3-fluoroazetidine;hydrochloride

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

Procedure: A 25 mL round-bottomed flask was charged with (2R,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxybutanoic acid (184 mg, 0.54 mmol), 3-fluoroazetidine hydrochloride (66 mg, 0.59 mmol), and HATU (242 mg, 0.64 mmol). Then added acetonitrile (1.1 mL) followed by N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then concentrated. The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc) to afford 112 mg (52%) of [(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid. MS: [M+H]+=399. then concentrated The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc)

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

Procedure: A 25 mL round-bottomed flask was charged with (2R,3R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxybutanoic acid (184 mg, 0.54 mmol), 3-fluoroazetidine hydrochloride (66 mg, 0.59 mmol), and HATU (242 mg, 0.64 mmol). Then added acetonitrile (1.1 mL) followed by N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then concentrated. The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc) to afford 112 mg (52%) of [(1R,2R)-1-(3-fluoro-azetidine-1-carbonyl)-2-hydroxy-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid. MS: [M+H]+=399. then concentrated The crude solid was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 10-80% EtOAc)

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

Procedure: A 25 mL round-bottomed flask was charged with (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid (0.40 g, 1.82 mmol), 3-fluoroazetidine hydrochloride (204 mg, 1.82 mmol), HBTU (989 mg, 2.74 mmol), and HOBt (375 mg, 2.74 mmol). Then added DMF (3.6 mL) followed by N,N-diisopropylethylamine (1.27 mL, 7.3 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-50% EtOAc) to afford 267 mg (53%) of [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid. then quenched with water extracted with EtOAc (30 mL) The organic layer was washed once with saturated NaHCO3 and water The combined aqueous layers were back extracted with EtOAc (25 mL) The combined organic layers was dried over sodium sulfate filtered concentrated The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-50% EtOAc)

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

Procedure: A 25 mL round-bottomed flask was charged with (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid (0.40 g, 1.82 mmol), 3-fluoroazetidine hydrochloride (204 mg, 1.82 mmol), HBTU (989 mg, 2.74 mmol), and HOBt (375 mg, 2.74 mmol). Then added DMF (3.6 mL) followed by N,N-diisopropylethylamine (1.27 mL, 7.3 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-50% EtOAc) to afford 267 mg (53%) of [(R)-2-(3-fluoro-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a white solid. then quenched with water extracted with EtOAc (30 mL) The organic layer was washed once with saturated NaHCO3 and water The combined aqueous layers were back extracted with EtOAc (25 mL) The combined organic layers was dried over sodium sulfate filtered concentrated The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-50% EtOAc)

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

Procedure: A round-bottomed flask was charged with Boc-D-norvaline (300 mg, 1.38 mmol) and 3-fluoroazetidine hydrochloride (216 mg, 1.93 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.65 ml, 3.72 mmol) and HATU (578 mg, 1.52 mmol). The yellow reaction mixture was stirred at room temperature for 48 h the quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 417 mg of [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester as a light yellow solid. quenched with water extracted with diethyl ether (2×) The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate filtered concentrated

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

Procedure: A round-bottomed flask was charged with Boc-D-norvaline (300 mg, 1.38 mmol) and 3-fluoroazetidine hydrochloride (216 mg, 1.93 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.65 ml, 3.72 mmol) and HATU (578 mg, 1.52 mmol). The yellow reaction mixture was stirred at room temperature for 48 h the quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 417 mg of [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester as a light yellow solid. quenched with water extracted with diethyl ether (2×) The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate filtered concentrated

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

Procedure: Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and 3-fluoroazetidine hydrochloride, Int06.04 was prepared analogously to the procedure for the preparation of Int02.06. was prepared analogously to the procedure for the preparation of Int02.06

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

Procedure: Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and 3-fluoroazetidine hydrochloride, Int06.04 was prepared analogously to the procedure for the preparation of Int02.06. was prepared analogously to the procedure for the preparation of Int02.06

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

Procedure: To a stirred solution of 4-bromo-3-methoxybenzoic acid (1.4 g) in DMF (15 mL) was added potassium carbonate (2.51 g), 3-fluoroazetidine hydrochloride (1.01 g) and HATU (3.69 g). The mixture was stirred at room temperature for 18 h. Water was added, the mixture was stirred for 15 minutes and the solvent was removed in vacuum. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 1.25 g of the title compound. the mixture was stirred for 15 minutes the solvent was removed in vacuum Water was added the mixture was extracted with ethyl acetate The organic phase was washed with water, saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

Procedure: A solution of {1-[4-(8-formyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (81 mg, 0.163 mmol) and 3-fluoroazetidine hydrochloride (23 mg, 0.245 mmol) in dichloroethane (5 mL) was stirred for 10 min. Sodium triacetoxyborohydride (87 mg, 0.409 mmol) was added and the reaction stirred at RT for 18 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution, diluted with DCM, filtered through a phase separation cartridge and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 50% EtOAc in DCM) to give the title compound as a gummy solid. LCMS (Method G): RT=2.71 min, [M+H]+=555. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution diluted with DCM filtered through a phase separation cartridge concentrated in vacuo

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

Procedure: From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-fluoro-azetidine hydrochloride in DMF. [α]D20=+19.7° (c=0.17, CHCl3), ES-MS m/e (%): 445 (M+H+, 100).

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

Procedure: A mixture of 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (100 mg), HATU (154 mg), 3-fluoroazetidine hydrochloride (45.0 mg), N,N-diisopropylethylamine (0.147 mL) and DMF (2 mL) was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (110 mg). the mixture was extracted with ethyl acetate The extract was washed with water and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) recrystallized from ethyl acetate/hexane