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CAS No. : | 146-77-0 | MDL No. : | MFCD00005734 |
Formula : | C10H12ClN5O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BIXYYZIIJIXVFW-UUOKFMHZSA-N |
M.W : | 301.69 | Pubchem ID : | 8974 |
Synonyms : |
Antibiotic AT-265B;NSC 36896;BRN 0043957;CADO
|
Chemical Name : | (2R,3R,4S,5R)-2-(6-Amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol |
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 : | 4.0 |
Molar Refractivity : | 67.68 |
TPSA : | 139.54 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) : | -8.4 cm/s |
Log Po/w (iLOGP) : | 0.97 |
Log Po/w (XLOGP3) : | -0.37 |
Log Po/w (WLOGP) : | -1.64 |
Log Po/w (MLOGP) : | -2.16 |
Log Po/w (SILICOS-IT) : | -1.72 |
Consensus Log Po/w : | -0.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.68 |
Solubility : | 6.33 mg/ml ; 0.021 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.1 |
Solubility : | 2.41 mg/ml ; 0.00799 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.19 |
Solubility : | 193.0 mg/ml ; 0.64 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P201-P202-P281-P308+P313-P405-P501 | UN#: | N/A |
Hazard Statements: | H361 | 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 |
---|---|---|
88% | With perchloric acid In water at 20℃; for 8 h; Inert atmosphere | [0042] Under N2(g), 2-chloroadenosine (Ila, 20 g, 66.3 mmol), 2,2-dimethoxypropane (DMOP, 60 mL) and aqueous HCIO4 (70percent wt, 3 mL) was stirred at room temperature for 8 h. The pH of the reaction mixture was slowly adjusted with a saturated aq. NaHC03 (ca.120 mL) to 7-9. After stirring in ice bath for 2 h, the mixture was filtered, washed with water (50 mL) and then dried under vacuum at 50°C for 6 h to afford the compound of formula lib with 99percent purity in 88percent yield. [0043] 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), δ 7.87 (s, 2H), δ 6.06 (d, J = 2.4 Hz, 1H), δ 5.28 (dd, J =6 Hz, 2.4 Hz, 1H), δ 5.08 (t, J = 5.6 Hz, 1H), δ 4.94 (dd, J = 6 Hz, 2 Hz, 1H), δ 4.21 (m, 1H), δ 3.54 (m, 2H, ), δ 1.54 (s, 3H), δ 1.33 (s, 3H). [0044] 13C NMR (100 MHz, DMSO-d6) δ 157.3, 153.6, 150.4, 140.4, 1 18.6, 1 13.6, 89.8, 87.2, 83.9, 81.7, 62.0, 27.5, 25.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | at 20℃; for 22 h; Cooling with ice; Inert atmosphere | A mixture of p-toluenesulfonic acid (PTSA) (1.72g, 10mmol) and dry acetone (20ml) was added dropwise into a stirring mixture of 2-chloro-adenosin (309mg, 1mmol) and dry acetone (20ml) in ice-water bath. The mixture was stirred at room temperature for 22h and then was poured into ice sodium bicarbonate solution (4percent w.t.) with stirring until the bubble disappeared. The liquid was then extracted with CH2Cl2 for three times. The organic layers were dried over anhydrous MgSO4 and concentrated to afford a faint yellow solid 7 (283mg, 83percent). 1H NMR (400MHz, DMSO-d6): δ=8.37 (s, 1H, imidazole-H), 7.89 (br., 2H, NH2), 6.06 (d, J=2.4Hz, 1H, 1′-H), 5.28–5.30 (m, 1H, 2′-H), 5.10–5.12 (m, 1H, OH), 4.93–4.95 (m, 1H, 3′-H), 4.21–4.23 (m, 1H, 4′-H), 3.54–3.57 (m, 2H, 5′-H), 1.55 (s, 3H, CH3), 1.33ppm (s, 3H, CH3); HRMS (ESI) m/z [M+H]+ calcd. for C13H17ClN5O4: 342.0969, found: 342.0968. |
83% | at 20℃; for 22 h; Cooling with ice | A mixture of 2-chloro-adenosine 309mg (1mmol) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone, p-toluenesulfonic acid 8 ~ 12mmol (preferably 10 mmol) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone. Acetone solution under ice-water bath and p-toluenesulfonic acid acetone solution was slowly dropped into 2-chloro-adenosine, and stirred at room temperature 12 ~ 36 h (preferably 22h). The reaction mixture was poured into 4percent aqueous sodium bicarbonate and ice, and extracted with methylene chloride, the organic layer was collected, dried over magnesium sulphate, filtered and concentrated to afford the product as a white powder after drying, a yield of 83percent. |
82% | With sulfuric acid In water at 20℃; for 2 h; Inert atmosphere | [0086] Under N2(g), 2-chloroadenosine (Ila, 10 g, 33.15 mmol), acetone (200 mL) and cone. H2SO4 (98percent wt, 5 mL) was stirred at room temperature for 2 h. The pH of the reaction mixture was slowly adjusted with a saturated aq. NaHC03 to 7-9. DCM (200 mLx2) was used to extract the aqueous phase twice. The combined organic phase was washed with brine (100 mL) and then dried with anhydrous Na2S04. The isolated dried organic phase was evaporated under vacuum at 50°C to give suspension. The mixture was filtered and dried to afford the compound of Formula lib with 99percent purity in 82percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 20℃; for 4 h; Inert atmosphere | To an adenosine 3 (1.0 g, 3.74 mmol, 1 equiv) in acetone (30 mL/mmol) was added dry tosylic acid (10 equiv) at room temperature under an argon atmosphere. The resulting mixture was stirred at room temperature for 4 h. After completion of reaction (indicated by TLC), the reaction mixture was cooled to 0 °C and sat. aq. NaHCO3 solution added until the pH of the mixture became slightly basic. Acetone was evaporated under reduced pressure and the residue was extracted in EtOAc (3 × 30 mL). The combined organic fractions were washed with brine (1 × 15 mL), dried over MgSO4 and evaporated under reduced pressure to afford the title compound 5 as white solid (0.625g, 54percent). Rf = 0.45 (10percent MeOH in DCM). Mp = 228−230 °C. 1H NMR (500 MHz, DMSO-d6) δH = 8.34 (s, 1H, HAr), 8.16 (s, 1H, HAr), 7.35 (bs, 2H, Ar-NH2), 6.12 (d, J = 3.1 Hz, 1H, CHribose), 5.34 (dd, J = 6.4, 3.1 Hz, 1H, CHribose), 5.24 (bs, 1H, 5-OH), 4.96 (dd, J = 6.15, 2.45 Hz, 1H, CHribose), 4.23-4.20 (m, 1H, CHribose), 3.58-3.51 (m, 2H, 5-CH2), 1.54 (s, 3H, CH3), 1.32 (s, 3H, CH3), general assignments were confirmed by 1H-1H gCOSY. 13C NMR (125 MHz, DMSO-d6) δC = 156.1 (Cquat), 152.6 (Cquat), 148.8 (Cquat), 139.7 (CHAr), 119.1 (Cquat), 113.0 (CHAr), 89.6 (CHribose), 86.4 (CHribose), 83.2 (CHribose), 81.4 (CHribose), 61.6 (5-CH2), 27.1 (CH3), 25.2 (CH3), general assignments were confirmed by 1H-13C HSQC. LRMS (ESI): 330 [M + Na]+, HRMS (ESI): calcd for [C13H17N5O4 + Na]+ 330.1172, found 330.1169 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In methanol for 18h; Heating; | |
With methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol; water at 100℃; for 132h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydrazine monohydrate at 20℃; for 4h; | |
87% | With hydrazine monohydrate In water monomer at 45 - 50℃; | 1 Preparation of 2-hydrazino adenosine Hydrazine hydrate (80% in water) solution (500.00 mL) was heated at 45° C. to 50° C. and charged 2-chloroadenosine (100.00 gm) at 45° C. to 50° C. in one lot. Heated reaction mass at 45° C. to 50° C. for 6-8 hours (until 2-chloro adenosine consumed completely) and reaction mass monitored by HPLC. Cooled reaction mass to 25-30° C. and started addition of 30% NaCl solution into reaction mass at 25-30° C. Stirred reaction mass at 25-30° C. overnight. Filtered the reaction mass and washed with process water (100.00 mL*3), Suction dried well. Dried at 50-60° C. Dry Weight: 80.00-85.00 gm (% of Yield: -80-87%) |
81.4% | With hydrazine at 40 - 55℃; for 2h; | 2.A; 2.B EXAMPLE 2 A. Preparation of 2-Hvdrazinoadenosine (2)[0060] A flask equipped with a mechanical stirrer, gas inlet, gas outlet and thermocouple was flushed with argon. 2-Chloroadenosine hemihydrate (53.1 g) was added, followed by hydrazine monohydrate (134 g). The mixture was stirred while heating to 40-450C for 2 hours. The progress of the reaction was followed by TLC analysis. When the reaction was complete, the heat source was removed and ethanol (800ml) was added. The mixture was stirred for 2 hours at ambient temperature, then the precipitate collected by filtration. The filter cake was washed with ethanol and dried under reduced pressure for 30 minutes. The solids were transferred to a clean flask equipped with a mechanical stirrer and water (300 ml) was added. The suspension was stirred at room temperature for 18 hours, and the solids isolated by filtration. The filter cake was washed with ice-cold water (300 ml) followed by a wash with ice-cold ethanol (300 ml). The solid was dried under reduced pressure to provide 2-hydrazinoadenosine (41.38g, 81.4% yield, 99.3% purity).; B. Alternative Preparation of 2-Hvdrazinoadenosine (2)[0061] A reaction vessel containing hydrazine hydrate (258 g, 250 ml) was heated to 40-50°C. To the warm mixture 2-chloroadenosine hemihydrate (100 g) was added in portions, maintaining the temperature between 45-55°C. The temperature was kept at this temperature for two hours, and then deionized water (500 ml) was added over a period of 30 minutes, maintaining the temperature at 45-55°C. The mixture was then gradually cooled to 0-50C over a period of 3 hours, then stirred at this temperature for a further 30 minutes. The solid was then filtered off, and washed with cold (2-5°C) deionized water (200 ml), followed by ethanol (400 ml). The solid was dried under vacuum for 12 hours, to provide 2-hydrazinoadenosine. |
81% | With hydrazine hydrate monohydrate In water monomer at 40 - 45℃; for 2.5h; | 1.A Preparation of 2-Hydrazinoadenosine (Compound 1) from 2-Chloroadenosine A mixture of 2-Chloroadenosine (100 g; 0.33 moles) and hydrazine hydrate (60-65% in water; 300 ml)was stirred while heating to 40-45 oc for 2.5 hours. The reaction mixture was then brought to 20-25°Cand diluted under stirring with 96% ethanol (900 ml); the reaction mixture was then maintained under stirring for 8-10 hours and the precipitate collected by filtration. The filter cake was sequentially washedwith water (400 ml) and ethanol cooled at ooc (400 ml); the solid recovered was dried under reducedpressure for 24 hours at 40°C to afford 2-hydrazinoadenosine (80 g, 0.27 moles; 81% molar yield). Compound 1 obtained according to methods A and B showed the same chemical-physical properties:1 H-NMR (DMSO-d6). o 3.55 (m, 1 H), 3.62 (m, 1 H), 3.0-4.0 (2bs partially overlapped to the previous system; 3H), 3.80 (dd, 1H), 4.15 (dd, 1H), 4.60 (t, 1H), 5.10 (bs, 2H), 5.90 (d, 1H), 6.90 (br s, 2 H), 7.25(s, 1H), 7.98 (s, 1H). MS (ESI positive): detectable the protonated molecular ion at m/z=298.4 IR (ATR). cm-1 : 3504, 3435, 3324, 3156,2941,2913, 1643, 1585, 1476, 1049, 1030. |
81.4% | With hydrazine at 40 - 62℃; for 2h; | 2.A; 2.B; 2.C [0067] A flask equipped with a mechanical stirrer, gas inlet, gas outlet and thermocouple was flushed with argon. 2-Chloroadenosine hemihydrate (53.1 g) was added, followed by hydrazine monohydrate (134 g). The mixture was stirred while heating to 40-450C for 2 hours. The progress of the reaction was followed by TLC analysis. When the reaction was complete, the heat source was removed and ethanol (800ml) was added. The mixture was stirred for 2 hours at ambient temperature, then the precipitate collected by filtration. The filter cake was washed with ethanol and dried under reduced pressure for 30 minutes. The solids were transferred to a clean flask equipped with a mechanical stirrer and water (300 ml) was added. The suspension was stirred at room temperature for 18 hours, and the solids isolated by filtration. The filter cake was washed with ice-cold water (300 ml) followed by a wash with ice-cold ethanol (300 ml). The solid was dried under reduced pressure to provide 2-hydrazinoadenosine (41.38g, 81.4% yield, 99.3% purity).; [0068] A reaction vessel containing hydrazine hydrate (258 g, 250 ml) was heated to 40-500C. To the warm mixture 2-chloroadenosine hemihydrate (100 g) was added in portions, maintaining the temperature between 45-55°C. The temperature was kept at this temperature for two hours, and then deionized water (500 ml) was added over a period of 30 minutes, maintaining the temperature at 45-55°C. The mixture was then gradually cooled to 0-50C over a period of 3 hours, then stirred at this temperature for a further 30 minutes. The solid was then filtered off, and washed with cold (2-5°C) deionized water (200 ml), followed by ethanol (400 ml). The solid was dried under vacuum for 12 hours, to provide 2-hydrazinoadenosine.; [0069] A reaction vessel is charged with hydrazine hydrate (1285 g). The solution is heated to approximately 62°C, and 2-chloroadenosine (500 g) is added while maintaining the temperature of approximately 62°C. The mixture is maintained at a target of 62°C for at least 2 hours, until the level of residual 2-chloroadenosine in the mixture is not more than 0.10%. The mixture is cooled to approximately 400C and the mixture is checked to verify the presence of solids. Water (2275 g) is slowly added while maintaining the temperature at approximately 400C. The mixture is cooled to approximately 100C and held for not less than 1 hour. The product is isolated by filtration, washed with water (1195 g) and then with absolute ethanol (1885 g). The product is dried under vacuum at up to 300C for not less than 12 hours, to give 2- hydrazinoadenosine. |
81.8% | With potassium carbonate; hydrazine hydrate monohydrate at 60 - 70℃; for 0.5h; | 1.1 Preparing 2-hydrazinoadenosine from 2-chloroadenosine. Add a compound of formula (1) 2-chloroadenosine (10 g, 33.147 mmol), potassium carbonate (5.04 g, 36.461 mmol), hydrazine hydrate (20 mL, 349.78 mmol) into a 500 mL round bottom flask, and place the mixture at 60 ° C to After stirring at 70°C (70°C in this example) until the solution is clear and transparent, stirring is continued for 25 to 45 minutes (30 minutes in this embodiment). After the stirring was completed, the mixture was cooled to room temperature (15° C to 35°C, hereinafter the same), 250 mL of methanol was added to the round bottom flask, and the mixture was stirred for 10 minutes.The reaction mass was subsequently stirred at 0 ° C. overnight (8-12 h) to obtain a white solid;After suction filtration under reduced pressure, the crude product was washed with 200 mL of methanol, and then dried at 50 ± 5 ° C. overnight (8-12 hours, the same applies hereinafter) to obtain the product 2-hydrazinoadenosine, as shown in formula (2).Yield in this step: 8.0612 g (81.8%). |
With hydrazine | ||
With hydrazine hydrate monohydrate at 20℃; | ||
With hydrazine monohydrate at 20℃; for 10h; | 5.1 General procedure for preparation of 2-(methyl)hydrazinoadenosine derivatives: Synthesis of compounds 8 and 9 General procedure: Solution of 7 (1.5 g, 5 mmol) in 5 mL of hydrazine hydrate for synthesis of 8 or methylhydrazine for synthesis of 9 was allowed to stir over night till disappearance of 7 determined by TLC (CH2Cl2:MeOH = 3:1). 2-Propanol (50 mL) was added to the reaction mixture and the formed gum was taken in water (100 mL) and stirred for additional 5 h. The precipitated product was filtered and washed with water and dried to give the pure product in about 80% overall yield after concentration of the mother liquor and collection of the remaining product. | |
80 g | With hydrazine hydrate monohydrate In water monomer at 40 - 45℃; for 2.5h; | 1.A Preparation of 2-Hydrazinoadenosine (Compound 1) from 2-Chloroadenosine A mixture of 2-Chloroadenosine (100 g; 0.33 moles) and hydrazine hydrate (60-65% in water; 300 ml) wasstirred while heating to 40-45 °C for 2.5 hours. The reaction mixture was then brought to 20-25°C and diluted understirring with 96% ethanol (900 ml); the reaction mixture was then maintained under stirring for 8-10 hours and theprecipitate collected by filtration. The filter cake was sequentially washed with water (400 ml) and ethanol cooled at 0°C(400 ml); the solid recovered was dried under reduced pressure for 24 hours at 40 °C to afford 2-hydrazinoadenosine(80 g, 0.27 moles; 81% molar yield). |
With hydrazine hydrate monohydrate In water monomer at 50 - 65℃; for 2h; | 1 Example 1 Example 1 Preparation of 2-Hydrazino Adenosine from 2-Chloro Adenosine Hydrazine hydrate (80% in water) solution (500.00 mL) was heated at 50° C.-55° C. and charged 2-chloroadenosine (100.00 gm) at 50° C.-55° C. in one lot. Heated reaction mass at 50° C.-65° C. for 2 hours (until 2-chloro adenosine consumed completely) and reaction mass monitored by HPLC. Distil out the reaction mass completely under vacuum at 70-75° C. and then charge process water (200 ml), again distil out reaction mass under vacuum at 70-75° C. followed by degassing. Charge process water in degassed material and then stirred reaction mass at 55-60° for 30 minutes. Cooled the reaction mass at 25-30° C. and stir for 1 hour. Filtered the reaction mass and washed with process water (100.00 mL*3), Suck dried well. Dried at 45-50° C. Dry Weight: 70.00-85.00 μm | |
With hydrazine hydrate monohydrate at 20℃; for 10h; | 1 Compound 1 (500 mg, 1.56 mmol) was dissolved in ammonia saturated methanol solution, added to a high pressure reaction flask, and stirred at 80 ° C for 7 h.Evaporate the solvent under reduced pressure.The product was purified through silica gel column (dichloromethane: methanol = 9: 1) to give compound 2.The compound 2 (380 mg, 1.25 mmol) was dissolved in 2 ml of hydrazine monohydrate, and the reaction was stirred at room temperature for 10 h, and the unreacted hydrazine was removed by evaporation under reduced pressure.The product was purified by column chromatography over silica gel (dichloromethane: methanol = 5: 1) to afford compound 3.Compound 3 (237 mg, 0.8 mmol) was suspended in 150 ml of ethanol, and methyl 2,2-diformylacetate (149 mg, 1.04 mmol) was added, and the mixture was refluxed for 2 h.The reaction solvent was removed by evaporation under reduced pressure, a yellow solid product was purified by silica gel column chromatography (dichloromethane: methanol = 5: 1) to obtain compound 4;.Compound 4 (202 mg, 0.5 mmol) was suspended in 10 ml of 1 M potassium hydroxide in methanol and stirred at room temperature for 20 h., To give an ester bond cleavage, the organic solvent was distilled off under reduced pressure, the solid was dissolved in ml of water, adjusted to pH 4.0 with 1M HCl, the precipitated solid was filtered, washed with Compound 5. Compound 5 (170 mg, 0.45 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (427 mg, 0.9 mol) and 1-hydroxybenzotriazole (171 mg, 0.9 mol) dissolved in 2 ml of anhydrous DMF,Add 95μl N- tert-butoxycarbonyl group - ethylenediamine, 17H reaction was stirred at room temperature, the solvent was distilled off under reduced pressure, the solid product was recrystallized from methanol to give compound 6.Compound 6 (150 mg, 0.27 mmol) was dissolved in 6 ml of a mixed solution of trifluoroacetic acid and dichloromethane, and stirred at room temperature for 4 h.The solvent was removed under reduced pressure to give the desired product as a white solid, a Reg-NH2 evaporated. | |
4.4 g | With hydrazine monohydrate In water monomer at 50℃; for 4h; | 2-Hydrazinoadenosine (11). First, 5 g of 2-chloroadenosine (10)in 25 ml of hydrazine hydrate (65% in water) was stirred while heating to 50 °C for 4 h until 2-chloroadenosine (11) disappearedaccording to TLC (CH2Cl2:MeOH 3:1). The reaction mixture wasthen brought to 25 °C and diluted with 2-propanol (50 ml) withstirring overnight. The resulting precipitate was isolated by filtrationto yield 4.4 g of 2-hydrazinoadenosine as a yellow solid. |
4.4 g | With hydrazine hydrate monohydrate In water monomer at 50℃; for 4h; | 1.3 1.3 Synthesis of (2R,3R,4S,5R)-2-(6-amino-2-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol (Compound of Formula V) 5g (0.017mol) of (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound of Formula IV) was added to 25ml of hydrazine hydrate (65wt% aqueous solution), the resulting mixture was heated to 50°C while stirring, continuously heated for 4 hours until the reactant (Compound of Formula IV) disappeared, in which the progress of the reaction was monitored by TLC (CH2Cl2:MeOH = 3:1 (v/v)). Then the reaction mixture was heated to 25°C, and 2-propanol (50ml) was added for dilution, then stirred overnight. The separated precipitate was filtered to obtain 4.4g of yellow solid (2R,3R,4S,5R)-2-(6-amino-2-hydrazino-9H-purin-9-yl)- 5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound of Formula V), which was directly used in the next reaction. |
4.4 g | With hydrazine hydrate monohydrate In water monomer at 50℃; for 4h; | 1.3 1.3 Synthesis of (2R,3R,4S,5R)-2-(6-amino-2-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol (Compound of Formula V) 5g (0.017mol) of (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound of Formula IV) was added to 25ml of hydrazine hydrate (65wt% aqueous solution), the resulting mixture was heated to 50°C while stirring, continuously heated for 4 hours until the reactant (Compound of Formula IV) disappeared, in which the progress of the reaction was monitored by TLC (CH2Cl2:MeOH = 3:1 (v/v)). Then the reaction mixture was heated to 25°C, and 2-propanol (50ml) was added for dilution, then stirred overnight. The separated precipitate was filtered to obtain 4.4g of yellow solid (2R,3R,4S,5R)-2-(6-amino-2-hydrazino-9H-purin-9-yl)- 5-(hydroxymethyl)tetrahydrofuran-3,4-diol (Compound of Formula V), which was directly used in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol; | Intermediate 12: 2-Chloroadenosine A stream of ammonia was bubbled through anhydrous methanol (25 ml) for 30 mins. at 0 C. The solution was added to a mixture of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine ** (2.000 g, 4.5 mmol) in dry methanol (5 ml) and allowed to warm to 20 C. over 24 h. More ammonia was bubbled through the solution after a further 6 h and subsequently after a further 20 h. Solvent was removed in vacuo and the residue was purified by column chromatography on flash silica (neat ethyl acetate) to afford the title compound as a white solid (1.152 g). TLC SiO2 (neat ethylacetate) Rf=0.15 ** M. J. Robins and B. Uznanski, Canad. J. Chem., 1981, 59(17), 2608 | |
With ammonia; In ethanol; at 20℃; for 72h; | Compound (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(2-amino-6-chloro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (6b) 0.6 g (2.34 mmol) and 0.92 g (11.76 mmol) of acetyl chloride were dissolved in 20 mL anhydrous dichloromethane under argon atmosphere in ice bath. To this benzyltriethylammonium nitrite4 0.8 g was added dropwise within one hour and the reaction mixture was stirred at 0 C for 60 min. The reaction mixture was taken into a separation funnel and washed with 100 mL of water and the dichloromethane was evaporated under reduced pressure. The residue was taken and to which 25 mL of a solution of saturated ammonia in ethanol solution was added and the reaction mixture was stirred at room temperature for 3 days, 10 mL excess of ammonia in ethanol was added to the reaction mixture every day during the 3 days reaction time. After this, no more progress in the reaction was observed, the solvent was removed under reduced pressure and the residue was subjected to column chromatography (dichloromethane : methanol = 9 : 1) to give the pure product in about 20% overall yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; for 24h; | 18 EXAMPLE 18-2-CHLORO-3, 5-O- (1, 1, 3, 3-tetraisopropyldisiloxan-1, 3- diyl) adenosine [70] To a solution of 2-chloroadenosine (5.0 g, 17 mmol) and 1,3-dichloro- 1, 1,3, 3-tetraisopro-pyldisiloxane (6.3 g, 20 mmol) in a mixture of 40 mL of anhydrous THF and 20 mL of DMF was added imidazole (7.91 g, 116 mmol) in portions. The solution was stirred at room temperature for 24 hours under nitrogen and then concentrated under reduced pressure. The residue was taken up in 100 mL of ethyl acetate and partitioned against 60 mL of water. The layers were separated and the organic portion was washed with 2M aqueous NAOH (2 x 60 mL). The organic layer was dried over MGS04 and concentrated to yield 15 g of a viscous oil The product was purified by chromatography on silica gel eluting with a gradient of 0-100% ethyl acetate in heptane to afford the desired compound as a white solid. Yield: 6.5 g (72%). [71] 1H NMR (CDC1s) : 8 0. 91-1. 17 (m, 28H) 3.37 (br s., 1H) 3.89-4. 19 (m, 3H) 4.59 (dd, J=5. 42,0. 93 Hz, 1H) 5.04 (dd, J=7. 18,5. 61 Hz, 1H) 5.91 (d, J=1. 17 HZ, 1H) 6.14 (BR S. , 2H) 7.91 (S, 1H); LC/MS (M/Z) = 544 (M+H). |
69% | With pyridine for 1h; Ambient temperature; | |
In pyridine at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | at 140℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | at 140℃; for 4h; | |
10 EXAMPLE 10 EXAMPLE 10 A mixture of 2-chloroadenosine (15.05 g) and 2-cyclohexylethylamine (31.75 g) is stirred under nitrogen at 140° over 6 hours. The reaction mixture is cooled to room temperature, diluted with ethanol (500 ml), propylene oxide (50 ml) is added and the mixture is stirred at room temperature for 3 hours. The solid is collected by vacuum filtration, washed with ethanol, then ether, and dried at 80°/0.1 mm over 16 hours. The white solid obtained is recrystallized from ethanol to yield 2-(2-cyclohexylethylamino)-adenosine, the compound of example 4q, m.p. 142°-145°, [alpha]D25 -30.5° (c=1, dimethyl sulfoxide). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 130℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With perchloric acid; In water; at 20℃; for 8h;Inert atmosphere; | [0042] Under N2(g), 2-chloroadenosine (Ila, 20 g, 66.3 mmol), 2,2-dimethoxypropane (DMOP, 60 mL) and aqueous HCIO4 (70percent wt, 3 mL) was stirred at room temperature for 8 h. The pH of the reaction mixture was slowly adjusted with a saturated aq. NaHC03 (ca.120 mL) to 7-9. After stirring in ice bath for 2 h, the mixture was filtered, washed with water (50 mL) and then dried under vacuum at 50°C for 6 h to afford the compound of formula lib with 99percent purity in 88percent yield. [0043] 1H NMR (400 MHz, DMSO-d6) delta 8.36 (s, 1H), delta 7.87 (s, 2H), delta 6.06 (d, J = 2.4 Hz, 1H), delta 5.28 (dd, J =6 Hz, 2.4 Hz, 1H), delta 5.08 (t, J = 5.6 Hz, 1H), delta 4.94 (dd, J = 6 Hz, 2 Hz, 1H), delta 4.21 (m, 1H), delta 3.54 (m, 2H, ), delta 1.54 (s, 3H), delta 1.33 (s, 3H). [0044] 13C NMR (100 MHz, DMSO-d6) delta 157.3, 153.6, 150.4, 140.4, 1 18.6, 1 13.6, 89.8, 87.2, 83.9, 81.7, 62.0, 27.5, 25.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine In ethanol at 120℃; for 156h; Sealed tube; | |
32% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | at 140℃; for 4h; | |
With methyloxirane In methanol; ethanol; dichloromethane | 13.a EXAMPLE 13 a) A mixture of 2-chloroadenosine (0.30 g) and 2-(1-cyclohexenyl)-ethylamine (0.63 g) is stirred under nitrogen for 6 hours at 140° C. The solution is concentrated to dryness at reduced pressure; the residue is dissolved in ethanol, treated with propylene oxide (2 ml) and stirred at room temperature for 16 hours. The mixture is concentrated to dryness at reduced pressure and flash chromatographed through a 25*150 mm column of silica gel using methylene chloride and methanol saturated with ammonia (9:1) as eluent. Fractions containing the desired product are combined, concentrated to dryness at reduced pressure; the residue is redissolved in hot ethanol, the solution is decolorized with charcoal and then concentrated to dryness. The residual solid is triturated with ethanol (2 ml) and collected to afford 2-[2-(1-cyclohexenyl)-ethylamino]adenosine, m.p. 135°-38°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine In i-Amyl alcohol at 140℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine at 140℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
140 mg | With hydrogenchloride; sodium nitrite In water at 4℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 2-Chloroadenosine; trimethyl orthoformate With toluene-4-sulfonic acid at 20℃; Stage #2: at 20℃; for 3h; | |
81% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 24h; | |
With toluene-4-sulfonic acid at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With toluene-4-sulfonic acid; at 20℃; for 22h;Cooling with ice; Inert atmosphere; | A mixture of p-toluenesulfonic acid (PTSA) (1.72g, 10mmol) and dry acetone (20ml) was added dropwise into a stirring mixture of 2-chloro-adenosin (309mg, 1mmol) and dry acetone (20ml) in ice-water bath. The mixture was stirred at room temperature for 22h and then was poured into ice sodium bicarbonate solution (4percent w.t.) with stirring until the bubble disappeared. The liquid was then extracted with CH2Cl2 for three times. The organic layers were dried over anhydrous MgSO4 and concentrated to afford a faint yellow solid 7 (283mg, 83percent). 1H NMR (400MHz, DMSO-d6): delta=8.37 (s, 1H, imidazole-H), 7.89 (br., 2H, NH2), 6.06 (d, J=2.4Hz, 1H, 1?-H), 5.28?5.30 (m, 1H, 2?-H), 5.10?5.12 (m, 1H, OH), 4.93?4.95 (m, 1H, 3?-H), 4.21?4.23 (m, 1H, 4?-H), 3.54?3.57 (m, 2H, 5?-H), 1.55 (s, 3H, CH3), 1.33ppm (s, 3H, CH3); HRMS (ESI) m/z [M+H]+ calcd. for C13H17ClN5O4: 342.0969, found: 342.0968. |
83% | With toluene-4-sulfonic acid; at 20℃; for 22h;Cooling with ice; | A mixture of 2-chloro-adenosine 309mg (1mmol) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone, p-toluenesulfonic acid 8 ~ 12mmol (preferably 10 mmol) was dissolved in 10 ~ 30ml (preferably 20 ml) of acetone. Acetone solution under ice-water bath and p-toluenesulfonic acid acetone solution was slowly dropped into 2-chloro-adenosine, and stirred at room temperature 12 ~ 36 h (preferably 22h). The reaction mixture was poured into 4percent aqueous sodium bicarbonate and ice, and extracted with methylene chloride, the organic layer was collected, dried over magnesium sulphate, filtered and concentrated to afford the product as a white powder after drying, a yield of 83percent. |
82% | With sulfuric acid; In water; at 20℃; for 2h;Inert atmosphere; | [0086] Under N2(g), 2-chloroadenosine (Ila, 10 g, 33.15 mmol), acetone (200 mL) and cone. H2SO4 (98percent wt, 5 mL) was stirred at room temperature for 2 h. The pH of the reaction mixture was slowly adjusted with a saturated aq. NaHC03 to 7-9. DCM (200 mLx2) was used to extract the aqueous phase twice. The combined organic phase was washed with brine (100 mL) and then dried with anhydrous Na2S04. The isolated dried organic phase was evaporated under vacuum at 50°C to give suspension. The mixture was filtered and dried to afford the compound of Formula lib with 99percent purity in 82percent yield. |
With perchloric acid; at 0℃; for 2h; | To a suspension of 2-chloro-adenosine in acetone at 0°C was added HC104 and stirring continued for 2h. Aq. NH3 was then added and the solution concentrated in vacuo. The solution was cooled to-20°C and the resulting white precipitate of 2'3'-O- isopropylidene-2-chloro-adenosine collected and washed with acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In methanol at 20℃; | ||
14 g | With ammonia In methanol at 100℃; for 24h; Autoclave; | II 2-Chloro-9-(beta-D-ribofuranosyl)adenine (Formula III) Example II 2-Chloro-9-(beta-D-ribofuranosyl)adenine (Formula III) A solution of Formula II (30 g) in 600 mL of methanolic ammonia was heated in an autoclave at 100° C. for 24 hours. The solution was evaporated to dryness and codistilled with methanol to remove ammonia. The residue was recrystallized from Acetone. The product was dried in vacuo at 50° C. for 12 hours to yield 14 g of 2-Chloro-9-(beta-D-ribofuranosyl)adenine as a solid. |
14 g | With ammonia In methanol at 100℃; for 24h; Autoclave; | 11 2-Chloro-9-(beta-D-ribofuranosyl)adenine (Formula III) A solution of Formula II (30 g) in 600 mL of methanolic ammonia was heated in an autoclave at 100° C. for 24 hours. The solution was evaporated to dryness and codistilled with methanol to remove ammonia. The residue was recrystallized from Acetone. The product was dried in vacuo at 50° C. for 12 hours to yield 14 g of 2-Chloro-9-(beta-D-ribofuranosyl)adenine as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 2-Chloroadenosine With hydrazine hydrate at 20℃; for 16h; Stage #2: With acetic acid; sodium nitrite In water for 1h; cooling; | |
Multi-step reaction with 2 steps 1: H2NNH2*H2O / 20 °C 2: NaNO2; acetic acid / H2O / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia In methanol at 60℃; for 11h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | In tetrahydrofuran at 150℃; for 0.5h; Microwave irradiation; | 9 Example 9; Preparation of (2R.3R.4tS'.5R)-2-(6-amino-2-(4-(3.4-dichlorophenvϖpiperazin-l-vϖ-9H- purin-9-yl)-5 -(hvdroxymethyl)tetrahydrofuran-3 ,4-diol 8; Scheme 8; To a solution of 2-chloro adenosine (80mg, 0.27mmol) in THF (4mL) was added 4-(3,4- dichlorophenyl)piperazine (122mg, 0.53mmol) and the resulting solution heated in a Biotage microwave (15O0C, absorption high, pre-stirring 30s) for 30min. The solvents were then removed in vacuo and the residue purified twice by reverse phase prep HPLC (Phenomenex Synergi, RP-Hydro 150 x 10mm, lOμ, 2OmL per min, gradient 5-100% acetonitrile in water over 18min, product eluted in 80% acetonitrile) and (Phenomenex Synergi, RP-Hydro 150 x 10mm, lOμ, 2OmL per min, gradient 5-100% acetonitrile in water over 9min, product eluted in 55% acetonitrile) to yield (2R,3R,4S,5R)-2-(6-ammo-2- (4-(3 ,4-dichlorophenyl)piperazin- 1 -yl)-9H-purin-9-yl)-5 -(hydroxymethyl)tetrahydrofuran- 3 ,4-diol 8 as a white solid (7.9mg, 6%)HPLC (Phenomenex Synergi, RP-Hydro, 15O x 4.6mm, 4u, 1.5mL per min, 3O0C, gradient 5-100% acetonitrile (+0.085% TFA) in water (+0.1% TFA) over 7min - held for 30s, 200- 300nm): Retention time 4.78min, 99.26%.LCMS (Phenomenex Synergi, RP-Hydro, 15O x 4.6mm, 4u, 1.5mL per min, 3O0C, gradient 5-100% acetonitrile (+0.085% TFA) in water (+0.1% TFA) over 7min - held for 30s, 200- 300nm): Retention time 5.82min, 100%, ES+: 496.3 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 69 percent / Py / 1 h / Ambient temperature 2: 93 percent / Et3N, 4-(dimethylamino)pyridine / CH2Cl2 / 16 h / Ambient temperature 3: 55 percent / LiN3 / hexamethylphosphoric acid triamide / Ambient temperature 4: 83 percent / n-Bu4NF / tetrahydrofuran / Ambient temperature 5: 40 percent / H2 / Pd-C / ethanol / 48 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 69 percent / pyridine / 24 h / Ambient temperature 2: 80 percent / acetonitrile / Ambient temperature 3: 1) AIBN, n-Bu3SnH, 2) aq.AcOH / 1) toluene, 110-120 deg C, 3.5 h, 2) 50 deg C, 30 min | ||
In water Enzymatic reaction; Phosphate buffer; | a (a) Adenosine Phosphorylase AssayEscherichia coli DHδalpha cells were used as the source of adenosine phosphorylase to test the compounds of the present invention. E. coli DH5 alpha cells were harvested in log phase and collected by centrifugation. Cells were lysed by sonication, centrifuged at 10,000 x g for30 min and the supernatant was recovered for assay or storage at -600C.Adenosine phosphorylase activity was assayed using the cell free lysate of E. coli as enzyme source for catalysis of the cleavage of nucleoside analogs to their corresponding base analogs in the presence of 50 m M phosphate at pH 7.4. Reaction products were subjected to separation by reverse phase high performance liquid chromatography (HPLC) equipped with continuous scanning diode array detector as described below. Substrates and products were identified by retention time and UV spectra of their peaks.Samples for HPLC were prepared post reaction by deproteination with 10% v/v of 50% TCA. Following centrifugation at 10,000 g for 5 min the supernatant was recovered for neutralization. A minimal amount of bromophenol blue was added and the sample was titrated with alamine- freon. Following a further centrifugation at 10,000 g for 5 min, the neutralized sample may be stored at -60'C.Nucleosides and bases in a 10 μl sample were separated on an HPLC equipped with a scanning UV detector from 220 to 320 nm at 5 nm intervals, utilizing a reverse phase Waters Symmetry C18, 4.6x150 mm, 5 um column in tandem with a Waters guard column. Gradient separation was achieved at 30'C with the mobile phases: A, methanol; C, 10 mM phosphate, pH 3.5; and D, water according to Table 2:DMSLegal045074TO1222265440vl EPO TABLE 2Compounds were identified by retention time and UV spectra at peak height as collected during separation.The relative rate of conversion of 100 μM nucleoside analog to the corresponding base in 20 min (measured as the % of analog converted) was determined for the following compounds: 5'-deoxyadenosine, 41 %; 2- chloroadenosine, 31%; 2-chloro-5'-deoxyadenosine, 8%; 2-fluoro-5'- deoxyadenosine, >80%; 6-thiopurine-5'-deoxyriboside, 61%; 2-amino-5'- deoxyadenosine, 7%. 5'-deoxyadenosine was used as a control to show that analogs having a δ'-deoxy-substition alone are accepted; the product being adenine, which is the natural base. 2-chloroadenosine was used as a control to demonstrate that a modification of adenosine at the 2-position did not alter its ability to act as a substrate for AP. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) | 1 Example 1;-Preparation OF 2-CHLORO-2, 3', 5-TRI-O- (TERT- butyldimethylsilyl) adenosine; [44] To a stirred solution of 2001 g (6.632 mol) of 2-chloroadenosine and 9,997 g (66.32 mol) of t-butyldimethylsilyl chloride in 26L of anhydrous tetrahydrofuran and 16L of DMF was added 9030 g (132.6 mol) of imidazole. Upon disappearance of the starting material (2-chloroadenosine) by TLC, the reaction was concentrated under reduced pressure. The resultant viscous oil was diluted with ethyl acetate (20L) and washed with 2M NAOH (20L), and three times with water (20L each time). The organic layer was dried over magnesium sulfate (1000 g), filtered and the solvent removed under reduced pressure. The residual oil was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; for 24h; | 4 Example 4-2-CHLORO-2, 3, 5-TRI-O- (TRIETHYLSILYL) ADENOSINE; [47] To a stirred solution of 2-chloroadenosine (5 g, 16.6 mmol) and triethylsilyl chloride (25 g, 166 mmol) in a mixture of anhydrous THF (70 mL) and DMF (30 mL) was added, in portions, imidazole (22.6 g, 332 mmol). The reaction was stirred at room temperature for 24 hours under nitrogen, at which time the reaction was complete by TLC (SILICA/5% MEOH in CH2CL2). The reaction was concentrated on a rotary evaporator, diluted with ethyl acetate (80 mL), followed by 2 M NAOH (60 mL). The layers were separated, and the organic layer washed with additional 2 M NAOH (2 x 60 mL). After drying over MGS04, the organic extract was filtered, concentrated to a viscous oil. After passing the oil through a plug of silica gel, the desired product was obtained as a gummy, white solid. 7.2 g (67%). [48] 1H-NMR (CDCLS) : 8 0.38-0. 56 (m, 6H), 0.58-0. 76 (M, 12H), 0.81- 0.92 (M, 9H), 0.93-1. 08 (M, 18H), 3.77 (dd, 1H, J = 11.2, 2.8 Hz), 3.93-4. 05 (M, 1H), 4.07-4. 16 (M, 1H), 4.34 (t, 1H, J = 4. 1 HZ), 4.72 (t, 1H, J = 4. 5 HZ), 5.96 (d, 1H, J = 4.8 Hz), 6.22 (bs, 2H), 8. 16 (s, 1H). LC/MS: m/z 644 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: triisopropylsilyl chloride; 2-Chloroadenosine With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; for 18h; Stage #2: With dmap In tetrahydrofuran; DMF (N,N-dimethyl-formamide) for 48h; | 6 Example 6-2-CHLORO-2, 3', 5-TRI-O- (TRIISOPROPYLSILYL) ADENOSINE; [51] To a stirred solution of 2-chloroadenosine (5 g, 16.6 mmol) and triisopropylsilyl chloride (32 g, 166 mmol) in a mixture of anhydrous THF (65 mL) and DMF (40 mL) was added, in portions, imidazole (22.6 g, 332 mmol). The reaction was stirred at room temperature for 18 hours under nitrogen, at which time the reaction was shown to consist of three products by TLC (silica/5% MEOH in CH2CL2). To the mixture was added 4-dimethyl-aminopyridine (50 mg) and stirring was continued an additional 48 hours. The reaction was then concentrated on a rotary evaporator, diluted with ethyl acetate (100 mL), followed by 2 M NAOH (50 mL). The layers were separated, and the organic layer washed with additional 2 M NAOH (2 x 50 mL). After drying over MGS04, the organic extract was filtered, concentrated to a viscous oil consisting of the desired product and two di-protected compounds. The crude product was used without further purification. LC/MS: m/z 770 (M+H); 614 (M+H for bis-protected compounds). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; for 18h; | 5 Example 5-2-CHLORO-2, 3, 5-TRI-0- (isopropyldimethylsilyl) adenosine; [49] To a stirred solution of 2-chloroadenosine (5 g, 16.6 mmol) and isopropyldimethylsilyl chloride (22.7 g, 166 mmol) in a mixture of anhydrous THF (70 mL) and DMF (30 mL) was added, in portions, imidazole (22.6 g, 332 mmol). The reaction was stirred at room temperature for 18 hours under nitrogen, at which time the reaction was complete by TLC (SILICA/5% MEOH in CH2C12). The reaction was then concentrated on a rotary evaporator, diluted with ethyl acetate (80 mL), followed by 2 M NAOH (60 mL). The layers were separated, and the organic layer washed with additional 2 M NAOH (2 x 50 mL). After drying over MGSO4, the organic extract was filtered, concentrated to afford the crude product as a white solid. After passing through a plug of silica gel, the desired product was isolated as a gummy white solid. 7.0 g (70%). [50] 1H-NMR (CDC1S) : 8-0. 06 (S, 3H), -0. 02 (S, 3H), 0.06-0. 17 (M, 12H), 0.84-0. 94 (m, 3H), 0.95-1. 06 (M, 18H), 3.75 (dd, 1H, J = 11.4, 2.8 Hz), 4.00 (dd, 1H, J = 11.4, 4.2 Hz), 4.08-4. 18 (M, 1H), 4.31 (t, 1H, J = 4. 3 HZ), 4.64 (t, 1H, J = 4.4 Hz), 5.96 (d, 1H, J = 4.5 Hz), 6.32 (s, 2H), 8.17 (s, lH). LC/MS: m/z 602 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; for 18h; | 7 Example 7-2-CHLORO-2, 3, 5-TRI-O- (ISOPROPYLDIETHYLSILYL) adenosine [52] To a stirred solution of 2-chloroadenosine (5 g, 16.6 mmol) and isopropyldiethylsilyl chloride (27.4 g, 166 mmol) in a mixture of anhydrous THF (70 mL) and DMF (30 mL) was added, in portions, imidazole (22.6 g, 332 mmol). The reaction was stirred at room temperature for 18 hours under nitrogen, at which time the reaction was complete by TLC (SILICA/5% methanol in CH2CL2). The reaction was then concentrated on a rotary evaporator, diluted with ethyl acetate (80 mL), followed by 2 M NAOH (60 mL). The layers were separated, and the organic layer washed with additional 2 M NAOH (3 x 50 mL). After drying over MGS04, the organic extract was filtered, concentrated to afford the crude product as a clear oil. The oil was passed through a plug of silica gel to afford the desired product as a clear viscous oil. 15 g (100%). [53] 1H-NMR (CDCLS) : 8 0.37-0. 76 (m, 15H), 0.80-0. 96 (m, 12H), 0.96- 1.08 (m, 30H), 3.80 (dd, 1H, J = 11. 1, 2.9 Hz), 4.01-4. 09 (m, 1H), 4.10-4. 16 (m, 1H), 4.39 (t, 1H, J = 3.8 Hz), 4.70-4. 91 (m, 1H), 5.95 (d, 1H, J = 5.2 Hz), 6.13 (br. s, 2H), 8.12 (s, 1H). LC/MS: M/Z 686 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran | 4 Preparation of 2-chloroadenosine Example 4 Preparation of 2-chloroadenosine A mixture of the compound of Example 3 (271 g, 606 M), concentrated ammonium hydroxide (4 L) and tetrahydrofuran (0.5 L) is stirred at room temperature under nitrogen for 4 days. The solvent volume is reduced in vacuo and the resulting residue is triturated with absolute ethanol. The title compound is precipitated out of the ethanolic solvent to yield a light brown solid, (159 g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In propan-1-ol; ethanol | 4.i i i 2-Propoxy-adenosine 2-Chloro-adenosine (3.5 g) was added to a hot solution of NaOH (3.2 g) in n-propanol (80 ml), the mixture was heated under reflux for 3 hours. The volatiles were removed in vacuo, the residue taken into water (40 ml), cooled and acidified with 1M hydrochloric acid to pH 7. After 15 min the suspension was filtered and the filtrate evaporated. The residue was taken up in ethanol, and adsorbed onto silica which was placed on a chromatography column. Elution with 9:1, and then 4:1 CHCl3 afforded the sub-title compound (0.65 g). MS (FAB) 326 (M+ +H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In 1,4-dioxane at 120℃; for 15h; | 279 2-Chloroadenosine (200 mg, 0.66 mmol, 1 equivalent), triphenylphosphine (175 mg, 0.66 mmol, 1 equivalent), and 1,2,3-triazole (138 μL, 2.4 mmol, 3.6 equivalents) were dissolved in anhydrous dioxane under a positive pressure of nitrogen.Diisopropylazodicarboxylate (392 μL, 2.0 mmol, 3.0 equivalents) was then added dropwise at 0 0C. The resulting mixture was stirred at 120 0C for 15 h. The solvents were evaporated to give a yellow material that was used directly in next step without additional purification. MS CESP): 353 (MH+) for C12HnClN8O3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 1,4-dioxane; water at 150℃; for 0.5h; Microwave irradation; | 115 2-Chloroadenosine (200mg), [(E)-2-phenylvinyl]boronic acid (196mg), palladium te?rafc(triphenylphosphine) (I52mg), and sodium carbonate (425mg) were suspended in a mixture of dioxane (5ml) and water (ImI). The reaction was heated to 150 0C for 0.5h in a microwave reactor. The resulting reaction mixture was diluted with DCM and filtered through diatomaceous earth; the filtrate was washed with water and dried over sodium sulfate. The residue was purified by Gilson reverse phase ΗPLC. Relevant fractions were combined to give the desired product. MS (ESP): 370.11 (MH+) for C18H19N5O41H NMR (300 MHz, MeOD) δ ppm 2.10 (d, 1 H) 3.70 - 3.84 (dd, 1 H) 3.89 - 3.98 (dd, IH) 4.21 (q, 1 H) 4.37 (dd, 1 H) 4.62 (s, 1 H) 5.97 (d, 1 H) 7.05 (d, 1 H) 7.29 - 7.42 (m, 3 H) 7.51 - 7.64 (m, 4 H) 7.70 - 7.82 (m, 1 H) 7.88 (d, 1 H) 8.25 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate In <i>N</i>-methyl-acetamide; water | 2 Synthesis of 2,8-Diazidoadenosine EXAMPLE 2 Synthesis of 2,8-Diazidoadenosine To 0.15 mmoles 2-chloroadenosine are added 2 ml of 1M sodium acetate, pH 3.8, in a 5 ml screw top test tube. To this mixture is added 2 ml of bromine water containing 0.2 micromoles bromine, and the mixture is allowed to stand for 4 hours at room temperature. Unreacted bromine is removed by bubbling air through the reaction mixture. The pH is adjusted to pH 6.8 by addition of 4 M NaOH, and 2-chloro-8-bromoadenosine is crystallized from water and dried. Five mmoles of the crystals are dissolved in 25 ml anhydrous dimethylformamide, followed by the addition of 10 ml lithium azide at 18.C and 5 ml water. The mixture is added to a Dowex 1 hydroxide column (10 ml*1 ml), and then displaced from the column with 70% aqueous methanol. The mixture is evaporated, and 2,8-diazidoadenosine is obtained as crystals. The 5'-monophosphates of 2-azidoadenosine and 2,8-diazidoadenosine may be prepared according to the method of Yoshikawa et al., Tetrahedron Letters 50:5065-5068 (1967), as described in Example 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methyloxirane | 14 EXAMPLE 14 EXAMPLE 14 A mixture of 2-chloroadenosine (0.30 g) and 4-(2-aminoethyl)-stilbene (1.11 g) is stirred at 140° under nitrogen over 6 hours. It is cooled, diluted with ethanol (25 ml), treated with propylene oxide (5 ml) and stirred 1 hour at room temperature. It is filtered free of starting material and the filtrate is concentrated at reduced pressure and purified by flash chromatography through a 25*200 mm column of silica gel with CH2 Cl2 and ammonia-saturated methanol (9:1) as eluent. Fractions containing the desired material are combined and evaporated at reduced pressure and the residual solid is recrystallized from acetonitrile with charcoal treatment. The product, 2-[2-(4-stilbenyl)ethylamino]-adenosine, [alpha]D25 =-28.6° in DMSO, has m.p. 165°-169°. The starting amine is prepared in the following manner: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methyloxirane In ethanol | 20 EXAMPLE 20 EXAMPLE 20 A mixture of 2-chloroadenosine (0.3 g) and 1,4-dioxaspiro[4.5]decane-8-ethanamine (1.0 g) is heated under nitrogen at 140° for 6 hours. It is evaporated to dryness at reduced pressure, the residue is dissolved in ethanol, the solution is treated with propylene oxide (2 ml) and stirred 4 hours. The precipitate is collected, washed with ethanol and dried in vacuo to give 2-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethylamino]adenosine, [alpha]D25 =-27.3° (MeOH), m.p. 133°-137°. The starting amine is prepared in the following manner: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate | 8.a EXAMPLE 8 a) A mixture of 2-chloroadenosine (3 g) and 2-(4-β-tert-butoxycarbonylvinyl-2-thienyl)-ethylamine (11.4 g) is heated under nitrogen at 140° over 6 hours. It is cooled, the residue is dissolved in ethyl acetate, the solution is washed with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated to dryness at reduced pressure. The residue is chromatographed over silica gel with 19:1 methylene chloride: methanol saturated with ammonia as eluent followed by a 5:1 mixture of the same solvents. The fractions containing the desired product are combined and concentrated to dryness. The residue is triturated with ether to afford 2-[2-(4-β-tert-butoxycarbonylvinyl-2-thienyl)-ethylamino]-adenosine, [alpha]D -18.7° (methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen sulfide; acetic acid In <i>N</i>-methyl-acetamide; water | R.2 REFERENCE EXAMPLE 2 REFERENCE EXAMPLE 2 2.0 g of 2-chloroadenosine was dissolved in a solution of 20 ml of anhydrous hydrogen sulfide and 1.5 g of sodium metal in 80 ml of dimethylformamide, and the mixture was allowed to react at a temperature of 80°C for 5 hours under anhydrous conditions. The reaction mixture was then diluted with 80 ml of water and neutralized with acetic acid followed by concentration. The resulting concentrate was dissolved in 75 ml of a mixture of n-butanol and water (2:1 by volume), and 25 ml of acetic acid was added to the solution. After allowing the mixture to cool, the precipitated crystals were filtered to obtain 21 g (100% yield) of crude 2-thioadenosine. The product thus-obtained was dissolved in dilute aqueous ammonia and adjusted to a pH of 4 with acetic acid to obtain pure 2-thioadenosine having a melting point of 196° ~ 199°C (with decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide | 3 Preparation of 2-Carboxymethylthioadenosine EXAMPLE 3 Preparation of 2-Carboxymethylthioadenosine 200 mg of 2-chloroadenosine was suspended in 5 ml of N,N-dimethylformamide, and 23 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 800 mg of mercaptoacetic acid was then added to the solution and the mixture was heated under refluxing for 10 hours. The resulting reaction mixture was concentrated under reduced pressure to dryness and the residue was washed with petroleum ether and dissolved in a small amount of water. The resulting aqueous solution was neutralized to obtain crystalline 2-carboxymethylthioadenosine. Recrystallization from water yielded 213 mg (90% yield) of pure product having a melting point of 236° ~ 238°C (with decomposition). Elemental Analysis: Calcd. for C12 H15 O6 N5 S.1/4 H2 O (%): C: 39.83, H: 4,32, N: 19.36 Found (%): C: 39.95, H: 4.18, N: 19.22 |
Yield | Reaction Conditions | Operation in experiment |
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58% | In N,N-dimethyl-formamide | 5 Preparation of 2-(o-Tolyl)thioadenosine EXAMPLE 5 Preparation of 2-(o-Tolyl)thioadenosine 310 mg of 2-chloroadenosine was suspended in 8 ml of N,N-dimethylformamide, and 150 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 995 mg of o-toluenethiol was then added to the solution and the mixture was heated under refluxing for 7 hours. The resulting reaction mixture was neutralized with hydrochloric acid and concentrated to dryness. The resulting residue was washed with petroleum ether and crystallized from 50% aqueous ethanol to obtain 226 mg (58% yield) of 2-(o-tolyl)thioadenosine having a melting point above 270°C (with decomposition). Elemental Analysis: Calcd. for C17 H19 O4 N5 S (%): C: 52.43, H: 4.92, N: 17.98 Found (%): C: 52.36, H: 4.87, N: 18.07 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In N,N-dimethyl-formamide | 4 Preparation of 2-Phenylthioadenosine EXAMPLE 4 Preparation of 2-Phenylthioadenosine 310 mg of 2-chloroadenosine was suspended in 8 ml of N,N-dimethylformamide, and 150 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 880 mg of benzenethiol was then added to the solution and the mixture was heated under refluxing for 7 hours. The resulting reaction mixture was neutralized with hydrochloric acid and concentrated to dryness. The resulting residue was washed with petroleum ether and crystallized from 50% aqueous ethanol to obtain 210 mg (56% yield) of 2-phenylthioadenosine having a melting point of 267° ~ 268.5°C (with decomposition). Elemental Analysis: Calcd. for C16 H17 O4 N5 S (%): C: 51.19, H: 4.56, N: 18.66 Found (%): C: 51.07, H: 4.57, H: 18.56 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In N,N-dimethyl-formamide | 1 Preparation of 2-(β-Hydroxyethyl)thioadenosine EXAMPLE 1 Preparation of 2-(β-Hydroxyethyl)thioadenosine 200 mg of 2-chloroadenosine was suspended in 5 ml of N,N-dimethylformamide, and 23 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 120 mg of β-mercaptoethanol was then added to the solution and the mixture was heated under refluxing for 10 hours. The resulting reaction mixture was concentrated to dryness and the residue was washed with petroleum ether and crystallized from water to obtain 160 mg (72% yield) of 2-(β-hydroxyethyl)thioadenosine having a melting point of 212° ~ 213°C (with decomposition). Elemental Analysis: Calcd. for C12 H17 O5 N5 S (%): C: 41.97, H: 4.99, N: 20.40 Found (%): C: 42.00, H: 4.96, N: 20.31 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In N,N-dimethyl-formamide | 6 Preparation of 2-(β-Pyridyl)thioadenosine EXAMPLE 6 Preparation of 2-(β-Pyridyl)thioadenosine 310 mg of 2-chloroadenosine was suspended in 8 ml of N,N-dimethylformamide, and 150 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 880 mg of 2-pyridinethiol was then added to the solution and the mixture was heated under refluxing for 7 hours. The resulting reaction mixture was concentrated to dryness, and the residue was washed with petroleum ether and crystallized from water to obtain 300 mg (80% yield) of 2-(β-pyridyl)thioadenosine having a melting point of 212° ~ 214°C (with decomposition). Elemental Analysis: Calcd. for C15 H16 O4 N6 S (%): C: 47.87, H: 4.28, N: 22.33 Found (%): C: 47.98, H: 4.22, N: 22.12 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In ethanol; N,N-dimethyl-formamide | 2 Preparation of 2-(α-Carboxyethyl)thioadenosine EXAMPLE 2 Preparation of 2-(α-Carboxyethyl)thioadenosine 200 mg of 2-chloroadenosine was suspended in 5 ml of N,N-dimethylformamide, and 23 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 140 mg of α-mercaptopropionic acid was then added to the solution and the mixture was heated under refluxing for 10 hours. The resulting reaction mixture was extracted with petroleum ether. The aqueous layer was then concentrated to a small volume and ethanol was added to the concentrate to obtain 146 mg (66% yield) of the sodium salt of 2-(α-carboxyethyl)thioadenosine having a melting point above 270°C. Elemental Analysis: Calcd. for C13 H16 O6 N5 S.Na (%): C: 39.69, H: 4.10, N: 17.81 Found (%): C: 39.67, H: 4.02, N: 17.87 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide | 7 Preparation of 2-(β-Adamantyl)thioadenosine EXAMPLE 7 Preparation of 2-(β-Adamantyl)thioadenosine 200 mg of 2-chloroadenosine was suspended in 8 ml of N,N-dimethylformamide, and 150 mg of sodium metal was then added to the suspension to dissolve the 2-chloroadenosine. 300 mg of 2-adamantanethiol as then added to the solution and the mixture was heated under refluxing for 18 hours. The resulting reaction mixture was concentrated to dryness and the resulting residue was washed with petroleum ether and crystallized from water to obtain 244 mg (85% yield) of 2-(β-adamantyl)thioadenosine having a melting point above 270°C (with decomposition). Elemental Analysis: Calcd. for C20 H27 O4 N5 S (%): C: 55.41, H: 6.28, N: 16.16 Found (%): C: 55.43, H: 6/20, N: 16.31 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide at 80℃; for 20h; | 18 To a solution of 2-chloro-adenosine (leq) in DMSO was added NaSEt (1. 3eq) and the resulting solution heated at 80°C for 20h. The solvents were then removed in vacuo and the residue purified by reverse phase column chromatography to yield 2- ethylthio-adenosine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; sodium acetate In water at 20℃; for 16h; | 30 To a solution of 2-chloroadenosine (leq) in 1M aq. NaOAc (buffered to pH 4) was added bromine (1. 2eq) and the resulting solution stirred at rt for 16h. The reaction mixture was then quenched with aq. NaHS03, adjusted to pH 7 and cooled to 4°C. The resulting precipitate of 2-chloro-8-bromo-adenosine was collected, washed with water and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | toluene-4-sulfonic acid; In N,N-dimethyl-formamide; | [0076] 2-Chloroadenosine (6) was protected as an acetonide (7) by reaction with methyl ketal, and the 5'-hydroxyl was converted a tosylate (8) using tosyl chloride and pyridine. The amine moiety was then introduced through nucleophilic displacement to yield intermediate 9. Deprotection of the BOC group from the primary amine and purification by column chromatography yielded the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With barium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dmap; triethylamine In acetonitrile at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | at 150℃; for 2h; Inert atmosphere; Neat (no solvent); | 4.2.1 A NEAT mixture of 2-chloroadenosine (1.15 g, 8.81 mmol) and tert-butyl N-(2-aminoethyl)carbamate (3.2 g, 20 mmol) under a nitrogen stream in a 250-mL round bottom flask was heated to 150° C. for two hours, over which time turned the mixture to a red oil. The mixture was subsequently cooled to room temperature and was treated with 9:1 v/v dichloromethane-methanol (about 60 mL) with stifling, generating an orange precipitate. The precipitate was collected by filtration and dried to afford the title intermediate (1.48 g, 91.4% yield) as a white solid; TLC Rf (9:1 v/v dichloromethane-methanol) 0.26; LC/MS (ESI+) m/z 426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N,N,N,N,N,N-hexamethylphosphoric triamide; thionyl chloride at 20℃; Inert atmosphere; | 4.1.1 To a flask containing hexamethylphosphoramide (10 mL) was added thionyl chloride (1.5 mL, 2.4 g, 21 mmol) at 0° C. with stifling. The solution was allowed to reach room temperature before 2-chloroadenosine (Toronto Research Chemicals, 1.0 g, 3.3 mmol) was added portionwise. The orange suspension was stirred under nitrogen at room temperature overnight. The mixture was poured into water (90 mL) and the resulting mixture was subsequently filtered. The yellow solids were washed with water then stirred in 1N NH4OH (50 mL) for two hours. The mixture was filtered then washed with cold water. The white solid was dried under high vacuum to obtain the title intermediate (0.80 g, 76% yield); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (dd, 1H), 3.91 (dd, 1H), 4.07 (dd, 1H), 4.16 (dd, 1H), 4.65 (dd, 1H), 5.46 (d, 1H), 5.60 (d, 1H), 5.84 (d, 1H), 7.84 (br s, 2H), 8.35 (s, 1H); MS (ESI+): m/z 291, 293 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine In ethanol at 120℃; for 144h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride; potassium dihydrogenphosphate; potassium hydroxide In water; dimethyl sulfoxide at 58 - 61℃; for 4h; Enzymatic reaction; | 1a Preparation of 2-chloroadenosine (III) from 2-chloroadenine and uridine 400 g of uridine and 150 g of KH2PO4 were dissolved with stirring in a mixture of water (52 l) and DMSO (1.8 l) at 58-61° C. To the resulting solution, a first portion (0.75 l) of a solution prepared from 2-chloroadenine (85 g), water (7 l), and KOH (120 g) was added. The pH of the resulting mixture was adjusted to 7.1-7.2 with aqueous KOH solution. |
With potassium phosphate; Geobacillus thermoglucosidasius purine nucleoside phosphorylase; Thermus thermophilus pyrimidine nucleoside phosphorylase In water at 70℃; for 1h; Enzymatic reaction; | ||
With dipotassium hydrogenphosphate; purine nucleoside phosphorylase; pyrimidine nucleoside phosphorylase; glycine In aq. buffer at 60℃; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With perchloric acid In water at 20℃; for 24h; Inert atmosphere; | 3 [0052] Under N2(g), 2-chloroadenosine (Ila, 5 g, 16.58 mmol), cyclohexanone (50 mL) and HCIO4 (70% wt, 0.75 mL) was stirred at room temperature for 24 h. The reaction mixture was slowly pH adjusted with 6 N KOH (3 mL) to 7-9 and diluted with water (100 mL). DCM (50 mL*2) was used to extract the aqueous phase twice. The combined organic phase was washed with water (100 mL) and then dried with anhydrous Na2SC>4. The isolated dried organic phase was evaporated under vacuum at 50°C to dryness. The residual were passed through a silicon column to afford the compound of formula lid with 99% purity in 51% yield. [0053] 1H NMR (400 MHz, CDCI3) δ 7.82 (s, 1H), 5.97 (s, 2H), 5.81 (d, J=5.0 Hz, 1H), 5.40 (dd, J= 1 1.6, 2.0 Hz, 1H), 5.20 (t, J= 5.4 Hz, 1H), 5.10 (dd, J= 5.9, 1.1 Hz, lH), 4.53 (s, 1H), 4.00 (dt, J= 12.8, 1.8 Hz, 1H), 3.88 - 3.74 (m, 1H), 2.95 (s, 3H), 1.91-1.77 (m, 2H), 1.71 (m, 2H), 1.62 (m, 2H), 1.59-1.49 (m, 2H), 1.49-1.36 (m, 2H). [0054] 13C NMR (100 MHz, CDCI3) δ 156.3, 154.0, 149.7, 140.8, 120.0, 115.0, 94.1 , 86.1, 82.5, 81.0, 63.4, 37.5, 34.5, 24.9, 24.1 , 23.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With perchloric acid In water at 20℃; Inert atmosphere; | 5 [0072] Under N2(g), 2-chloroadenosine (Ila, 5 g, 26.53 mmol), benzaldehyde (80 mL) and HCIO4 (70% wt, 3 mL) was stirred at room temperature for overnight, and then neutralized with aq. NaHC03 to pH 7-8. The mixture was extracted with DCM for three times. The combined organic phase was washed with saturated Na2S03 to remove benzaldehyde and dried with anhydrous a2S04. The isolated dried organic phase was evaporated under vacuum at 40°C to give yellow oily residual. Then, -heptane was charged to give suspension. After filtration, the filter cake was washed with -heptane twice, followed dried at 40°C to afford Ilf (the HPLC purity of two isomers were 40.7% and 50.4%) in 48.7% net yield. [0073] 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.40 (s, 1H), 7.89 (bs, 4H), 7.61 - 7.57 (m, 2H), 7.54 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 6.26 (s, 1H), 6.24 (d, J= 4.4 Hz, 1H), 6.23 (d, J= 2.9 Hz, 1H),6.04 (s, 1H), 5.46 (dd, J= 6.5, 2.6 Hz, 1H), 5.42 (dd, J= 6.5, 3.1 Hz, 1H), 5.14 (t, J= 5.4 Hz, 1H), 5.10 (t, J= 5.6 Hz, 1H), 5.08 - 5.04 (m, 2H), 4.39 (td, J= 5.0, 2.3 Hz, 1H), 4.31 (dd, J= 9.2, 4.8 Hz, 1H), 3.63 (td, J= 5.3, 2.5 Hz, 2H), 3.58 (td, J= 5.2, 3.3 Hz, 2H). [0074] 13C NMR (100 MHz, d6-DMSO) δ 157.3, 153.7, 153.6, 150.4, 140.6, 140.4, 136.6, 136.5, 135.1, 130.3, 130.2, 130.0, 129.7, 129.6, 129.0, 128.9, 128.8, 127.5, 127.4, 118.6, 1 18.5, 107.0, 103.5, 89.8, 88.3, 87.1 , 85.0, 84.6, 83.6, 83.1 , 81.1 , 61.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 70℃; for 10h; Inert atmosphere; | 1 Example 1. Preparation of 2- {4-[(methylamino)carbonyll- lH-pyrazo 1-1 -yl} adenosine (Regadenoson) with compound of formula Ila [0040] Under N2(g), 2-chloroadenosine (5 g, 16.6 mmol), methyl pyrazole-4-carboxamide (3.11 g, 24.9 mmol), solid i-BuOK (2.79 g, 24.9 mmol) and anhydrous DMF (40 mL) were stirred at 70°C for 10 h. After cooling, water (80 mL) was charged to the reaction mixture, and stirred at room temperature overnight. The solid product was filtered, washed with water (5 mL), then with EtOH (5 mL), and dried under vacuum at 50°C for 6 h to give regadenoson with 83% purity in 16% yield. The total conversion rate was 39%. The amount of one impurity was 16%. LC- MS analysis indicated its molecular weight is 655 ([M+H]+ m/z 656), it is possibly one of the dimeric derivatives, 2 '-0-(adenosin-2-yl)-2- {4-[(methylamino)carbonyl]- 1 H-pyrazol- 1 -yl} - adenosine and/or 3 '-0-(adenosin-2-yl)-2- {4- [(methylamino)carbonyl] - 1 H-pyrazol- 1 -yl} - adenosine. | |
With caesium carbonate In N,N-dimethyl acetamide for 4h; Inert atmosphere; Reflux; | III.D 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide (Formula I) Method D 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide (Formula I) A solution of 2-Chloro-9-(beta-D-ribofuranosyl)adenine (1 eq) and 1H-pyrazole-4-carboxylic acid amide (1.1 eq) in DMA is treated with cesium carbonate in a round bottom flask under an inert atmosphere. The mixture is refluxed for 4 hand then the solvent distilled off. The crude is then slurried in acetonitrile to yield 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide. The product was further purified from DMA to provide a pure compound. The compound was recrystallized in methanol water mixtures to provide a product of >99.5% purity. Anomer content <0.15% | |
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 100 - 150℃; for 5h; Sealed tube; Inert atmosphere; | III.A 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide (Formula I) A solution of 2-Chloro-9-(beta-D-ribofuranosyl)adenine (1 eq) and 1H-pyrazole-4-carboxylic acid amide (1.1 eq) in NMP is treated with potassium carbonate (1.5 eq) in a sealed reactor under an inert atmosphere. The mixture is heated at 100-150° C. for five hours and then diluted with aqueous HCl. Purification of the crude mixture by column chromatography to yield 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-6-aminopurin-2-yl}pyrazole-4-yl)-N-methylcarboxamide. The product was further purified by recrystallization from methanol to provide a pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 2-Chloroadenosine With pyridine; trichlorothiophosphine at -15 - 0℃; Inert atmosphere; Stage #2: triethylamine With water for 4h; | General procedure for synthesis of nucleoside 5'-monothiophosphates Nucleoside analog (0.5 mmol) was dissolved in 10 ml dry pyridine with heating, if necessary. The solution wasevaporated under vacuum, and the residue was re-dissolved in 5 ml dry pyridine under Ar. The mixture was cooled in a NaCl/ice bath to -15°C, and thiophosphorylchloride (93.2 mg, 57 μl, 0.55 mmol) was added dropwise. The NaCl /ice bath was replaced by an ice bath, and 10 min after the reaction mixture reached 0°C it was poured into 100 ml water containing 385 μl triethylamine. This mixture was stirred for 4 h and then evaporated under vacuum. The residue was dissolved in water (10 ml), filtered through a 0.45 μm filter, and the product was purified by preparative ion-exchange HPLC as described in the general section. The fractions containing the product were evaporated under vacuum, and then repeatedly evaporated from methanol toremove the residual buffer. The resulting bis-triethyl ammonium salt of the modified nucleoside 5’-thiomonophosphate was dried for 8 h at high vacuum at rt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium fluoride In methanol at 80℃; for 24h; | 3.5. General Procedure for the Desilylation of Ribose Cladribine Analogues General procedure: To a 0.1 M solution of the silylated compound in anhydrous MeOH, KF (2 equiv/silyl group) wasadded. The mixture was heated at 80 °C for 24 h, cooled, and silica gel was added. The mixture wasevaporated to dryness and the compound-impregnated silica gel was loaded onto a wet-packed silica gelcolumn. The products were obtained by elution with appropriate solvents (see the individual compoundheadings for details). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetoxyisobutyryl bromide In water; acetonitrile at 20℃; for 1h; | 1 General Procedure 5 (for preparing 3' -deoxy adenosine and 3'-deoxy-2-chloroadenosine employed in the examples): A solution of H2O/CH3CN 1 :9 and then a-AIBBr (4.0 mol/eq) were added sequentially to a suspension of dried adenosine or 2-chloroadenosine in anhydrous CH3CN and stirring was continued at room temperature (20 °C). After 1 h, a saturated solution of NaHC03 was added cautiously and the solution was extracted with EtOAc. The combined organic phase was washed with brine. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over Na2S04, filtered and evaporated to give a white gum. The crude mixture was dissolved in anhydrous MeOH and stirred for 1 h with Amberlite (2 x OH") resin previously washed well with anhydrous MeOH. The solution was then filtered and the resin carefully washed with anhydrous methanol. Evaporation of the combined filtrate afforded 2',3'- dehydroadenosine or 2',3'-dehydro-2-chloroadenosine as a white solid. Using General Procedure 5: 2',3'-dehydro-2-chloroadenosine was prepared from 5.0 g (16.6 mmol) of 2-chloroadenosine, 3.0 mL of H20/CH3CN (1/9), 9.7 mL (66.2 mmol) of a-AIBBr in 38 mL of anhydrous CH3CN, and 150 mL of Amberlite (2 x OH") resin in 200 mL of anhydrous methanol. 2',3'-dehydro-2-chloroadenosine was obtained as a white solid (3.03 g, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride; potassium dihydrogenphosphate; potassium hydroxide In water; dimethyl sulfoxide at 58 - 61℃; for 4h; Enzymatic reaction; | 1b Preparation of 2-chloroadenosine (III) from 2-chloroadenine and guanosine 229 g of guanosine and 75 g of KH2PO4 were dissolved with stirring in a mixture of water (521) and DMSO (1.8 l) at 58-61° C. To the resulting solution, a first portion (0.75 l) of a solution prepared from 2-chloroadenine (42 g), water (7 l), and KOH (60 g) was added. The pH of the resulting mixture was adjusted to 7.1-7.2 with aqueous KOH solution. |
With Trypanosoma brucei purine nucleoside 2'-deoxyribosyltransferase, Y5F mutant In aq. phosphate buffer at 50℃; for 0.5h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In acetonitrile at -5 - 5℃; for 0.5h; | 2 Benzoylation of 2-chloroadenosine A solution of 2-chloroadenosine (750 g) in pyridine (7.5 l) was cooled down to -5-0° C. Afterwards, a solution of benzoyl chloride (720 g) in acetonitrile (1440 ml) was slowly added to the reaction mixture with stirring and cooling. Thereby, the internal temperature of the reaction mixture should not be higher than 5° C. The mixture was incubated for 30 min under the same conditions. Thereafter, the solvents were evaporated under reduced pressure at a temperature of 60° C. The residue was dissolved in CH2Cl2. and successively washed with 1M aqueous H2SO4 solution, saturated aqueous NaHCO3 solution, and water. The organic phase was evaporated under reduced pressure to obtain a mixture of 2-chloro-9-(2′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine and 2-chloro-9-(3′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine (both together about 65% in total by HPLC), as well as 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine (about 30% by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
880 g | Stage #1: 2-Chloroadenosine; benzoyl chloride With pyridine In acetonitrile at -5 - 5℃; for 0.5h; Stage #2: With methanol Reflux; | 3 Isomerization of 2-chloro-9-(2′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine (V) to 2-chloro-9-(3′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine (VI) A solution of 2-chloroadenosine (750 g) in pyridine (7.5 l) was cooled down to -5-0° C. Afterwards, a solution of benzoyl chloride (720 g) in acetonitrile (1440 ml) was slowly added to the reaction mixture with stirring and cooling. Thereby, the internal temperature of the reaction mixture should not be higher than 5° C. The mixture was incubated for 30 min under the same conditions. Thereafter, the solvents were evaporated under reduced pressure at a temperature of 60° C. The residue was dissolved in CH2Cl2. and successively washed with 1M aqueous H2SO4 solution, saturated aqueous NaHCO3 solution, and water. The organic phase was evaporated under reduced pressure to obtain a mixture of 2-chloro-9-(2′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine and 2-chloro-9-(3′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine (both together about 65% in total by HPLC), as well as 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine (about 30% by HPLC). The mixture of 2-chloro-9-(2′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine and 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine as prepared in Example 2 was added to 25 l of MeOH. The resulting mixture was refluxed for 40-45 hours with vigorous stirring. Afterwards, the mixture was hot-filtrated under vacuum, and the filter cake washed with MeOH. The filtrate containing 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine and 2-chloro-9-(2′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine was directed to reworking in order to obtain 2-chloroadenosine by hydrolysis. The solid was dried in vacuum at 50° C. to obtain 880 g of 2-chloro-9-(3′,5′-di-O-benzoyl-β-D-ribofuranosyl)-adenine with an HPLC purity of >98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium <i>tert</i>-butylate; palladium diacetate; triphenylphosphine; potassium thioacetate In dimethyl sulfoxide at 120℃; Inert atmosphere; | 36 Example 36 Under a nitrogen atmosphere,The substrate 2-chloroadenosine 1aa (0.1 mmol, 30.0 mg) was added to a 25 mL test tube reactor, KSAc(0.3mmol,34.2mg),DMC(0.5mmol,45mg),Pd(OAc)2(0.01mmol,2.3mg),PPh3 (0.02mmol,5.9mg),tBuOK(0.3mmol,34.6mg),and DMSO(1.5mL). The reaction was heated to 120 ° C to carry out the reaction.After the TLC detection reaction was completed,The system was cooled to room temperature.The reaction was quenched with saturated aqueous ammonium chloride,And extracted with ethyl acetate (3 * 10 mL)The column chromatography gave the product 3a 24.1 mg (77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium methylate In methanol at 20℃; for 7h; | 2 6-Amino-2-chloro-9-(b-D-ribofuranosyl)-9H-purine (6) A solution of sodium methoxide (30% in methanol, 0.1 mL) wasadded to a solution of 16 (2.5 g, 4.1 mmol) in methanol (15 mL),and the resulting solution was stirred at room temperature for 7h. After cooling the mixture to room temperature, glacial aceticacid (0.025 mL) was added, and the mixture was stirred at 10C for 1 h. The precipitate was filtered and washed with a smallamount of cold methanol followed by drying to afford 6 as a whitesolid (823 mg, 67% yield). 1H NMR (400 MHz, DMSO d6) d: 8.40 (s,1H), 7.87 (s, 2H), 5.81 (d, J = 5.9 Hz, 1H), 5.13 (s, 1H), 4.49 (t, J = 5.4Hz, 1H), 4.15-4.09 (m, 1H), 3.93 (q, J = 3.7 Hz, 1H), 3.69-3.50 (m,2H). ESI-MS m/z 302.0 [M+H]+; HRMS (ESI) m/z calcd C10H13ClN5O4[M+H]+ 302.0656, found 302.0658. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide for 5h; Reflux; | 3.1 Example 3.1 Preparation of 2- (3,3,3-trifluoropropylthio) adenosine of formula (IV) In a 50 mL single-necked flask,1.0 g (1.0 eq) of compound of formula (III)10 mL of N, N-dimethylformamide was added,1.38 g (3.0 eq) of potassium carbonate,1.30 g (3.0 eq) of 3,3,3-trifluoropropylsulfide,Heated to reflux for 5 hours,TLC detection reaction is complete;The system was extracted with ethyl acetate, hydrochloric acid solution was added to 1mol / L washed acidic, washed with water several times,The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by beating with a 1: 1 volume ratio of ethyl acetate to petroleum ether,1.12 g of a light yellow solid was obtained in a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With methanol; sodium methylate for 1h; Reflux; | 2.1 Example 2.1 Preparation of Compounds of Formula (III) In a 50 mL single-necked flask,1.0 g (1 eq) of compound of formula (II)Add methanol 10mL,Raw materials were dissolved, sodium methoxide 0.063g (0.5eq)The system is clear and transparent, refluxed for 1 hour,TLC detection reaction is complete.Added glacial acetic acid 6.0eq, stirred for 30 minutes, the solvent was evaporated to dryness,Beating with ethyl acetate gave 0.68 g of pure compound of formula (III) in 96% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol; at 80℃; for 7.0h;High pressure; | Compound 1 (500 mg, 1.56 mmol) was dissolved in ammonia saturated methanol solution, added to a high pressure reaction flask, and stirred at 80 C for 7 h.Evaporate the solvent under reduced pressure.The product was purified through silica gel column (dichloromethane: methanol = 9: 1) to give compound 2.The compound 2 (380 mg, 1.25 mmol) was dissolved in 2 ml of hydrazine monohydrate, and the reaction was stirred at room temperature for 10 h, and the unreacted hydrazine was removed by evaporation under reduced pressure.The product was purified by column chromatography over silica gel (dichloromethane: methanol = 5: 1) to afford compound 3.Compound 3 (237 mg, 0.8 mmol) was suspended in 150 ml of ethanol, and methyl 2,2-diformylacetate (149 mg, 1.04 mmol) was added, and the mixture was refluxed for 2 h.The reaction solvent was removed by evaporation under reduced pressure, a yellow solid product was purified by silica gel column chromatography (dichloromethane: methanol = 5: 1) to obtain compound 4;.Compound 4 (202 mg, 0.5 mmol) was suspended in 10 ml of 1 M potassium hydroxide in methanol and stirred at room temperature for 20 h., To give an ester bond cleavage, the organic solvent was distilled off under reduced pressure, the solid was dissolved in ml of water, adjusted to pH 4.0 with 1M HCl, the precipitated solid was filtered, washed with Compound 5. Compound 5 (170 mg, 0.45 mmol), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (427 mg, 0.9 mol) and 1-hydroxybenzotriazole (171 mg, 0.9 mol) dissolved in 2 ml of anhydrous DMF,Add 95mul N- tert-butoxycarbonyl group - ethylenediamine, 17H reaction was stirred at room temperature, the solvent was distilled off under reduced pressure, the solid product was recrystallized from methanol to give compound 6.Compound 6 (150 mg, 0.27 mmol) was dissolved in 6 ml of a mixed solution of trifluoroacetic acid and dichloromethane, and stirred at room temperature for 4 h.The solvent was removed under reduced pressure to give the desired product as a white solid, a Reg-NH2 evaporated. | |
4.5 g | at 20℃; for 24.0h; | First, 10 g of 2,6-dichloro-9-(2',3',5'-tri-O-acetyl-beta-D- ribofuranosyl)-purine (8) in 200 mL of methanolicammonia solution was heated to 100 C for 24 h in an autoclave.The solution was further stirred for an additional 24 h at roomtemperature, and then the solutionwas subsequently evaporated todryness under reduced pressure to remove ammonia. The residuewas purified by flash chromatography using an appropriatemixture of CHCl3 and MeOH as an eluent. The product was dried at 50 C to yield 4.5 g of 2-chloroadenosine as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In acetone; at 20℃; for 4h;Inert atmosphere; | To an adenosine 3 (1.0 g, 3.74 mmol, 1 equiv) in acetone (30 mL/mmol) was added dry tosylic acid (10 equiv) at room temperature under an argon atmosphere. The resulting mixture was stirred at room temperature for 4 h. After completion of reaction (indicated by TLC), the reaction mixture was cooled to 0 °C and sat. aq. NaHCO3 solution added until the pH of the mixture became slightly basic. Acetone was evaporated under reduced pressure and the residue was extracted in EtOAc (3 × 30 mL). The combined organic fractions were washed with brine (1 × 15 mL), dried over MgSO4 and evaporated under reduced pressure to afford the title compound 5 as white solid (0.625g, 54percent). Rf = 0.45 (10percent MeOH in DCM). Mp = 228?230 °C. 1H NMR (500 MHz, DMSO-d6) deltaH = 8.34 (s, 1H, HAr), 8.16 (s, 1H, HAr), 7.35 (bs, 2H, Ar-NH2), 6.12 (d, J = 3.1 Hz, 1H, CHribose), 5.34 (dd, J = 6.4, 3.1 Hz, 1H, CHribose), 5.24 (bs, 1H, 5-OH), 4.96 (dd, J = 6.15, 2.45 Hz, 1H, CHribose), 4.23-4.20 (m, 1H, CHribose), 3.58-3.51 (m, 2H, 5-CH2), 1.54 (s, 3H, CH3), 1.32 (s, 3H, CH3), general assignments were confirmed by 1H-1H gCOSY. 13C NMR (125 MHz, DMSO-d6) deltaC = 156.1 (Cquat), 152.6 (Cquat), 148.8 (Cquat), 139.7 (CHAr), 119.1 (Cquat), 113.0 (CHAr), 89.6 (CHribose), 86.4 (CHribose), 83.2 (CHribose), 81.4 (CHribose), 61.6 (5-CH2), 27.1 (CH3), 25.2 (CH3), general assignments were confirmed by 1H-13C HSQC. LRMS (ESI): 330 [M + Na]+, HRMS (ESI): calcd for [C13H17N5O4 + Na]+ 330.1172, found 330.1169 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine In 2-methoxy-ethanol at 125℃; for 72h; | 7 4.7 2-(Furfurylamino)adenosine (14) To a solution of 13 (241mg, 0.8mmol) in 2-methoxyethanol (3ml) was added furfurylamine (699mg, 7.2mmol) and DIPEA (931mg, 7.2mmol), and the whole was heated at 125°C for 72h, then evaporated. The residue was subjected to chromatography on silica gel column with CH2Cl2-MeOH (92:8→9:1) which gave 14 as the yellowish oily material. It was next rechromatographed with EtOAc-MeOH (9:1) to obtain white solid (194mg, 67% yield). 1H NMR spectrum of 14 as in lit [15]. 13C NMR data are given in Supplementary data section. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With sodium acetate at 65℃; for 12h; | 1.1; 2.1 2-Chloroadenosine (50g, 0.166mol) was added to acetic anhydride (169g, 1.66mol), then sodium acetate (13.6g, 0.166mol) was added as a catalyst, and the reaction mass was heated at 60°C to 70°C (The reaction was carried out at 65° C) reaction for 10 to 15 hours (12 hours in the present example).After the reaction was completed, the material was cooled to room temperature (15°C to 35°C), 200 mL of water was added to it and stirred for 0.5 hours, extracted with dichloromethane 200 mL*3 for 3 times, the extracts were combined, and the obtained organic phase was washed with water 200 mL*2 time, dried with anhydrous sodium sulfate; filtered, and the obtained filtrate was concentrated to dryness to obtain 75.3 g of the compound of formula (1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 mg | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In methanol; 1,2-dimethoxyethane at 100℃; Inert atmosphere; | 1.5 (5) Synthesis of 1-{4-{6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl]-9H-purin-2-yl}phenyl}-3-(pyridin-3-yl)urea (VIII, i.e., Compound 1) (5) Synthesis of 1-{4-{6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl]-9H-purin-2-yl}phenyl}-3-(pyridin-3-yl)urea (VIII, i.e., Compound 1) 0.5g (0.0017mol) of (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (VII) was added to 0.6g (0.0018mol) of 1-(pyridin-3-yl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (III, 1.1 equivalent), then 3ml of ethylene glycol dimethyl ether, 10ml of methanol, 5ml of 2M Na2CO3 aqueous solution were added and stirred, 1.0g (0.0009mol) of Pd(PPh3)4 (0.5 equivalent) was added and then the air in the reaction flask was evacuated by introducing nitrogen gas, it was heated to 100°C and refluxed overnight. Then the heating was stopped and it was cooled to room temperature, 300ml of methanol was added and stirred for dissolution, after filtration a crude product was separated by silica gel column chromatography from the filtrate mixture . The crude product was further purified by medium pressure preparative chromatography using C18 reverse phase column to obtain 116 mg of white solid (Compound 1). m.p. 230°C; 1H NMR (DMSO-d6): δ (ppm) 9.05(s, 1H), 8.94(s, 1H), 8.63(s, 1H), 8.36(s, 1H), 8.29(d, 2H, J=8.0Hz), 8.21(d, 2H, J=4.8Hz), 7.98(d, 1H, J=9.6Hz), 7.57(d, 2H, J=8.0Hz), 7.35-7.32(m, 2H), 5.99(d, 1H, J=5.2Hz), 5.51(s, 1H), 5.27(s, 1H), 5.07(s, 1H), 4.75(s, 1H), 4.23(s, 1H), 3.97(s, 1H), 3.72-3.57(m, 2H); HRMS (ESI+) m/z [M + H]+ calculated for C22H22N8O5: 479.1786; found: 479.1786. |
116 mg | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In methanol; 1,2-dimethoxyethane at 100℃; Inert atmosphere; | 1.5 (5) Synthesis of 1-{4-{6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl]-9H-purin-2-yl}phenyl}-3-(pyridin-3-yl)urea (VIII, i.e., Compound 1) (5) Synthesis of 1-{4-{6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl]-9H-purin-2-yl}phenyl}-3-(pyridin-3-yl)urea (VIII, i.e., Compound 1) 0.5g (0.0017mol) of (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (VII) was added to 0.6g (0.0018mol) of 1-(pyridin-3-yl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (III, 1.1 equivalent), then 3ml of ethylene glycol dimethyl ether, 10ml of methanol, 5ml of 2M Na2CO3 aqueous solution were added and stirred, 1.0g (0.0009mol) of Pd(PPh3)4 (0.5 equivalent) was added and then the air in the reaction flask was evacuated by introducing nitrogen gas, it was heated to 100°C and refluxed overnight. Then the heating was stopped and it was cooled to room temperature, 300ml of methanol was added and stirred for dissolution, after filtration a crude product was separated by silica gel column chromatography from the filtrate mixture . The crude product was further purified by medium pressure preparative chromatography using C18 reverse phase column to obtain 116 mg of white solid (Compound 1). m.p. 230°C; 1H NMR (DMSO-d6): δ (ppm) 9.05(s, 1H), 8.94(s, 1H), 8.63(s, 1H), 8.36(s, 1H), 8.29(d, 2H, J=8.0Hz), 8.21(d, 2H, J=4.8Hz), 7.98(d, 1H, J=9.6Hz), 7.57(d, 2H, J=8.0Hz), 7.35-7.32(m, 2H), 5.99(d, 1H, J=5.2Hz), 5.51(s, 1H), 5.27(s, 1H), 5.07(s, 1H), 4.75(s, 1H), 4.23(s, 1H), 3.97(s, 1H), 3.72-3.57(m, 2H); HRMS (ESI+) m/z [M + H]+ calculated for C22H22N8O5: 479.1786; found: 479.1786. |
116 mg | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In methanol; 1,2-dimethoxyethane; lithium hydroxide monohydrate at 100℃; Inert atmosphere; | 1.5 (5) Synthesis of 1-{4-{6-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl]-9H-purin-2-yl}phenyl}-3-(pyridin-3-yl)urea (VIII, i.e., Compound 1) 0.5g (0.0017mol) of (2R,3R,4S,5R)-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (VII) was added to 0.6g (0.0018mol) of 1-(pyridin-3-yl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (III, 1.1 equivalent), then 3ml of ethylene glycol dimethyl ether, 10ml of methanol, 5ml of 2M Na2CO3 aqueous solution were added and stirred, 1.0g (0.0009mol) of Pd(PPh3)4 (0.5 equivalent) was added and then the air in the reaction flask was evacuated by introducing nitrogen gas, it was heated to 100°C and refluxed overnight. Then the heating was stopped and it was cooled to room temperature, 300ml of methanol was added and stirred for dissolution, after filtration a crude product was separated by silica gel column chromatography from the filtrate mixture . The crude product was further purified by medium pressure preparative chromatography using C18 reverse phase column to obtain 116 mg of white solid (Compound 1). m.p. 230°C; 1H NMR (DMSO-d6): δ (ppm) 9.05(s, 1H), 8.94(s, 1H), 8.63(s, 1H), 8.36(s, 1H), 8.29(d, 2H, J=8.0Hz), 8.21(d, 2H, J=4.8Hz), 7.98(d, 1H, J=9.6Hz), 7.57(d, 2H, J=8.0Hz), 7.35-7.32(m, 2H), 5.99(d, 1H, J=5.2Hz), 5.51(s, 1H), 5.27(s, 1H), 5.07(s, 1H), 4.75(s, 1H), 4.23(s, 1H), 3.97(s, 1H), 3.72-3.57(m, 2H); HRMS (ESI+) m/z [M + H]+ calculated for C22H22N8O5: 479.1786; found: 479.1786. |
Tags: 146-77-0 synthesis path| 146-77-0 SDS| 146-77-0 COA| 146-77-0 purity| 146-77-0 application| 146-77-0 NMR| 146-77-0 COA| 146-77-0 structure
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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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