azetidine;hydrochloride

Conditions: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-chloropyrazine-2-carboxylic acid (1.0 eq), DMF (0.069 eq) and toluene (5.52 vols) under a nitrogen atmosphere. The mixture was heated to 60-65° C., and thionyl chloride (1.5 eq) added drop-wise to the batch over approximately 2 hours. The thionyl chloride was washed into the flask with toluene (0.2 vols). The reaction mixture was heated at 60-65° C. for at least 4 hours, then cooled to 40-45° C. and distilled under vacuum, removing approximately 4.5 vol distillates, and distilling to a final volume of 3.2 vols. Toluene (10.6 vol) was added, and the mixture distilled under vacuum at 40-45° C., removing approximately 9.1 vol distillates, and distilling to a final volume of 4.7 vols. The mixture was then cooled to 20-25° C., and dichloromethane (10.6 vols) added. The mixture was cooled to 0-5° C. Meanwhile, to a second flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added azetidine hydrochloride (0.284 eq), dichloromethane (5.2 vols) under a nitrogen atmosphere. Triethylamine (2.57 eq) was added over at least 15 minutes maintaining the reaction temperature from 20-25° C., the triethylamine was washed into the flask with dichloromethane (0.13 vols), and the mixture cooled to −5° C. to −10° C. The acid chloride solution in the first flask was added to the second flask in portions maintaining the reaction temperature at −5° C. to −10° C. over a time period of 2-5 hours. The pH was tested and adjusted to pH>7 after the acid chloride addition. The reaction mixture was agitated for at least 30 minutes at −5° C. to −10° C. Water (10.6 vols) was added to the second flask and the temperature was allowed to increase to 20-25° C. The mixture was agitated for approximately 25 minutes and then the layers were separated. A 3.17% w/w solution (1.46 eq) of hydrochloric acid (prepared from 32% w/w hydrochloric acid and water) was added to the organic layer B keeping the batch temperature at 20-25° C. The mixture was agitated for 30 minutes at this temperature. The layers were separated, and the organic phase was treated with 26% w/w sodium chloride solution (approximately 8.9 vols) and the batch agitated at 20-25° C. for at least 15 minutes. The layers were separated and the organic layers was heated to reflux, and dichloromethane was removed by atmospheric distillation, distilling to a final volume of approximately 1-2 vols, collecting approximately 11.9 vols distillates. The resulting mixture was cooled to 20-25° C., and heptane (10.5 vols) added. The mixture was heated to reflux for 60 minutes, and then cooled to 90-100° C. The hot solution was filtered through a filter containing 10% w/w of activated charcoal into a clean dry vessel. The filter was washed with heptane (0.43 vols) and the solution cooled to 20-25° C. over at least 2 hours. The resulting crystallised slurry was filtered, and the solid washed with pentane (0.94 vols). After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 65-78%). 1H NMR δ (400 MHz CDCl3): 2.35-2.42 (2H, m), 4.26 (2H, t), 4.67 (2H, t), 8.52 (1H, d), 9.09 (1H, d); m/z 198 (M+H)+. To a flask fitted with overhead stirrer, condenser The thionyl chloride was washed into the flask with toluene (0.2 vols) The reaction mixture was heated at 60-65° C. for at least 4 hours cooled to 40-45° C. distilled under vacuum removing approximately 4.5 vol distillates distilling to a final volume of 3.2 vols Toluene (10.6 vol) was added the mixture distilled under vacuum at 40-45° C. removing approximately 9.1 vol distillates distilling to a final volume of 4.7 vols The mixture was then cooled to 20-25° C. dichloromethane (10.6 vols) added The mixture was cooled to 0-5° C Meanwhile, to a second flask fitted with overhead stirrer, condenser maintaining the reaction temperature from 20-25° C. the triethylamine was washed into the flask with dichloromethane (0.13 vols) the mixture cooled to −5° C. to −10° C The acid chloride solution in the first flask was added to the second flask in portions maintaining the reaction temperature at −5° C. to −10° C. over a time period of 2-5 hours after the acid chloride addition Water (10.6 vols) was added to the second flask to increase to 20-25° C The mixture was agitated for approximately 25 minutes the layers were separated at 20-25° C The mixture was agitated for 30 minutes at this temperature The layers were separated the organic phase was treated with 26% w/w sodium chloride solution (approximately 8.9 vols) and the batch agitated at 20-25° C. for at least 15 minutes The layers were separated the organic layers was heated to reflux dichloromethane was removed by atmospheric distillation distilling to a final volume of approximately 1-2 vols collecting approximately 11.9 vols distillates The resulting mixture was cooled to 20-25° C. heptane (10.5 vols) added The mixture was heated to reflux for 60 minutes cooled to 90-100° C The hot solution was filtered through a filter containing 10% w/w of activated charcoal into a clean dry vessel The filter was washed with heptane (0.43 vols) the solution cooled to 20-25° C. over at least 2 hours The resulting crystallised slurry was filtered the solid washed with pentane (0.94 vols) After drying in the vacuum oven at 40° C. overnight

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

Procedure: A 50 mL round bottom flask was charged with lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.500 g, 2.28 mmol), methylene chloride (15 ml), and 12 drops of DMF. Oxalyl chloride (0.298 ml, 3.42 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours and concentrated to yield a tan solid. This was redissolved in methylene chloride (15 ml). Azetidine hydrochloride (0.426 g, 4.55 mmol) was added in one portion and Hunig's Base (1.59 ml, 9.11 mmol) was added dropwise. This mixture was stirred at room temperature overnight, then diluted with methylene chloride (15 mL) and washed with water (25 mL), sat. NaHCO3 (25 mL), and brine (25 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield azetidin-1-yl(7-chlorothieno[3,2-b]pyridin-2-yl)methanone (0.58 g, 100% yield) as a tan solid. concentrated to yield a tan solid was added dropwise This mixture was stirred at room temperature overnight washed with water (25 mL), sat. NaHCO3 (25 mL), and brine (25 mL) The organic layer was dried with MgSO4 filtered concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 350 mL of dry seal pressure flask (Chemglass) were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 3.6 g, 6.85 mmol) and 150 mL of absolute ethanol. Azetidine hydrochloride (2.56 g, 27.4 mmol) was added and then followed by triethylamine (4.16 g, 41.1 mmol). The suspension was stirred and heated to 70° C. while sealed for 5 hours. All the starting material was consumed but the benzoyl groups remained as shown by TLC. Sodium methoxide (7.8 mL, 34.3 mmol, 25% solution in methanol) was added to the mixture and heated at 50° C. The reaction was complete after 3.5 h. The reaction mixture was allowed to cool to room temperature and neutralized by addition of glacial acetic acid (0.41 g, 6.85 mmol). The mixture was concentrated under reduced pressure and then the residue was triturated with ethyl acetate. The resulting solid was removed by filtration and the solid was washed with EtOAc (2×15 mL). The filtrate was concentrated under reduced pressure and the residue was purified via column chromatography (Analogix, 120 g cartridge, gradient of 0 to 15% MeOH in DCM). The pure product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a light pink colored foam solid (2.15 g, 6.35 mmol, 93%). To a 350 mL of dry seal pressure flask (Chemglass) while sealed for 5 hours All the starting material was consumed heated at 50° C to cool to room temperature The mixture was concentrated under reduced pressure the residue was triturated with ethyl acetate The resulting solid was removed by filtration the solid was washed with EtOAc (2×15 mL) The filtrate was concentrated under reduced pressure the residue was purified via column chromatography (Analogix, 120 g cartridge, gradient of 0 to 15% MeOH in DCM) The pure product containing fractions concentrated under reduced pressure

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

Procedure: To a solution of 5-chloro-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (107) (3.6 g, 15.02 mmol, 1.00 equiv) in CH3CN (40 mL) was added triethylamine (3.03 g, 29.94 mmol) and azetidine hydrochloride (1.68 g, 17.96 mmol). The resulting solution was stirred for 1 hour at room temperature, concentrated under vacuum and purified by prep-HPLC to afford 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (108) as a white solid. MS m/z 261.1 (M+1)+. concentrated under vacuum purified by prep-HPLC

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

Procedure: The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and azetidine hydrochloride (84 mg, 0.90 mmol). Yield: 41 mg (47%). The compound was prepared

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

Procedure: A mixture of (4-bromophenyl)acetic acid (1 g, 4.65 mmol), azetidine hydrochloride (481 mg, 5.12 mmol), HATU (1.95 g, 5.12 mmol) and NMM (1.03 g, 10.23 mmol) in DMF (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with 1N HCl (15 mL×2) and 1M aqueous K2CO3 (15 mL×2). The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1-(azetidin-1-yl)-2-(4-bromophenyl)ethanone (1.37 g) as a solid which was used directly in the next step without purification. 1H NMR (400 MHz, CD3OD) δ 7.47 (d, 2H), 7.197 (d, 2H), 4.26 (t, 2H), 4.01 (t, 2H), δ 3.45 (s, 2H), δ 2.30 (p, 2H). washed with 1N HCl (15 mL×2) and 1M aqueous K2CO3 (15 mL×2) The organic phase was washed with brine dried over sodium sulfate concentrated in vacuo

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

Procedure: A vial charged with potassium carbonate (0.338 g, 2.444 mmol), (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.100 g, 0.244 mmol), azetidine hydrochloride (0.209 g, 3.67 mmol), copper(i) iodide (4.65 mg, 0.024 mmol), and palladiumtetrakistriphenylphosphine (0.028 g, 0.024 mmol) was treated with 2 mL DMF and was thoroughly degassed with argon gas. 3-chloro-3-methylbut-1-yne (0.125 g, 1.222 mmol) was added, the vial was placed under argon, and was heated to 80° C. for 4 hours. The reaction mixture was poured into water and was extracted with EtOAc. The organics were washed with brine, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-3-(3-(azetidin-1-yl)-3-methylbut-1-ynyl)-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine was thoroughly degassed with argon gas was extracted with EtOAc The organics were washed with brine dried over MgSO4 concentrated Purification of the crude residue by column chromatography

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile and 4-[4-(3-bromo-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (7.5 g, 27 mmol), K2CO3 (9.6 g, 70 mmol) and azetidine hydrochloride (4.0 g, 43 mmol) in acetonitrile (80 mL) was heated at 40° C. for 18 hours. The mixture was concentrated in vacuo then partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was extracted with 2M HCl solution (2×100 mL) and the combined acid layers basified with 40% potassium hydroxide solution, then extracted with DCM (2×150 mL). The DCM layers were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the title compound (1.1 g, 57%) as a clear, viscous oil. 1H NMR (400 MHz, DMSO) δ 1.80 (quintet, 2H), 2.00-2.14 (m, 6H), 2.58 (t, 2H), 3.20 (t, 4H), 3.88 (m, 2H), 4.00-4.11 (m, 4H), 6.90 (d, 2H), 7.38 (d, 2H). LRMS (APCI+) m/z 301 (MH)+. The mixture was concentrated in vacuo then partitioned between water (150 mL) and ethyl acetate (150 mL) The organic layer was extracted with 2M HCl solution (2×100 mL) extracted with DCM (2×150 mL) dried over sodium sulphate filtered concentrated under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile and 4-[4-(3-bromo-propoxy)-phenyl]-tetrahydropyran-4-carbonitrile (7.5 g, 27 mmol), K2CO3 (9.6 g, 70 mmol) and azetidine hydrochloride (4.0 g, 43 mmol) in acetonitrile (80 mL) was heated at 40° C. for 18 hours. The mixture was concentrated in vacuo then partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was extracted with 2M HCl solution (2×100 mL) and the combined acid layers basified with 40% potassium hydroxide solution, then extracted with DCM (2×150 mL). The DCM layers were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the title compound (1.1 g, 57%) as a clear, viscous oil. 1H NMR (400 MHz, DMSO) δ 1.80 (quintet, 2H), 2.00-2.14 (m, 6H), 2.58 (t, 2H), 3.20 (t, 4H), 3.88 (m, 2H), 4.00-4.11 (m, 4H), 6.90 (d, 2H), 7.38 (d, 2H). LRMS (APCI+) m/z 301 (MH)+. The mixture was concentrated in vacuo then partitioned between water (150 mL) and ethyl acetate (150 mL) The organic layer was extracted with 2M HCl solution (2×100 mL) extracted with DCM (2×150 mL) dried over sodium sulphate filtered concentrated under reduced pressure

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

Procedure: 4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 0.58 mmol), azetidine hydrochloride (81 mg, 0.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol), 1-hydroxybenzotriazole hydrate (97 mg, 0.63 mmol) and triethylamine (210 μL, 1.51 mmol) were stirred in dichloromethane (8 mL) at room temperature for 18 hours. The reaction was diluted with dichloromethane (60 mL) and washed with aqueous sodium bicarbonate. The aqueous were extracted again with dichloromethane. The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume) to provide the title compound (97 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.11 (d, 6H), 1.77-1.82 (m, 2H), 1.88-1.95 (m, 2H), 2.01-2.08 (m, 4H), 2.26-2.29 (m, 2H), 2.47-2.52 (m, 2H), 2.76-2.86 (m, 3H), 3.66-3.74 (m, 4H), 3.79-3.82 (m, 2H), 3.92-3.96 (m, 2H), 4.40 (m, 1H), 6.95 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 387.2634 [MH]+. washed with aqueous sodium bicarbonate The aqueous were extracted again with dichloromethane dried over sodium sulphate filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume)

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

Procedure: 4-{4-[(1-Isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carboxylic acid (200 mg, 0.58 mmol), azetidine hydrochloride (81 mg, 0.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol), 1-hydroxybenzotriazole hydrate (97 mg, 0.63 mmol) and triethylamine (210 μL, 1.51 mmol) were stirred in dichloromethane (8 mL) at room temperature for 18 hours. The reaction was diluted with dichloromethane (60 mL) and washed with aqueous sodium bicarbonate. The aqueous were extracted again with dichloromethane. The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume) to provide the title compound (97 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.11 (d, 6H), 1.77-1.82 (m, 2H), 1.88-1.95 (m, 2H), 2.01-2.08 (m, 4H), 2.26-2.29 (m, 2H), 2.47-2.52 (m, 2H), 2.76-2.86 (m, 3H), 3.66-3.74 (m, 4H), 3.79-3.82 (m, 2H), 3.92-3.96 (m, 2H), 4.40 (m, 1H), 6.95 (d, 2H), 7.22 (d, 2H). HRMS ESI+ m/z 387.2634 [MH]+. washed with aqueous sodium bicarbonate The aqueous were extracted again with dichloromethane dried over sodium sulphate filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.5, by volume)

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

Procedure: A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester (Example 2, step 1) (500 mg, 1.57 mmol), azetidine hydrochloride (588 mg, 6.29 mmol) and K2CO3 (1.08 g, 7.87 mmol) in DMF (5 mL) is heated at 80° C. in a sealed tube overnight. On cooling, water (20 mL) and EtOAc (20 mL) are added. The organic layer is separated and the aqueous layer is extracted with EtOAc (10 mL). The combined organic layer is washed with water, dried, and concentrated to give 4-azetidin-1-yl-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester as a crude product. A solution of LiAlH4 (1M in THF, 4.5 mL) is added to a solution of this crude product in THF (5 mL). The reaction mixture is stirred at room temperature overnight, diluted with ether (10 mL), and the reaction quenched with solid Na2SO4.10H2O (1.0 g). The resulting mixture is stirred for 1 hour, filtered through celite and concentrated at reduced pressure. The crude product is purified by PTLC (10% MeOH in CH2Cl2) to give the title product. 1H NMR (CDCl3) 7.20 (t, 1H), 7.10 (d, 2H), 6.09 (s, 1H), 4.66 (s, 2H), 4.17 (t, 4H), 2.58 (s, 3H), 2.38 (m, 6H), 1.08 (t, 6H). On cooling The organic layer is separated the aqueous layer is extracted with EtOAc (10 mL) The combined organic layer is washed with water dried concentrated