oxetan-2-ylmethanol

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

Procedure: The title compound was prepared from 4-bromo-3-fluorophenol and rac-2-hydroxymethyl-oxetane in analogy to Example 9c): MS (EI): 260 and 262 M+.

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized as described for Intermediate example I-81 in 42% yield starting from ethyl 6-chloronicotinate and oxetan-2-ylmethanol. The reduction was performed using 3 equiv of lithium hydroxide while heating to 75° C. for 3.5 h. The final aqueous solution was extracted with ethyl acetate in order to collect the product; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.16 (dd, 1 H), 6.96 (dd, 1 H), 4.96-5.06 (m, 1 H), 4.41-4.57 (m, 4 H), 2.64-2.75 (m, 1 H), 2.46-2.56 (m, 1 H); S (ESI) m/z 210[M+H+], m/z 208[M−H+]. The final aqueous solution was extracted with ethyl acetate in order to collect the product

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

Procedure: 2-Hydroxymethyloxetane (0.71 g, 8.10 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (0.89 mL, 8.10 mmol) and 4-nitrophenyl chloroformate (1.63 g, 8.10 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (1.16 g, 3.90 mmol) and DIPEA (2.69 mL, 15.4 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 18 h. The solvents were removed in vacuo, the residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (120 mL), the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (93.4 mg, 8.7%) as a white solid. the resulting solution was stirred for 18 h The solvents were removed in vacuo the residue was dissolved in MeOH (10 mL) 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h concentrated in vacuo The residue was dissolved in EtOAc (120 mL) the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min)

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

Procedure: To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine was added p-toluenesulfonyl chloride (6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 243 (M+H)+, 260 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate)

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

Procedure: To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine was added p-toluenesulfonyl chloride (6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 243 (M+H)+, 260 (M+NH4)+. was quenched with 10 mL of saturated, aqueous NaHCO3 The layers were separated the aqueous layer was extracted with three 5 mL portions of CH2Cl2 The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate)

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

Procedure: a mixture of 171 mg of phenyl(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate, 0.04 cm3 of 2-hydroxymethyloxetane and 0.06 cm3 of triethylamine in 3 cm3 of tetrahydrofuran is heated for 7.5 h in a bath at 80° C. The reaction is left to stand overnight at 20° C. and then the mixture is evaporated to dryness under vacuum. The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 96/04. 52 mg of oxetan-2-ylmethyl(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows: The reaction is left the mixture is evaporated to dryness under vacuum The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution

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

Procedure: a mixture of 756 mg of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 0.352 cm3 of 2-hydroxymethyloxetane and 552 mg of potassium carbonate in 8 cm3 of N,N-dimethylformamide is heated at 100° C. for 6 h and then stirred at 20° C. overnight. The reaction medium is concentrated to dryness under vacuum. The residue obtained is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 97/03. 701 mg of 3-chloro-6-(oxetan-2-ylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a beige solid, the characteristics of which are as follows: The reaction medium is concentrated to dryness under vacuum The residue obtained is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution

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

Procedure: a mixture of 171 mg of phenyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate, 0.04 cm3 of 2-hydroxymethyloxetane and 0.06 cm3 of triethylamine in 3 cm3 of tetrahydrofuran is heated for 7.5 h in a bath at 80° C. The reaction is left to stand overnight at 20° C. and then the mixture is evaporated to dryness under vacuum. The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 96/04. 52 mg of oxetan-2-ylmethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows: The reaction is left the mixture is evaporated to dryness under vacuum The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution

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

Procedure: a mixture of 171 mg of phenyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate, 0.04 cm3 of 2-hydroxymethyloxetane and 0.06 cm3 of triethylamine in 3 cm3 of tetrahydrofuran is heated for 7.5 h in a bath at 80° C. The reaction is left to stand overnight at 20° C. and then the mixture is evaporated to dryness under vacuum. The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 96/04. 52 mg of oxetan-2-ylmethyl (6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a white solid, the characteristics of which are as follows: The reaction is left the mixture is evaporated to dryness under vacuum The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution

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

Procedure: a mixture of 756 mg of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine, 0.352 cm3 of 2-hydroxymethyloxetane and 552 mg of potassium carbonate in 8 cm3 of N,N-dimethylformamide is heated at 100° C. for 6 h and then stirred at 20° C. overnight. The reaction medium is concentrated to dryness under vacuum. The residue obtained is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a dichloromethane/methanol gradient of 100/0 to 97/03. 701 mg of 3-chloro-6-(oxetan-2-ylmethoxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a beige solid, the characteristics of which are as follows: The reaction medium is concentrated to dryness under vacuum The residue obtained is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution

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

Procedure: 2-Hydroxymethyloxetane (0.71 g, 8.10 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (0.89 mL, 8.10 mmol) and 4-nitrophenyl chloroformate (1.63 g, 8.10 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (1.16 g, 3.90 mmol) and DIPEA (2.69 mL, 15.4 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 18 h. The solvents were removed in vacuo, the residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (120 mL), the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (93.4 mg, 8.7%) as a white solid. the resulting solution was stirred for 18 h The solvents were removed in vacuo the residue was dissolved in MeOH (10 mL) 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h concentrated in vacuo The residue was dissolved in EtOAc (120 mL) the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min)

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

Procedure: 2-Hydroxymethyloxetane (0.71 g, 8.10 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (0.89 mL, 8.10 mmol) and 4-nitrophenyl chloroformate (1.63 g, 8.10 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (1.16 g, 3.90 mmol) and DIPEA (2.69 mL, 15.4 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 18 h. The solvents were removed in vacuo, the residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (120 mL), the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (93.4 mg, 8.7%) as a white solid. the resulting solution was stirred for 18 h The solvents were removed in vacuo the residue was dissolved in MeOH (10 mL) 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h concentrated in vacuo The residue was dissolved in EtOAc (120 mL) the organic layer was washed with 1M aq Na2CO3 solution (4×100 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4% and 5% MeOH in DCM (200 mL)) YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min)