1384, 1337, 1259, 1202, 1154, 1136, 1108, 1080 cm-?; ?H NMR (CDC13, 600 MHz) oe 8.79 (1 H, s), 8.25 (1 H, s), 6.00 (1 H, d, J= 4.6 Hz), 5.24-5.21 (1 H, m), 5.14 (1 H, dd, J 5.6, 1.5 Hz), 4.93 (1 H, dd, J 10.6, 2.0 Hz), 4.57 (1 H, d, J= 1.5 Hz), 4.00 (1 H, dt, J 12.7, 2.0 Hz), 3.84 (1 H, ddd, J 12.7, 10.6, 2.3 Hz), 1.68 (3 H, s), 1.41 (3 H, s); ?3C NMR (CDC13, 150 MHz) oe 152.4, 151.7, 150.4, 144.7, 133.4, 114.5,94.1, 86.3, 83.2, 81.5, 63.2, 27.6, 25.2; ESJ-HRMS calcd. for C13H1635C1N404: 327.0855, found: m/z327.0868 [M + Hj. |
Example 2 2',3'-Isopropylidene-6-chloropurineriboside 6-Chloropurineriboside (10.0 g) was suspended in acetone (70 ml), 2,2-dimethoxypropane (7.3 g) and p-toluenesulfonic acid monohydrate (3.3 g) was added thereto, and the mixture was stirred at 10C for 3 hr. The reaction mixture was added to a solution of sodium hydrogen carbonate (1.8 g) and water (70 ml). The mixture was concentrated under reduced pressure, and stirred at 20C for 3 hr. The precipitate was collected by filtration, washed with water, and dried overnight at 40C under reduced pressure to give 2',3'-isopropylidene-6-chloropurineriboside (9.7 g). 1H-NMR(DMSO-d6, ppm) delta: 1.34 (3H, s), 1.55(3H, s), 3.50-3.58(2H, m), 4.30-4.32(1H, m), 4.97-4.99(1H, m), 5.09-5.11(1H, s), 5.41-5.43(1H, s), 6.28(1H, d, J=2.4Hz), 8.82(1H, s), 8.87(1H, s). ; Reference Example 12',3'-Isopropylidene-6-chloropurineriboside 6-Chloropurineriboside (640 g, 2.23 mol) was suspended in acetone (5120 ml), and dimethoxypropane (494 g) and p-toluenesulfonic acid monohydrate (212 g) were added. The mixture was stirred at 17-23C for 5 hr. This reaction mixture was added to an aqueous solution of sodium hydrogen carbonate (99 g) and water (4480 ml). The aqueous solution was concentrated under reduced pressure, and stirred at 60C for 2 hr and further at room temperature for about 17 hr. The obtained slurry was filtered, and the separated crystals were washed with water to give 2',3'-isopropylidene-6-chloropurineriboside as crystals (612 g, 1.87 mol). | ||
With (1S)-10-camphorsulfonic acid; In acetone; | Example 1 Preparation of 5'-deoxy-6-N-phenyl-adenosine 5'-N-(N-L-phenylalanyl)sulfamide To a slurry of 6-chloropurine riboside (5.015 g) in acetone (100 ml) was added 2,2-dimethoxypropane (10 ml) and 10-camphorsulfonic acid (100 mg). The mixture was stirred at room temperature for 1 day. The mixture was diluted with ethyl acetate (500 ml) washed with saturated sodium chloride (2*200 ml) and dried over anhydrous magnesium sulfate. Evaporation gave a white solid which was purified by silica gel chromatography (1:1 ethylacetate hexanes) to give 6-chloro-2',3'-O-(1-methylethylidene)purine riboside as a white crystalline solid (5.06 g) | |
(1S)-10-camphorsulfonic acid; In acetone; at 20℃; for 11h;Product distribution / selectivity; | First step, 6-chloropurine riboside (2.0 g) and 2, 2-dimethoxypropane (5.80 g) in dry acetone (100 ml), (1S)-(+)-camphor-10-sulfonic acid (1.60 g) was added as a catalyst. The reaction mixture was stirred at room temperature for 11 h. After evaporating the solvent, the mixture was dissolved in chloroform (200 ml), and a NaHCO3 solution (3× 30 ml) was added. The water layer was extracted with chloroform (30 ml), then the chloroform layer was dried by anhydrous sodium sulfate and filtered. After evaporation of the solvent, the mixture was separated by column chromatography over silica gel eluting with CHCl3-CH3OH (100 : 1) to yield 2',3'-O-isopropylidene-6-chloropurine riboside (2.24 g) as a white solid. Second step, a mixture of hydrochloric salt of 1-(3,4,5-trimethoxyphenyl)- ethylamine (2.0 g) prepared in the above example, 2',3'-O-isopropylidene-6-chloropurine riboside (1.60 g) and triethylamine (1.20 g) in EtOH (70 ml) was refluxed for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (100 : 1) to yield 2',3'-O--isopropylidene-N6-(3,4,5-trimethoxybenzyl)-adenosine(1.4 g) as a white solid. Third step, a mixture of N6-(3,4,5-trimethoxybenzyl)-adenosine(700 mg), caprylic acid (241 mg), EDCI (537 mg), and DMAP (427.6 mg) in dry CH2Cl2 (60 ml) was stirred at room temperature for 3 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (100 : 1) to yield N6-[(+/-)-1-(3,4,5-trimethoxyphenyl)-ethyl]-2',3'-O--isopropylidene-adenosine-5'-caprylate (450 mg). Fourth step, N6-[(+/-)-1-(3, 4, 5-trimethoxyphenyl)-ethyl]-2',3'-O-isopropylidene-adenosine-5'-caprylate (450 mg) was added to a formic acid solution (20 ml, 50% V/V), and the mixture was stirred at room temperature for 12 h, After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (50 : 1) to yield N6-[(+/-)-1-(3, 4, 5-trimethoxyphenyl)-ethyl]- adenosine -5'-caprylate (360 mg) as a white solid: positive ESIMS m/z 588[M + H]+, 610[M + Na]+ and 626 [M + K]+; 1H NMR (300MHz, DMSO-d6): positive delta 8.35 (1H, s, H-8), 8.23 (1H, s, H-2), 8.18 (1H, brd, J = 8.1 Hz, NH), 5.97 (1H, d, J = 4.2 Hz, H-1'), 5.61 (1H, brs, -OH), 5.41 (1H, brs, -OH), 4.70 (1H, m, H-2'), 4.34 (1H, dd, J= 11.7, 1.8 Hz, H-5'a), 4.32 (1H, m, H-3'), 4.22 (1H, dd, J = 11.7, 5.7 Hz, H-5'b), 4.15 (1H, m, H-4'); the 1-(3, 4, 5-trimethoxyphenyl)-ethyl moiety delta 6.83 (2H, s, H-2", H-6"), 5.50 (1H, m, H-7"), 3.75 (6H, s, -OMe), 3.62 (3H, s, -OMe), 1.52 (3H, d, J = 6.6 Hz, H-8"); the capryl moiety delta 2.25 (2H, t, H-2'"), 1.45 (2H, m, H-3'"), 1.14 (8H, m, H-4'" - H-7"'), 0.77 (3H, t, H-8'"). 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (C-6), 152.6 (C-4), 148.5 (C-2), 140.9 (C-8), 119.8 (C-5) 88.1 (C-1'), 81.6 (C-4'), 73.1 (C-3'), 70.4 (C-2'), 63.8 (C-5'); the 1-(3,4,5-trimethoxyphenyl)-ethyl moiety delta 152.8 (C-3", C-5"), 139.6 (C-1"), 136.3 (C-4"), 103.8 (C-2", C-6"), 59.9 (MeO-4"), 55.9 (MeO-3'",5'"), 49.2 (C-7"), 22.8 (C-8'"); the capryl moiety delta 172.8 (C-1'"), 33.4 (C-2'"), 31.2 (C-3'"), 28.4 (C-4'"), 28.4 (C-5"'), 24.5 (C-6'"), 22.1 (C-7'"), 13.9 (C-8'"). | |
2.24 g | With (R)-10-camphorsulfonic acid; In acetone; at 20℃; for 11h; | First step, 6-chloropurine riboside (2.0 g) and 2,2-dimethoxypropane (5.80 g) in dry acetone (100 ml), (1S)-(+)-camphor-10-sulfonic acid (1.60 g) was added as a catalyst. The reaction mixture was stirred at room temperature for 11 h. After evaporating the solvent, the mixture was dissolved in chloroform (200 ml), and a NaHCO3 solution (3*30 ml) was added. The water layer was extracted with chloroform (30 ml), then the chloroform layer was dried by anhydrous sodium sulfate and filtered. After evaporation of the solvent, the mixture was separated by column chromatography over silica gel eluting with CHCl3-CH3OH (100:1) to yield 2',3'-O-isopropylidene-6-chloropurine riboside (2.24 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).1H NMR (600 MHz, MeOD) delta 8.30 (s, 1H), 8.28 (s, 1H), 7.43 (d,J=7.5 Hz, 2H), 7.36 (t, J=7.6 Hz, 2H), 7.29 (t, J=7.3 Hz, 1H), 6.01(d, J = 6.4 Hz, 1H), 4.82-4.77 (m, 1H), 4.37 (dd, J = 4.9, 2.5 Hz, 1H),4.22 (d, J = 2.4 Hz, 1H), 3.93 (dd, J = 12.5, 2.3 Hz, 1H), 3.79 (dd,J = 12.5, 2.5 Hz, 1H) ppm. HRMS (ESI-Q-TOF) m/z [M + H] + Calcd.for C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
80% | With triethylamine; In ethanol; at 60℃; for 18h; | A mixture of 5a (100mg, 0.35 mmol), benzylamine (0.04m1, 0.35mmol), Et3N(0.05m1, 0.35mmol) in ethanol (5mL) was stirred at 60 C for 18 h. After cooled to roomtemperature, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title product Sb as white solids (100.5mg, 80%): MS (ESI): m/z =358 [M+H] 1H NMR (500 MHz, DMSO-d6) 8.49 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.33-7.27 (m, 4H), 7.22-7.19 (m, 1H), 5.88 (d, J= 6.2 Hz, 1H), 5.46 (d, J= 6.1 Hz,1H), 5.41-5.38 (m, 1H), 5.20 (d, J= 6.2 Hz, 1H), 4.70 (s, 2H), 4.63-4.60 (m, 1H), 4.14 (d, J =3.0 Hz, 1H), 3.96 (d, J= 3.0 Hz, 1H), 3.67 (d, J 12.1 Hz, 1H), 3.54 (ddd, J 11.7, 7.2, 3.5 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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88% | With triethylamine; In ethanol; | Example 41 This example describes the synthesis of N6 -(3-iodobenzyl)-9-[beta-D-ribofuranosyl]-adenine. A mixture of 6-chloropurine riboside (Aldrich Chemical Co., 100 mg, 0.35 mmol), triethylamine (0.146 ml, 1.05 mmol), and <strong>[3718-88-5]3-iodobenzylamine hydrochloride</strong> (103 mg, 0.38 mmol) in ethanol (2 ml) was heated for 18 h at 85 C. in a sealed bottle. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1) to yield N6 -(3-iodobenzyl)-9-[beta-D-ribofuranosyl]-adenine (148 mg, 88%) as a colorless solid: m.p. 172 C.; 1 H NMR (DMSO-d6) d 3.54 (m, 1H, H-5'a), 3.67 (m, 1H, H-5'b), 3.96 (d, J=3.3 Hz, 1H, H-4'), 4.14 (m, 1H, H-3'), 4.60 (m, 1H, H-2'), 4.66 (br s, 2H, CH2), 5.16 (d, J=4.4 Hz, 1H, exchangeable with D2 O, 3'-OH), 5.34 (br s, 1H, exchangeable with D2 O, 5'-OH), 5.43 (d, J=6.1 Hz, 1H, exchangeable with D2 O, 2'-OH), 5.89 (d, J=6.0 Hz, 1H, H-1'), 7.11 (pseudo t, J=8.0 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.6 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.72 (s, 1H, H-2"), 8.21 (s, 1H, H-2 or 8), 8.40 (s, 1H, H-2 or 8), 8.48 (br s, 1H, exchangeable with D2 O, N6 H,). |
Yield | Reaction Conditions | Operation in experiment |
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70% | N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; | N-[(2-methylphenyl)methyl]adenosine The title compound was prepared by reacting (2-methylphenyl)methylamine (1.51 g, 12.5 mmol) with 6-chloropurine riboside (2.87 g, 10.0 mmol) in dioxan (100 ml) in the presence of diisopropylethylamine (1.94 g, 15.0 mmol). The reaction mixture was heated at 60 C. for 6 h, cooled, filtered and evaporated. The residue was purified by flash chromatography, eluding initially with dichloromethane, and later increasing polarity to dichloromethanethanol (9:1), to provide the product (2.6 g, 70%) as a solid which was recrystallized from methanol to give N-[(2-methylphenyl)methyl]adenosine as white crystals (1.75 g, 47%), mp 161.5-163.5 C., 1 H NMR (DMSO-d6)delta 2.35 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.65-3.72 (1H, m, H-5'b), 3.98 (1H, q, H-4'), 4.16 (1H, m, H-3'), 4.64 (1H, q, H-2'), 5.41 (1H, t, 5'-0H), 5.21, 5.48 (2H, 2d, 2'- and 3'-OH), 5.92 (1H, d, H-1'), 7.06-7.24 (4H, m, Ar--H), 8.20 and 8.40 (3H, s and br s, H-2, H-8 and N--H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In neat (no solvent); at 210℃; under 12929 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
With triethylamine; In prpopanol, 1-; at 70℃; for 8h; | First step, of p-fluorobenzylaldehyde (2 g), hydroxyamine hydrochloride (1.97 g), and NaOAc (2.64 g) were dissolved in EtOH (80 ml). The reaction mixture was stirred at room temperature for 6h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield p-fluorobenzaldehyde oxime (1.8 g) as a pale yellowish solid. Second step, p-fluorobenzaldehyde oxime (1.8 g) and zinc dust (5.05 g) in HOAc (25 ml) was stirred at room temperature for 6 h. The reaction solution was filtered to remove the excess zinc dust and ZnOAc residue, and the filtrate was concentrated to yield p-fluorobenzylamine (1.25 g) as a yellowish oil. Third step, a mixture of p-fluorobenzylamine (339 mg), 6-chloropurine riboside (300 mg), and triethylamine (3 ml) in PrOH (60 ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(p-fluoroxybenzyl)-adenosine(335 mg) as a white solid: positive ESIMS m/z 376 [M + H]+ and 398 [M + Na]+; negative ESIMS m/z 374 [M - H]-; 1H NMR (300MHz, DMSO-d6): the adenosine moiety delta 8.48 (1H, brs, -NH), 8.41 (1H, s, H-2), 8.24 (1H, s, H-8), 5.94 (1H, d, J= 6.0 Hz, H-1'), 5.52 (2H, m, -OH), 5.29 (1H, m, -OH), 4.67 (1H, m, m, H-2'), 4.21 (1H, m, H-3'), 4.02 (1H, m, H-4'), 3.72 (1H, m, H-5'a), 3.59 (1H, m, H-5'b); the p-fluorobenzyl moiety delta 7.37 (2H, m, H-2", H-6"), 7.09 (2H, m, H-3", H-5"), 4.68 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.6 (s, C-6), 152.5 (d, C-2),148.6 (s, C-4), 140.2 (d, C-8), 120.0 (s, C-5), 88.3 (d, C-1'), 86.2 (d, C-4'), 73.8 (d, C-2'), 70.9 (d, C-3'), 61.9 (t, C-5'); the p-fluorobenzyl moiety delta 162.9, 159.7 (240.67 Hz, C-4"),136.3 (s, C-1"), 129.3 (d, J = 82.5 Hz, C-2", C-6"), 115.1 (d, J = 200.5 Hz, C-3", C-5"), 42.4 (t, C-7")o | |
335 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Third step, a mixture of p-fluorobenzylamine (339 mg), 6-chloropurine riboside (300 mg), and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(p-fluoroxybenzyl)-adenosine (335 mg) as a white solid: positive ESIMS m/z 376 [M+H]+ and 398 [M+Na]+; negative ESIMS m/z 374 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.48 (1H, brs, -NH), 8.41 (1H, s, H-2), 8.24 (1H, s, H-8), 5.94 (1H, d, J=6.0 Hz, H-1'), 5.52 (2H, m, -OH), 5.29 (1H, m, -OH), 4.67 (1H, m, m, H-2'), 4.21 (1H, m, H-3'), 4.02 (1H, m, H-4'), 3.72 (1H, m, H-5'a), 3.59 (1H, m, H-5'b); the p-fluorobenzyl moiety delta 7.37 (2H, m, H-2", H-6"), 7.09 (2H, m, H-3", H-5"), 4.68 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.6 (s, C-6), 152.5 (d, C-2), 148.6 (s, C-4), 140.2 (d, C-8), 120.0 (s, C-5), 88.3 (d, C-1'), 86.2 (d, C-4'), 73.8 (d, C-2'), 70.9 (d, C-3'), 61.9 (t, C-5'); the p-fluorobenzyl moiety delta 162.9, 159.7 (240.67 Hz, C-4"), 136.3 (s, C-1"), 129.3 (d, J=82.5 Hz, C-2", C-6"), 115.1 (d, J=200.5 Hz, C-3", C-5"), 42.4 (t, C-7"). |
335 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 339 mg of p-fluorophenylmethylamine was taken and dissolved in propanol (60 mL), 6-chloropurine nucleoside (300 mg) and triethylamine(4.5 mL) was added, the mixture was heated to 70 C., reacted for 8 hours, the solvent was recovered with the reaction solution, and the solvent was removed by silica gel column chromatography and washed with chloroform-methanol (20: 1) 335 mg of N6-(P-fluorobenzyl-yl) -adenosine as a white solid are obtained: |
Yield | Reaction Conditions | Operation in experiment |
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89% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In methanol; at 80℃; for 40h; | [0154] 3. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled and concentrated under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with methylene chloride/methanol/propylamine (90/10/1). The fractions containing the product were combined and concentrated under reduced pressure. The residue was chromatographed on a chromatotron (2 mm plate, 92.5/7.5/1, methylene chloride/methanol/propylamine). The resulting white solid was recrystallized from methanol/ethyl acetate to give 0.27 gm of (4S,2R,3R,5R)-2-hydroxymethyl-5-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol as white crystals (mp 128° C.-130° C.). |
Yield | Reaction Conditions | Operation in experiment |
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65% | With calcium carbonate; In ethanol; for 15.0h;Heating / reflux; | A mixture of <strong>[2004-06-0]6-chloropurine riboside</strong> (10,100 mg, 0.35 mmol), (mono-NO2)- 1,2, 3,4-tetrahydroisoquinoline (0.88 mmol) and calcium carbonate (70 mg, 0. 70mmole) in EtOH (5mL) is stirred under refluxing for 15 hours. The reaction mixture is filtered and the filtrate is removed by rotavapor. The residue is purified by chromatography followed by recrystalization in MeOH. Compound 2: yield 65%; mp 159-160C ; IR: 3438,1604, 1528,1352 cm-1 ;'H NMR (300MHz, CDCL3) 8 8.15 (1H, s, H-2), 7.86 (1H, d, H-6"), 7.84 (1H, s, H-8), 7.49 (1H, d, H-8"), 7.36 (1H, t, H-7"), 6.53 (1H, br d, OH-2'), 5.81 (1H, d, H-1'), 5.36 (1H, br s, OH-3'), 5.07 (1H, q, H-2'), 4.53-4. 45 (3H, br m, OH-5', H-3', 1"A), 4. 35 5 (1 H, s, H-1"B), 3.94 (1H, d, H-4'), 3.76 (2H, br m, H- 5'), 3.28 (2H, t, H3"or H4"). Anal. Calcd. For C19H20N6O6 (428.405) : C, 53.27% ; H, 4.71% ; N, 19.62%. Found : C, 53.14% ; H, 4.76% ; N, 19.32%. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In methanol; | Step 3. Preparation of 6-(3-(S)-aminotetrahydrofuranyl)purine Riboside A mixture of 6-chloropurine riboside (30 mg, 0.10 mmol), 3-(S)-aminotetrahydrofuran hydrochloride (19 mg, 0.15 mmol), and triethylamine (45 ml, 0.32 mmol) in methanol (0.5 ml) was heated to 80 C. for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (methylene chloride/methanol), to give 8 mg of 6-(3-(S)-aminotetrahydrofuranyl)purine riboside, as a white solid. | |
8 mg (24%) | With triethylamine; In methanol; | Preparation of 6-(3-(S)-aminotetrahydrofuranyl)purine Riboside A mixture of 6-chloropurine riboside (30 mg, 0.10 mmol), 3-(S)-aminotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol (0.5 ml) was heated to 80 C. for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (CH2 Cl2 /MeOH) to give 8 mg (24%) of a white solid. |
8 mg (24%) | With triethylamine; In methanol; | Step 3. Preparation of 6-(3-(S)-aminotetrahydrofuranyl)purine riboside A mixture of 6-chloropurine riboside (30 mg, 0.10 mmol), 3-(S)-aminotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol (0.5 ml) was heated to 80 C. for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (CH2Cl2/MeOH) to give 8 mg (24%) of 6-(3-(S)-aminotetrahydrofuranyl)purine riboside as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; In methanol; water; N,N-dimethyl-formamide; | EXAMPLE 5 N-[(4-Nitrophenyl)methoxy]adenosine The title compound was prepared according to Method A described above (R2, R3 =H) by reacting <strong>[2086-26-2]O-[(4-nitrophenyl)methyl]hydroxylamine hydrochloride</strong> (1.43 g, 7 mmol) with 6-chloropurine riboside (i.e. 9-beta-D-ribofuranosyl-6-chloro-9H-purine) (1.0 g, 3.5 mmol) in DMF (40 ml) at 110 C. for 2 h with diisopropylethylamine (1.80 g, 14 mmol) present. The reaction mixture was evaporated and to the resultant residue was added saturated sodium bicarbonate solution (20 ml) and water (20 ml). Methanol was gradually added until the residue dissolved, and the solid which gradually precipitated was removed by filtration. The flitrate was concentrated to a residue which was purified by flash chromatography on silica gel. Elution with ethyl acetate/ethanol (30/1) initially, followed by a (8/1) mixture of these solvents provided a solid which was recrystallized from ethanol. The first crop of material was discarded, but the second crop was confirmed as the title compound (70 mg, 7%) mp 115-117 C. TLC rf 0.20 [SiO2, ethyl acetate/methanol (9/1)]; 1 H NMR (DMSO-d6)gamma 3.46-3.57 (2H, m, H-5'a and H-5'b), 3.90 (1H, q, H-4'), 4.08 (1H, q, H-3'), 4.43 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.44, 5.74 (2H, 2d, 2'and 3'-OH), 5.82 (1H, d, H-1'), 7.67 (2H, d, Ar-H), 8.08 (1h, s, H-8), 8.22 (2H, d, Ar-H), 9.34 (1H, br s, N-H). C17 H18 N6 O7.0.75 H2 O requires C, 47.3; H, 4.6; N, 19.45. Found: C, 48.8; H, 4.55; N, 19.45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; | Preparation of 6-(<strong>[88675-24-5]3-aminotetrahydrofuran</strong>yl)purine Riboside A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), <strong>[88675-24-5]3-aminotetrahydrofuran</strong> (0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C. for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluding with 90/10/1 (CH2 Cl2 /MeOH/PrNH2) the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1, CH2 CL2 /MeOH/Pr NH2). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128°-130° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium carbonate; In methanol; ethanol; dichloromethane; | EXAMPLE 15 9-beta-D-Ribofuranosyl-N-(1H-pyrrol-1-yl)-9H-purin-6-amine A mixture of 6-chloropurine riboside (3 g, 10.5 mmole), <strong>[765-39-9]1H-<strong>[765-39-9]pyrrol-1-amine</strong></strong> (2.6 g, 31.5 mmole) and calcium carbonate (2.1 g, 21 mmole) in 150 ml ethanol was stirred two hours at reflux, then was cooled, filtered, evaporated with 25 g silica, eluted with ethyl acetate and then 10% methanol in dichloromethane via flash chromatography to give 3.5 g of a solid, m.p. 125 C. The solid was combined with 2.1 g product obtained from another condensation and purified by high pressure liquid chromatography (silica, 10% methanol in dichloromethane) to give 4 g of a solid. This solid was recrystallized from acetonitrile to give 3.6 g (62%) of 9-beta-D-ribofuranosyl-N-(1H-pyrrol-1-yl)-9H-purin-6-amine, m.p. 193-195 C. Analysis: Calculated for C14 H16 N6 O4: 50.60% C; 4.85% H; 25.29% N. Found: 50.63% C; 4.81% H; 25.38% N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.3 g (49%) | In methanol; ethanol; dichloromethane; calcium carbonate; | EXAMPLE 16 9-beta-D-Ribofuranosyl-N-(1H-indol-1-yl)-9H-purin-6-amine A solution of 6-chloropurine riboside (5 g, 17.4 mmole) and <strong>[53406-38-5]1H-indol-1-amine</strong> (5 g, 37.8 mmole) in 250 ml absolute ethanol containing calcium carbonate (5 g, 50 mmole) was stirred at reflux for four hours, then was cooled, filtered and evaporated to 11 g of a solid. This solid was purified by high pressure liquid chromatography (silica, 10% methanol in dichloromethane) to give 5.5 g of a solid. This solid was recrystallized twice from acetonitrile to give 3.3 g (49%) of 9-beta-D-ribofuranosyl-N-(1H-indol-1-yl)-9H-purin-6-amine, m.p. 155 C. Analysis: Calculated for C18 H18 N6 O4: 56.53% C; 4.74% H; 21.98% N. Found: 56.12% C; 4.72% H; 21.75% N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; water; | EXAMPLE 1 N6 -Fluorenyladenosine 4.0 g of 6-chloropurine riboside, 3.79 g of <strong>[5978-75-6]9-aminofluorene hydrochloride</strong> and 3.52 g of triethylamine are refluxed in 100 ml ethanol under nitrogen for 20 hrs. the solvent is evaporated to dryness and residue is treated with 100 ml of cold water. Precipitated solid is filtered and treated with 50 ml of methanol-chloroform (1:1) affording 3.8 g (63%) of N6 -fluorenyladenosine having a m.p of 210-212 C. Anals. Calcd. for C23 H21 N5 O4. 10 H2 O 0.3HCl C=60.00; H=5.09; N=15.21. Found: C=59.95; H=4.72; N=15.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 10 N6-((1-Phenylcyclopentyl)methyl)adenosine (1-Phenylcyclopentyl)methylamine is prepared as its hydrochloride salt, m.p. 185-6 C. from 1-phenylcyclopentane carbonitrile as described in Example 11. The above amine hydrochloride (5.0 g, 24 mmol) is reacted with 6-chloropurine riboside (6.8 g, 24 mmol) as described in Example 11 infra to give after column chromatography N6-((1-phenylcyclopentyl)methyl)adenosine (3.80 g, 37%) as a solid white foam m.p. 74-8 C. Found: C, 59.02; H, 5.94; N, 15.25%. C22 H27 N5 O4 calculated requires: C, 62.12; H, 6.35; N, 16.47%. C22 H27 N5 O4 0.25 CHCl3 requires C, 58.69; H, 6.03; N, 15.38%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In propan-1-ol; ethanol; | EXAMPLE 3 Preparation of N6 -methyl-N6 -(3-carboxypropyl)adenosine A mixture of 10.0 g (34.9 mmole) of 6-chloropurine riboside, 11.0 g (71.6 mmole) of <strong>[6976-17-6]4-(methylamino)butanoic acid hydrochloride</strong>, and 20.0 g (108 mmole) of tributylamine in 300 ml of propanol was heated at reflux for two days. The solution was allowed to cool and concentrated in vacuo to a thick oil. The oil was treated with several portions of diethyl ether to remove soluble organic material. Two crops of crude product were crystallized from ethanol and redissolved in 100 ml of 50percent aqueous ethanol. The resulting solution was decolorized with charcoal, filtered, and the volume was reduced to about 30 ml by boiling. Upon cooling, 4.3 g (11.7) mmole) of N6 -methyl-N6 -(3-carboxypropyl)adenosine was obtained as a fluffy white solid. Anal. Calcd. for C15 H21 N5 O6: C, 49.04; H, 5.76; N, 19.06. Found: C, 48.91; H, 5.83; N, 18.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributyl-amine; In ethanol; | EXAMPLE 2 Preparation of N6 -[4-(ethoxycarbonyl)butyl]adenosine A mixture of 10.0 g (34.9 mmole) of 6-chloropurine riboside, 9.5 g (52.3 mmole) of ethyl-5-aminopentanoate hydrochloride (prepared by the method of Example 7), and 18.0 g (97.1 mmole) of tributylamine in 200 ml of absolute ethanol was heated at reflux for 18 hours, then allowed to cool to about 0 C. The resulting crude product was collected and washed with ethanol, redissolved in 100 ml of boiling ethanol and filtered. Upon cooling, two crops of N6 -[4-(ethoxycarbonyl)butyl]adenosine totalling 7.9 g (20.0 mmole) were collected as a fluffy white powder. Anal. Calcd for C17 H25 N5 O6: C, 51.64; H, 6.37; N, 17.71. Found: C, 51.41; H, 6.45; N, 17.68. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; | EXAMPLE 1 N(6)-(2-Indanyl)adenosine Two grams 6-chloropurine riboside, 1.48 grams <strong>[2338-18-3]2-aminoindane hydrochloride</strong> and 1.74 g triethylamine are refluxed in ethanol under nitrogen for 20 hours. Upon cooling, solid material crystallizes. The reaction mixture is diluted with 70 ml ethanol, filtered and washed with ethanol. Solid thus obtained is suspended in approximately 25 to 30 ml methanol, filtered, and washed with methanol and dried affording 1.95 g (73%) N(6)-(2-indanyl)adenosine having a melting point of 166-168 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.15 g (78%) | With triethylamine; In methanol; dichloromethane; | Example 10 N-[2-(dipropylamino)ethyl]adenosine The experiment of Example 1 was repeated in very essential detail with the following exceptions. A suspension of 2.0g (6.98 mmol) of 6-chloropurine riboside in 30 ml of absolute ethanol was formed. To the suspension was added 1.17 g (8.37 mmol) of N,N-di-n-propylethylene diamine (commercially available) and 1.5ml (10.5 mmol) of triethylamine. The reaction mixture was refluxed for 72 hours at which time the residue was separated by chromatography on a silica gel column using an eluant of 20 parts methanol, 79 parts dichloromethane and 1 part ammonium hydroxide to yield 2.15 g (78%) of the title compound DSC=130.7 - 134.4. MS: Calculated, 395; observed, 395. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; for 16h; | To a solution of 6-chloroadenosine (leq) in MeOH or DMSO was added amine RR'NH (RR'N = N (Me) CH2 (3-bromophenyl) (44) or N (Me) CH2 (3- trifluoromethylphenyl) (45) or N (Me) CH2CH20Me (47) ) (3-5eq) and the resulting solution stirred for 16h. The solvents were then removed in vacuo and the residue purified by reverse phase column chromatography to yield the 6-dialkylamino derivative |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; at 80℃; for 6h; | A mixture of (R)-1-(3-methoxyphenyl)-ethylamine (635 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80C for 6 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(R)-1-(3-methoxyphenyl)-ethyl]-adenosine(335 mg) as a white solid: positive ESIMS mlz 402 [M + H]+; negative ESIMS mlz 400 [M - H]-; 1H NMR (300 MHz, DMSO-d6):the adenosine moietydelta 8.39 (1H, s, H-2), 8.30 (1H, brd, J = 4.8 Hz, -NH), 8.18 (1H, s, H-8), 5.90 (1H, d, J = 6.3 Hz, H-1'), 5.46 (2H, m, 2*-OH), 5.21 (1H, m, -OH), 4.63 (1H, m, H-2'), 4.17 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.68 (1H, m, H-5'a), 3.58 (1H, m, H-5'b); the (R)-1-(3-methoxyphenyl)-ethyl moiety delta 7.19 (1H, t, J= 7.5Hz, H-5'), 7.03 (1H, brs, H-2'), 7.00 (1H, brd, J = 7.5 Hz, H-6'), 6.74 (1H, dd, J = 7.5, 1.5Hz, H-4'), 5.49 (1H, m, H-7'), 3.70 (3H, s, -OCH3), 1.52 (1H, d, J = 6.6 Hz, H-8'); 13CNMR (75MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 139.9 (d, C-8), 119.8 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.5 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (R)-1-(3-methoxyphenyl)-ethyl moiety delta 159.3 (s, C-3'), 146.9 (s, C-1'), 129.3 (d, C-5'), 118.5 (d, C-6'), 112.2 (d, C-2'), 111.7 (d, C-4'), 55.0 (q, -OCH3), 48.9 (d, C-7'), 22.6 (q, C-8')o | |
335 mg | In propan-1-ol; at 80℃; for 6h; | A mixture of (R)-1-(3-methoxyphenyl)-ethylamine (635 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80 C. for 6 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(R)-1-(3-methoxyphenyl)-ethyl]-adenosine (335 mg) as a white solid: positive ESIMS m/z 402 [M+H]+; negative ESIMS m/z 400 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.39 (1H, s, H-2), 8.30 (1H, brd, J=4.8 Hz, -NH), 8.18 (1H, s, H-8), 5.90 (1H, d, J=6.3 Hz, H-1'), 5.46 (2H, m, 2*-OH), 5.21 (1H, m, -OH), 4.63 (1H, m, H-2'), 4.17 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.68 (1H, m, H-5'a), 3.58 (1H, m, H-5'b); the (R)-1-(3-methoxyphenyl)-ethyl moiety delta 7.19 (1H, t, J=7.5 Hz, H-5"), 7.03 (1H, brs, H-2"), 7.00 (1H, brd, J=7.5 Hz, H-6"), 6.74 (1H, dd, J=7.5, 1.5 Hz, H-4"), 5.49 (1H, m, H-7"), 3.70 (3H, s, -OCH3), 1.52 (1H, d, J=6.6 Hz, H-8"); 13CNMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 139.9 (d, C-8), 119.8 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.5 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (R)-1-(3-methoxyphenyl)-ethyl moiety delta 159.3 (s, C-3"), 146.9 (s, C-1"), 129.3 (d, C-5"), 118.5 (d, C-6"), 112.2 (d, C-2"), 111.7 (d, C-4"), 55.0 (q, -OCH3), 48.9 (d, C-7"), 22.6 (q, C-8"). |
335 mg | In propan-1-ol; at 80℃; for 6h; | (R)-1-(3-methoxyphenyl)-ethylamine (635 mg) was dissolved in normal propyl alcohol (50 mL), 6-chloropurine nucleoside (300 mg) Heat up to 80 C and let it react for 6 h. The solvent was recovered with the reaction solution, chromatographed through a gel column and eluted with ethanol to obtain white solid N6-[(R)-1-(3-methoxyphenyl)-ethyl]-adenosine (335 mg) It was |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 12h;Reflux; | A mixture of (S)-1-(4-chlorophenyl)-ethylamine (490 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(4-chlorophenyl)-ethyl]-adenosine(340 mg) as a white solid: positive ESIMS m/z 406 [M + H]+ and 428 [M + Na]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.41 (1H, s, H-2), 8.38 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.92 (1H, d, J = 5.4 Hz, H-1'), 5.47 (1H, d, J = 5.7 Hz, -OH), 5.40 (1H, m, -OH), 5.22 (1H, d, J = 3.6 Hz, -OH), 4.62 (1H, m, H-2'), 4.18 (1H, m, H-3'), 3.99 (1H, m, H-4'), 3.68 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (S)-1-(4-chlorophenyl)-ethyl moiety delta 7.45 (1H, d, J= 7.8 Hz, H-2', H-6'), 7.33 (1H, d, J= 7.8 Hz, H-3', H-5'), 5.47 (1H, m, H-7'), 1.53 (3H, d, J = 6.3 Hz, H-8'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (s, C-6), 152.3 (d, C-2), 148.7 (s, C-4), 139.9 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 85.9 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(4-chlorophenyl)-ethyl moiety delta 144.3 (s, C-1'), 131.1 (s, C-4'), 128.2 (d, C-2', C-6'), 128.1 (d, C-3', C-5'), 48.4 (d, C-7'), 22.3 (q, C-8')o | |
340 mg | In ethanol; for 12h;Reflux; | A mixture of (S)-1-(4-chlorophenyl)-ethylamine (490 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(4-chlorophenyl)-ethyl]adenosine (340 mg) as a white solid: positive ESIMS m/z 406 [M+H]+ and 428 [M+Na]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.41 (1H, s, H-2), 8.38 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.92 (1H, d, J=5.4 Hz, H-1'), 5.47 (1H, d, J=5.7 Hz, -OH), 5.40 (1H, m, -OH), 5.22 (1H, d, J=3.6 Hz, -OH), 4.62 (1H, m, H-2'), 4.18 (1H, m, H-3'), 3.99 (1H, m, H-4'), 3.68 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (S)-1-(4-chlorophenyl)-ethyl moiety delta 7.45 (1H, d, J=7.8 Hz, H-2", H-6"), 7.33 (1H, d, J=7.8 Hz, H-3", H-5"), 5.47 (1H, m, H-7"), 1.53 (3H, d, J=6.3 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (s, C-6), 152.3 (d, C-2), 148.7 (s, C-4), 139.9 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 85.9 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(4-chlorophenyl)-ethyl moiety delta 144.3 (s, C-1"), 131.1 (s, C-4"), 128.2 (d, C-2", C-6"), 128.1 (d, C-3", C-5"), 48.4 (d, C-7"), 22.3 (q, C-8"). |
340 mg | In ethanol; for 12h;Reflux; | (S)-1-(4-chlorophenyl)-ethylamine (490 mg) and 6-chloropurine nucleoside (300 mg) were dissolved in ethanol (50 mL) Reflux by heating at 12 h. The solvent was recovered with the reaction solution, chromatographed through a gel column, eluted with ethanol, To obtain white N6-[(R)-1-(4-chlorophenyl)-ethyl]-adenosine (340 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; at 70℃; for 8h; | A mixture of (S)-1-(4-methoxyphenyl)-ethylamine (475 mg) and 6-chloropurine riboside (300 mg) in PrOH (70 ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(4-methoxyphenyl)-ethyl]-adenosine(345 mg) as a white solid: positive ESIMS m/z 402 [M + H]+ and 424 [M + Na]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.23 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.90 (1H, d, J= 6.3 Hz, H-1'), 5.46 (1H, d, J= 6.3 Hz, -OH), 5.42 (1H, m, -OH), 5.20 (1H, d, J= 4.5 Hz, -OH), 4.61 (1H, m, H-2'), 4.16 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (S)-1-(4-methoxyphenyl)-ethyl moiety delta 7.35 (1H, d, J = 8.4 Hz, H-2', H-6'), 6.84 (1H, d, J = 8.4 Hz, H-3', H-5'), 5.48 (1H, m, H-7'), 3.71 (3H, s, -OCH3), 1.51 (3H, d, 7.2Hz, H-8'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta,153.9 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 85.9 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(4-methoxyphenyl)-ethyl moiety delta 158.0 (s, C-4'), 137.1 (s, C-1'), 127.3 (d, C-2', C-6'), 113.6 (d, C-3', C-5'), 55.0 (q, -OCH3), 48.2 (d, C-7'), 22.5 (q, C-8')o | |
345 mg | In propan-1-ol; at 70℃; for 8h; | A mixture of (S)-1-(4-methoxyphenyl)-ethylamine (475 mg) and 6-chloropurine riboside (300 mg) in PrOH (70 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(4-methoxyphenyl)-ethyl]adenosine (345 mg) as a white solid: positive ESIMS m/z 402 [M+H]+ and 424 [M+Na]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.23 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.90 (1H, d, J=6.3 Hz, H-1'), 5.46 (1H, d, J=6.3 Hz, -OH), 5.42 (1H, m, -OH), 5.20 (1H, d, J=4.5 Hz, -OH), 4.61 (1H, m, H-2'), 4.16 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (S)-1-(4-methoxyphenyl)-ethyl moiety delta 7.35 (1H, d, J=8.4 Hz, H-2", H-6"), 6.84 (1H, d, J=8.4 Hz, H-3", H-5"), 5.48 (1H, m, H-7"), 3.71 (3H, s, -OCH3), 1.51 (3H, d, 7.2 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety 5153.9 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 85.9 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(4-methoxyphenyl)-ethyl moiety delta 158.0 (s, C-4"), 137.1 (s, C-1"), 127.3 (d, C-2", C-6"), 113.6 (d, C-3", C-5"), 55.0 (q, -OCH3), 48.2 (d, C-7"), 22.5 (q, C-8"). |
345 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | (S)-4-methoxyphenylethylamine (475 mg) was dissolved in n-propyl alcohol (70 mL), 6-chloropurine nucleoside (300 mg) And triethylamine (4.5 mL) were added, and the mixture was heated to 70 C. and reacted for 8 h. The solvent was recovered with the reaction solution, chromatographed through a gel column, eluted with ethanol, Was obtained as a white solid N6-[(S)-1-(4-methoxyphenyl)ethyl]adenosine (345 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With bis(isopropyl)ethylamine; In propan-1-ol; at 80℃; for 7h; | A mixture of 2-(aminomethyl)thiophene (0.25 mL, 2.5 mmol), 6-chloropurine ribofuranoside (143 mg, 0.5 mmol), and diisopropylethylamine (2 mL, 12 mmol) in 1-propanol (25 mL) was heated at 80 C for 7 h. The mixture was concentrated by rotary evaporation, and recrystallized from MeOH to yield the desired product JMF3462 (154 mg, 85% yield). The purity of product was 99% as shown by HPLC on an HC-C18 column (Agilent, 4.6 250 mm, 5 mupiiota) with elution of gradients of 50% aqueous MeOH. C15H17N5O4S; white powder; mp 149.2-149.7 C; [a]25D= -68.2 (DMSO, c = 1.0); TLC (2-propanol/hexane, (2:3)) Rf= 0.35; NMR (DMSO- ;, 400 MHz) 6 8.51 (1 H, br s), 8.39 (1 H, s), 8.27 (1 H, br s), 7.32 (1 H, d, J = 5.2 Hz), 7.28 (1 H, d, J= 3.2 Hz), 6.93 (1 H, dd, J= 1.8, 2.6 Hz), 5.89 (1 H, d, J = 6.0 Hz), 5.46-5.45 (1 H, m), 5.36 (1 H, q, J= 4.6 Hz), 5.20-5.18 (1 H, m), 4.64 (2 H, s), 4.16-4.13 (1 H, m), 3.97-3.95 (1 H, m), 3.70-3.65 (1 H, m), 3.58-3.52 (1 H, m), 3.57- 3.52 (1 H, m),13C NMR (DMSO-c/e, 100 MHz) delta 154.1, 152.2, 148.5, 142.9, 140.0, 126.5, 125.3, 124.7, 120.0, 87.9, 85.9, 73.5, 70.6, 61.6, 42.9; ESI-MS calcd for C15H18N5O4S: 364.1080, found: m/z 364.1081 [M + H]+. |
85% | With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 80℃; for 7h; | 2-(aminomethyl)thiophene (0.25 mL '2.5 mmol), 6-chloropurine nucleofuranoside (143 mg, 0.5 mmol) ' and diisopropylethylamine (2 mL, 12 mmol) of a 1-propanol mixture (25 mL) was heated at 80 C for 7 h. The mixture was concentrated by rotary evaporation and recrystallised from MeOH to give the desired product JMF 3462 ( 154 mg, 85% yield). The product purity was 99% as indicated by HPLC on an HC-C18 column (Agilent, 4.6 chi 250 mm, 5 mueta) with a gradient of 50% MeOH in water. |
With triethylamine; In propan-1-ol; at 70℃; for 8h; | First step, hydroxyamine hydrochloride (3.27 g) and NaOAc (4.39 g) were added to a solution of 2-thiophenecarbaldehyde (3.0 g) in EtOH (80 ml). The reaction mixture was stirred at room temperature for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 2-thiophenecarbaldehyde oxime (2.75 g) as a pale yellowish solid. Second step, 2-thiophenecarbaldehyde oxime (2.75 g) and zinc dust (8.63 g) in HOAc (25 ml) was stirred at room temperature for 6 h. The reaction solution was filtered to remove the excess zinc dust and ZnOAc residue, and the filtrate was concentrated to yield 2-thiopheneylmethanamine (1.25 g) as a yellowish oil. Third step, a mixture of 2-thiopheneylmethanamine (592 mg), 6-chloropurine riboside (500 mg) and triethylamine (7.3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(2-thiopheneylmethyl)-adenosine(490 mg) as a white solid: positive ESIMS m/z 364[M + H]+, 386[M + Na]+ and 402[M + K]+; negative ESIMS m/z 399[M + Cl]-; 1H NMR (300MHz, DMSO-d6): the adenosine moiety delta 8.50 (1H, brs, -NH), 8.38 (1H, s, H-2), 8.26 (1H, s, H-8), 5.88 (1H, d, 6.3Hz, H-1), 5.43 (1H, brs, -OH), 5.19 (1H, brs, -OH), 4.61 (1H, m, H-2'), 4.14 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, dd, 12.0Hz, 3.6Hz, H-5a'), 3.54 (1H, dd, 12.0Hz, 3.6Hz, H-5b'); the 2-thiopheneylmethyl delta 7.32 (1H, m, H-5"), 7.02 (1H, m, H-3"), 6.92 (1H, m, H-4"), 4.85 (2H, brs, H-7"); 13C NMR (75MHz, DMSO-d6): the adenosine moiety delta 154.1 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 140.2 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-6'); the 2-thiopheneylmethyl moiety delta 143.0 (s, C-2"), 126.7 (d, C-4"), 125.6 (d, C-3"), 124.9 (d, C-5"), 38.3 (t, C-6)o |
490 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Third step, a mixture of 2-thiopheneylmethanamine (592 mg), 6-chloropurine riboside (500 mg) and triethylamine (7.3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(2-thiopheneylmethyl)-adenosine (490 mg) as a white solid: positive ESIMS m/z 364[M+H]+, 386[M+Na]+ and 402[M+K]+; negative ESIMS m/z 399[M+Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.50 (1H, brs, -NH), 8.38 (1H, s, H-2), 8.26 (1H, s, H-8), 5.88 (1H, d, 6.3 Hz, H-1'), 5.43 (1H, brs, -OH), 5.19 (1H, brs, -OH), 4.61 (1H, m, H-2'), 4.14 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, dd, 12.0 Hz, 3.6 Hz, H-5a'), 3.54 (1H, dd, 12.0 Hz, 3.6 Hz, H-5b'); the 2-thiopheneylmethyl delta 7.32 (1H, m, H-5"), 7.02 (1H, m, H-3"), 6.92 (1H, m, H-4"), 4.85 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.1 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 140.2 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.1 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-6'); the 2-thiopheneylmethyl moiety delta 143.0 (s, C-2"), 126.7 (d, C-4"), 125.6 (d, C-3"), 124.9 (d, C-5"), 38.3 (t, C-6"). |
490 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 592 mg of 2-thiophene methylamine was taken and dissolved in propanol (60 mL). To a solution of 6-chloropurine nucleoside (500 mg) and triethylamine (7.3 mL)The mixture was heated to 70 C., reacted for 8 hours, and the solvent was recovered with a reaction solution. Chloroform-methanol (20: 1) separated by silica gel column chromatography,To obtain 490 mg of N6-(2-thiophene methyl)-adenosine as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 12h;Reflux; | A mixture of (R)-1-(4-chlorophenyl)-ethylamine (490 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(R)-1-(4-chlorophenyl)-ethyl]-adenosine(345 mg) as a white solid: negative ESIMS m/z 406 [M + H]+ and 428 [M + Na]+; 1H NMR (300 MHz, DMSO-d6):the adenosine moietydelta 8.38 (2H, m, H-2, -NH), 8.16 (1H, s, H-8), 5.88 (1H, d, J= 6.0 Hz, H-1'), 5.43 (1H, d, J= 6.0 Hz, -OH), 5.38 (1H, m, -OH), 5.19 (1H, d, J= 4.2 Hz, -OH), 4.60 (1H, m, H-2'), 4.14 (1H, m, H-3'), 3.96 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (R)-1-(4-chlorophenyl)-ethyl moiety delta 7.44 (1H, d, J= 8.4 Hz, H-2', H-6'), 7.33 (1H, d, J= 8.4 Hz, H-3', H-5'), 5.45 (1H, m, H-7'), 1.51 (3H, d, J= 7.2 Hz, H-8'); 13C NMR (75 MHz, DMSO-d6):the adenosine moietydelta 153.8 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 140.0 (d, C-8), 119.8 (s, C-5), 88.0 (d, C-1'), 85.9 (d, C-4'), 73.5 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the [(R)-1-(4-chlorophenyl)-ethyl moiety delta 144.2 (s, C-1'), 131.1 (s, C-4'), 128.2 (d, C-2', C-6'), 128.1 (d, C-3', C-5'), 48.4 (d, C-7'), 22.3 (q, C-8'). | |
345 mg | In ethanol; for 12h;Reflux; | A mixture of (R)-1-(4-chlorophenyl)-ethylamine (490 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(R)-1-(4-chlorophenyl)-ethyl]-adenosine (345 mg) as a white solid: negative ESIMS m/z 406 [M+H]+ and 428 [M+Na]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (2H, m, H-2, -NH), 8.16 (1H, s, H-8), 5.88 (1H, d, J=6.0 Hz, H-1'), 5.43 (1H, d, J=6.0 Hz, -OH), 5.38 (1H, m, -OH), 5.19 (1H, d, J=4.2 Hz, -OH), 4.60 (1H, m, H-2'), 4.14 (1H, m, H-3'), 3.96 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (R)-1-(4-chlorophenyl)-ethyl moiety delta 7.44 (1H, d, J=8.4 Hz, H-2", H-6"), 7.33 (1H, d, J=8.4 Hz, H-3", H-5"), 5.45 (1H, m, H-7"), 1.51 (3H, d, J=7.2 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety 153.8 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 140.0 (d, C-8), 119.8 (s, C-5), 88.0 (d, C-1'), 85.9 (d, C-4'), 73.5 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the RR)-1-(4-chlorophenyl)-ethyl moiety delta 144.2 (s, C-1"), 131.1 (s, C-4"), 128.2 (d, C-2", C-6"), 128.1 (d, C-3", C-5"), 48.4 (d, C-7"), 22.3 (q, C-8"). |
345 mg | In ethanol; for 12h;Reflux; | (R)-1-(4-chlorophenyl)-ethylamine (490 mg) and 6-chloropurine nucleoside (300 mg) were dissolved in ethanol (50 mL) Reflux by heating at 12 h. The solvent was recovered with the reaction solution, It was chromatographically separated via a gel column and eluted with ethanol to obtain white N6-[(R)-1-(4 chlorophenyl)-ethyl]-adenosine (345 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; at 80℃; for 6h; | A mixture of (S)-1-(3-methoxyphenyl)-ethylamine (635 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80C for 6 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(3-methoxyphenyl)-ethyl]-adenosine(340 mg) as a white solid: positive ESIMS mlz 402 [M + H]+; negative ESIMS mlz 400 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.40 (1H, s, H-2), 8.28 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.91 (1H, d, J= 6.0 Hz, H-1'), 5.47 (1H, m, -OH), 5.42 (1H, m, -OH), 5.21 (1H, d, J = 3.9 Hz, -OH), 4.62 (1H, m, H-2'), 4.17 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 7.19 (1H, t, J = 7.5 Hz, H-5'), 7.02 (1H, brs, H-2'), 7.00 (1H, brd, J = 7.5 Hz, H-6'), 6.74 (1H, d, J = 7.5 Hz, H-4'), 5.49 (1H, m, H-7'), 3.70 (4H, m, H-5a', -OCH3), 1.52 (3H, d, J= 6.9 Hz, H-8'); 13C NMR (75MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.4 (d, C-2), 148.6 (s, C-4), 139.9 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 159.3 (s, C-3'), 146.9 (s, C-1'), 129.3 (d, C-5'), 118.5 (d, C-6'), 112.2 (d, C-2'), 111.7 (d, C-4'), 55.0 (q, -OCH3), 48.9 (d, C-7'), 22.6 (q, C-8')o | |
340 mg | In propan-1-ol; at 80℃; for 6h; | A mixture of (S)-1-(3-methoxyphenyl)-ethylamine (635 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80 C. for 6 h.After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(3-methoxyphenyl)-ethyl]-adenosine (340 mg) as a white solid: positive ESIMS m/z 402 [M+H]+; negative ESIMS m/z 400 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.40 (1H, s, H-2), 8.28 (1H, brs, -NH), 8.18 (1H, s, H-8), 5.91 (1H, d, J=6.0 Hz, H-1'), 5.47 (1H, m, -OH), 5.42 (1H, m, -OH), 5.21 (1H, d, J=3.9 Hz, -OH), 4.62 (1H, m, H-2'), 4.17 (1H, m, H-3'), 3.98 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 7.19 (1H, t, J=7.5 Hz, H-5"), 7.02 (1H, brs, H-2"), 7.00 (1H, brd, J=7.5 Hz, H-6"), 6.74 (1H, d, J=7.5 Hz, H-4"), 5.49 (1H, m, H-7"), 3.70 (4H, m, H-5a', -OCH3), 1.52 (3H, d, J=6.9 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.4 (d, C-2), 148.6 (s, C-4), 139.9 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (S)-1-(3-methoxyphenyl)-ethyl moiety delta 159.3 (s, C-3"), 146.9 (s, C-1"), 129.3 (d, C-5"), 118.5 (d, C-6"), 112.2 (d, C-2"), 111.7 (d, C-4"), 55.0 (q, -OCH3), 48.9 (d, C-7"), 22.6 (q, C-8"). |
340 mg | In propan-1-ol; at 80℃; for 6h; | (S)-1-(3-methoxyphenyl)-ethylamine (635 mg) was dissolved in normal propyl alcohol (50 mL), 6-chloropurine nucleoside (300 mg) Heat up to 80 C and let it react for 6 h. The solvent was recovered in the reaction solution, chromatographed through a gel column and eluted with ethanol to obtain white solid N6 -[(S)-1-(3-methoxyphenyl)-ethyl]-adenosine(340 mg) It was |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; at 80℃; for 7h; | A mixture of (S)-1-(4-methylphenyl)-ethylamine (568 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80C for 7 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(4-methylphenyl)-ethyl]-adenosine(320 mg) as a white solid: positive ESIMS mlz 386 [M + H]+ and 408 [M + Na]+; negative ESIMS mlz 384 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (1H, s, H-2), 8.26 (1H, brs, -NH), 8.14 (1H, s, H-8), 5.86 (1H, d, J= 6.0 Hz, H-1'), 5.42 (1H, d, J= 6.3 Hz, -OH), 5.36 (1H, m, -OH), 5.17 (1H, d, J = 4.8 Hz, -OH), 4.57 (1H, m, H-2'), 4.12 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.64 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (S)-1-(4-methylphenyl)-ethyl moiety delta 7.30 (2H, s, H-2', H-6'), 7.07 (2H, s, H-3', H-5'), 5.48 (1H, m, H-7'), 2.22 (3H, s, -CH3), 1.50 (3H, s, H-8'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 87.9 (d, C-1'), 85.9 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); part for (S)-1-(4-methylphenyl)-ethyl moiety delta 142.2 (s, C-1'), 135.6 (s, C-4'), 128.7 (d, C-2', C-6'), 126.1(d, C-3', C-5'), 48.6 (d, C-7' ), 22.5 (q, C-8'), 20.7 (q, -CH3). | |
320 mg | In propan-1-ol; at 80℃; for 7h; | A mixture of (S)-1-(4-methylphenyl)-ethylamine (568 mg) and 6-chloropurine riboside (300 mg) in PrOH (50 ml) was heated to 80 C. for 7 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with ethanol to yield N6-[(S)-1-(4-methylphenyl)-ethyl]adenosine (320 mg) as a white solid: positive ESIMS m/z 386 [M+H]+ and 408 [M+Na]+; negative ESIMS m/z 384 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (1H, s, H-2), 8.26 (1H, brs, -NH), 8.14 (1H, s, H-8), 5.86 (1H, d, J=6.0 Hz, H-1'), 5.42 (1H, d, J=6.3 Hz, -OH), 5.36 (1H, m, -OH), 5.17 (1H, d, J=4.8 Hz, -OH), 4.57 (1H, m, H-2'), 4.12 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.64 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (S)-1-(4-methylphenyl)-ethyl moiety delta 7.30 (2H, s, H-2", H-6"), 7.07 (2H, s, H-3", H-5"), 5.48 (1H, m, H-7"), 2.22 (3H, s, -CH3), 1.50 (3H, s, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.3 (d, C-2), 148.6 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 87.9 (d, C-1'), 85.9 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); part for (S)-1-(4-methylphenyl)-ethyl moiety delta 142.2 (s, C-1"), 135.6 (s, C-4"), 128.7 (d, C-2", C-6"), 126.1 (d, C-3", C-5"), 48.6 (d, C-7"), 22.5 (q, C-8"), 20.7 (q, -CH3). |
320 mg | In propan-1-ol; at 80℃; for 7h; | (S)-1-(4-methylphenyl) -ethylamine (568 mg) was dissolved in normal propyl alcohol (50 mL), 6-chloropurine nucleoside (300 mg) Heat up to 80 C and react for 7 h. The solvent was recovered in the reaction solution, chromatographed through a gel column and eluted with ethanol to obtain white solid N6-[(S)-1-(4-methylphenyl)-ethyl]-adenosine (320 mg) It was |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 80℃; for 8h; | A mixture of L-tyrosine ethyl ester (686 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80°C for 10 h.After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8 : 1) to yield preparation of N-(6-adenosine)-(L) -tyrosine ethyl ester (260 mg) as white solid: positive ESIMS m/z 460 [M + H]+; negative ESIMS m/z 458 [M - H]- and 494 [M + Cl]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.39 (1H, s, H-2), 8.17 (1H, s, H-8), 8.01 (1H, brd, J = 6.9 Hz, -NH), 5.87 (1H, d, J = 6.0 Hz, H-1?), 5.43 (1H, d, J = 6.0 Hz, -OH), 5.29 (1H, m, -OH), 5.16 (1H, d, J = 4.5 Hz, -OH), 4.58 (1H, H-2'), 4.12 (1H, m, H-3'), 3.93 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (L)-tyrosine ethyl ester moiety delta 9.17 (1H, s, -OH), 7.07 (2H, d, J= 8.1 Hz, H-2', H-6'), 6.62 (2H, d, J = 8.1 Hz, H-3', H-5'), 4.84 (1H, m, H-8'), 4.06 (2H, q, J = 7.2 Hz, -OCH2CH3)), 3.10 (2H, m, H-7'), 1.11 (3H, t, J = 7.2 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (d, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1?), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (L)-tyrosine ethyl ester moiety delta 172.3 (s, C-9'), 156.1 (s, C-4'), 130.2 (d, C-2', C-6'), 127.9 (s, C-1?), 115.2 (d, C-3', C-5'), 60.7 (t, -OCH2CH3), 55.1 (d, C-8'), 35.7 (t, C-7'), 14.2 (q, -OCH2CH3)omicron | |
260 mg | With triethylamine; In propan-1-ol; at 80℃; for 10h; | A mixture of L-tyrosine ethyl ester (686 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80° C. for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8:1) to yield preparation of N-(6-adenosine)-(L)-tyrosine ethyl ester (260 mg) as white solid: positive ESIMS m/z 460 [M+H]+; negative ESIMS m/z 458 [M-H]- and 494 [M+Cl]+; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.39 (1H, s, H-2), 8.17 (1H, s, H-8), 8.01 (1H, brd, J=6.9 Hz, -NH), 5.87 (1H, d, J=6.0 Hz, H-1'), 5.43 (1H, d, J=6.0 Hz, -OH), 5.29 (1H, m, -OH), 5.16 (1H, d, J=4.5 Hz, -OH), 4.58 (1H, H-2'), 4.12 (1H, m, H-3'), 3.93 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (L)-tyrosine ethyl ester moiety delta 9.17 (1H, s, -OH), 7.07 (2H, d, J=8.1 Hz, H-2", H-6"), 6.62 (2H, d, J=8.1 Hz, H-3", H-5"), 4.84 (1H, m, H-8"), 4.06 (2H, q, J=7.2 Hz, -OCH2CH3)), 3.10 (2H, m, H-7"), 1.11 (3H, t, J=7.2 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (d, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (L)-tyrosine ethyl ester moiety delta 172.3 (s, C-9"), 156.1 (s, C-4"), 130.2 (d, C-2", C-6"), 127.9 (s, C-1"), 115.2 (d, C-3", C-5"), 60.7 (t, -OCH2CH3), 55.1 (d, C-8"), 35.7 (t, C-7"), 14.2 (q, -OCH2CH3). |
250 mg | With triethylamine; In propan-1-ol; at 80℃; for 10h; | <strong>[4089-07-0]L-<strong>[4089-07-0]tyrosine ethyl ester hydrochloride</strong></strong> (686 mg) was taken and 6-chloropurine nucleoside (200 mg) and triethylamine (3 mL) dissolved in propanol (50 mL) were added and the mixture was heated to 80 ° C. and reacted for 10 hours The solvent is recovered with the reaction solution,Separation by silica gel column chromatography, washing out with chloroform-methanol (8: 1), white solid N-(6-adenosine)-(L)-tyrosine ethyl (260 mg) is obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,4-dioxane; water; for 8h;Reflux; | A mixture of <strong>[351-50-8]D-histidin</strong>e (217 mg), 6-chloropurine riboside (200 mg) and K2CO3 (192 mg) in a mixed solvent of 1, 4-dioxane and H2O (1 : 1, 6 ml) was refluxed for 8 h. HOAc was added to neutralize the excess K2CO3. After evaporation of the reaction mixture, the residue was separated by column chromatography over reverse phase ODS gel and eluted with CH3OH/H2O (0%, 15%, 45%) to yield N-(6-adenosine)-(D)-<strong>[351-50-8]histidine</strong> (230 mg) as a pale yellowish solid: positive ESIMS m/z 406 [M + H]+, 428 [M + Na]+ and 444 [M + K]+; negative ESIMS m/z 404 [M - H]- and 440 [M + Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.21 (1H, s, H-8), 7.85 (1H, d, J= 6.9 Hz, -NH), 5.89 (1H, d, J= 6.3 Hz, H-1?), 5.75 (3H, m, 3*-OH), 4.61 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.96 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.55 (1H, m, H-5'b); the <strong>[351-50-8]D-histidin</strong>e moiety delta 7.71 (1H, s, H-2'), 6.89 (1H, s, H-5'), 4.89 (1H, m, H-7'), 3.17 (2H, m, H-6'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (s, C-6), 152.2 (d, C-2), 148.6 (s, C-4), 140.3 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1?), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the <strong>[351-50-8]D-histidin</strong>e moiety delta 173.5 (s, C-8'), 134.8 (d, C-2'), 133.6 (s, C-4'), 116.7 (d, C-5'), 53.4 (d, C-7'), 28.4 (t, C-6?)omicron | |
230 mg | A mixture of <strong>[351-50-8]D-histidin</strong>e (217 mg), 6-chloropurine riboside (200 mg) and K2CO3 (192 mg) in a mixed solvent of 1,4-dioxane and H2O (1:1, 6 ml) was refluxed for 8 h. HOAc was added to neutralize the excess K2CO3. After evaporation of the reaction mixture, the residue was separated by column chromatography over reverse phase ODS gel and eluted with CH3OH/H2O (0%, 15%, 45%) to yield N-(6-adenosine)-(D)-<strong>[351-50-8]histidine</strong> (230 mg) as a pale yellowish solid: positive ESIMS m/z 406 [M+H]+, 428 [M+Na]+ and 444 [M+K]+; negative ESIMS m/z 404 [M-H]- and 440 [M+Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.21 (1H, s, H-8), 7.85 (1H, d, J=6.9 Hz, -NH), 5.89 (1H, d, J=6.3 Hz, H-1'), 5.75 (3H, m, 3*-OH), 4.61 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.96 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.55 (1H, m, H-5'b); the <strong>[351-50-8]D-histidin</strong>e moiety delta 7.71 (1H, s, H-2"), 6.89 (1H, s, H-5"), 4.89 (1H, m, H-7"), 3.17 (2H, m, H-6"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (s, C-6), 152.2 (d, C-2), 148.6 (s, C-4), 140.3 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the <strong>[351-50-8]D-histidin</strong>e moiety delta 173.5 (s, C-8"), 134.8 (d, C-2"), 133.6 (s, C-4"), 116.7 (d, C-5"), 53.4 (d, C-7"), 28.4 (t, C-6"). | |
230 mg | With potassium carbonate; In 1,4-dioxane; water; for 8h;Reflux; | (D)-<strong>[351-50-8]histidine</strong> (217 mg) was precisely weighed and dissolved in a mixed solvent of 1,4-dioxane and water (1: 1, 6 mL), and 6-chloropurine nucleoside (200 mg) and potassium carbonate (192 mg) were added The reaction was heated to reflux and allowed to react for 8 hours, HOAc was added to the reaction solution to neutralize the excess potassium carbonate, the reaction solution was concentrated, separated by RP - ODS column chromatography, washed with methanol / Wash out with water system (0%, 15%, 45%), N-(6-adenosine)-(D)-<strong>[351-50-8]histidine</strong> (230 mg) as a pale yellow solid is obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 80℃; for 10h; | A mixture of L-tryptophan ethyl ester (752 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80C for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8 : 1) to yield preparation of N-(6-adenosine)-(L)- tryptophan ethyl ester (260 mg) as white solid: positive ESIMS m/z 483 [M + H]+ and 521 [M + K]+; negative ESIMS m/z 481 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.17 (1H, s, H-8), 7.97 (1H, d, J= 8.1 Hz, -NH), 5.87 (1H, d, J= 5.7 Hz, H-1?), 5.44 (1H, d, J= 5.7 Hz, -OH), 5.29 (1H, m, -OH), 5.18 (1H, d, J = 4.8 Hz, -OH), 4.57 (1H, m, H-2'), 4.11 (1H, m, H-3'), 4.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the L-tryptophan ethyl ester moiety delta 10.81 (1H, s, -NH), 7.54 (1H, d, J = 7.5 Hz, H-7'), 7.31 (1H, d, J = 7.5 Hz, H-4'), 7.20 (1H, s, H-2'), 7.05 (1H, t, J = 7.5 Hz, H-5'), 6.97 (1H, t, J= 7.5 Hz, H-6'), 4.96 (1H, m, H-9'), 4.06 (2H, q, J= 7.5 Hz, -OCH2CH3), 3.35 (2H, m, H-8'), 1.10 (3H, t, J= 7.5 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (s, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1?), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the L-tryptophan ethyl ester moiety delta 172.5 (s, C-10'), 136.3 (d, C-2'), 127.2 (s, C-7'a), 124.0 (d, C-3'a), 121.1 (d, C-4'), 118.6 (d, C-5'), 118.2 (d, C-7'), 111.6 (s, C-3'), 110.0 (d, C-6'), 60.7 (t, -OCH2CH3), 54.2 (d, C-9'), 26.8 (t, C-8'), 14.1 (q, -OCH2CH3)omicron | |
260 mg | With triethylamine; In propan-1-ol; at 80℃; for 10h; | A mixture of L-tryptophan ethyl ester (752 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (50 ml) was heated to 80 C. for 10 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (8:1) to yield preparation of N-(6-adenosine)-(L)-tryptophan ethyl ester (260 mg) as white solid: positive ESIMS m/z 483 [M+H]+ and 521 [M+K]+: negative ESIMS m/z 481 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.38 (1H, s, H-2), 8.17 (1H, s, H-8), 7.97 (1H, d, J=8.1 Hz, -NH), 5.87 (1H, d, J=5.7 Hz, H-1'), 5.44 (1H, d, J=5.7 Hz, -OH), 5.29 (1H, m, -OH), 5.18 (1H, d, J=4.8 Hz, -OH), 4.57 (1H, m, H-2'), 4.11 (1H, m, H-3'), 4.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the L-tryptophan ethyl ester moiety delta 10.81 (1H, s, -NH), 7.54 (1H, d, J=7.5 Hz, H-7"), 7.31 (1H, d, J=7.5 Hz, H-4"), 7.20 (1H, s, H-2"), 7.05 (1H, t, J=7.5 Hz, H-5"), 6.97 (1H, t, J=7.5 Hz, H-6"), 4.96 (1H, m, H-9"), 4.06 (2H, q, J=7.5 Hz, -OCH2CH3), 3.35 (2H, m, H-8"), 1.10 (3H, t, J=7.5 Hz, -OCH2CH3); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.2 (s, C-6), 152.2 (d, C-2), 148.8 (s, C-4), 140.4 (d, C-8), 119.9 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.7 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the L-tryptophan ethyl ester moiety delta 172.5 (s, C-10"), 136.3 (d, C-2"), 127.2 (s, C-7"a), 124.0 (d, C-3"a), 121.1 (d, C-4"), 118.6 (d, C-5"), 118.2 (d, C-7"), 111.6 (s, C-3"), 110.0 (d, C-6"), 60.7 (t, -OCH2CH3), 54.2 (d, C-9"), 26.8 (t, C-8"), 14.1 (q, -OCH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,4-dioxane; water; for 8.0h;Reflux; | A mixture of 5-hydroxy tryptophan (308 mg), 6-chloropurine riboside (200 mg) and K2CO3 (192 mg) in a mixed solvent of 1, 4-dioxane and H2O (1 : 1, 6 ml) was refluxed for 8 h. HOAc was added to neutralize the excess K2CO3. After evaporation of the reaction mixture, the residue was separated by column chromatography over reverse phase ODS gel and eluted with CH3OH/H2O (0%, 15%, 45%) to yield N-(6-adenosine)-5-hydroxy tryptophan (265 mg) as a pale yellowish solid: negative ESIMS m/z 469 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.24 (1H, s, H-2), 8.20 (1H, s, H-8), 7.16 (1H, d, J = 6.0 Hz, -NH), 5.83 (1H, d, J = 6.3 Hz, H-1?), 4.33 (1H, m, H-2'), 4.11 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.52 (1H, m, H-5'b); the 5-hydroxy tryptophan moiety delta 10.26 (1H, brs, -OH), 7.00 (1H, d, J= 9.0 Hz, H-7'), 6.87 (1H, d, J= 1.5 Hz, H-2'), 6.75 (1H, d, J= 2.0 Hz, H-4'), 6.45 (1H, dd, J = 9.0Hz, 2.0Hz, H-6'), 5.51 (2H, brs, 2*OH), 4.57 (1H, t, J = 5.4Hz, H-9'), 3.43 (1H, m, H-8'a), 3.16 (1H, m, H-8'b); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.6 (d, C-2), 148.0 (s, C-4), 139.7 (d, C-8), 119.9 (s, C-5), 88.2 (d, C-1?), 86.0 (d, C-4'), 73.8 (d, C-2'), 70.7 (d, C-3'), 61.8 (t, C-5'); the 5-hydroxy tryptophan moiety delta 174.6 (s, C-10'),150.2 (s, C-5'), 130.5 (s, C-7a'), 129.1 (s, C-3a'), 123.9 (d, C-2'), 111.3 (d, C-6'), 111.0 (d, C-7'), 110.3 (d, C-4'), 102.8 (s, C-3'), 55.5 (d, C-8'), 27.4 (t, C-9')o |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 12h;Reflux; | A mixture of L-methioninol (568 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with EtOH to yield N6-[(L)-2-(1-hydroxy-4-methylthioyl)-butyl]-adenosine (325 mg) as a white solid: positive ESIMS m/z 386 [M + H]+ and 408 [M + Na]+; negative ESIMS m/z 384 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.34 (1H, s, H-2), 8.18 (1H, s, H-8), 7.50 (1H, brd, J= 8.4 Hz, -NH), 5.86 (1H, d, J= 6.3 Hz, H-1?), 5.40 (2H, m, 2*-OH), 5.17 (1H, d, J = 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (L)-2-(1-hydroxy-4-methylthioyl)-butyl moiety delta 4.76 (1H, m, -OH), 4.40 (1H, m, H-2'), 3.52 (1H, m, H-1a?), 3.42 (1H, m, H-1b?), 2.48 (2H, m, H-4'), 2.0 (3H, s, - SCH3), 1.92 (1H, m, H-3'a), 1.83 (1H, m, H-3'b); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.8 (s, C-6), 152.3 (d, C-2), 148.4 (s, C-4), 139.8 (d, C-8), 119.8 (d, C-5), 88.1 (d, C-1?), 85.9 (d, C-4'), 73.5 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (L)-2-(1-hydroxy-4-methylthioyl)-butyl moiety delta 63.1 (t, C-1?), 50.9 (d, C-2'), 30.5 (t, C-4'), 30.3 (t, C-3'), 14.7 (q, -SCH3)omicron | |
325 mg | In ethanol; for 12h;Reflux; | A mixture of L-methioninol (568 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with EtOH to yield N6-[(L)-2-(1-hydroxy-4-methylthioyl)-butyl]-adenosine (325 mg) as a white solid: positive ESIMS m/z 386 [M+H]+ and 408 [M+Na]+; negative ESIMS m/z 384 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.34 (1H, s, H-2), 8.18 (1H, s, H-8), 7.50 (1H, brd, J=8.4 Hz, -NH), 5.86 (1H, d, J=6.3 Hz, H-1'), 5.40 (2H, m, 2*-OH), 5.17 (1H, d, J=4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.65 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the (L)-2-(1-hydroxy-4-methylthioyl)-butyl moiety delta4.76 (1H, m, -OH), 4.40 (1H, m, H-2"), 3.52 (1H, m, H-1a"), 3.42 (1H, m, H-1b"), 2.48 (2H, m, H-4"), 2.0 (3H, s, -SCH3), 1.92 (1H, m, H-3"a), 1.83 (1H, m, H-3"b); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.8 (s, C-6), 152.3 (d, C-2), 148.4 (s, C-4), 139.8 (d, C-8), 119.8 (d, C-5), 88.1 (d, C-1'), 85.9 (d, C-4'), 73.5 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the (L)-2-(1-hydroxy-4-methylthioyl)-butyl moiety delta 63.1 (t, C-1"), 50.9 (d, C-2"), 30.5 (t, C-4"), 30.3 (t, C-3"), 14.7 (q, -SCH3). |
325 mg | In ethanol; for 12h;Reflux; | Weigh precisely L-methionine alcohol (568 mg) and 6-chloropurine nucleoside (300 mg), dissolve in ethanol (50 mL), heat to reflux, react for 12 hours, recover the solvent with the reaction solution, on a silica gel column Separate by chromatography, wash with ethanol,To obtain N6-[(L)-(1-hydroxy-4-(methylthio))-D-2-yl]-adenosine (325 mg) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 12h;Reflux; | A mixture of L-isoleucinol (492 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h.After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with EtOH to yield N6-[(L)-2-(1-hydroxy-3 -methyl)-pentyl]-adenosine(315 mg) as a white solid: positive ESIMS m/z 368 [M + H]+ and 390 [M + Na]+; negative ESIMS m/z 366 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.33 (1H, s, H-2), 8.17 (1H, s, H-8), 7.28 (1H, brd, J = 9.3 Hz, -NH), 5.86 (1H, d, J = 6.3 Hz, H-1?), 5.44 (2H, m, 2*-OH), 5.17 (1H, d, J = 4.8 Hz, -OH), 4.62 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.53 (1H, m, H-5'b); the (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 4.59 (1H, m, -OH), 4.21 (1H, m, H-2'), 3.53 (2H, m, H-1?), 1.75 (1H, m, H-3'), 1.49 (1H, m, H-4a'), 1.09 (1H, m, 4b'), 0.89 (3H, d, J= 6.6 Hz, -CH3), 0.82 (3H, t, J= 7.2 Hz, C-5'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.3 (s, C-4), 139.9 (d, C-8), 119.8 (s, C-5), 88.3 (d, C-1?), 86.1 (d, C-4'), 73.6 (d, C-2'), 70.9 (d, C-3'), 61.9 (t, C-5');thethe (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 61.3 (t, C-1?), 55.7 (d, C-2'), 35.3 (t, C-3'), 25.3 (d, C-4'), 15.6 (q, C-5'), 11.4 (q, -CH3)omicron | |
315 mg | In ethanol; for 12h;Reflux; | A mixture of L-isoleucinol (492 mg) and 6-chloropurine riboside (300 mg) in EtOH (50 ml) was refluxed for 12 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over Sephadex LH-20 gel and eluted with EtOH to yield N6-[(L)-2-(1-hydroxy-3-methyl)-pentyl]-adenosine (315 mg) as a white solid: positive ESIMS m/z 368 [M+H]+ and 390 [M+Na]+; negative ESIMS m/z 366 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.33 (1H, s, H-2), 8.17 (1H, s, H-8), 7.28 (1H, brd, J=9.3 Hz, -NH), 5.86 (1H, d, J=6.3 Hz, H-1'), 5.44 (2H, m, 2*-OH), 5.17 (1H, d, J=4.8 Hz, -OH), 4.62 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.53 (1H, m, H-5'b); the (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 4.59 (1H, m, -OH), 4.21 (1H, m, H-2"), 3.53 (2H, m, H-1"), 1.75 (1H, m, H-3"), 1.49 (1H, m, H-4-a"), 1.09 (1H, m, 4b"), 0.89 (3H, d, J=6.6 Hz, -CH3), 0.82 (3H, t, J=7.2 Hz, C-5"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.3 (s, C-4), 139.9 (d, C-8), 119.8 (s, C-5), 88.3 (d, C-1'), 86.1 (d, C-4'), 73.6 (d, C-2'), 70.9 (d, C-3'), 61.9 (t, C-5'); the (L)-2-(1-hydroxy-3-methyl)-pentyl moiety delta 61.3 (t, C-1"), 55.7 (d, C-2"), 35.3 (t, C-3"), 25.3 (d, C-4"), 15.6 (q, C-5"), 11.4 (q, -CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70℃; for 8h; | First step, hydroxyamine hydrochloride (670 mg) and NaOAc (900 mg) were added to a solution of benzophenone (1.0 g) in EtOH (80 ml). The reaction mixture was stirred at 60C for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and the resulting solution was extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield benzophenone oxime (900 mg) as a pale yellowish solid. Second step, benzophenone oxime (900 mg) and concentrated HCl (1.84 ml) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (100 mg). The reaction solution was filtered and the filtrate was concentrated. The residue was suspended in EtOAc, and the suspension was filtered to yield <strong>[5267-34-5]diphenylmethylamine hydrochloride</strong> (2.17 g) as a white solid. Third step, a mixture of diphenylmethylamine (583 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (9 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(diphenylmethyl)-adenosine(240 mg) as a white solid: positive ESIMS m/z 434 [M + H]+ and 456[M + Na]+; negative ESIMS m/z 432 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.72 (1H, d, J = 9.3 Hz, -NH), 8.42 (1H, s, H-2), 8.23 (1H, s, H-8), 5.89 (1H, d, J = 6.0 Hz, H-1), 5.44 (1H, d, J = 5.7 Hz, -OH), 5.33 (1H, m, -OH), 5.17 (1H, d, J= 4.2Hz, -OH), 4.60 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the diphenylmethyl moiety delta 7.43 (4H, d, J= 7.5Hz, H-2", H-2"', H-6", H-6), 7.31 (4H, t, J= 7.5Hz, H-3", H-3"', H-5", H-5), 7.23 (2H, t, J = 7.5Hz, H-4", H-4), 6.82 (1H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.5 (d, C-2), 149.0 (s, C-4), 140.3 (d, C-8), 119.9 (s, C-5), 88.2 (d, C-1), 86.1 (d, C-4'), 73.8 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the diphenylmethyl moiety delta 142.6 (s, C-1, C-1), 128.6 (d, C-2, C-6, C-2, C-6), 127.8 (d, C-3, C-5, C-3, C-5), 127.2 (d, C-4, C-4), 57.0 (d, C-7")o | |
240 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Third step, a mixture of diphenylmethylamine (583 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (9 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(diphenylmethyl)-adenosine (240 mg) as a white solid: positive ESIMS m/z 434 [M+H]+ and 456[M+Na]+; negative ESIMS m/z 432 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.72 (1H, d, J=9.3 Hz, -NH), 8.42 (1H, s, H-2), 8.23 (1H, s, H-8), 5.89 (1H, d, J=6.0 Hz, H-1'), 5.44 (1H, d, J=5.7 Hz, -OH), 5.33 (1H, m, -OH), 5.17 (1H, d, J=4.2 Hz, -OH), 4.60 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the diphenylmethyl moiety delta 7.43 (4H, d, J=7.5 Hz, H-2", H-2'", H-6", H-6'"), 7.31 (4H, t, J=7.5 Hz, H-3", H-3'", H-5", H-5'"), 7.23 (2H, t, J=7.5 Hz, H-4", H-4'"), 6.82 (1H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.5 (d, C-2), 149.0 (s, C-4), 140.3 (d, C-8), 119.9 (s, C-5), 88.2 (d, C-1'), 86.1 (d, C-4'), 73.8 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the diphenylmethyl moiety delta 142.6 (s, C-1", C-1'"), 128.6 (d, C-2", C-6", C-2", C-6"), 127.8 (d, C-3", C-5", C-3', C-5"), 127.2 (d, C-4", C-4'"), 57.0 (d, C-7"). |
240 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | <strong>[5267-34-5]diphenylmethylamine hydrochloride</strong> (583 mg) was taken and 6-chloropurine nucleoside (200 mg), dissolved in propanol (60 mL)And triethylamine (3 mL) were added, the mixture was heated to 70 C. and reacted for 8 hours,The solvent is recovered with a reaction solution, separated by silica gel column chromatography, and washed out with chloroform-methanol (20: 1) to obtain white solid N6-(diphenylmethyl)-adenosine (240 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70.0℃; for 8.0h; | First step, hydroxyamine hydrochloride (4.18 g) and NaOAc (9.93 g) were added to a solution of p-aminoacetophenone (5 g) in EtOH (80 ml). The reaction mixture was stirred at 60C for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield p-aminoacetophenone oxime (5.56 g) as a pale yellowish solid. Second step, a solution of p-aminoacetophenone oxime (5.56 g) and concentrated HCl (20 ml) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (784 mg). The reaction solution was filtered and the filtrate was concentrated to yield <strong>[1129278-89-2]1-(p-aminophenyl)-ethylamine hydrochloride</strong> (7.5 g) as a white solid. Third step, a mixture of 1-(p-aminophenyl)-ethylamine (363 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70C for 8h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-[(+/-)-1-(4-aminophenyl)-ethyl] -adenosine(220 mg) as a white solid: positive ESIMS m/z 387 [M + H]+ and 409 [M + Na]+; negative ESIMS m/z 385 [M - H]- and 421 [M + Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.34 (1H, s, H-2), 8.15 (1H, s, H-8), 8.00 (1H, d, J= 8.4 Hz, -NH), 5.86 (1H, d, J= 5.7 Hz, H-1), 5.40 (2H, m, 2×-OH), 5.15 (1H, d, J= 4.5Hz, -OH), 4.58 (1H, m, H-2'), 4.12 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 353 (1H, m, H-5'b); the (+/-)-1-(4-aminophenyl)-ethyl moiety delta 7.08 (2H, d, J = 8.4 Hz, H-2", H-6"), 6.46 (1H, d, J = 8.4 Hz, H-3", H-5"), 5.43 (1H, m, H-7"), 4.88 (1H, brs, -NH2), 1.46 (1H, d, J = 6.9 Hz, H-8"); 13CNMR (75MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.4 (d, C-2), 148.5 (s, C-4), 139.7 (d, C-8), 119.8 (s, C-5), 88.0 (d, C-1), 86.0 (d, C-4), 73.6 (d, C-2), 70.8 (d, C-3), 61.8 (t, C-5'); the (+/-)-1-(4-aminophenyl)-ethyl moiety delta 147.4 (s, C-4"), 132.1 (s, C-1), 127.0 (d, C-2, C-6), 113.7 (d, C-3, C-5), 48.2 (d, C-7), 22.4 (q, C-8")o Example 49: preparation of N6-{(+)-1-[4-(2-methyl-propyl)-phenyl]-ethyl}-adenosine | |
220 mg | With triethylamine; In propan-1-ol; at 70.0℃; for 8.0h; | Third step, a mixture of 1-(p-aminophenyl)-ethylamine (363 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-[(+-)-1-(4-aminophenyl)-ethyl]-adenosine (220 mg) as a white solid: positive ESIMS m/z 387 [M+H]+ and 409 [M+Na]+; negative ESIMS m/z 385 [M-H]- and 421 [M+Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.34 (1H, s, H-2), 8.15 (1H, s, H-8), 8.00 (1H, d, J=8.4 Hz, -NH), 5.86 (1H, d, J=5.7 Hz, H-1'), 5.40 (2H, m, 2*-OH), 5.15 (1H, d, J=4.5 Hz, -OH), 4.58 (1H, m, H-2'), 4.12 (1H, m, H-3'), 3.94 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 353 (1H, m, H-5'b); the (+-)-1-(4-aminophenyl)-ethyl moiety delta 7.08 (2H, d, J=8.4 Hz, H-2", H-6"), 6.46 (1H, d, J=8.4 Hz, H-3", H-5"), 5.43 (1H, m, H-7"), 4.88 (1H, brs, -NH2), 1.46 (1H, d, J=6.9 Hz, H-8"); 13CNMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.9 (s, C-6), 152.4 (d, C-2), 148.5 (s, C-4), 139.7 (d, C-8), 119.8 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.8 (d, C-3'), 61.8 (t, C-5'); the (+-)-1-(4-aminophenyl)-ethyl moiety delta 147.4 (s, C-4"), 132.1 (s, C-1"), 127.0 (d, C-2", C-6"), 113.7 (d, C-3", C-5"), 48.2 (d, C-7"), 22.4 (q, C-8"). |
220 mg | With triethylamine; In propan-1-ol; at 70.0℃; for 8.0h; | 4-hydroxybenzene (288 mg) was dissolved in normal propyl alcohol (60 mL), 6-chloropurine nucleoside (200 mg) and triethylamine (3 ml) were added, the mixture was heated to 70 C. and the reaction for 8 h . The solvent was evaporated in a reaction solution, chromatographed through a silica gel column, and eluted with chloroform-methanol (20: 1) to give a white solid N6-[1-(4-hydroxycyclohexylphenylketone)-ethyl]-adenosine (220 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70℃; for 8.0h; | First step, hydroxyamine hydrochloride (5.07 g) and NaOAc (12.05 g) were added to a solution of 4-hydroxyacetophenone (5 g) in EtOH (80 ml). The reaction mixture was stirred at 60C for 6 h. EtOH was removed under reduced pressure. H2O (40 ml) was added to the residue, and extracted with EtOAc (3 × 40 ml). The EtOAc of the combined organic layer was removed by rotary evaporation under reduced pressure to yield 4-hydroxyacetophenone oxime (4.53 g) as a pale yellowish solid. Second step, a solution of 4-hydroxyacetophenone oxime (4.53 g) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (502 mg). The reaction solution was filtered and the filtrate was concentrated to yield the 1-(4-hydroxyphenyl)-ethylamine (5.2 g) as a white solid. Third step, a mixture of 1-(4-hydroxyphenyl)-ethylamine (288 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70C for 8h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-[(+/-)-1-(4-hydroxyphenyl)-ethyl] -adenosine(220 mg) as a white solid: positive ESIMS m/z 388 [M + H]+[Show Image] 410 [M + Na]+; negative ESIMS m/z 386 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (1H, s, H-2), 8.17 (1H, s, H-8), 8.12 (1H, d, J= 8.4 Hz, -NH), 5.88 (1H, d, J= 5.7 Hz, H-1), 5.45 (2H, m, 2×-OH), 5.19 (1H, d, J = 4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.97 (1H, m, H-4'), 3.66 (1H, m, H-5a'), 3.55 (1H, m, H-5'b); the (+/-)-1-(4-hydroxyphenyl)-ethyl moiety delta 9.27 (1H, s, -OH), 7.23 (1H, d, J = 8.1 Hz, H-2", H-6"), 6.67 (1H, d, J = 8.1 Hz, H-3", H-5"), 5.42 (1H, m, H-7"), 1.49 (1H, d, J= 6.9 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (s, C-6), 152.3 (d, C-2), 148.5 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.8 (t, C-5'); the (+/-)-1-(4-hydroxyphenyl)-ethyl moiety delta 156.1 (s, C-4"), 135.3 (s, C-1), 127.3 (d, C-2", C-6"), 114.9 (d, C-3", C-5"), 48.3 (d, C-7"), 22.5 (q, C-8")o | |
220 mg | With triethylamine; In propan-1-ol; at 70℃; for 8.0h; | Third step, a mixture of 1-(4-hydroxyphenyl)-ethylamine (288 mg), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-[(+/-)-1-(4-hydroxyphenyl)-ethyl]-adenosine (220 mg) as a white solid: positive ESIMS m/z 388 [M+H]+ 410 [M+Na]+; negative ESIMS m/z 386 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.36 (1H, s, H-2), 8.17 (1H, s, H-8), 8.12 (1H, d, J=8.4 Hz, -NH), 5.88 (1H, d, J=5.7 Hz, H-1'), 5.45 (2H, m, 2*-OH), 5.19 (1H, d, J=4.5 Hz, -OH), 4.60 (1H, m, H-2'), 4.15 (1H, m, H-3'), 3.97 (1H, m, H-4'), 3.66 (1H, m, H-5a'), 3.55 (1H, m, H-5'b); the (+-)-1-(4-hydroxyphenyl)-ethyl moiety delta 9.27 (1H, s, -OH), 7.23 (1H, d, J=8.1 Hz, H-2", H-6"), 6.67 (1H, d, J=8.1 Hz, H-3", H-5"), 5.42 (1H, m, H-7"), 1.49 (1H, d, J=6.9 Hz, H-8"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 153.8 (s, C-6), 152.3 (d, C-2), 148.5 (s, C-4), 139.8 (d, C-8), 119.7 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.8 (t, C-5'); the (+-)-1-(4-hydroxyphenyl)-ethyl moiety delta 156.1 (s, C-4"), 135.3 (s, C-1"), 127.3 (d, C-2", C-6"), 114.9 (d, C-3", C-5"), 48.3 (d, C-7"), 22.5 (q, C-8"). |
220 mg | With triethylamine; In propan-1-ol; at 70℃; for 8.0h; | 4-hydroxybenzene(288 mg) was dissolved in n-propyl alcohol (60 mL), 6-chloropurine nucleoside (200 mg) and triethylamine (3 ml) were added, heated to 70 C. and reacted for 8 h. The solvent was evaporated with the reaction solution, chromatographed through a silica gel column and eluted with chloroform-methanol (20: 1) to give a white solidWas obtained to obtain N6-[1-(4-hydroxycyclohexylphenyl ketone)-ethyl]-adenosine (220 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70℃; for 8h; | A mixture of p-nitrobenzylamine (158 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (10 : 1) to yield N6-(p-aminobenzyl)-adenosine(250 mg) as a white solid: positive ESIMS m/z 403 [M + H]+ and 425 [M + Na]+; negative ESIMS m/z 401 [M - H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.62 (1H, brs, -NH), 8.41 (1H, s, H-2), 8.19 (1H, s, H-8), 5.89 (1H, d, J = 6.3 Hz, H-1'), 5.44 (1H, d, J = 6.0 Hz, -OH), 5.33 (1H, m, -OH), 5.18 (1H, d, J = 7.2 Hz, -OH), 4.62 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the p-nitrobenzyl moiety delta 8.16 (1H, d, J= 8.4 Hz, H-3', H-5'), 7.56 (1H, d, J = 8.4 Hz, H-2', H-6'), 4.81 (2H, brs, H-7'); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.4 (s, C-6), 152.4 (d, C-2), 148.7 (s, C-4), 140.3 (d, C-8), 119.9 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'),the p-nitrobenzyl moiety delta 148.3 (s, C-4'), 146.4 (s, C-1'), 128.1 (d, C-2', C-6'), 123.5 (d, C-3', C-5'), 42.7 (t, C-7')o | |
250 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | A mixture of p-nitrobenzylamine (158 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (10:1) to yield N6-(p-aminobenzyl)-adenosine (250 mg) as a white solid: positive ESIMS m/z 403 [M+H]+ and 425 [M+Na]+; negative ESIMS m/z 401 [M-H]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.62 (1H, brs, -NH), 8.41 (1H, s, H-2), 8.19 (1H, s, H-8), 5.89 (1H, d, J=6.3 Hz, H-1'), 5.44 (1H, d, J=6.0 Hz, -OH), 5.33 (1H, m, -OH), 5.18 (1H, d, J=7.2 Hz, -OH), 4.62 (1H, m, H-2'), 4.13 (1H, m, H-3'), 3.95 (1H, m, H-4'), 3.66 (1H, m, H-5'a), 3.54 (1H, m, H-5'b); the p-nitrobenzyl moiety delta 8.16 (1H, d, J=8.4 Hz, H-3", H-5"), 7.56 (1H, d, J=8.4 Hz, H-2", H-6"), 4.81 (2H, brs, H-7"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 154.4 (s, C-6), 152.4 (d, C-2), 148.7 (s, C-4), 140.3 (d, C-8), 119.9 (s, C-5), 88.0 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'), the p-nitrobenzyl moiety delta 148.3 (s, C-4"), 146.4 (s, C-1"), 128.1 (d, C-2", C-6"), 123.5 (d, C-3", C-5"), 42.7 (t, C-7"). |
250 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 158 mg of <strong>[18600-42-5]p-nitrophenylmethylamine hydrochloride</strong> was taken and 6-chloropurine nucleoside (200 mg) and triethylamine (3 mL) were dissolved in propanol (60 mL), and the mixture was heated to 70 C. and reacted for 8 hours , Recovering the solvent with the reaction solution, separation by silica gel column chromatography,250 mg of white solid N6- (p-nitrobenzyl base) -adenosine, which is washed off with chloroform-methanol (10: 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In propan-1-ol; at 70℃; for 8h; | First step, 9-fluorenone oxime (400 mg) and concentrated HCl (0.86 ml) in EtOH (50 ml) was subjected to hydrogenation at atmospheric pressure in the presence of 10% Pd/C (33 mg). The reaction solution was filtered and the filtrate was concentrated. The residue was suspended in EtOAc, and the suspension was filtered to yield fluorenamine hydrochloride (240 mg) as a white solid. Second step, a mixture of fluorenamine (304 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60ml) was heated to 70C and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20 : 1) to yield N6-(fluorene-9-yl)-adenosine(208 mg) as a white solid: positive ESIMS m/z 432 [M + H]+ and 454 [M + Na]+; negative ESIMS m/z 430 [M - H]- and 466 [M + Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.46. (1H, d, J = 8.1 Hz, -NH), 8.38 (2H, s, H-2, H-8), 5.94 (1H, d, J = 5.4 Hz, H-1), 5.52 (1H, d, J = 5.7 Hz, -OH), 5.44 (1H, m, -OH), 5.25 (1H, d, J = 4.8 Hz, -OH), 4.66 (1H, m, H-2'), 4.19 (1H, m, H-3'), 4.01 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the 9-fluorene moiety delta 7.86 (2H, d, J = 7.5 Hz, H-4", H-5"), 7.46 (2H, d, J = 7.5 Hz, H-1, H-8), 7.40 (2H, t, J= 7.5 Hz, H-2", H-7"), 7.26 (2H, t, J= 7.5 Hz, H-3", H-6), 6.69 (1H, d, J = 8.1 Hz, H-9"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.8 (s, C-4), 140.3 (d, C-8), 120.2 (s, C-5), 88.1 (d, C-1), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the 9-fluorene moiety delta 145.0 (s, C-8"a, C-9"a), 140.3 (s, C-4"a, C-5a ), 128.3 (d, C-1, C-8"), 127.5 (d, C-3", C-6"), 124.8 (d, C-2", C-7"), 120.2 (d, C-4", C-5"), 54.9 (d, C-9")o | |
208 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | Second step, a mixture of fluorenamine (304 mg, the hydrochloride), 6-chloropurine riboside (200 mg) and triethylamine (3 ml) in PrOH (60 ml) was heated to 70 C. and reacted for 8 h. After evaporation of the reaction mixture, the residue was separated by column chromatography over silica gel and eluted with CHCl3-CH3OH (20:1) to yield N6-(fluorene-9-yl)-adenosine (208 mg) as a white solid: positive ESIMS m/z 432 [M+H]+and 454 [M+Na]+; negative ESIMS m/z 430 [M-H]- and 466 [M+Cl]-; 1H NMR (300 MHz, DMSO-d6): the adenosine moiety delta 8.46 (1H, d, J=8.1 Hz, -NH), 8.38 (2H, s, H-2, H-8), 5.94 (1H, d, J=5.4 Hz, H-1'), 5.52 (1H, d, J=5.7 Hz, -OH), 5.44 (1H, m, -OH), 5.25 (1H, d, J=4.8 Hz, -OH), 4.66 (1H, m, H-2'), 4.19 (1H, m, H-3'), 4.01 (1H, m, H-4'), 3.67 (1H, m, H-5'a), 3.56 (1H, m, H-5'b); the 9-fluorene moiety delta 7.86 (2H, d, J=7.5 Hz, H-4", H-5"), 7.46 (2H, d, J=7.5 Hz, H-1", H-8'"), 7.40 (2H, t, J=7.5 Hz, H-2", H-7"), 7.26 (2H, t, J=7.5 Hz, H-3", H-6'"), 6.69 (1H, d, J=8.1 Hz, H-9"); 13C NMR (75 MHz, DMSO-d6): the adenosine moiety delta 155.1 (s, C-6), 152.4 (d, C-2), 148.8 (s, C-4), 140.3 (d, C-8), 120.2 (s, C-5), 88.1 (d, C-1'), 86.0 (d, C-4'), 73.6 (d, C-2'), 70.7 (d, C-3'), 61.7 (t, C-5'); the 9-fluorene moiety delta 145.0 (s, C-8"a, C-9"a), 140.3 (s, C-4"a, C-5"a), 128.3 (d, C-1", C-8"), 127.5 (d, C-3", C-6"), 124.8 (d, C-2", C-7"), 120.2 (d, C-4", C-5"), 54.9 (d, C-9"). |
208 mg | With triethylamine; In propan-1-ol; at 70℃; for 8h; | 6-Chloropurine nucleoside (200 mg) and triethylamine (3 mL) were added to a solution of 9-fluorene hydrochloride (304 mg) and dissolved in propanol (60 mL)The mixture was heated to 70 C., reacted for 8 hours, and the solvent was recovered with a reaction solution. The residue was separated by silica gel column chromatography and washed with chloroform-methanol (20: 1) to obtain a white solid N6-(fluoren-9-yl)-adenosine (208 mg) is obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With palladium diacetate; sodium carbonate; triphenylphosphine-3,3?,3?-trisulfonic acid trisodium salt; In water; acetonitrile; at 100℃; for 4h;Inert atmosphere; | General procedure: Method E. To a stirred solution of 6-chloropurine riboside (2) (1equiv) in H2O/CH3CN (2:1, 6mL/mmol), Pd(OAc)2 (0.05equiv), TPPTS (0.15equiv), arylboronic acid (1.25equiv) and sodium carbonate (3equiv) were added under argon atmosphere. The reaction mixture was warmed to 100C (or 80C when mentioned) and monitored by LC-MS and TLC. When the reaction was complete, the mixture was cooled to room temperature, neutralized by addition of 1M aqueous HCl, and concentrated under reduce pressure. The residue was purified by silica gel chromatography or by preparative HPLC on a C18 reverse-phase column to yield the title compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40%; 9% | With palladium diacetate; sodium carbonate; triphenylphosphine-3,3?,3?-trisulfonic acid trisodium salt; In water; acetonitrile; at 100℃; for 1h;Inert atmosphere; | General procedure: Method E. To a stirred solution of 6-chloropurine riboside (2) (1equiv) in H2O/CH3CN (2:1, 6mL/mmol), Pd(OAc)2 (0.05equiv), TPPTS (0.15equiv), arylboronic acid (1.25equiv) and sodium carbonate (3equiv) were added under argon atmosphere. The reaction mixture was warmed to 100C (or 80C when mentioned) and monitored by LC-MS and TLC. When the reaction was complete, the mixture was cooled to room temperature, neutralized by addition of 1M aqueous HCl, and concentrated under reduce pressure. The residue was purified by silica gel chromatography or by preparative HPLC on a C18 reverse-phase column to yield the title compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With palladium diacetate; sodium carbonate; triphenylphosphine-3,3?,3?-trisulfonic acid trisodium salt; In water; acetonitrile; at 100℃; for 4h;Inert atmosphere; | General procedure: Method E. To a stirred solution of 6-chloropurine riboside (2) (1equiv) in H2O/CH3CN (2:1, 6mL/mmol), Pd(OAc)2 (0.05equiv), TPPTS (0.15equiv), arylboronic acid (1.25equiv) and sodium carbonate (3equiv) were added under argon atmosphere. The reaction mixture was warmed to 100°C (or 80°C when mentioned) and monitored by LC?MS and TLC. When the reaction was complete, the mixture was cooled to room temperature, neutralized by addition of 1M aqueous HCl, and concentrated under reduce pressure. The residue was purified by silica gel chromatography or by preparative HPLC on a C18 reverse-phase column to yield the title compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(isopropyl)ethylamine; In ethanol; at 80℃; for 0.5h;Sealed tube; Microwave irradiation; | A mixture of <strong>[214759-22-5](5-chlorothien-2-yl)methanamine</strong> (35.4 mg, 0.24 mmol), 6-chloropurineribofuranoside (0.12 mmol) and diisopropylethylamine (0.36 mL, 2 mmol) in EtOH (1 mL) was stirred in a seal tube at 80 C by microwave irradiation for 30 min. The mixture was cooled to room temperature, and concentrated under reduced pressure to give pale yellow oil, which was washed successively with H20 and MeOH to give the title compound JMF3818. C1JH16CIN5O4S; white solid; 1H NMR (400 MHz, CD3OD) 6 8.29 (1 R s), 8.27 (1 H, s), 6.88 (1 H, d,J= 3.6 Hz), 6.79 (1 H, d, J = 3.6 Hz), 5.96 (1 H, d, J = 6.8 Hz), 4.74-4.77 (1 H, m), 4.32-4.34 (1 H, m), 4.17 (1 H, d,J= 2.8 Hz), 3.89 (1 H, dd, 7= 12.4, 2.0 Hz), 3.75 (1 H, dd, J= 12.4, 2.8 Hz);13C NMR (100 MHz, CD3OD) 6 156.0, 153.6, 142.8, 142.0, 129.9, 127.0, 126.6, 121.7, 91.5, 88.4, 75.6, 72.9, 63.7, 40.4; ESI- HRMS calcd for C13H17CIN5O4S: 398.0690, found: m/z 398.0692 [M + H]+. | |
With N-ethyl-N,N-diisopropylamine; In ethanol; at 80℃; for 0.5h;Sealed tube; Microwave irradiation; | <strong>[214759-22-5](5-chlorothiophen-2-yl)methanamine</strong> (35.4 mg, 0.24 mmol), 6-chlorofuran nucleofuranoside (0.12 mmol), and dipropylethylamine (0.36 mL, 2 mmol) of EtOH The mixture (1 mL) was stirred in a sealed tube at 80 C for 30 minutes by microwave irradiation. The mixture was cooled to room temperature and concentrated under reduced pressure to give a pale yellow oil which was washed with H20 andTo obtain the title compound JMF3818. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine; In propan-1-ol; at 100℃; for 2h; | 6-Chloropurine riboside (2g, 6.98mmol) was dissolved in PrOH (30mL). Piperidine hydrochloride (0.9g, 7.4mmol) and Et3N (6mL, 43.05mmol) were then added. The mixture was refluxed at 100C for 2h and then evaporated. The residue was dissolved in EtOAc and distilled H2O was added. The emerged precipitate was filtered off, washed with distilled H2O, and air-dried. Yield: 0.93g (40%). HPLC purity>99%. MS ESI+ (CV 20) m/z (rel. %): 336.4 (100) [M+H]+. 1H NMR (500MHz, DMSO-d6) delta (ppm): 1.55-1.58 (m, 4H, piper), 1.65-1.68 (m, 2H, piper), 3.54 (ddd, J=12.0, 7.0, 3.6Hz, 1H), 3.66 (ddd, J=12.1, 4.5, 3.6Hz, 1H), 3.95 (q, J=3.5Hz, 1H), 4.13 (td, J=4.8, 3.5Hz, 1H), 4.19 (bs, 4H), 4.57 (td, J=6.1, 4.9Hz, 1H), 5.18 (d, J=4.6Hz, 1H); 5.36 (dd, J=7.0, 4.5Hz, 1H), 5.45 (d, J=6.2Hz, 1H), 5.89 (d, J=5.9Hz, 1H); 8.20 (s, 1H, pur), 8.36 (s, 1H, pur). 13C NMR (125MHz, DMSO-d6) delta (ppm): 24.2, 25.7, 61.5, 70.5, 73.4, 85.8, 87.8, 119.5, 138.5, 150.1, 151.8, 153.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In neat (no solvent); at 210℃; under 12929.0 Torr; for 0.0166667h;Irradiation; | General procedure: Synthesis of (2R, 3R, 4S, 5R)-2-(6-(benzylamino)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol, 2. In a 7 mL MW vessel, 6-chloropurinoriboside 3 (20 mg, 0.07 mmol), benzylamine 4 (7.5 mg,0.07 mmol, 7.7 muL) and triethylamine (7.08 mg, 0.07 mmol, 9.8 muL)were mixed. The solid mixture was stirred in CEM Explorer. MWMethod: T = 210 C, Power: 300 W, Hold Time: 1 min, P = 250 PSI,Power Max activated. After cooling, the solvent was removed in vacuoand the crude was dissolved in methanol and then purified on PTLC(DCM/MeOH 9:1) to afford compound 2 as white solid (24 mg, 94%).C17H20N5O4: 358.1510; Found 358.1515. Rt: 8.92 min. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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