tert-butyl N-(3-hydroxycyclobutyl)carbamate

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

Procedure: To a 0° C. cold solution of 2.00 g (10.8 mmol) of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester in 20 mL of ethanol was added portionwise 204 mg (5.40 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature until complete conversion was achieved. The solvent was evaporated, the crude product was taken up in dichloromethane and treated with sat. sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with dichloromethane. The organic phases were combined, dried over magnesium sulfate and concentrated to give crude (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester. Rt=0.76 min (Method C). Detected mass: 132.2 (M-tBu+H+). The solvent was evaporated treated with sat. sodium bicarbonate solution The phases were separated the aqueous phase extracted twice with dichloromethane dried over magnesium sulfate concentrated

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

Procedure: To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (481 mg, 1.4 mmol) in THF (12 mL) was added a 1:1 cis:trans mixture of tert-butyl (3-hydroxycyclobutyl)carbamate (see Radchenko et al., Journal of Organic Chemistry, 75(17):5941-5952 (2010)) (288 mg, 1.54 mmol) and KHMDS (419 mg, 2.1 mmol). The reaction solution was stirred at rt for 1 hr. The reaction was quenched with brine (5 mL), then partitioned between EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a light yellow gum. The gum was purified using flash chromatography eluting with a gradient of 0%-40% EtOAc in heptanes. The product fractions were combined and evaporated to afford the title compound (508 mg, 73 yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H) 7.27-7.52 (m, 1H) 5.63 (s, 2H) 5.04-5.60 (m, 1H) 3.73-4.32 (m, 1H) 3.53-3.69 (m, 2H) 2.88 (m, J=9.35, 6.91, 6.91, 3.02 Hz, 1H) 2.50-2.56 (m, 2H) 2.13-2.28 (m, 1H) 1.46 (d, J=4.78 Hz, 9H) 0.92 (t, J=8.06 Hz, 2H) 0.00 (d, J=1.51 Hz, 9H). m/z (APCI+) for C22H32ClN5O4Si 440.0 (M−tBu+H)+. The reaction was quenched with brine (5 mL) partitioned between EtOAc (120 mL) and water (30 mL) The organic layer was separated washed with brine (20 mL) dried over Na2SO4 evaporated to give a light yellow gum The gum was purified eluting with a gradient of 0%-40% EtOAc in heptanes evaporated

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

Procedure: To a 0° C. cold solution of 2.00 g (10.8 mmol) of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester in 20 mL of ethanol was added portionwise 204 mg (5.40 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature until complete conversion was achieved. The solvent was evaporated, the crude product was taken up in dichloromethane and treated with sat. sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with dichloromethane. The organic phases were combined, dried over magnesium sulfate and concentrated to give crude (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester. Rt=0.76 min (Method C). Detected mass: 132.2 (M-tBu+H+). The solvent was evaporated treated with sat. sodium bicarbonate solution The phases were separated the aqueous phase extracted twice with dichloromethane dried over magnesium sulfate concentrated

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

Procedure: 18.7 g (100 mmol) tert.butyl (3-hydroxy-cyclobutyl)-carbamate and 12.1 g (120 mmol) triethylamine are placed in 500 ml chloroform. 20.5 g (105 mmol) tosyl chloride, dissolved in 150 ml chloroform, is added dropwise to this solution at 0° C. with stirring. Then the mixture is left to come up to ambient temperature and stirred for 2 h. The organic phase is washed successively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. is added dropwise to this solution at 0° C. Then the mixture is left to come up to ambient temperature stirred for 2 h The organic phase is washed successively with water, dilute hydrochloric acid, sodium hydrogen carbonate solution and water The organic phase is dried with magnesium sulphate

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.77 g (10 mmol) tert.butyl (3-benzyloxy-cyclobutyl)-carbamate are suspended in 100 ml of methanol and combined with 200 mg palladium hydroxide. The reaction mixture is stirred for 5 h at 45° C. and 45 bar H2 pressure. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The residue is taken up in chloroform and washed three times with aqueous sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo. Then the catalyst is filtered off washed three times with aqueous sodium hydrogen carbonate solution The organic phase is dried with magnesium sulphate

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

Procedure: To a solution of (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester (2.5 g, 13.3 mmol) in THF (40 mL) were added Cs2CO3 (8.6 g, 26.6 mmol) and 5-bromo-2,4-dichloro-pyrimidine (3 g, 13.3 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was filtered and concentrated, diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel to give the product (4.75 g, 12.6 mmol, yield: 95%). ESI-MS (M+1): 378 calc. for C13H17BrClN3O3 377. The reaction mixture was heated at reflux overnight The reaction mixture was filtered concentrated diluted with EtOAc and water The aqueous phase was extracted with EtOAc (3×100 mL) the combined organic extracts were washed with brine (60 mL) dried over MgSO4 filtered concentrated Purification by flash column chromatography on silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2,3-dichloro-pyrazine (3.0 g, 20 mmol) and tert-butyl (3-hydroxycyclobutyl)carbamate (see PREPARATION 4B; 3.65 g, 20 mmol) in DMSO (50 mL) was added Cs2CO3 (13.2 g, 40 mmol), and then the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with water and filtered. The filtrate cake was washed with water, and dried to give tert-butyl (3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)carbamate (4.5 g, 15.2 mmol, 76%). ESI-MS (M+1): 300 calc. for C13H18ClN3O3 299. filtered The filtrate cake was washed with water dried

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

Procedure: To tert-butyl (3-oxocyclobutyl)carbamate (see PREPARATION 4A, STEP 1; 110 g, 0.594 mol, 1 eq) in ethanol (600 mL) was slowly added sodium borohydride (11.23 g, 0.297 mol, 0.5 eq) at 0° C. Reaction mixture was warmed to RT and stirred at this temperature for 2 h. It was quenched with water (1 L). Solvent was removed under reduced pressure. Water layer was extracted with EtOAc (3×2 L). Combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Residue was purified by column chromatography with aluminum oxide (Eluent: 20% EtOAc in hexane to 10% MeOH in DCM) to get 64 g of tert-butyl (3-hydroxycyclobutyl)carbamate as a white solid in 58% yield. at 0° C Reaction mixture It was quenched with water (1 L) Solvent was removed under reduced pressure Water layer was extracted with EtOAc (3×2 L) Combined organic layer was washed with brine dried over magnesium sulfate filtered concentrated Residue was purified by column chromatography with aluminum oxide (Eluent: 20% EtOAc in hexane to 10% MeOH in DCM)

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

Procedure: To a solution of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (481 mg, 1.4 mmol) in THF (12 mL) was added a 1:1 cis:trans mixture of tert-butyl (3-hydroxycyclobutyl)carbamate (see Radchenko et al., Journal of Organic Chemistry, 75(17):5941-5952 (2010)) (288 mg, 1.54 mmol) and KHMDS (419 mg, 2.1 mmol). The reaction solution was stirred at rt for 1 hr. The reaction was quenched with brine (5 mL), then partitioned between EtOAc (120 mL) and water (30 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and evaporated to give a light yellow gum. The gum was purified using flash chromatography eluting with a gradient of 0%-40% EtOAc in heptanes. The product fractions were combined and evaporated to afford the title compound (508 mg, 73 yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1H) 7.27-7.52 (m, 1H) 5.63 (s, 2H) 5.04-5.60 (m, 1H) 3.73-4.32 (m, 1H) 3.53-3.69 (m, 2H) 2.88 (m, J=9.35, 6.91, 6.91, 3.02 Hz, 1H) 2.50-2.56 (m, 2H) 2.13-2.28 (m, 1H) 1.46 (d, J=4.78 Hz, 9H) 0.92 (t, J=8.06 Hz, 2H) 0.00 (d, J=1.51 Hz, 9H). m/z (APCI+) for C22H32ClN5O4Si 440.0 (M−tBu+H)+. The reaction was quenched with brine (5 mL) partitioned between EtOAc (120 mL) and water (30 mL) The organic layer was separated washed with brine (20 mL) dried over Na2SO4 evaporated to give a light yellow gum The gum was purified eluting with a gradient of 0%-40% EtOAc in heptanes evaporated

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

Procedure: To a 0° C. cold solution of 2.00 g (10.8 mmol) of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester in 20 mL of ethanol was added portionwise 204 mg (5.40 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature until complete conversion was achieved. The solvent was evaporated, the crude product was taken up in dichloromethane and treated with sat. sodium bicarbonate solution. The phases were separated and the aqueous phase extracted twice with dichloromethane. The organic phases were combined, dried over magnesium sulfate and concentrated to give crude (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester. Rt=0.76 min (Method C). Detected mass: 132.2 (M-tBu+H+). The solvent was evaporated treated with sat. sodium bicarbonate solution The phases were separated the aqueous phase extracted twice with dichloromethane dried over magnesium sulfate concentrated