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0076] 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]
With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 18 h;
A round bottomed flask containing methyl azetidine-3-carboxylate hydrochloride(3 g, 20 mmol), THF (30 mL) and H20 (30 mL) was added with an aqueous solution ofNaOH (4 M, 5 mL, 20 mmol) at 0 °C, followed by benzyl chloroformate (2.84 mL, 20 mmol). The reaction was vigorously stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between Et20 (100 mL) and H20 (30 mL). The aqueous phase was back-extracted withEt20 (3 x 50 mL), the combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (5 g, 99percent) as a colourless oil, which was used in subsequent steps without further purification.‘H NMR (400 MHz, CDC13): ö 7.43-7.25 (m, 5 H), 5.10 (s, 2 H), 4.23-4.13 (m, 4 H), 3.74 (s, 3 H), 3.38 (q, J = 7.2 Hz, 1 H).
Stage #1: at 0℃; Stage #2: With acetic acid In methanol; hexanes; toluene
1-BENZYLOXYCARBONYL-3-AZETIDINECARBOXYLIC acid (from step (i); 9.3g, 39. 6MMOL) was dissolved in methanol (LOOML) and toluene (100mL), and cooled to 0°C. A solution of 2M trimethylsilyldiazomethane in hexanes was then added dropwise until bubbling had ceased and the yellow colour persisted. Acetic acid was then added dropwise until the yellow colour disappeared. Concentration of the solution yielded the title compound as an oil (9.48G, 38mmol, 96percent). IH NMR (400MHZ, CDC13) : 8 7.36-7. 31 (5H, m), 5.10 (2H, s), 4.19 (4H, D, J7. 8Hz), 3.75 (3H, s), 3.39 (1H, quintet, J 7. 8HZ).
EXAMPLE 27B; 1-benzyl 3-methylazetidine-1,3-dicarboxylate A solution of Example 27A (4.8 g, 20.3 mmol) in ether (100 ml) was treated with diazomethane (100 ml in ether, 60 mmol) at room temperature for 4 hours. Removal of the volatiles gave Example 27B (4.8 g Yield: 98percent). MS (DCI/NH3) m/z 250 (M+H)+.
1-BENZYLOXYCARBONYL-3-AZETIDINECARBOXYLIC acid (from step (i); 9.3g, 39. 6MMOL) was dissolved in methanol (LOOML) and toluene (100mL), and cooled to 0°C. A solution of 2M trimethylsilyldiazomethane in hexanes was then added dropwise until bubbling had ceased and the yellow colour persisted. Acetic acid was then added dropwise until the yellow colour disappeared. Concentration of the solution yielded the title compound as an oil (9.48G, 38mmol, 96percent). IH NMR (400MHZ, CDC13) : 8 7.36-7. 31 (5H, m), 5.10 (2H, s), 4.19 (4H, D, J7. 8Hz), 3.75 (3H, s), 3.39 (1H, quintet, J 7. 8HZ).
EXAMPLE 27B; 1-benzyl 3-methylazetidine-1,3-dicarboxylate A solution of Example 27A (4.8 g, 20.3 mmol) in ether (100 ml) was treated with diazomethane (100 ml in ether, 60 mmol) at room temperature for 4 hours. Removal of the volatiles gave Example 27B (4.8 g Yield: 98percent). MS (DCI/NH3) m/z 250 (M+H)+.
With sodium hexamethyldisilazane; In tetrahydrofuran; at -70 - -20℃; for 3h;
EXAMPLE 27C; 1-benzyl 3-methyl 3-methylazetidine-1,3-dicarboxylate A solution of Example 27B (250 mg, 1 mmol) and iodomethane (0.12 ml, 2.0 mmol) in THF (5 mL) was treated with NaN(TMS)2 in THF (1.0 M, 2 mL, 2.0 mmol) at -70 C. under nitrogen. The temperature of the cooling bath was slowly raised to -20 C. within 1 h and the mixture was stirred at the same temperature for additional 2 h. After quenching with water, the mixture was partitioned between water and EtOAc. The organic phase was washed with water and concentrated. The residue was purified by flash chromatography to give Example 27C (220 mg, 85% yield). MS (DCI/NH3) m/z 264 (M+H)+.
Methyl l-benzyloxycarbonyl-3-azetidinecarboxylate (from step (ii); 10. 1G, 40MMOL) was dissolved in tetrahydrofuran (120mL) and cooled TO-78C. A solution of lithium HEXAMETHYLDISILAZIDE in tetrahydrofuran (1M, 58mL, 58mmol) was slowly added and the solution warmed to 0C. After 15 mins. at this temperature, the resulting solution was cooled back to-78C and tert-butyldimethylsilyloxy acetaldehyde was added and stirred to room temperature over 2hrs and quenched with water (200mL). This suspension was extracted with ethyl acetate (2x200mL). The extracts were dried (MgSO4) and concentrated. The residue was flushed through silica with 25% ethyl acetate in hexanes to give A 1: 2 mixture of 1-benzyl 3-methyl 3-(2-F [RE7T- butyl (dimethyl) SILYL] OXY}-L-HYDROXYETHYL) AZETIDINE-1, 3-DICARBOXYLATE : STARTING material (4.24g). This mixture was dissolved in tetrahydrofuran (30mL) and treated with lithium borohydride (395mg, 18MMOL). After 2hrs at room temperature, the mixture was quenched with IN sodium hydroxide solution (100mL) and extracted with ethyl acetate (2XLOOML). The extracts were dried (MGS04) and concentrated to give crude benzyl 3-(2-{ [TER-BUTYL (dimethyl) silyl] oxy}-1-hydroxyethyl)-3-(hydroxylmethyl) AZETIDINE-1-CARBOXYLATE. This was dissolved in tetrahydrofuran (100mL) and treated with 1M tetra-n-butylammonium fluoride in tetrahydrofuran (10mL, lOmmol). After stirring for lhr at room temperature, water (200mL) was added and the mixture extracted with ethyl acetate (2X200ML). The combined extracts were dried (MGS04) and concentrated. The residue was purified by silica chromatography to give the title compound as an oil (956mg, 3. 4mmol). H NMR (400 MHz, CDC13) : 8 7.37-7. 29 (5H, m), 5.09 (2H, s), 3.96-3. 64 (9H, m), 3.13 (2H, br m), 1.69 (1H, BR M).
With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 18h;
A round bottomed flask containing <strong>[100202-39-9]methyl azetidine-3-carboxylate hydrochloride</strong>(3 g, 20 mmol), THF (30 mL) and H20 (30 mL) was added with an aqueous solution ofNaOH (4 M, 5 mL, 20 mmol) at 0 C, followed by benzyl chloroformate (2.84 mL, 20 mmol). The reaction was vigorously stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between Et20 (100 mL) and H20 (30 mL). The aqueous phase was back-extracted withEt20 (3 x 50 mL), the combined organic phases were dried (Na2SO4) and concentrated in vacuo to give the title compound (5 g, 99%) as a colourless oil, which was used in subsequent steps without further purification.?H NMR (400 MHz, CDC13): oe 7.43-7.25 (m, 5 H), 5.10 (s, 2 H), 4.23-4.13 (m, 4 H), 3.74 (s, 3 H), 3.38 (q, J = 7.2 Hz, 1 H).
With triethylamine; In dichloromethane; at 20℃;
(i) 1-Benzyl 3-methyl 1,3-azetidinedicarboxylate 10 g of azetidine-3-carboxylic methyl ester hydrochloride and then 23 ml of triethylamine are added to 150 ml of CH2Cl2. The mixture is cooled and 13.5 g of benzyl chloroformate are added. After leaving overnight at AT, washing is carried out with water and then with HCl (N). After drying, concentrating to dryness and purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 50%)), 13.1 g of the expected compound are obtained.
With tris(dibenzylideneacetone)dipalladium/tri-tert-butylphosphonium tetrafluoroborate; lithium hexamethyldisilazane; In toluene; at 0 - 20℃; for 18.83h;Inert atmosphere;
To a round bottomed flask containing Pd2(dba)3.HP(tBu)3BF4 (500 mg, 0.38 mmol) under N2 was added with a solution of LiHMDS (1 M in toluene, 48 mL, 48mol). The reaction was stirred for 20 minutes and cooled to 0 C. Bromobenzene (4.4 mL,42 mmol) was added, followed by a solution of 01-benzyl 03-methyl azetidine-1,3-dicarboxylate (5 g, 20 mmol) in degassed toluene (60 mL) dropwise under N2. Thereaction was stirred for a further 30 minutes at 0 C, then stirred at room temperature for18 hours. The reaction was diluted with 10% citric acid solution (50 mL) and extractedwith EtOAc (2 x 100 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc in isohexane to give the title compound, as an oil (420 mg, 6% yield).?H NMR (400 MHz, CDC13): oe 7.42-7.22 (m, 10 H), 5.10 (s, 2 H), 4.69 (d, J = 8.3Hz, 2 H), 4.39 (d, J = 9.0 Hz, 2 H), 3.71 (s, 3 H). LCMS (Method 2): [MH+] = 326 at3.92 mm.
(ii) 1-Benzyl 3-methyl 3-phenyl-1,3-azetidinedicarboxylate 5.11 ml of bromobenzene, then 0.5 g of Pd(dba)2, 2.15 ml of a 10% solution of tri(tert-butyl)phosphine (P(tBu)3) in hexane and then 8.4 g of LiHMDS are added to 40 ml of toluene. 11 g of the compound obtained in the preceding stage (i) in 10 ml of toluene are added while maintaining the temperature between 15 and 20 C. After leaving overnight, the mixture is poured onto a saturated NH4Cl solution, extraction is carried out with ether and the extract is dried with MgSO4 and concentrated to dryness. After purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 30%)), 3.25 g of the expected compound are obtained.
0076] 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]
With sodium hydroxide; In methanol; at 20℃; for 3h;
Step 1 : l-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (1-2) 1-1 (4.5 g, 18.05 mmol) was dissolved in MeOH (90 mL) and 2 M NaOH (27 mL, 54.2 mmol) was added. After stirring at room temperature for 3 h, the solution was concentrated to ~20 mL. 1 M HC1 was added to the resulting solution until pH reached 4 and the solution was extracted with EtOAc (2x). The combined organic layer was dried over Na2S04, filtered, and concentrated to provide 1-2 as a white solid. MS: m/z = 236.2 (M+H).
A solution of 01-benzyl-03-methyl azetidine-1,3-dicarboxylate (6.80 g,27.3 mmol) in MeOH (100 mL) was added with a 2 N NaOH solution (41 mL,81.9 mmol) and the mixture was stirred at room temperature for 3 hours. The organic solvent was removed in vacuo, the residual solution cooled to 0C and acidified to pH 4-5 with iN HC1 and extracted with DCM (3 x 20 mL). The combined organic extracts were filtered through a phase separator and the solvent was removed in vacuo. The residue waspurified by chromatography on silica gel eluting with MeOH/DCM to give a colourless oil. t-BuOH (2.36 g, 31.9 mmol) in DCM (30 mL), DMAP (0.78 g, 6.4 mmol) and EDCI (3.67 g, 19.1 mmol) were added successively to the oil, and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was taken up in EtOAc and washed with 10% citric acid ( 2 x 20 mL), and saturated NaHCO3solution. The organic phase was dried over MgSO4, filtered and solvent was removed in vacuo to give 01-benzyl 03-tert-butyl azetidine-1,3-dicarboxylate as a colourless oil.?H NMR (400 MHz, CDC13): oe 7.36-7.34 (m, 5 H), 5.10 (s, 2 H), 4.14 (d, J = 7.7 Hz, 4 H), 3.32-3.24 (m, 1 H), 1.46 (s, 9 H).
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