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CAS No. : | 2096-10-8 | MDL No. : | MFCD00053556 |
Formula : | C10H14N6O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZDTFMPXQUSBYRL-UUOKFMHZSA-N |
M.W : | 282.26 | Pubchem ID : | 72200 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 5.0 |
Molar Refractivity : | 67.08 |
TPSA : | 165.56 Ų |
GI absorption : | Low |
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) : | -9.21 cm/s |
Log Po/w (iLOGP) : | -0.98 |
Log Po/w (XLOGP3) : | -1.68 |
Log Po/w (WLOGP) : | -2.71 |
Log Po/w (MLOGP) : | -2.82 |
Log Po/w (SILICOS-IT) : | -3.08 |
Consensus Log Po/w : | -2.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.73 |
Solubility : | 52.2 mg/ml ; 0.185 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.28 |
Solubility : | 14.7 mg/ml ; 0.0519 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.77 |
Solubility : | 1670.0 mg/ml ; 5.92 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.97 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319 | 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 |
---|---|---|
With tetrafluoroboric acid; water; sodium nitrite | ||
0.708 g (62.1%) | With sodium nitrite In pyridine; HF | 2 Production of 2-fluoroadenosine Example 2 Production of 2-fluoroadenosine As described in example 1, 1.13 g (4 mmol) of finely powdered 2-aminoadenosine is suspended at -25° C. in 7 ml of 50% HF in pyridine and 0.55 g (8 mmol) of sodium nitrite is added in portions with stirring within 15 minutes at -25° C. After 1 hour at -25° C., it is worked up with CaCO3 as described in example 1, and 1.4 g of crude product is obtained, which, with chromatography on silica gel, yields 0.708 g (62.1%) of pure, homogeneous 2-fluoroadenosine. |
Stage #1: adenosine-2-amine With pyridine; potassium nitrite; hydrogen fluoride In water at -10℃; for 2h; Stage #2: With calcium carbonate In water at 0℃; | 2 2-Fluoroadenosine 2-Fluoroadenosine To a stirred solution of 0.15 g (0.53 mmol) 2-aminoadenosine in 0.5 ml 56% HF/pyridine cooled to -10° C. was added a concentrated solution of 0.05 g of KNO2 (0.57 mmol) in water drop-wise. Stirring was continued for 2 hours after which the mixture was poured on a stirred ice cold slurry of 1 g of powdered CaCO3 in water. After letting stand overnight the solution was filtered and the filtrate evaporated to afford 2-Fluoroadenosine. This was washed with water, ethanol and methyl-tert-butyl ether and recrystallized from ethanol to afford 120 mg of pure 2-Fluoroadenosine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With ammonia In ethanol at 100℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: G With trimethylsilyl trifluoromethanesulfonate; 1,1,1,3,3,3-hexamethyl-disilazane In toluene at 150℃; for 120h; Stage #2: In methanol; water for 16h; Heating; Further stages.; | |
With chloro-trimethyl-silane; trimethylsilyl trifluoromethanesulfonate; ammonia; 1,1,1,3,3,3-hexamethyl-disilazane 1.) reflux, 16 h; 2.) 150 deg C, 3 d (sealed bomb); Yield given. Multistep reaction; | ||
Multi-step reaction with 5 steps 1: pyridine / dimethylformamide / Heating 2: POCl3, Me2NPh, Et4NCl / acetonitrile / Heating 3: NaN3 / acetonitrile 4: H2 / Pd-C 5: NH3 / methanol |
Stage #1: G With pyridine; trifluoroacetic anhydride at 0℃; for 1h; Stage #2: With ammonia In water for 1.5h; | 2 2-aminoadenosine 2-aminoadenosine To 1.0 gm of dry guanosine (7.06 mmol) was added dry pyridine and this was cooled to 0° C. in a ice bath. This was followed by drop-wise addition of trifluoroacetic anhydride (4.9 ml, 35.3 mmol). The above solution was stirred for 30 minutes after which an additional 2.5 ml trifluoroacetic anhydride was added and the solution was stirred for an additional 30 minutes. 20 ml of cold, concentrated aqueous ammonia was then added to the above solution and stirring was continued for an additional 1.5 hrs, after which the mixture was evaporated to dryness and the residue dissolved in water and purified using reversed phase HPLC (Luna C18;; Flow rate=80 ml/min; Gradient: 0-15% mobile phase B over 40 minutes; Mobile phase A=0.1% trifluoroacetic acid in water and Mobile phase B=0.1% trifluoroacetic acid in 90% acetonitrile). This yielded 510 mg of 2-amino adenosine as the pure product. | |
Multi-step reaction with 3 steps 1: dmap; triethylamine / acetonitrile / 0.5 h / 20 °C 2: diethylamine; triethylamine; trichlorophosphate / acetonitrile / 0.08 h / 100 °C 3: ammonia / 16 h / -80 - 70 °C | ||
Multi-step reaction with 4 steps 1: N,N-dimethyl-ethanamine; dmap / acetonitrile 2: tetraethylammonium chloride; trichlorophosphate; <i>N</i>,<i>N</i>-dimethyl-aniline / Inert atmosphere 3: sodium methylate; methanol / 24 h / 20 °C 4: ammonia / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With ammonia In methanol at 150℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 90% 2: 10% | Stage #1: adenosine-2-amine With tin(ll) chloride In N,N-dimethyl-formamide at 50℃; for 0.25h; Stage #2: diazomethane In N,N-dimethyl-formamide at 50℃; Title compound not separated from byproducts; | |
1: 34% 2: 64% | With tin(ll) chloride In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 50℃; | |
1: 47% 2: 51% | With tin(ll) chloride In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine for 6h; Ambient temperature; | |
90% | With pyridine at 20℃; for 12h; | |
89% | In pyridine; N,N-dimethyl-formamide at 0 - 20℃; |
In pyridine for 3h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dmap In pyridine at 60℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: adenosine-2-amine With di(n-butyl)tin oxide In methanol for 0.75h; Heating; Stage #2: p-toluenesulfonyl chloride With triethylamine In methanol for 0.0833333h; Further stages.; | |
With di(n-butyl)tin oxide; triethylamine 1.) MeOH, reflux, 2 h, 2.) 15 min; Yield given. Multistep reaction; | ||
With di(n-butyl)tin oxide; triethylamine 1.) methanol, reflux, 3 h; 2.) reflux, 20 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bromine In water at 20℃; | |
92% | With bromine for 1h; Ambient temperature; | |
71% | With N-Bromosuccinimide In water for 0.0833333h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With ammonia at 25℃; | |
With ammonia In methanol at 25℃; for 24h; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Stage #1: adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 2-(3-bromopropyl)isoindole-1,3-dione In N,N-dimethyl-formamide at 0 - 20℃; | |
With sodium hydride 1.) DMF, 1 h. 2.) DMF, 30 deg C, 16 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,2'-azobis(isobutyronitrile); acetoxyisobutyryl bromide; ammonia; tri-n-butyl-tin hydride Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 3-chloro-benzenecarboperoxoic acid In methanol Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | With acetic acid; sodium nitrite In water at 50℃; for 0.0833333h; | |
90% | With acetic acid; sodium nitrite In water at 50℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethyl phosphate; trichlorophosphate at 0℃; for 1.5h; | |
51% | With trimethyl phosphite; trichlorophosphate at 0℃; | |
With water; trichlorophosphate In various solvent(s) at 0℃; for 18h; |
With triethyl phosphate; water; trichlorophosphate at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.92 g | Stage #1: allyl bromide; adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide Stage #2: With adenosine deaminase In water at 20℃; for 60h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With perchloric acid In acetone at 20℃; for 1h; | |
With perchloric acid In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium hydroxide In dimethyl sulfoxide at 20℃; for 7h; | |
34.4% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 9h; Cooling with ice; Inert atmosphere; | 2 Preparation of 2'-O-MOE-2- amino - adenosine 2-Aminoadenosine (7 g, 1.0 eq) was dissolved in anhydrous DMF (200 mL) The mixture was stirred under ice-cooling with nitrogen for 30 min, After stirring for 30 min, 2-bromoethyl methyl ether (MOE-Br) (2.8 mL, 1.2 eq) was added dropwise, followed by the addition of a solution of NaH (1.5 g, 1.5 eq) Stirring was continued for 30 min and the ice bath was removed, Stir at room temperature for 8 h. Plus ice water 5mL, stirring 10min, concentrated reaction solution, The product was isolated by column chromatography to give the object product (2.9 g) in a yield of 34.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium hydride In N,N-dimethyl-formamide for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: adenosine-2-amine With tin(ll) chloride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: diazomethane In N,N-dimethyl-formamide at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In methanol at 50℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In methanol at 50℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With thionyl chloride In N,N,N,N,N,N-hexamethylphosphoric triamide at 0 - 20℃; | |
44% | Stage #1: adenosine-2-amine With pyridine; thionyl chloride In acetonitrile at 0 - 20℃; for 19h; Stage #2: With ammonium hydroxide In methanol; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 74 percent / thionyl chloride / hexamethylphosphoric acid triamide / 0 - 20 °C 2: 47 percent / aq. NaOH / 3 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 74 percent / thionyl chloride / hexamethylphosphoric acid triamide / 0 - 20 °C 2: 47 percent / aq. NaOH / 3 h / 80 °C 3: 17 percent / ammonium molybdate; aq. perchloric acid; aq. H2O2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h 7: 70 percent / NaN3; 18-crown-6 / dimethylformamide / 5 h / 60 °C 8: H2 / Pd/C / ethanol / 12 h 9: Et3N / tetrahydrofuran / 12 h 10: 0.190 g / TBAF / tetrahydrofuran / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h 7: 70 percent / NaN3; 18-crown-6 / dimethylformamide / 5 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h 7: 70 percent / NaN3; 18-crown-6 / dimethylformamide / 5 h / 60 °C 8: H2 / Pd/C / ethanol / 12 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0.5 h / 0 °C 7: 0.156 g / TBAF / tetrahydrofuran / 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h 7: 70 percent / NaN3; 18-crown-6 / dimethylformamide / 5 h / 60 °C 8: H2 / Pd/C / ethanol / 12 h 9: Et3N / tetrahydrofuran / 12 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h 7: 70 percent / NaN3; 18-crown-6 / dimethylformamide / 5 h / 60 °C 8: H2 / Pd/C / ethanol / 12 h 9: Et3N / tetrahydrofuran / 12 h 10: 0.190 g / TBAF / tetrahydrofuran / 6 h / 20 °C 11: 83 percent / pyridine / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0.5 h / 0 °C 7: 0.156 g / TBAF / tetrahydrofuran / 3 h 8: 68 percent / pyridine / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h 7: 70 percent / NaN3; 18-crown-6 / dimethylformamide / 5 h / 60 °C 8: H2 / Pd/C / ethanol / 12 h 9: Et3N / tetrahydrofuran / 12 h 10: 0.190 g / TBAF / tetrahydrofuran / 6 h / 20 °C 11: 83 percent / pyridine / 18 h / 20 °C 12: 80 percent / 4,5-dicyanoimidazole / CH2Cl2 / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: diisopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 0.5 h / 0 °C 7: 0.156 g / TBAF / tetrahydrofuran / 3 h 8: 68 percent / pyridine / 12 h / 20 °C 9: 61 percent / 4,5-dicyanoimidazole / CH2Cl2 / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h | ||
Multi-step reaction with 5 steps 1: NaH / dimethylformamide 2: adenosine deaminase / dimethylsulfoxide / Tris, Na3PO4 buffer (pH 7.4) 3: imidazole / dimethylformamide 4: pyridine 5: H2 / 20percent Pd(OH)2/C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 33 percent / NaH / various solvent(s); dimethylformamide / 18 h 2: 82 percent / adenosine deaminase type II; Tris; sodium phosphate / dimethylsulfoxide / 36 h / 20 °C 3: 73 percent / imidazole / dimethylformamide / 12 h / 20 °C 4: 98 percent / pyridine / 0.75 h 5: 88 percent / H2 / Pd/C / ethanol / 12 h 6: 98 percent / Et3N / CH2Cl2 / 1 h | ||
Multi-step reaction with 6 steps 1: NaH / dimethylformamide 2: adenosine deaminase / dimethylsulfoxide / Tris, Na3PO4 buffer (pH 7.4) 3: imidazole / dimethylformamide 4: pyridine 5: H2 / 20percent Pd(OH)2/C / methanol 6: pyridine / CH2Cl2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 40 percent / KOH / dimethylsulfoxide / 7 h / 20 °C 2: adenosine deaminase; sodium phosphate buffer / pH 7.2 3: acetonitrile / 3 h / 20 °C 4: 3 h / 20 °C 5: ammonia / acetonitrile; H2O; acetone / pH 6.4 | ||
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 9 h / 20 °C / Cooling with ice; Inert atmosphere 2.1: pyridine; chloro-trimethyl-silane / 1.67 h / -10 °C / Inert atmosphere; Cooling with ice 2.2: 3 h / 20 °C / Cooling with ice 3.1: sodium nitrite; acetic acid / water / 24 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 20 - 100 °C 1.2: 16.33 h / 50 °C 2.1: pyridine; chloro-trimethyl-silane / 0.5 h / 20 °C 2.2: 3.5 h / -20 - 20 °C 3.1: sodium nitrite / acetic acid; water / 20 h / 20 °C |
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 20 - 100 °C 1.2: 16.33 h / 50 °C 2.1: pyridine; chloro-trimethyl-silane / 0.5 h / 20 °C 2.2: 3.5 h / -20 - 20 °C 3.1: trimethylamine / methanol / 24 h / 20 °C 4.1: sodium nitrite / acetic acid; water / 20 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: lithium hydroxide monohydrate / dimethyl sulfoxide / 0.5 h / 20 - 35 °C / Inert atmosphere; Large scale 1.2: 19 h / 15 - 35 °C / Inert atmosphere; Large scale 2.1: sodium phosphate; sodium dihydrogenphosphate; adenosine deaminase ADA-101 from Codexis / water / 20.25 h / 25 - 30 °C / pH 7.3 / Large scale; Enzymatic reaction 3.1: pyridine / 0.5 h / 10 - 15 °C / Inert atmosphere; Large scale 3.2: 7 h / 10 - 30 °C / Inert atmosphere; Large scale 3.3: 7 h / 10 - 30 °C / Inert atmosphere; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 40 percent / KOH / dimethylsulfoxide / 7 h / 20 °C 2: adenosine deaminase; sodium phosphate buffer / pH 7.2 3: acetonitrile / 3 h / 20 °C 4: 3 h / 20 °C 5: ammonia / acetonitrile; H2O; acetone / pH 6.4 6: 85 percent / 2,6-lutidine / acetonitrile / 3 h / 45 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 9 h / 20 °C / Cooling with ice; Inert atmosphere 2.1: pyridine; chloro-trimethyl-silane / 1.67 h / -10 °C / Inert atmosphere; Cooling with ice 2.2: 3 h / 20 °C / Cooling with ice 3.1: sodium nitrite; acetic acid / water / 24 h / 20 °C 4.1: pyridine / 4 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 20 - 100 °C 1.2: 16.33 h / 50 °C 2.1: pyridine; chloro-trimethyl-silane / 0.5 h / 20 °C 2.2: 3.5 h / -20 - 20 °C 3.1: sodium nitrite / acetic acid; water / 20 h / 20 °C 4.1: pyridine / methanol / 3.5 h / 0 °C |
Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 20 - 100 °C 1.2: 16.33 h / 50 °C 2.1: pyridine; chloro-trimethyl-silane / 0.5 h / 20 °C 2.2: 3.5 h / -20 - 20 °C 3.1: trimethylamine / methanol / 24 h / 20 °C 4.1: sodium nitrite / acetic acid; water / 20 h / 20 °C 5.1: pyridine / methanol / 3.5 h / 0 °C | ||
Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate / dimethyl sulfoxide / 0.5 h / 20 - 35 °C / Inert atmosphere; Large scale 1.2: 19 h / 15 - 35 °C / Inert atmosphere; Large scale 2.1: sodium phosphate; sodium dihydrogenphosphate; adenosine deaminase ADA-101 from Codexis / water / 20.25 h / 25 - 30 °C / pH 7.3 / Large scale; Enzymatic reaction 3.1: pyridine / 0.5 h / 10 - 15 °C / Inert atmosphere; Large scale 3.2: 7 h / 10 - 30 °C / Inert atmosphere; Large scale 3.3: 7 h / 10 - 30 °C / Inert atmosphere; Large scale 4.1: 2,6-dimethylpyridine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere; Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 71 percent / tetrabutylammonium nitrate (TBAN); trifluoroacetic anhydride (TFAA) / CH2Cl2 / 2.5 h / 0 °C 2: NaN3 / dimethylformamide 4: HOAc / H2O 5: 68 percent / KCN / methanol 6: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 55 percent / tetrabutylammonium nitrate (TBAN); trifluoroacetic anhydride (TFAA) / CH2Cl2 / 0 °C 2: 10 percent / KCN / methanol 3: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: NaN3 / dimethylformamide 3: HOAc / H2O 4: 68 percent / KCN / methanol 5: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 2: HOAc / H2O 3: 68 percent / KCN / methanol 4: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 68 percent / KCN / methanol 2: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 10 percent / KCN / methanol 2: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: HOAc / H2O 2: 68 percent / KCN / methanol 3: 80 percent / H2 / Raney Ni |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 97 percent / pyridine / 6 h / Ambient temperature 2: DMAP / acetonitrile / 1 h / Ambient temperature 3: 1.) AIBN, Bu3SnH, 2.) TBAF / 1.) toluene, 80 deg C, overnight, 2.) toluene, THF, 80 deg C, 3 h | ||
Multi-step reaction with 4 steps 1: 92 percent / saturated bromine-water / 1 h / Ambient temperature 2: 1.) dibutyltin oxide, 2.) triethylamine / 1.) methanol, 5 h, reflux, 2.) methanol, 1 h, room temperature 3: 88 percent / 40 percent sodium hydrogensulfide aq. / dimethylformamide / 6 h / 60 °C 4: 18 percent / Raney nickel / H2O / 3 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: NaH / dimethylformamide 2: adenosine deaminase / dimethylsulfoxide / Tris, Na3PO4 buffer (pH 7.4) 3: imidazole / dimethylformamide 4: pyridine 5: H2 / 20percent Pd(OH)2/C / methanol 6: pyridine / CH2Cl2 7: 1.) thiobenzoic acid, Et3N, 2.) HF, 3.) LiOH / 1.) DMF, 2.) MeCN; 3.) THF, MeOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: NaH / dimethylformamide 2: adenosine deaminase / dimethylsulfoxide / Tris, Na3PO4 buffer (pH 7.4) 3: imidazole / dimethylformamide 4: pyridine 5: H2 / 20percent Pd(OH)2/C / methanol 6: pyridine / CH2Cl2 7: 1.) thiobenzoic acid, Et3N, 2.) HF, 3.) LiOH / 1.) DMF, 2.) MeCN; 3.) THF, MeOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) dibutyltin oxide; 2.) triethylamine / 1.) methanol, reflux, 3 h; 2.) reflux, 20 min 2: 92 percent / LiEt3BH / dimethylsulfoxide | ||
Multi-step reaction with 2 steps 1: 1.) dibutyltin oxide, 2.) Et3N / 1.) MeOH, reflux, 2 h, 2.) 15 min 2: 94 percent / lithium triethylborohydride / dimethylsulfoxide; tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1.) dibutyltin oxide; 2.) triethylamine / 1.) methanol, reflux, 3 h; 2.) reflux, 20 min 2: 92 percent / LiEt3BH / dimethylsulfoxide 3: 98 percent / adenosine deaminase / H2O / Ambient temperature | ||
Multi-step reaction with 6 steps 2: pyridine / Ambient temperature 3: 86 percent / NH3 / methanol / Ambient temperature 4: NaNO2 / acetic acid; H2O / Ambient temperature 5: 59 percent / NH3 / methanol / Ambient temperature 6: 93 percent / lithium triethylborohydride / tetrahydrofuran; dimethylsulfoxide / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 2: 87 percent / H2 / 5percent Pd/C / ethanol / 20 h / 19 - 22 °C / 517.1 Torr | ||
Multi-step reaction with 2 steps 2: 87 percent / H2 / 5percent Pd/C / ethanol / 20 h / 19 - 22 °C / 517.1 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With ammonia at -80 - 70℃; for 16h; | |
Multi-step reaction with 3 steps 1: NaN3 / acetonitrile 2: H2 / Pd-C 3: NH3 / methanol | ||
Multi-step reaction with 2 steps 1: sodium methylate; methanol / 24 h / 20 °C 2: ammonia / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: POCl3, Me2NPh, Et4NCl / acetonitrile / Heating 2: NaN3 / acetonitrile 3: H2 / Pd-C 4: NH3 / methanol | ||
Multi-step reaction with 2 steps 1: diethylamine; triethylamine; trichlorophosphate / acetonitrile / 0.08 h / 100 °C 2: ammonia / 16 h / -80 - 70 °C | ||
Multi-step reaction with 3 steps 1: tetraethylammonium chloride; trichlorophosphate; <i>N</i>,<i>N</i>-dimethyl-aniline / Inert atmosphere 2: sodium methylate; methanol / 24 h / 20 °C 3: ammonia / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide | 5 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1H NMR (DMSO-d6) δ0.84 (t, 3, CH2), 1.22 (m, 32, O-CH2-CH2-(CH2)16), 1.86 (m, 2, O-CH2CH2), 3.25 (m, 2, O-CH2), 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H), 4.38 (t, 1, 2'H), 5.08 (d, 1, 3'-OH), 5.48 (t, 1, 5'-OH), 5.75 (s, 2, 6-NH2), 5.84 (d, 1, 1'-H), 6.8 (s, 2, 2-NH2), and 7.95 (s, 1, 8-H). | |
In N,N-dimethyl-formamide | 24 Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine EXAMPLE 24 Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2C2. The appropriate fractions were evaporated to yield the product (11 g). 1H NMR (DMSO-d5) δ0.84 (t, 3, CH2); 1.22 (m, 32, O-CH2-CH2-(CH2)16); 1.86 (m, 2, O-CH2CH2); 3.25 (m, 2, O-H2); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (d, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H). | |
In N,N-dimethyl-formamide | 5 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1H NMR (DMSO-d6) δ 0.84 (t, 3, CH2), 1.22 (m, 32, O-CH2-CH2-(CH2)16), 1.86 (m, 2, O-CH2CH2), 3.25 (m, 2, O-CH2), 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H), 4.38 (t, 1, 2'H), 5.08 (d, 1, 3'-OH), 5.48 (t, 1, 5'-OH), 5.75 (s, 2, 6-NH2), 5.84 (d, 1, 1'-H), 6.8 (s, 2, 2-NH2), and 7.95 (s, 1, 8-H). |
In N,N-dimethyl-formamide | 5 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solyent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6) δ 0.84 (t, 3, CH2), 1.22 (m, 32, O--CH2 --CH2 --(CH2)16), 1.86 (m, 2, O--CH2 CH2), 3.25 (m, 2, O--CH2), 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H), 4.38 (t, 1, 2' H), 5.08 (d, 1, 3'-OH), 5.48 (t, 1, 5'-OH, 5.75 (s, 2, 6-NH2), 5.84 (d, 1, 1'-H), 6.8 (s, 2, 2-NH2), and 7.95 (s, 1, 8-H). | |
In N,N-dimethyl-formamide | 19 Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine EXAMPLE 19 Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6) δ 0.84 (t, 3, CH2); 1.22 (m, 32, O--CH2 --CH2 --(CH2)16); 1.86 (m, 2, O--CH2 CH2); 3.25 (m, 2, O--CH2); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (d, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H) | |
In N,N-dimethyl-formamide | 3.a Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl) purine EXAMPLE 3-a Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl) purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6)δ0.84 (t, 3, CH2); 1.22 (m, 32, O-CH2 --CH2 --(CH2)16); 1.86 (m, 2, O--CH2 CH2); 3.25 (m, 2, O--CH2); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (d, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H). | |
In N,N-dimethyl-formamide | 5 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl) purine 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl) purine 2,6-Diamino-9-(β-D-ribofuranosyl) purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6) δ 0.84 (t, 3, CH2), 1.22 (m, 32, O-CH2 --CH2 --(CH2)16), 1.86 (m, 2, O-CH2 CH2), 3.25 (m, 2, O-CH2), 3.93 (d, 1, 4'H), 4.25 (m, 1,3'H), 4.38 (t, 1,2'H), 5.08 (d, 1, 3'-OH), 5.48 (t, 1,5'-OH), 5.75 (s, 2,6-NH2), 5.84 (d, 1, 1'-H), 6.8 (s, 2,2-NH2), and 7.95 (s, 1,8-H). | |
In N,N-dimethyl-formamide | 5 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6) δ 0.84 (t, 3, CH2), 1.22 (m, 32, O--CH2 --CH2 --(CH2)16), 1.86 (m, 2, O--CH2 CH2), 3.25 (m, 2, O--CH2), 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H), 4.38 (t, 1, 2'H), 5.08 (d, 1, 3'-OH), 5.48 (t, 1, 5'-OH), 5.75 (s, 2, 6-NH2), 5.84 (d, 1, 1'-H), 6.8 (s, 2, 2-NH2), and 7.95 (s, 1, 8-H). | |
In N,N-dimethyl-formamide | 3.a Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine EXAMPLE 3-a Synthesis of 2,6-Diamino-9-(2-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6)δ 0.84 (t, 3, CH2); 1.22 (m, 32, O--CH2 --CH2 --(CH2)16); 1.86 (m, 2, O--CH2 CH2); 3.25 (m, 2, O--CH2); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (cl, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H) | |
In N,N-dimethyl-formamide | 42 2,6-Diamino-9-(2'-O-octadecyl-β-D-ribofuranosyl)purine Example 42 2,6-Diamino-9-(2'-O-octadecyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 l) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2 Cl2. The product containing fraction were evaporated to yield the product (11 g). 1 H NMR (DMSO-d6) δ 0.84 (t, 3, CH2); 1.22 [m, 32, O--CH2 --CH2 --(CH2)16 --]; 1.86 (m, 2, O--CH2 CH2 --); 3.25 (m, 2, O--CH2 --); 3.93 (d, 1, 4'H), 4.25 (m, 1, 3'H); 4.38 (t, 1, 2'H); 5.08 (d, 1, 3'-OH); 5.48 (t, 1, 5'-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1'-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In methanol | 100 Example 100 Example 100 Reaction of 2,6-diaminopurine with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribose followed by treatment of the intermediate 2,6-diamino-9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine with ammonia in methanol in an analogous manner to that described in example 99 gave 2,6-diamino-9-(β-D-ribofuranosyl)purine (also available commercially from ICN Biomedicals Inc.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; toluene | 7.A A. A. 2.6-Diaminopurine riboside To a 2 L stainless steel Parr bomb was added guanosine hydrate (100 g, 0.35 mol, Aldrich), hexamethyl) disilazane (320 mL, 1.52 mol, 4.4 eq.), trimethyl) silyl trifiouromethanesulfonate (8.2 mL), and toluene (350 mL). The bomb was sealed and partially submerged in an oil bath (170° C.; internal T 150° C., 150 psi) for 5 days. The bomb was cooled in a dry ice/acetone bath and opened. The contents were transferred with methanol (300 mL) to a flask and the solvent was evaporated under reduced pressure. Aqueous methanol (50%, 1.2 L)was added. The resulting brown suspension was heated to reflux for 5 h. The suspension was concentrated under reduced pressure to one half volume in order to remove most of the methanol. Water (600 mL) was added and the solution was heated to reflux, treated with charcoal (5 g) and hot filtered through Celite. The solution was allowed to cool to 25° C. The resulting precipitate was collected, washed with water (200 mL) and dried at 90° C./0.2 mmHg for 5 h to give a constant weight of 87.4 g (89%) of tan, crystalline solid; mp 247° C. (shrinks), 255° C. (dec, lit. (1) mp 250-252° C.); TLC homogenous (Rf 0.50, isopropanol-ammonium hydroxide-water 16:3:1); PMR (DMSO), δ5.73 (d, 2, 2-NH2), 5.78 (s, 1, H-1), 6.83 (br s, 2, 6-NH2). | |
In methanol; water; toluene | 7.A A. A. 2,6-Diaminopurine riboside To a 2 L stainless steel Parr bomb was added guanosine hydrate (100 g, 0.35 mol, Aldrich), hexamethyl) disilazane (320 mL, 1.52 mol, 4.4 eq.), trimethyl) silyl triflouromethanesulfonate (8.2 mL), and toluene (350 mL). The bomb was sealed and partially submerged in an oil bath (170° C.; internal T 150° C., 150 psi) for 5 days. The bomb was cooled in a dry ice/acetone bath and opened. The contents were transferred with methanol (300 mL, Note 3) to a flask and the solvent was evaporated under reduced pressure. Aqueous methanol (50%, 1.2 L) was added. The resulting brown suspension was heated to reflux for 5 h. The suspension was concentrated under reduced pressure to one half volume in order to remove most of the methanol. Water (600 mL) was added and the solution was heated to reflux, treated with charcoal (5 g) and hot filtered through Celite. The solution was allowed to cool to 25° C. The resulting precipitate was collected, washed with water (200 mL) and dried at 90° C./0.2 mmHg for 5 h to give a constant weight of 87.4 g (89%) of tan, crystalline solid; mp 247° C. (shrinks), 255° C. (dec, lit. (1) mp 250-252° C.); TLC homogenous (Rf 0.50, isopropanol-ammonium hydroxide-water 16:3:1); PMR (DMSO), δ5.73 (d, 2, 2-NH2), 5.78 (s, 1, H-1), 6.83 (br s, 2, 6NH2). | |
In methanol; water; toluene | 7.A A. A. 2,6-Diaminopurine Riboside To a 2 L stainless steel Parr bomb was added guanosine hydrate (100 g, 0.35 mol, Aldrich), hexamethyl) disilazane (320 mL, 1.52 mol, 4.4 eq.), trimethyl) silyl triflouromethanesulfonate (8.2 mL), and toluene (350 mL). The bomb was sealed and partially submerged in an oil bath (170° C.; internal T 150° C., 150 psi) for 5 days. The bomb was cooled in a dry ice/acetone bath and opened. The contents were transferred with methanol (300 mL) to a flask and the solvent was evaporated under reduced pressure. Aqueous methanol (50%, 1.2 L) was added. The resulting brown suspension was heated to reflux for 5 h. The suspension was concentrated under reduced pressure to one half volume in order to remove most of the methanol. Water (600 mL) was added and the solution was heated to reflux, treated with charcoal (5 g) and hot filtered through Celite. The solution was allowed to cool to 25° C. The resulting precipitate was collected, washed with water (200 mL) and dried at 90° C./0.2 mmHg for 5 h to give a constant weight of 87.4 g (89%) of tan, crystalline solid; mp 247° C. (shrinks), 255° C. (dec, lit. (1) mp 250-252° C.); TLC homogenous (Rf 0.50, isopropanol-ammonium hydroxide-water 16:3:1); PMR (DMSO), δ 5.73 (d, 2, 2-NH2), 5.78 (s, 1, H-1), 6.83 (br s, 2, 6-NH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; dichloromethane; N,N-dimethyl-formamide; mineral oil | 62 2'/3'-O-allyl-2,6-diaminopurine Riboside (121 and 122) EXAMPLE 62 2'/3'-O-allyl-2,6-diaminopurine Riboside (121 and 122) 2,6-Diaminopurine riboside (30 g, 106.4 mmol) was suspended in anhydrous DMF (540 ML). Reaction vessel was flushed with argon. Sodium hydride (3.6 g, 106.4 mmol, 60% dispersion in mineral oil) was added and the reaction stirred for 10 min. Allyl bromide (14.14 mL, 117.22 mmol) was added dropwise over 20 min. The resulting reaction mixture stirred at room temperature for 20 hr. TLC (10% MeOH in CH2Cl2) showed complete disappearance of starting material. DMF was removed under vacuum and the residue absorbed on silica was placed on a flash column and eluted with 10% MeOH in CH2Cl2. Fractions containing mixture of 2' and 3' allylated product was pooled together and concentrated to dryness to yield a mixture of 121 and 122 (26.38 g, 77%). Rf 0.26, 0.4 (10% MeOH in CH2Cl2) | |
In methanol; dichloromethane; N,N-dimethyl-formamide; mineral oil | 73 2'/3'-O-Allyl-2,6-diaminopurine Riboside EXAMPLE 73 2'/3'-O-Allyl-2,6-diaminopurine Riboside 2,6-Diaminopurine riboside (30 g, 106.4 mmol) was suspended in anhydrous DMF (540 mL). Reaction vessel was flushed with argon. Sodium hydride (3.6 g, 106.4 mmol, 60% dispersion in mineral oil) was added and the reaction stirred for 10 min. Allyl bromide (14.14 mL, 117.22 mmol) was added dropwise over 20 min. The resulting reaction mixture stirred at room temperature for 20 hr. TLC (10% MeOH in CH2Cl2) showed complete disappearance of starting material. DMF was removed under vacuum and the residue absorbed on silica was placed on a flash column and eluted with 10% MeOH in CH2Cl2. Fractions containing mixture of 2' and 3' allylated product was pooled together and concentrated to dryness to yield a mixture of the title compounds (26.38 g, 77%). Rf 0.26, 0.4 (10% MeOH in CH2Cl2). | |
In methanol; dichloromethane; N,N-dimethyl-formamide; mineral oil | 62 2'/3'-O-allyl-2,6-diaminopurine riboside (121 and 122) EXAMPLE 62 2'/3'-O-allyl-2,6-diaminopurine riboside (121 and 122) 2,6-Diaminopurine riboside (30 g, 106.4 mmol) was suspended in anhydrous DMF (540 ML). Reaction vessel was flushed with argon. Sodium hydride (3.6 g, 106.4 mmol, 60% dispersion in mineral oil) was added and the reaction stirred for 10 min. Allyl bromide (14.14 mL, 117.22 mmol) was added dropwise over 20 min. The resulting reaction mixture stirred at room temperature for 20 hr. TLC (10% MeOH in CH2Cl2) showed complete disappearance of starting material. DMF was removed under vacuum and the residue absorbed on silica was placed on a flash column and eluted with 10% MeOH in CH2Cl2. Fractions containing mixture of 2' and 3' allylated product was pooled together and concentrated to dryness to yield a mixture of 121 and 122 (26.38 g, 77%). Rf 0.26, 0.4 (10% MeOH in CH2Cl2) |
In methanol; dichloromethane; N,N-dimethyl-formamide; mineral oil | 62 2'/3'--O-allyl-2,6-diaminopurine riboside (121 and 122) Example 62 2'/3'--O-allyl-2,6-diaminopurine riboside (121 and 122) 2,6-Diaminopurine riboside (30 g, 106.4 mmol) was suspended in anhydrous DMF (540 mL). Reaction vessel was flushed with argon. Sodium hydride (3.6 g, 106.4 mmol, 60% dispersion in mineral oil) was added and the reaction stirred for 10 min. Allyl bromide (14.14 mL, 117.22 mmol) was added dropwise over 20 min. The resulting reaction mixture stirred at room temperature for 20 hr. TLC (10% MeOH in CH2 Cl2) showed complete disappearance of starting material. DMF was removed under vacuum and the residue absorbed on silica was placed on a flash column and eluted with 10% MeDH in CH2 Cl2. Fractions containing mixture of 2' and 3' allylated product was pooled together and concentrated to dryness to yield a mixture of 121 and 122 (26.38 g, 77%). Rf 0.26, 0.4 (10% MeOH in CH2 Cl2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In NaH; N,N-dimethyl-formamide | 12 2,6-Diamino-9-(2'-O-nonyl-β-D-ribofuranosyl)purine Example 12 2,6-Diamino-9-(2'-O-nonyl-β-D-ribofuranosyl)purine 2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) was treated with sodium hydride (8.8 g, 220 mmol) and bromononane (59 g, 54.4 ml, 285 mmol) in DMF (700 ml) as per the procedure of Example 2 (the diamino compound in DMF was cooled in an ice bath during the addition of NaH) to yield 83 g of crude product. 50 g of crude product was purified by silica gel chromatography. Fraction containing 2'-O-nonyl and 3'-O-nonyl product were combined to give a 77:23 mixture (29 g) of the 2' and 3' product. Pure 2'-O-nonyl product is obtained by chromatography. 1 H NMR (DMSO-d6) δ 0.95 (t, 3, CH3); 1.17 [m, 12, O--CH2 --CH2 --(CH2)6 ]; 1.42 [m, 2, O--CH2 CH2 (CH2)6 ]; 3.27-3.70 (m, 2, H-5'); 3.50-3.70 [m, 2, O--CH2 (CH2)7 ]; 3.95 (m, 1, H-4'), 4.24 (m, 1, H-3'); 4.40 (m, 1, H-2'); 5.10 (d, 1, 3'-OH, J=5 Hz); 5.50 (t, 1, 5'-OH, J=6 Hz); 5.76 (s, 2, 2-NH2); 5.83 (d, 1, H-1', J=6.0 Hz); 6.81 (s, 2, 6-NH2); and 7.96 (s, 1, 8-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.261 g (~91%) | With pyridine; calcium hydroxide; tert.-butylnitrite; CO2 In ammonium hydroxide; methanol-H2 O; isopropyl alcohol | 3 Production of 2-fluoroadenosine Example 3 Production of 2-fluoroadenosine 0.282 g (1 mmol) of 2-aminoadenosine is suspended in a mixture of 7 ml of 50% HF-pyridine and 0.35 ml of H2 O at -30° C. and within 30 minutes, 1.2 ml (~9 mol) of tert-butyl nitrite is instilled slowly with vigorous stirring at -30° C. After another 30 minutes at -25°→-30° C., the reaction mixture is instilled slowly in 120 ml of 33% aqueous ammonia at -10° C. with stirring and stirred for 1 hour at 0° C. After adding 7 g of solid calcium hydroxide, it is stirred for another 15 minutes at 0° C., filtered and washed with 40 ml of H2 O. The light yellow filtrate is carefully concentrated by evaporation at about 25° C.-30° C. to about 15 ml and CO2 is introduced. After filtering off the small amount of precipitate and after washing the precipitate with 10 ml of H2 O, the filtrate is concentrated by evaporation at a 10 mm vacuum. The yellowish-brown residue (0.39 g) is dissolved in 15 ml of methanol-H2 O (1:1), mixed with 10 g of silica gel (40% H2 O) and evaporated at a 10 mm vacuum. After feeding dry silica gel containing the substance on a column of 15 g of silica gel (40% H2 O), which was taken up with isopropanol, elution with about 300 ml of isopropanol yields 0.261 g (~91%) of crude 2-fluoroadenosine, which still contains a little 2-aminoadenosine as well as isoguanosine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide | 28 2,6-Diamino-9-[2'-O-(N-phthalimido)pent-5-yl]-β-D-ribofuranosyl]purine Example 28 2,6-Diamino-9-[2'-O-(N-phthalimido)pent-5-yl]-β-D-ribofuranosyl]purine 2,6-Diamino-(9-β-D-ribofuranosyl)purine (6.7 g) was treated with sodium hydride (1.3 g) and N-(5-bromopentyl)phthalimide (7.8 g, 1.1 eq) in DMF (60 ml) at room temperature for three days. The reaction mixture was proportioned between H2 O and CH2 Cl2 and extracted 4*CH2 Cl2. The combined organic layers were dried over MgSO4 and evaporated. The residue was purified by silica gel chromatography eluted with 5→10% MeOH/CH2 Cl2. The 2'-O-(N-phthalimido)pentyl containing fractions were collected and evaporated to a yellow foam to give 2.2 g of product. An analytical sample was crystallized from EtOH. m.p. 173°-175° C. 1 H NMR (DMSO-d6) δ 1.2 (m, 2, --CH2 --), 1.47 (m, 4, 2*CH2), 3.55, 3.65 (m, 6, O--CH2, H-5', NCH2), 3.95 (m, 1), 4.28 (m, 1), 4.4 (m, 1), 5.13 (d, 1, 3'-OH), 5.5 (t, 1, 5'-OH), 5.77 (br s, 2, 6-NH2), 5.84 (br d, 1, H-1') 6.8 (br s, 2, 2-NH2), 7.86 (M, 4, phthal) and 7.95 (s, 1, H-8). Anal. Calcd. for C23 H27 N7 O6: C, 55.50; H, 5.47; N, 19.71. Found: C, 55.44; H, 5.51; N, 19.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In dimethyl sulfoxide; N,N-dimethyl-formamide at 20℃; for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: adenosine-2-amine With sodium hydride In DMF (N,N-dimethyl-formamide) for 1h; Stage #2: 1-(4-bromobutyl)-imidazole In DMF (N,N-dimethyl-formamide) for 16h; | 91.A Step A: [2'-O-4- (IMIDAZOLYL-L) BUTYLL-2-AMINOADENOSINE] [A] solution 2-aminoadenosine (7.36 g, 26 mmol) in dry DMF (260 mL) was treated portionwise with [60%] NaH (3.92 g, 1000 mmol). After 1 hr. , a solution of bromobutylimidazole (9.4 g, 286 mmol) in DMF [(20ML)] was added. After 16 hrs., the solution was [CONC.] in vacuo, partitioned between [HZO/ETOAC] and separated. The aqueous layer was evaporated, and the residue was chromatographed on silica gel [(CHCL3/MEOH)] to afford the title nucleoside as a white solid; yield 4.2 g. [1H NMR (DMSO-D6)] : [8] 1.39 (t, 2H), 1.67 (t, 2H), 3.3-3. 7 (m, 4H), 3.93 (m, 3H), 4.29 (m, 2H), 4.40 (d, 1H), 5.50 (5, 1H), 5.72 (d, 1H), 5. 82 (bs, 2H), 6.72 (bs, 2H), 6. 86 (s, 1H), 7.08 (s, 1H), 7.57 (s, [1H).] 7.91 (s, 1H). | |
4.2 g | Stage #1: adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil for 1h; Stage #2: 1-(4-bromobutyl)-imidazole In N,N-dimethyl-formamide; mineral oil for 16h; | 91.A Step A: 2′-O-[4-(Imidazolyl-1)butyl]-2-aminoadenosine A solution 2-aminoadenosine (7.36 g, 26 mmol) in dry DMF (260 mL) was treated portionwise with 60% NaH (3.92 g, 1000 mmol). After 1 hr., a solution of bromobutylimidazole (9.4 g, 286 mmol) in DMF (20 ml) was added. After 16 hrs., the solution was conc. in vacuo, partitioned between H2O/EtOAc and separated. The aqueous layer was evaporated, and the residue was chromatographed on silica gel (CHCl3/MeOH) to afford the title nucleoside as a white solid; yield 4.2 g. 1H NMR (DMSO-d6): δ 1.39 (t, 2H), 1.67 (t, 2H), 3.3-3.7 (m, 4H), 3.93 (m, 3H), 4.29 (m, 2H), 4.40 (d, 1H), 5.50 (5, 1H), 5.72 (d, 1H), 5.82 (bs, 2H), 6.72 (bs, 2H), 6.86 (s, 1H), 7.08 (s, 1H), 7.57 (s, 1H). 7.91 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With barium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dmap; triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: 2-(6-bromohexyl)isoindole-1,3-dione at 70 - 80℃; Overall yield = 58 %; | 73 Compound 1 (30.0 g, 106 mmol) was dissolved in DMF (300 ml) and cooled in an ice bath.NaH (3.86 g, 159 mmol) was added and the mixture stuffed for 1 hour. N(Bromohexyl)phthalimide (37.8 g, 122 mmol) was then added and the reaction heated to 70°Cover night. DMF was evaportaed in vacuo to a brown gum. The brown gum was dissolved in a1 to 1 mixture of DCM and MeOH for adsorbtion to silica gel. The solvent mixture wasremoved in vacuo and the crude product was purified to yield 8.10 g of 2 (15.83 mmol, 14.9%)as well as a mixture of 2 and its 3’-O-alkylated regioisomer (23.45 g, 45.84 mmol, 43.2%). Thetotal yield of 2 and the regioisomer was 58%. ‘H NMR (400 MHz, DMSO-d6) ö 7.95 (s, 1H), 7.89 - 7.77 (m, 4H), 6.78 (s, 2H, D20 exchangeable), 5.81 (d, J = 6.7 Hz, 1H), 5.74 (s, 2H, D20 exchangeable), 5.51 - 5.43 (m, 1H, D20 exchangeable), 5.08 (d, J = 4.9 Hz, 1H, D20 exchangeable), 4.37 (dd, J = 6.6, 5.0 Hz, 1H), 4.27 - 4.21 (m, 1H), 3.92 (q, J = 3.3 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.52 (q, J = 7.9, 7.0 Hz, 4H),3.34-3.30 (m, 1H), 1.45 (dt, J= 38.0, 6.6 Hz, 4H), 1.24- 1.12 (m, 4H). ‘3C NMR (100 MHz, DMSO-d6) ö 167.90, 160.03, 156.21, 151.36, 136.06, 134.31, 131.55, 122.95, 113.48, 86.18, 85.11, 80.52, 69.50, 69.12, 61.68, 54.88, 28.94, 27.84, 26.00, 24.86. LRMS calculated for C24 H29N706 511.5304, found mlz 512.2 (M+1), 534.2 (M+23), 546.2 (M+35)c. Rf= 0.50 in5% MeOH/DCM v/v. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: 2-(6-bromohexyl)isoindole-1,3-dione at 70 - 80℃; Stage #3: 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane With pyridine at 20℃; for 72h; | 73 Compound 1 (30.0 g, 106 mmol) was dissolved in DMF (300 ml) and cooled in an ice bath.NaH (3.86 g, 159 mmol) was added and the mixture stuffed for 1 hour. N(Bromohexyl)phthalimide (37.8 g, 122 mmol) was then added and the reaction heated to 70°Cover night. DMF was evaportaed in vacuo to a brown gum. The brown gum was dissolved in a1 to 1 mixture of DCM and MeOH for adsorbtion to silica gel. The solvent mixture wasremoved in vacuo and the crude product was purified to yield 8.10 g of 2 (15.83 mmol, 14.9%)as well as a mixture of 2 and its 3’-O-alkylated regioisomer (23.45 g, 45.84 mmol, 43.2%). Thetotal yield of 2 and the regioisomer was 58%. ‘H NMR (400 MHz, DMSO-d6) ö 7.95 (s, 1H), 7.89 - 7.77 (m, 4H), 6.78 (s, 2H, D20 exchangeable), 5.81 (d, J = 6.7 Hz, 1H), 5.74 (s, 2H, D20 exchangeable), 5.51 - 5.43 (m, 1H, D20 exchangeable), 5.08 (d, J = 4.9 Hz, 1H, D20 exchangeable), 4.37 (dd, J = 6.6, 5.0 Hz, 1H), 4.27 - 4.21 (m, 1H), 3.92 (q, J = 3.3 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.52 (q, J = 7.9, 7.0 Hz, 4H),3.34-3.30 (m, 1H), 1.45 (dt, J= 38.0, 6.6 Hz, 4H), 1.24- 1.12 (m, 4H). ‘3C NMR (100 MHz, DMSO-d6) ö 167.90, 160.03, 156.21, 151.36, 136.06, 134.31, 131.55, 122.95, 113.48, 86.18, 85.11, 80.52, 69.50, 69.12, 61.68, 54.88, 28.94, 27.84, 26.00, 24.86. LRMS calculated for C24 H29N706 511.5304, found mlz 512.2 (M+1), 534.2 (M+23), 546.2 (M+35)c. Rf= 0.50 in5% MeOH/DCM v/v. Compound 2 (100 mg, 0.195 mmol) was treated with 1,3-Dichloro-1,1,3,3- tetraisopropyldisiloxane (90 mg, 1.5 eq) in pyridine (1 ml). After 3 days at room temperature, the reaction was quenched with MeOH, washed with saturated bicarbonate, and extracted with DCM. The organic layer was dried with Na2SO4 and the crude product was purified with silica gel chromatography to yield 120 mg of 3 (0.159 mmol, 82%).‘H NMR (500 MHz, DMSO-d6) ö 7.83 (dtd, J = 8.7, 6.2, 3.4 Hz, 4H), 7.73 (s, 1H), 6.76 (s, 2H), 5.73 (d, J= 10.5 Hz, 3H), 4.52 (dd, J= 8.6, 4.9 Hz, 1H), 4.18 (d, J= 4.8 Hz, 1H), 4.03 (dd, J=12.9, 2.1 Hz, 1H), 3.96-3.85 (m, 2H), 3.78-3.70 (m, 1H), 3.66-3.58 (m, 1H), 3.53 (t, J= 7.0 Hz, 2H), 1.53 (dp, J = 20.7, 6.8 Hz, 4H), 1.30 (ddt, J = 44.2, 14.5, 7.2 Hz, 4H), 1.07 - 0.95 (m, 28H). ‘3C NMR (125 MHz, DMSO-d6) ö 167.89, 160.32, 156.12, 150.97, 134.39, 134.33,131.55, 122.95, 113.27, 86.56, 80.81, 80.63, 70.46, 69.75, 60.23, 29.19, 27.95, 26.09, 25.25,17.30, 17.18, 17.13, 17.08, 16.96, 16.85, 16.81, 16.74, 12.75, 12.37, 12.23, 12.07. LRMS calculated for C36H55N7O7Si2 754.0356, found mlz 754.3 (M+1), 776.3 (M+23), 753.3 (M-1) 788.2 (M+35)c. Rf= 0.31 in 5% MeOH/DCM v/v. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide | 45 2,6-Diamino-9-[2'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine Example 45 2,6-Diamino-9-[2'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine 2,6-Diamino-(9-β-D-ribofuranosyl)purine (5.0 g) in DMF (400 ml) was treated with sodium hydride (0.78 g). After stirring an additional 30 min a further portion of sodium hydride (2.6 g) was added immediately followed by bromobutylimidazole (9.9 g) in DMF (25 ml). The reaction mixture was stirred overnight and quenched with H2 O. The reaction mixture was filtered through celite and evaporated to yield an oily product. TLC showed a mixture of isomers. | |
With NaH In N,N-dimethyl-formamide | 91.A 2'-O-[4-(Imidazolyl-1)butyl]-2-aminoadenosine STEP A 2'-O-[4-(Imidazolyl-1)butyl]-2-aminoadenosine A solution 2-aminoadenosine (7.36 g, 26 mmol) in dry DMF (260 mL) was treated portionwise with 60% NaH (3.92 g, 1000 mmol). After 1 hr., a solution of bromobutylimidazole (9.4 g, 286 mmol) in DMF (20 ml) was added. After 16 hrs., the solution was conc. in vacuo, partitioned between H2O/EtOAc and separated. The aqueous layer was evaporated, and the residue was chromatographed on silica gel (CHC13/MeOH) to afford the title nucleoside as a white solid; yield 4.2 g. 1H NMR (DMSO-d6):δ 1.39 (t, 2H), 1.67 (t, 2H), 3.3-3.7 (m, 4H), 3.93 (m, 3H), 4.29 (m, 2H), 4.40 (d, 1H), 5.50 (5, 1H), 5.72 (d, 1H), 5.82 (bs, 2H), 6.72 (bs, 2H), 6.86 (s, 1H), 7.08 (s, 1H), 7.57 (s, 1H). 7.91 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With purine nucleoside phosphorylase; uridine phosphorylase In aq. phosphate buffer; dimethyl sulfoxide at 60℃; for 5h; Enzymatic reaction; | 12.1 Assays were performed in 5 and 10% of aprotic dipolar co-solvents, at 60°C, twelve units/ml cell lysate wereadded to 150 ml of a solution kept thermostatically at 60 °C, and having the following composition of substrate solutions:1. 15 mM Uridine/2’-Deoxyuridine,2. 5 mM 2,6-Diaminopurine, and3. 30 mM potassium phosphate buffer, pH 7.[0084] After 5 hours, the reaction mixture was filtered by centrifugation at 2000 3g for 30 min, at 4°C, through anAmicon ultra-4 Centrifugal Filter Devices (Millipore, Bedford, MA) with a 3000-Da cut-off, and the filtrate was recovered.In table 3, the production yields of 2,6-Diaminopurine nucleosides prepared in the presence of co-solvents is shown.The resulting 2,6-Diaminopurine nucleosides (2,6-Diaminopurine riboside or 2,6-Diaminopurine deoxyriboside) wereanalyzed by HPLC. In these reactions, the products were obtained in high yields (over 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20 - 100℃; for 1h; Stage #2: 2-methoxy-ethyl p-toluenesulfonyloxy ester In N,N-dimethyl-formamide; mineral oil at 50℃; for 16.3333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.8% | Weigh 2,6-diaminopurine nucleoside (CAS No.: 2096-10-8) and dissolve 135.58kg in 1350L DMF.The reaction solution is cooled to 0 ± 2 C,Add NaH 29.10kg under argon protection.The temperature of the addition process was 0 C to 5 C, and the mixture was stirred at 0 C for 1 h.After the above reaction system naturally returns to room temperature,Drop into the system2-bromoethyl ethyl ether 73.64 kg,The reaction was stirred at room temperature.The reaction to the product no longer increases.The water quenching reaction was slowly added to the system at 0 ± 2 C.A 2 M HCl solution was slowly added to the system to adjust the pH to neutral.Concentrate in a vacuum at 65 C until it drops.The residual solid is crystallized in ethanol72.91kg of pale yellow solid,It is a 2'-EOE-2,6-diaminopurine nucleoside.The purity was 98.3%, and the yield was 42.8%. | |
42.8% | Weigh 2,6-diaminopurine nucleoside (CAS No.: 2096-10-8, compound C) 135.58kg dissolved in 1350LDMF, the reaction solution was cooled to 0±2C, and NaH 29.10kg was added under argon protection. The process temperature was 0 C - 5 C, and the mixture was stirred at 0 C for 1 h. After naturally returning to room temperature, 73.64 kg of 2-bromoethylethyl ether was added dropwise to the system, and the reaction was stirred at room temperature. The reaction to the product no longer increases. The reaction was quenched by slowly adding water to the system at 0 ± 2 C. A 2 M HCl solution was slowly added to the system to adjust the pH to neutral. Concentrate in a vacuum at 65 C until it drops.The residual solid is crystallized in ethanol72.91 kg of pale yellow solid. The purity was 98.3%, and the yield was 42.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: adenosine-2-amine With potassium hydroxide In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; Industrial scale; Stage #2: 1-Bromotetradecane In N,N-dimethyl-formamide at 60℃; Inert atmosphere; Industrial scale; | 1; 4-26 Weigh 13 kg of 2,6-diaminopurine nucleoside (CAS number: 2096-10-8) and dissolve it in 1300 L DMF. The reaction solution was heated to 60 ° C, and 0.52 kg of KOH was added under the protection of argon.After the addition was completed, the mixture was stirred at 60 ° C for 2 hours. 19.2 kg of 1-bromotetradecane was then added dropwise to the system, and the reaction was stirred at 60 ° C after the drop was completed.The reaction was continued until the product no longer increased. It was then concentrated under vacuum at 65 ° C until no drops, and the residual solid was crystallized from ethanol (80% ethanol by volume, and 260 kg of ethanol) to obtain 18 kg of a pale yellow solid, the isoguanine nucleoside intermediate.The purity was 98.94% and the yield was 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.08% | Stage #1: adenosine-2-amine With potassium hydroxide In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; Industrial scale; Stage #2: 1-dodecylbromide In N,N-dimethyl-formamide at 60℃; Inert atmosphere; Industrial scale; | 2 Weigh 13 kg of 2,6-diaminopurine nucleoside (CAS number: 2096-10-8) and dissolve it in 1300 L DMF. The reaction solution was heated to 60 ° C, and 0.52 kg of KOH was added under the protection of argon.After the addition was completed, the mixture was stirred at 60 ° C for 2 hours. Then, 17.2 kg of 1-bromododecane was added dropwise to the system, and the reaction was stirred at 60 ° C.The reaction was continued until the product no longer increased. It was then concentrated under vacuum at 65 ° C until no drops, and the residual solid was crystallized from ethanol (80% ethanol by volume, and 260 kg of ethanol) to obtain 15.2 kg of a pale yellow solid, the isoguanine nucleoside intermediate,The purity was 98.62% and the yield was 73.08%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.38% | Stage #1: adenosine-2-amine With potassium hydroxide In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; Industrial scale; Stage #2: hexadecanyl bromide In N,N-dimethyl-formamide at 60℃; Inert atmosphere; Industrial scale; | 3 Weigh 13 kg of 2,6-diaminopurine nucleoside (CAS number: 2096-10-8) and dissolve it in 1300 L DMF. The reaction solution was heated to 60 ° C, 0.52 kg of KOH was added under the protection of argon, and stirred at 60 ° C. 2 hour. Then, 21.1 kg of 1-bromohexadecane was added dropwise to the system. After the dropwise addition was completed, the reaction was stirred at 60 ° C. The reaction was continued until the product no longer increased. It was then concentrated under vacuum at 65 ° C until no drops. The residual solid was crystallized from ethanol (80% ethanol by volume and 260kg ethanol) to obtain 16.4kg of a pale yellow solid, the isoguanine nucleoside intermediate, with a purity of 98.62% The yield is 70.38%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl 16-bromohexadecanoate; adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 45℃; for 5.5h; Stage #2: Enzymatic reaction; Stage #3: 4,4'-dimethoxytrityl chloride With pyridine at 22℃; for 24h; | 1 Compounds 219 and 220: To the suspension of Compound 218 in dry dimethylformamide, sodium hydride (60% dispersion in mineral oil) is added at 0 °C and stirred for 30 minutes. Ice bath is removed, and the reaction mixture is warmed to 45 °C and stirred for 5 hours, after which the solvent is evaporated in high vacuum pump and solid mass is purified by combiflash chromatography to afford a mixture of Compounds 219 and 220; Compounds 221 and 222: Compounds 219 and 220 are converted to Compounds 221 and 222 respectively with adenosine deaminase (ADA), as described in Robins et. al. (Can. J. Chem.1997, 75, 762-767); Compounds 223 and 224: To a clear solution of a mixture of Compounds 221 and 222 in dry pyridine is added 4,4'-dimethoxytrityl chloride in three portions. The reaction mixture is stirred for 24 hour at 22 °C and then quenched with saturated NaHCO3 solution. The resulting mixture is extracted with DCM. The combined organic layer is separated, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate is evaporated to dryness. The crude compound is purified by combiflash chromatography to afford Compounds 223 and 224. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 45℃; for 5.5h; | 1 Compounds 219 and 220: To the suspension of Compound 218 in dry dimethylformamide, sodium hydride (60% dispersion in mineral oil) is added at 0 °C and stirred for 30 minutes. Ice bath is removed, and the reaction mixture is warmed to 45 °C and stirred for 5 hours, after which the solvent is evaporated in high vacuum pump and solid mass is purified by combiflash chromatography to afford a mixture of Compounds 219 and 220. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl 16-bromohexadecanoate; adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 45℃; for 5.5h; Stage #2: Enzymatic reaction; | 1 Compounds 219 and 220: To the suspension of Compound 218 in dry dimethylformamide, sodium hydride (60% dispersion in mineral oil) is added at 0 °C and stirred for 30 minutes. Ice bath is removed, and the reaction mixture is warmed to 45 °C and stirred for 5 hours, after which the solvent is evaporated in high vacuum pump and solid mass is purified by combiflash chromatography to afford a mixture of Compounds 219 and 220; Compounds 221 and 222: Compounds 219 and 220 are converted to Compounds 221 and 222 respectively with adenosine deaminase (ADA), as described in Robins et. al. (Can. J. Chem.1997, 75, 762-767). |
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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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