tert-butyl N-[1-(2-hydroxyethyl)piperidin-4-yl]carbamate

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

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

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

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

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl piperidin-4-ylcarbamate (5 g, 25 mmol), 2-bromoethanol (1.77 mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol) in acetonitrile (20 mL) was heated in a sealed tube at 50° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate (300 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was back-extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (4:1) gave 4.04 g (66% yield) of product as a colorless solid, mp 66° C. The solvent was removed under reduced pressure washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) The aqueous phase was back-extracted once with ethyl acetate (100 mL) the combined organic phases were dried over sodium sulfate concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl piperidin-4-ylcarbamate (5 g, 25 mmol), 2-bromoethanol (1.77 mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol) in acetonitrile (20 mL) was heated in a sealed tube at 50° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate (300 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was back-extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (4:1) gave 4.04 g (66% yield) of product as a colorless solid, mp 66° C. The solvent was removed under reduced pressure washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) The aqueous phase was back-extracted once with ethyl acetate (100 mL) the combined organic phases were dried over sodium sulfate concentrated under reduced pressure

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

Procedure: A mixture of tert-butyl [1-(2-hydroxyethyl)piperidin-4-yl]carbamate (Intermediate 7, 1.7 g, 7 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.4 mL, 9.8 mmol) was treated at 0° C. with methanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate buffer (pH 7, 1M, 50 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice-cold ethyl acetate (2×100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step. dichloromethane was removed under reduced pressure and it was extracted with ice-cold ethyl acetate (2×100 mL) dried over sodium sulfate The solvent was removed under reduced pressure the crude preparation of the mesylate

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

Procedure: A mixture of tert-butyl [1-(2-hydroxyethyl)piperidin-4-yl]carbamate (Intermediate 7, 1.7 g, 7 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.4 mL, 9.8 mmol) was treated at 0° C. with methanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf 0.54). Potassium phosphate buffer (pH 7, 1M, 50 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice-cold ethyl acetate (2×100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step. dichloromethane was removed under reduced pressure and it was extracted with ice-cold ethyl acetate (2×100 mL) dried over sodium sulfate The solvent was removed under reduced pressure the crude preparation of the mesylate

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

Procedure: Diethyl azodicarboxylate (5.48 g, 31.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol (4.44 g, 15.73 mmol, 1.0 eq), [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (5.76 g, 23.59 mmol, 1.5 eq) and triphenylphosphine (8.25 g, 31.46 mmol, 2.0 eq) in tetrahydrofuran (150 mL). After 15 hours stirring at room temperature, tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: ethyl acetate:methanol, 10:0 to 9:1, v/v) to afford {1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a light brown viscous oil (9.31 g, 88% yield). tetrahydrofuran is evaporated the resulting crude product is purified by column chromatography (silica gel, eluent

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

Procedure: Diethyl azodicarboxylate (5.48 g, 31.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ol (4.44 g, 15.73 mmol, 1.0 eq), [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (5.76 g, 23.59 mmol, 1.5 eq) and triphenylphosphine (8.25 g, 31.46 mmol, 2.0 eq) in tetrahydrofuran (150 mL). After 15 hours stirring at room temperature, tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: ethyl acetate:methanol, 10:0 to 9:1, v/v) to afford {1-[2-(4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as a light brown viscous oil (9.31 g, 88% yield). tetrahydrofuran is evaporated the resulting crude product is purified by column chromatography (silica gel, eluent

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

Procedure: The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Examples 2 and 9 using 7-fluoro-6-methoxy-quinolin-3-ol, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as starting materials.