1-Benzyloxycarbonylazetidine-3-carboxylic acid

3-AZETIDINECARBOXYLIC acid (4. uG, 39. 6 mmol) was dissolved in IN sodium hydroxide solution (4uML) and cooled to 0°C. Benzyl CHLOROFORMATE (5. 9mL, 41mmol) was added followed by further IN sodium hydroxide solution (41mL) dropwise. The mixture was stirred vigorously for 16hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2XLOOML) and the extracts dried over MGS04. CONCENTRATION yielded the title compound (9.3g, 39.6mmol, 100percent). 1H NMR (400MHZ, CDC13) : 8 7.37-7. 29 (5H, m), 5.10 (2H, s), 4.21 (4H, d, J 7. 5HZ), 3.43 (1H, quintet, J 7. 5Hz).EXAMPLE 27; 2-(3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide; EXAMPLE 27A; 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid A suspension of azetidine-3-carboxylic acid (2.5 g, 24.75 mmol) and potassium carbonate (4.0 g) in a mixture of 1, 4dioxane (25 ml) and water (50 ml) was treated with benzyl chloroformate (4.0 ml, 27.23 mmol) at room temperature for 6 hours. Piperazine (5 drops) was added and the mixture was stirred for additional 0.5 hour. The organic volatiles were removed and the residue was partitioned between ethyl acetate and 2 N HCl solution. The organic layer was washed with brine, dried over MgSOTo a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in dioxane (325 ml) were added IN sodium hydroxide (124 ml, 124 mmol) and benzyl chloroformate (8.44 ml, 59.3 mmol). The reaction was allowed to stir for 18 h. The reaction was diluted with 3N HCl until pH 2 was obtained. The product was extracted with EtOAc (2x), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-70percent methanol(0.5percent acetic acid)/dichloromethane) to yield 1- [(benzyloxy)carbonyl]azetidine-3-carboxylic acid as a yellow oil (73percent). To a 0 To an ice cold solution of 3-azetidine carboxylic acid (2 g, 19.8 mmol) in 5:1 dioxane-water (15 mL) was added successively K2CO3 (4 g, 29.7 mmol) and CBz-Cl (4 g, 23.7 mmol). The reaction mixture was treated at a temperature in the range of 20 0C to 35 0C over a period of 12 h. The volatiles were evaporated under reduced pressure and the residue was worked up with chloroform. The crude product obtained was further purified by column chromatography to afford azetidine-l, 3-dicarboxylic acid monobenzyl ester (2.2 g, 47.8percent).1H NMR (CDC13, 200MHz): d 7.35 (bs, 5H), 5.10 (s, 2H), 4.2 l(d, J=7.2 Hz, 4H), 3.50-3.39 (m, IH).Preparation of Intermediate 1 (Int. l); (Z)-tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int.1-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid [00103] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2, 5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent HPreparation of Intermediate 1 (Int. l); tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int.1-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid; [00109] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2, 5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent HPreparation 25A: l-(Benzyloxycarbonyl)azetidine-3 -carboxylic acidCbZlM^-COINTERMEDIATE 6tert-Butyl azetidine-3 -carboxylate acetic acid saltStep A: l-(Benzyloxycarbonyl)azetidine-3-carboxylic acidCbzN-1-A: l-(Benzyloxycarbonyl)azetidine-3 -carboxylic acid[0119] To a solution of azetidine-3 -carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2, 5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3 -carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: Column: YMC Combiscreen ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent HPreparation of Intermediate 1 (Int. l); tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int. l-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid; [00101] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2, 5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H0076] 1-1 (4.5 g, 18.05 mmol) was dissolved in methanol (90 mL) and 2 M NaOH (27 mL, 54.2 mmol) was added.After stirring at ambient temperature for 3 hours, the solution was concentrated to be about 20 mL. 1 M HCl was addedto the resulting solution until pH reached 4 and the solution was extracted with EtOAc two times. The combined organiclayers were dried over Na2SO4 and concentrated to provide 1-2 (4.4 g, 100percent) as a white solid. MS: m/z = 236.2 (M+H).benzyl 3-(1-methyl-1H-benzimidazol-2-yl)azetidine-1-carboxylate (1-3)[0077] 1-2 (3.0 g, 12.75 mmol) was dissolved in THF (64 mL) and N-methylbenzene-1, 2-diamine (2.02 g, 16.58 mmol), EDC (2.93 g, 15.30 mmol), HOAt (2.08 g, 15.30 mmol), and Hunig’s base (6.7 mL, 38.3 mmol) were added. After stirringfor 18 hours at ambient temperature, the reaction solution was concentrated. The residue was then dissolved in aceticacid (30 mL). After stirring at ambient temperature for 2 hours, the solvent was removed. The residue was partitionedbetween ethyl acetate and 5percent aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. Theresidue was purified by silica gel chromatography (EtOAc/Hexanes) to provide 1-3 as a off-white solid (3.32 g, 81percent).MS: m/z = 322.4 (M+H).2-(azetidin-3-yl)-1-methyl-1H-benzimidazole (Intermediate 1)[0078]3-AZETIDINECARBOXYLIC acid (4. uG, 39. 6 mmol) was dissolved in IN sodium hydroxide solution (4uML) and cooled to 0C. Benzyl CHLOROFORMATE (5. 9mL, 41mmol) was added followed by further IN sodium hydroxide solution (41mL) dropwise. The mixture was stirred vigorously for 16hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2XLOOML) and the extracts dried over MGS04. CONCENTRATION yielded the title compound (9.3g, 39.6mmol, 100%). 1H NMR (400MHZ, CDC13) : 8 7.37-7. 29 (5H, m), 5.10 (2H, s), 4.21 (4H, d, J 7. 5HZ), 3.43 (1H, quintet, J 7. 5Hz).Benzylchloroformate (ALFA-AESAR, 7.93 mL, 55.5 mmol) was added dropwise to a solution of azetidine-3-carboxylic acid (FLUOROCHEM, 4.32 g, 42.7 mmol) and K2C03 (SIGMA- ALDRICH, 13.6 g, 98.3 mmol) in H20 (50 mL) at 0 °C. The reaction was allowed to warm to rt and stirred overnight. The reaction was washed with EtOAc (50 mL) and partitioned. Then the aq. phase was acidified with HCI (1 N) until pH = 2 and extracted with EtOAc (x2), dried, and concentrated to afford title compound (9.2 g, 91 percent). 1H NMR (300 MHz, CD2CI2) delta ppm: 10.03 (s, 1 H), 7.43-7.27 (m, 5H), 5.12 (s, 2H), 4.31-4.15 (m, 4H), 3.51-3.41 (m, 1 H). [ES+ MS] m/z 236 (MH+).EXAMPLE 27; 2-(3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide; EXAMPLE 27A; To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in dioxane (325 ml) were added IN sodium hydroxide (124 ml, 124 mmol) and benzyl chloroformate (8.44 ml, 59.3 mmol). The reaction was allowed to stir for 18 h. The reaction was diluted with 3N HCl until pH 2 was obtained. The product was extracted with EtOAc (2x), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-70% methanol(0.5% acetic acid)/dichloromethane) to yield 1- [(benzyloxy)carbonyl]azetidine-3-carboxylic acid as a yellow oil (73%). 1H NMR (400 MHz, CD3OD) delta 7.37-7.26 (m, 5H), 5.08 (s, 2H), 4.18 (m, 2H), 4.1 1 (br s, 2H), 3.44 (m, IH).To a 0 0C stirred solution of 3-azetidine carboxylic acid (500 mg, 4.95 mmol) in 2 M K2CO3 aqueous (5 ml) and dioxane (5 ml), benzyl chlorocarbonate (929 mg / 0.78 ml, 5.45 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stirred for 15 hours. The reaction was monitored by TLC. Upon completion the reaction mixture was quenched with piperazine (42 mg, 0.50 mmol), concentrated at reduced pressure and treated with 2 M aqueous HCl (10 ml). The aqueous layer was extracted with EtOAc (5 x 10 ml), the phases separated, dried (MgSO4), filtered and concentrated at reduced pressure. The crude orange oil was purified by silica FCC to give the title compound (760 mg, 65% yield) as a white solid.LCMS data (reaction IPC): Calculated MH+ (236); Found 7% (MH+) m/z 236, Rt = 1.09 min. NMR data: 1H NMR (500 MHz, Chloroform-J) delta ppm 8.49 (1 H, br. s.), 7.30 - 7.42 (5 H, m), 5.10 - 5.15 (2 H, m), 4.18 - 4.27 (4 H, m), 3.43 (1 H, m).To an ice cold solution of 3-azetidine carboxylic acid (2 g, 19.8 mmol) in 5:1 dioxane-water (15 mL) was added successively K2CO3 (4 g, 29.7 mmol) and CBz-Cl (4 g, 23.7 mmol). The reaction mixture was treated at a temperature in the range of 20 0C to 35 0C over a period of 12 h. The volatiles were evaporated under reduced pressure and the residue was worked up with chloroform. The crude product obtained was further purified by column chromatography to afford azetidine-l, 3-dicarboxylic acid monobenzyl ester (2.2 g, 47.8%).1H NMR (CDC13, 200MHz): d 7.35 (bs, 5H), 5.10 (s, 2H), 4.2 l(d, J=7.2 Hz, 4H), 3.50-3.39 (m, IH).ATo 500 mg (4.95 mmol) azetidine-3-carboxylic acid was added 10 ml. dioxane and 10 ml_ H2O and the solution cooled to 0 C. 1.38 g (10 mmol) potassium carbonate was added followed by 0.78 ml. (11 mmol) benzylchloroformate, and the reaction stirred at room temperature for 18 hours. The mixture was acidified with 25 ml. 1 M HCI, extracted with DCM (2 x 20 ml_), the combined organic layers dried over Na2SO4. After filtration the solvent was evaporated to give the desired product which was used in the next step without further purification.Ci2H13NO4 (M= 235.24) predicted: Molecular ion (M+H)+: 236 observed: Molecular ion (M+H)+: 236 HPLC-MS: 1.14 minutes (Method A)A mixture of To a solution of

Molecular Weight:235.24
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:235.08445790
Monoisotopic Mass:235.08445790
Topological Polar Surface Area:66.8
Heavy Atom Count:17
Complexity:293
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes