methyl azetidine-3-carboxylate;hydrochloride

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

Procedure: To a stirred solution of azetidine-3-carboxylic acid methyl ester hydrochloride (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10 h and was quenched with water. The aqueous layer was extracted with EtOAc (3×20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): δ 7.38–7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31–1.63 (m, 8H). LRMS: M+309. was added to the stirring reaction mixture was quenched with water The aqueous layer was extracted with EtOAc (3×20 mL) Combined organic layers were dried over Na2SO4 concentrated to yield an oil This crude material was purified

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

Procedure: To a stirred solution of azetidine-3-carboxylic acid methyl ester hydrochloride (762 mg, 4.60 mmoles) and 1-(4-chloro-phenyl)-cyclobutane carboxylic acid (2.09 g, 9.90 mmoles) in anhydrous DCM (20 mL) was added di-isopropyl ethyl amine (4.6 mL, 26.4 mmoles) dropwise. After completion of addition solid PyBroP (4.63 g, 9.94 mmoles) was added to the stirring reaction mixture. The reaction mixture continued stirring at RT for 10 h and was quenched with water. The aqueous layer was extracted with EtOAc (3×20 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield an oil. This crude material was purified using silica gel chromatography (9:1 hexanes:EtOAc-1:1 hexane:EtOAc) to yield the desired amide (1.0 g, 65%). 1H NMR (300 MHz, CDCl3): δ 7.38–7.29 (m, 4H), 4.16 (m, 2H), 3.88 (m, 1H), 3.72 (s, 3H), 3.31–1.63 (m, 8H). LRMS: M+309. was added to the stirring reaction mixture was quenched with water The aqueous layer was extracted with EtOAc (3×20 mL) Combined organic layers were dried over Na2SO4 concentrated to yield an oil This crude material was purified

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

Procedure: A solution of methyl azetidine-3-carboxylate hydrochloride (1.236 g, 8.15 mmol) and N-methylmorpholine (2.338 ml, 21.26 mmol) in dimethylformamide (10 mL) was treated with a solution of 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) in dimethylformamide (7 mL) and the reaction was allowed to stir at room temperature for 60 hours. Water (50 mL) was added and the resulting suspension was stirred 10 minutes and filtered. The collected solid was washed with water and dried under vacuum. Flash chromatography of the collected solid provided the title compound. the resulting suspension was stirred 10 minutes filtered The collected solid was washed with water dried under vacuum

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

Procedure: Methanol (70 mL) was added dropwise under stirring at 0° C. to thionyl chloride (23.4 mL), and azetidine-3-carboxylic acid (CAS No. 36476-78-5, 25 g) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated, to thereby obtain the title compound (36 g) having the following physical properties. 36476-78-5, 25 g) was added The reaction solution was concentrated

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

Procedure: Methanol (70 mL) was added dropwise under stirring at 0° C. to thionyl chloride (23.4 mL), and azetidine-3-carboxylic acid (CAS No. 36476-78-5, 25 g) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated, to thereby obtain the title compound (36 g) having the following physical properties. 36476-78-5, 25 g) was added The reaction solution was concentrated

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

Procedure: The procedure of Example 6 was similarly performed while using 6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde as a substitute for the compound prepared in Example 5 and using methyl-β-alaninate as a substitute for methyl azetidine-3-carboxylate hydrochloride. Thus, the title compound having the following physical properties was obtained.

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

Procedure: The procedure of Example 6 was similarly performed while using 6-{[(2S)-3-(4-chlorophenyl)-2-methylpropyl]oxy}-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde as a substitute for the compound prepared in Example 5 and using methyl-β-alaninate as a substitute for methyl azetidine-3-carboxylate hydrochloride. Thus, the title compound having the following physical properties was obtained.

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

Procedure: A mixture of {6-Methyl-8-[4-(1-phenyl-1H-pyrazol-3-ylmethyl)-[1,4]diazepan-1-yl]-quinolin-7-yloxy}-acetic acid (100 mg, 0.21 mmol), 3-Azetidinecarboxylic methyl ester HCl salt (35.4 mg, 0.23 mmol), HATU (97 mg, 0.25 mmol) and DIEA (0.222 ml) in DMF (1 ml) was stirred at rt for 2 hrs. After an aqueous workup, the mixture was purified by flash chromatography to give a light yellow solid (70 mg, 59%). MS (ES) m/z 569.3 (M+H+). After an aqueous workup, the mixture was purified by flash chromatography

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

Procedure: A stirred solution of methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate (419 mg, 0.84 mmol) in THF (2 mL) and methanol (2 mL) was added with an aqueous solution of 1 N lithium hydroxide (1.7 mL, 1.68 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. This crude material was dissolved in dimethylformamide (5 mL) and ⅔ of the solution was used in the next step. Methyl azetidine-3-carboxylate hydrochloride (104 mg, 0.69 mmol), 4-(dimethylamino)pyridine (38 mg, 0.32 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol) were then added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water. The organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound as an oil that solidifies on standing (190 mg, 52% yield over two steps). The mixture was cooled to 0° C. to warm to room temperature the solvent removed in vacuo azeotroped with toluene to dryness This crude material was dissolved in dimethylformamide (5 mL) were then added the reaction mixture was stirred at room temperature for 18 hours The solvent was removed in vacuo the residue was partitioned between EtOAc (50 mL) and water The organic phase was dried over Na2SO4 filtered the solvent was removed in vacuo

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

Procedure: A stirred solution of methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoate (419 mg, 0.84 mmol) in THF (2 mL) and methanol (2 mL) was added with an aqueous solution of 1 N lithium hydroxide (1.7 mL, 1.68 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. This crude material was dissolved in dimethylformamide (5 mL) and ⅔ of the solution was used in the next step. Methyl azetidine-3-carboxylate hydrochloride (104 mg, 0.69 mmol), 4-(dimethylamino)pyridine (38 mg, 0.32 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (182 mg, 0.95 mmol) were then added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water. The organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound as an oil that solidifies on standing (190 mg, 52% yield over two steps). The mixture was cooled to 0° C. to warm to room temperature the solvent removed in vacuo azeotroped with toluene to dryness This crude material was dissolved in dimethylformamide (5 mL) were then added the reaction mixture was stirred at room temperature for 18 hours The solvent was removed in vacuo the residue was partitioned between EtOAc (50 mL) and water The organic phase was dried over Na2SO4 filtered the solvent was removed in vacuo

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-nitrophenyl 4-cyclobutyl-1,4-diazepane-1-carboxylate (2.4 g, 7.5 mmol) in isopropyl alcohol (6 ml) and methanol (3 ml) was added DIPEA (3.80 ml, 24 mmol) followed by methyl azetidine-3-carboxylate hydrochloride (1.70 g, 11 mmol) portion wise over 2 minutes. The resulting suspension was heated at 85° C. for 72 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with 1M sodium carbonate solution (3×30 ml), dried (Na2SO4), filtered and evaporated at reduced pressure. Purification by FCC on silica provided the title compound as pale yellow oil (0.95 g, 43%). to cool the solvent was removed in vacuo The residue was dissolved in DCM (100 ml) washed with 1M sodium carbonate solution (3×30 ml) dried (Na2SO4) filtered evaporated at reduced pressure Purification by FCC on silica

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-nitrophenyl 4-cyclobutyl-1,4-diazepane-1-carboxylate (2.4 g, 7.5 mmol) in isopropyl alcohol (6 ml) and methanol (3 ml) was added DIPEA (3.80 ml, 24 mmol) followed by methyl azetidine-3-carboxylate hydrochloride (1.70 g, 11 mmol) portion wise over 2 minutes. The resulting suspension was heated at 85° C. for 72 h. The mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with 1M sodium carbonate solution (3×30 ml), dried (Na2SO4), filtered and evaporated at reduced pressure. Purification by FCC on silica provided the title compound as pale yellow oil (0.95 g, 43%). to cool the solvent was removed in vacuo The residue was dissolved in DCM (100 ml) washed with 1M sodium carbonate solution (3×30 ml) dried (Na2SO4) filtered evaporated at reduced pressure Purification by FCC on silica