methyl 2-(3-oxocyclobutyl)acetate

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 solution 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.88 mmol) and methyl 2-(3-oxocyclobutyl)acetate (100 mg, 0.70 mmol) [prepared using the procedure found in US Patent Application Publication 2009/0118287] in 1,2-dichloroethane (12 mL) was treated dropwise with acetic acid (50 uL, 0.88 mmol). The solution was treated with sodium triacetoxyborohydride (260 mg, 1.2 mmol) in one portion and allowed to stir at room temperature until complete by HPLC. After 4 h, HPLC indicated the reaction was about 80% complete. An additional 20 mg of ketone was added and stirring was continued for 2.5 h. The reaction mixture was diluted with 30 mL CH2Cl2 and washed with 15 mL sat NaHCO3. The aqueous phase was washed with 15 mL CH2Cl2 and the combined organic phase was dried over Na2SO4. The organic phase was filtered and concentrated to yield a light yellow glass that was purified by flash chromatography (70 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (270 mg, 66%) as a colorless glass: MS (ESI+) for C30H39N5O7 m/z 582.2 (M+H)+; HPLC purity >95% (ret. time, 2.88 min). stirring was continued for 2.5 h washed with 15 mL The aqueous phase was washed with 15 mL CH2Cl2 the combined organic phase was dried over Na2SO4 The organic phase was filtered concentrated to yield a light yellow glass that was purified by flash chromatography (70 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2)

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

Procedure: To a solution of (3-oxo-cyclobutyl)-acetic acid methyl ester (700 mg, 4.92 mmol) in MeOH (20 ml), NaBH4 (205 mg, 5.41 mmol) is added at 0° C. The mixture is stirred at room temperature for 5 hours. To the mixture, H2O is added and a portion of MeOH is removed under reduced pressure. The mixture is extracted with AcOEt and the organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give cis (3-hydroxy-cyclobutyl)-acetic acid methyl ester (578 mg, 80%); TLC (hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm 1.56-1.65 (m, 1H), 1.76 (m, 1H), 2.08-2.16 (m, 2H), 2.44 (d, 2H), 2.51-2.59 (m, 2H), 3.66 (s, 3H), 4.16 (m, 1H). a portion of MeOH is removed under reduced pressure The mixture is extracted with AcOEt the organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g, 13.8 mmol) in AcOH (100 ml), zinc powder (4.51 g, 69.0 mmol) is added. The mixture is stirred at 100° C. for 15 hours. The mixture is filtrated and washed with AcOH. The filtrate is concentrated under reduced pressure, and the residue is dissolved in AcOEt, and washed with saturated aqueous NaHCO3 and brine. The organic layer is dried over MgSO4, and concentrated under reduced pressure to give (3-oxo-cyclobutyl)-acetic acid methyl ester (710 mg, 36%); 1H NMR (400 MHz, chloroform-d) δ ppm 2.64-2.66 (m, 2H), 2.78-2.86 (m, 3H), 3.22-3.32 (m, 2H), 3.70 (s, 3H). The mixture is filtrated washed with AcOH The filtrate is concentrated under reduced pressure the residue is dissolved in AcOEt washed with saturated aqueous NaHCO3 and brine The organic layer is dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a solution of (3-oxo-cyclobutyl)-acetic acid methyl ester (700 mg, 4.92 mmol) in MeOH (20 ml), NaBH4 (205 mg, 5.41 mmol) is added at 0° C. The mixture is stirred at room temperature for 5 hours. To the mixture, H2O is added and a portion of MeOH is removed under reduced pressure. The mixture is extracted with AcOEt and the organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give cis (3-hydroxy-cyclobutyl)-acetic acid methyl ester (578 mg, 80%); TLC (hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm 1.56-1.65 (m, 1H), 1.76 (m, 1H), 2.08-2.16 (m, 2H), 2.44 (d, 2H), 2.51-2.59 (m, 2H), 3.66 (s, 3H), 4.16 (m, 1H). a portion of MeOH is removed under reduced pressure The mixture is extracted with AcOEt the organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g, 13.8 mmol) in AcOH (100 ml), zinc powder (4.51 g, 69.0 mmol) is added. The mixture is stirred at 100° C. for 15 hours. The mixture is filtrated and washed with AcOH. The filtrate is concentrated under reduced pressure, and the residue is dissolved in AcOEt, and washed with saturated aqueous NaHCO3 and brine. The organic layer is dried over MgSO4, and concentrated under reduced pressure to give (3-oxo-cyclobutyl)-acetic acid methyl ester (710 mg, 36%); 1H NMR (400 MHz, chloroform-d) δ ppm 2.64-2.66 (m, 2H), 2.78-2.86 (m, 3H), 3.22-3.32 (m, 2H), 3.70 (s, 3H). The mixture is filtrated washed with AcOH The filtrate is concentrated under reduced pressure the residue is dissolved in AcOEt washed with saturated aqueous NaHCO3 and brine The organic layer is dried over MgSO4 concentrated under reduced pressure

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: To a solution of (3-oxo-cyclobutyl)-acetic acid methyl ester (700 mg, 4.92 mmol) in MeOH (20 ml), NaBH4 (205 mg, 5.41 mmol) is added at 0° C. The mixture is stirred at room temperature for 5 hours. To the mixture, H2O is added and a portion of MeOH is removed under reduced pressure. The mixture is extracted with AcOEt and the organic layer is dried over MgSO4, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give cis (3-hydroxy-cyclobutyl)-acetic acid methyl ester (578 mg, 80%); TLC (hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm 1.56-1.65 (m, 1H), 1.76 (m, 1H), 2.08-2.16 (m, 2H), 2.44 (d, 2H), 2.51-2.59 (m, 2H), 3.66 (s, 3H), 4.16 (m, 1H). a portion of MeOH is removed under reduced pressure The mixture is extracted with AcOEt the organic layer is dried over MgSO4 concentrated under reduced pressure The obtained residue is purified by silica gel column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g, 13.8 mmol) in AcOH (100 ml), zinc powder (4.51 g, 69.0 mmol) is added. The mixture is stirred at 100° C. for 15 hours. The mixture is filtrated and washed with AcOH. The filtrate is concentrated under reduced pressure, and the residue is dissolved in AcOEt, and washed with saturated aqueous NaHCO3 and brine. The organic layer is dried over MgSO4, and concentrated under reduced pressure to give (3-oxo-cyclobutyl)-acetic acid methyl ester (710 mg, 36%); 1H NMR (400 MHz, chloroform-d) δ ppm 2.64-2.66 (m, 2H), 2.78-2.86 (m, 3H), 3.22-3.32 (m, 2H), 3.70 (s, 3H). The mixture is filtrated washed with AcOH The filtrate is concentrated under reduced pressure the residue is dissolved in AcOEt washed with saturated aqueous NaHCO3 and brine The organic layer is dried over MgSO4 concentrated under reduced pressure

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

Procedure: A solution 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.88 mmol) and methyl 2-(3-oxocyclobutyl)acetate (100 mg, 0.70 mmol) [prepared using the procedure found in US Patent Application Publication 2009/0118287] in 1,2-dichloroethane (12 mL) was treated dropwise with acetic acid (50 uL, 0.88 mmol). The solution was treated with sodium triacetoxyborohydride (260 mg, 1.2 mmol) in one portion and allowed to stir at room temperature until complete by HPLC. After 4 h, HPLC indicated the reaction was about 80% complete. An additional 20 mg of ketone was added and stirring was continued for 2.5 h. The reaction mixture was diluted with 30 mL CH2Cl2 and washed with 15 mL sat NaHCO3. The aqueous phase was washed with 15 mL CH2Cl2 and the combined organic phase was dried over Na2SO4. The organic phase was filtered and concentrated to yield a light yellow glass that was purified by flash chromatography (70 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (270 mg, 66%) as a colorless glass: MS (ESI+) for C30H39N5O7 m/z 582.2 (M+H)+; HPLC purity >95% (ret. time, 2.88 min). stirring was continued for 2.5 h washed with 15 mL The aqueous phase was washed with 15 mL CH2Cl2 the combined organic phase was dried over Na2SO4 The organic phase was filtered concentrated to yield a light yellow glass that was purified by flash chromatography (70 g silica gel; 2% 7N NH3 in CH3OH/CH2Cl2)