2-(diethoxyphosphorylmethoxy)ethanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-6-chloropurine (890 mg, 4.2 mmol), diethyl 2-hydroxyethoxymethane-phosphonate 2b (710 mg, 4.2 mmol) and triphenylphosphine (1.65 g, 6.3 mmol) in anhydrous DMF (10 mL) was stirred at ambient temperature under N2 for 30 min. The reaction mixture was then cooled to -10° C. and diethyl azodicarboxylate (0.67 mL, 4.2 mmol) in DMF (2 mL) was added dropwise at such a rate that the reaction temperature was maintained at -10° C. The reaction mixture was stirred at that temperature for 2 h and then allowed to warm to ambient temperature gradually and stirred for 5 h. Any unreacted 2-amino-6-chloropurine was removed by filtration and the solvent removed under vacuum. The crude product was purified by silica gel column chromatography, eluting with CH2Cl2 /MeOH (9:1), to afford 650 mg (42 % yield) of the desired N9 -product 1d. 1H NMR (CDCl3) δ 7.90 (s, 1 H, H-8), 5.20 (s, broad, 2 H, NH2), 4.30 (t, J=4.8 Hz, 2 H, CH2N), 4.12 (dq, J=8.4 Hz, J=7.0 Hz, 4 H, 2 OCH2CH3), 3.92 (t, J=5.0 Hz, 2 H, CH2O), 3.79 (d, J=8.4 Hz, 2 H, CH2O), 1.30 (t, J=7.1 Hz, 6 H, 2 CH3); 13C NMR (CDCl3) δ 159.20, 153.78, 151.20, 143.29, 124.99 (purine ring carbons), 70.82 (d, 2JC,P=10.3 Hz, OCH2CH3), 65.17 (d, 1JC,P=166.0 Hz, CH2P), 62.42 (d, 3JC,P=5.7 Hz, CH2O), 43.19 (CH2N), 16.27 (d, 3J,P=5.7 Hz, CH3); UV (MeOH) λmax 247 (14,600), 310 (18,300) nm; IR (KBr, cm-1) 3327 and 3210 (m, broad, NH2), 1612 and 1562 (vs, purine ring), 1229 (s, P=O), 1026 (s, P--O--C); MS (CI) m/e 366 and 364 (40.5, 100, M+1), 3328 (22.3, M--Cl); Anal. calcd. for C12H19ClN5O4P: C, 39.63; H, 5.26; N, 19.25. Found: C, 39.53; H, 5.48; N, 18.99. The reaction mixture was then cooled to -10° C. was maintained at -10° C The reaction mixture was stirred at that temperature for 2 h to warm to ambient temperature gradually stirred for 5 h Any unreacted 2-amino-6-chloropurine was removed by filtration the solvent removed under vacuum The crude product was purified by silica gel column chromatography eluting with CH2Cl2 /MeOH (9:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,6-diaminopurine (350 mg, 2.36 mmol), diethyl 2-hydroxyethoxymethane-phosphonate 2b (500 mg, 2.36 mmol) and triphenylphosphine (930 mg, 3.54 mmol) in anhydrous DMF (10 mL) was stirred at ambient temperature under N2 for 30 min. The reaction mixture was then cooled to -30° C. and diethyl azodicarboxylate (0.56 mL, 3.54 mmol) was added dropwise at such a rate that the reaction temperature was maintained below -25° C. The reaction mixture was stirred at that temperature for 2 h and then allowed to warm to ambient temperature gradually and stirred overnight. Any unreacted 2,6-diaminopurine was removed by filtration and the solvent removed under vacuum. The crude product was purified by silica gel column chromatography, eluting with CH2Cl2 /MeOH (9:1), to afford 190 mg (23 % yield) of the desired N9 - product 1c. An analytical sample was obtained from recrystallization using EtOAc/MeOH (5:1). mp. 152°-154° C. 1H NMR (CDCl3) δ 7.66 (s, 1 H, H-8), 6.67 (s, 2 H, NH2), 5.79 (s, 2 H, NH2), 4.13 (t, J=5.0 Hz, 2 H, CH2N), 3.95 (apparent quintet, J=7.3 Hz, 4 H, 2 OCH2CH3), 3.84 (d, J=8.4 Hz, 2 H, CH2P), 3.81 (t, J=5.0 Hz, 2 H, CH2O), 1.17 (t, J=7.1 Hz, 6 H, 2 CH3); 13C NMR (CDCl3) d 160.01, 156.08, 151.87, 138.79, 114.03 (purine ring carbons), 71.36 (d, 2JC,P= 10.8 Hz, OCH2CH3), 65.26 (d, 1JC,P=166.5 Hz, CH2P), 62.50 (d, 3JC,P=6.5 Hz, CH2O), 42.92 (CH2N), 16.44 (d, 3JC,P=5.7 Hz, CH3); UV (MeOH) λmax 255 (10,300), 281(12,000) nm; IR (KBr, cm-1) 3345 and 3177 (s, broad, NH2), 1669, 1636 and 1599 (s, purine ring), 1242 (s, P=O), 1020 (s, P--O--C); MS (CI) m/e 345 (100, M+1), 344 (29.5, M+); Anal. calcd. for C12H21N6O4P.1/4H2O: C, 41.32; H. 6.21; N, 24.09. Found: C, 41.36; H. 6.02; N, 23.72. The reaction mixture was then cooled to -30° C. was maintained below -25° C The reaction mixture was stirred at that temperature for 2 h to warm to ambient temperature gradually stirred overnight Any unreacted 2,6-diaminopurine was removed by filtration the solvent removed under vacuum The crude product was purified by silica gel column chromatography eluting with CH2Cl2 /MeOH (9:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-diethylphosphonomethoxy-1-ethanol (40.7 g, 192 mmol) in 500 mL of CH2Cl2 was cooled to 0° C. and then triethylamine (29.1 g, 288 mmol) was added in one portion, followed by addition of methanesulfonyl chloride (26.4 g, 230 mmol) dropwise over 20 min. The reaction mixture was kept at 0° C. for 0.5 hours and then poured into water. The aqueous phase was extracted with two portions of CH2Cl2 and the combined organic phases dried over MgSO4, filtered and concentrated to afford 54.4 g (98%) of 1-methanesulfonyloxy-2-(diethylphosphonomethoxy)ethane as a clear, pale orange oil. The mesylate could be employed without purification or purified by column chromatography on silica gel (5% methanol in CH2Cl2). 1H NMR (200 MHz, CDCl3): 4.46-4.50 (m,2H), 4.26 (quintet, J=6.8 Hz,4H), 3.92-3.99(m,4H), 3.20 (s,3H), and 1.40 (t, J=7 Hz, 6H). The aqueous phase was extracted with two portions of CH2Cl2 the combined organic phases dried over MgSO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-diethylphosphonomethoxy-1-ethanol (40.7 g, 192 mmol) in 500 mL of CH2Cl2 was cooled to 0° C. and then triethylamine (29.1 g, 288 mmol) was added in one portion, followed by addition of methanesulfonyl chloride (26.4 g, 230 mmol) dropwise over 20 min. The reaction mixture was kept at 0° C. for 0.5 hours and then poured into water. The aqueous phase was extracted with two portions of CH2Cl2 and the combined organic phases dried over MgSO4, filtered and concentrated to afford 54.4 g (98%) of 1-methanesulfonyloxy-2-(diethylphosphonomethoxy)ethane as a clear, pale orange oil. The mesylate could be employed without purification or purified by column chromatography on silica gel (5% methanol in CH2Cl2). 1H NMR (200 MHz, CDCl3): 4.46-4.50 (m,2H), 4.26 (quintet, J=6.8 Hz,4H), 3.92-3.99(m,4H), 3.20 (s,3H), and 1.40 (t, J=7 Hz, 6H). The aqueous phase was extracted with two portions of CH2Cl2 the combined organic phases dried over MgSO4 filtered concentrated

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15 mL of concentrated hydrochloric acid was added in one portion to a solution of 1-acetoxy-2-(diethylphosphonomethoxy)ethane (76.5 g, 300 mmol) in 600 mL of absolute ethanol and the resulting mixture was heated at 55° C. for 12 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting clear liquid could be used without purification or purified by distillation (1.5 mmHg, 128°-132° C.) to give 52.1 g (82%) of 2-diethylphosphonomethoxy-1-ethanol. The reaction mixture was then cooled to room temperature concentrated in vacuo The resulting clear liquid could be used without purification purified by distillation (1.5 mmHg, 128°-132° C.)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15 mL of concentrated hydrochloric acid was added in one portion to a solution of 1-acetoxy-2-(diethylphosphonomethoxy)ethane (76.5 g, 300 mmol) in 600 mL of absolute ethanol and the resulting mixture was heated at 55° C. for 12 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting clear liquid could be used without purification or purified by distillation (1.5 mmHg, 128°-132° C.) to give 52.1 g (82%) of 2-diethylphosphonomethoxy-1-ethanol. The reaction mixture was then cooled to room temperature concentrated in vacuo The resulting clear liquid could be used without purification purified by distillation (1.5 mmHg, 128°-132° C.)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Paladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in accordance with the process of Example II above (0.9 g,2.8 mmol) and cyclohexene (2.0 ml, 20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate. The resulting slurry was heated to reflux overnight The catalyst was filtered off the solution concentrated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Paladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in accordance with the process of Example II above (0.9 g,2.8 mmol) and cyclohexene (2.0 ml, 20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate. The resulting slurry was heated to reflux overnight The catalyst was filtered off the solution concentrated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The method of claim 1 wherein in step (a) a solution of (i) the diethyl ester of hydroxymethylphosphonic acid and (ii) 2-benzyloxyethyl p-toluene sulfonate in ethylene glycol dimethyl ether is added to a slurry of sodium hydride in ethylene glycol dimethyl ether under a nitrogen atmosphere to form diethyl 2-(benzyloxy)ethoxymethylphosphonate as a first intermediate; wherein, in step (b), said first intermediate is dissolved together with cyclohexene in ethanol, paladium on carbon is added to the ethanol solution, and the resulting slurry is heated under nitrogen to form diethyl 2-hydroxyethoxymethylphosphonate as a second intermediate; wherein in step(c), said second intermediate is dissolved in dichloromethane under a nitrogen atmosphere, toluene sulfonyl chloride is added to the dichloromethane solution, and a solution of pyridine in dichloromethane is added to the resulting mixture to form diethyl 2-(phosphonomethoxy)ethyl p-toluene sulfonate as a third intermediate; and wherein in step (d), said third intermediate is dissolved together with the diethyl ester of hydroxymethylphosphonic acid in ethylene glycol dimethyl ether, and a slurry of sodium hydride in ethylene glycol dimethyl ether is added thereto under a nitrogen atmosphere to form tetraethyl ethyleneglycol di-(phosphonomethyl) ether. the resulting slurry is heated under nitrogen

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Paladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in accordance with the process of Example II above (0.9 g,2.8 mmol) and cyclohexene (2.0 ml,20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate. The resulting slurry was heated to reflux overnight The catalyst was filtered off the solution concentrated under vacuum