ethyl 3-(3-oxocyclobutyl)propanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl 3-(3-oxocyclobutyl)propanoate (200 mg, 1.18 mmol) in methanol (4 mL) was treated with water (0.75 mL) and a 2N solution of sodium hydroxide (0.75 mL, 1.41 mmol) and the solution was heated at 55° C. till the starting material was consumed by TLC (25% EA/hept). After 1 h the starting material was found to be consumed. The reaction mixture was cooled to room temperature and concentrated to remove the MeOH. The aqueous phase was diluted with 2 mL H2O and made acidic to pH˜2 with 1N HCl. The solution was saturated with NaCl and extracted with three 10 mL portions of ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated to yield the title compound (157 mg, 94%) as a light orange viscous oil that was used as is in the next step: GC purity 63.2% (ret. time, 4.27 min). was consumed by TLC (25% EA/hept) to be consumed concentrated to remove the MeOH The aqueous phase was diluted with 2 mL H2O extracted with three 10 mL portions of ethyl acetate The organic phase was dried over Na2SO4 filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl 3-(2,2-dichloro-3-oxocyclobutyl)propanoate (10.49 g, 43.87 mmol) and ammonium chloride (12 g, 220 mmol) in methanol (310 mL, 7600 mmol) was treated in small portions with zinc powder (14 g, 220 mmol). The reaction mixture was heated at reflux for 3 h after which time GC indicated the reaction was complete. The reaction mixture was cooled to room temperature and was filtered through Celite, washing the pad with Et2O. The filtrate was concentrated in vacuo to afford pale yellow solution. The solution was diluted with 200 mL Et2O and washed with 100 mL water. The separated aqueous layer was back extracted with 100 mL Et2O and the combined organic phase was washed with 100 mL 1:1 water/brine, 50 mL water, and 150 mL saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (4.49 g, 60%) as a pale yellow oil which was of sufficient purity for use in the next step: GC purity >95% (ret. time, 4.24 min). The reaction mixture was heated at reflux for 3 h after which time GC was filtered through Celite washing the pad with Et2O The filtrate was concentrated in vacuo to afford pale yellow solution washed with 100 mL water The separated aqueous layer was back extracted with 100 mL Et2O the combined organic phase was washed with 100 mL 1:1 water/brine, 50 mL water, and 150 mL saturated aqueous NaHCO3 The organic layer was dried over MgSO4 filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl 3-(3-oxocyclobutyl)propanoate (200 mg, 1.18 mmol) in methanol (4 mL) was treated with water (0.75 mL) and a 2N solution of sodium hydroxide (0.75 mL, 1.41 mmol) and the solution was heated at 55° C. till the starting material was consumed by TLC (25% EA/hept). After 1 h the starting material was found to be consumed. The reaction mixture was cooled to room temperature and concentrated to remove the MeOH. The aqueous phase was diluted with 2 mL H2O and made acidic to pH˜2 with 1N HCl. The solution was saturated with NaCl and extracted with three 10 mL portions of ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated to yield the title compound (157 mg, 94%) as a light orange viscous oil that was used as is in the next step: GC purity 63.2% (ret. time, 4.27 min). was consumed by TLC (25% EA/hept) to be consumed concentrated to remove the MeOH The aqueous phase was diluted with 2 mL H2O extracted with three 10 mL portions of ethyl acetate The organic phase was dried over Na2SO4 filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (8.00 g, 15.2 mmol) in 1,2-Dichloroethane (119.5 mL, 1517 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (2.58 g, 15.2 mmol) and Acetic acid (0.86 mL, 15 mmol) dropwise followed by Sodium triacetoxyborohydride (3.86 g, 18.2 mmol) and the mixture was stirred at RT for 19 h. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 150 mL sat NaHCO3. The aqueous phase was washed with 70 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a tan glass that produced a sticky foam when placed under high vac. The crude material was purified by flash chromatography (SiO2 eluting with 3-4% 7N NH3 in CH3OH/CH2Cl2) to yield a light yellow viscous oil that producted a sticky foam under high vacuum (5.03 g). MS 608.3 (M+H). washed with 150 mL The aqueous phase was washed with 70 mL CH2Cl2 the combined organic phase was dried over Na2SO4 filtered concentrated to yield a tan glass that produced a sticky foam when The crude material was purified by flash chromatography (SiO2 eluting with 3-4% 7N NH3 in CH3OH/CH2Cl2) to yield a light yellow viscous oil that

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9.50 g, 15.3 mmol) in 1,2-Dichloroethane (75 mL, 950 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (3.92 g, 23.0 mmol) and Acetic acid (1.0 mL, 18 mmol) dropwise followed by Sodium triacetoxyborohydride (4.58 g, 21.6 mmol) and the mixture was stirred at RT for 6 days. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 100 mL sat NaHCO3. The aqueous phase was washed with 100 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a light brown viscous glass. washed with 100 mL The aqueous phase was washed with 100 mL CH2Cl2 the combined organic phase was dried over Na2SO4 filtered concentrated to yield a light brown viscous glass

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-6-((isopropylamino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (9.50 g, 15.3 mmol) in 1,2-Dichloroethane (75 mL, 950 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (3.92 g, 23.0 mmol) and Acetic acid (1.0 mL, 18 mmol) dropwise followed by Sodium triacetoxyborohydride (4.58 g, 21.6 mmol) and the mixture was stirred at RT for 6 days. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 100 mL sat NaHCO3. The aqueous phase was washed with 100 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a light brown viscous glass. washed with 100 mL The aqueous phase was washed with 100 mL CH2Cl2 the combined organic phase was dried over Na2SO4 filtered concentrated to yield a light brown viscous glass

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium triacetoxyborohydride (2.43 g, 11.5 mmol) was added to a solution of (1S,2R,3R,5R)-3-(aminomethyl)-5-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (2.6 g, 5.7 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.976 g, 5.73 mmol) and Acetic acid (0.326 ml, 5.73 mmol) in 1,2-Dichloroethane (20 ml) and reaction was stirred at RT overnight. NaHCO3 was added and the aqueous layer was extracted 3× with DCM. The combined organics were dried with MgSO4, filtered, concentrated and purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 90:10) to give the desired compound (1.8 g) as a thick yellow resin. the aqueous layer was extracted 3× with DCM The combined organics were dried with MgSO4 filtered concentrated purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 90:10)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium triacetoxyborohydride (2.43 g, 11.5 mmol) was added to a solution of (1S,2R,3R,5R)-3-(aminomethyl)-5-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (2.6 g, 5.7 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.976 g, 5.73 mmol) and Acetic acid (0.326 ml, 5.73 mmol) in 1,2-Dichloroethane (20 ml) and reaction was stirred at RT overnight. NaHCO3 was added and the aqueous layer was extracted 3× with DCM. The combined organics were dried with MgSO4, filtered, concentrated and purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 90:10) to give the desired compound (1.8 g) as a thick yellow resin. the aqueous layer was extracted 3× with DCM The combined organics were dried with MgSO4 filtered concentrated purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 90:10)