tert-butyl (2S)-2-(hydroxymethyl)azetidine-1-carboxylate

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(S)-Hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (prepared as described in Abreo, et al. J. Med. Chem. 1996, 39, 817-825) (9.7 g, 52 mmol) was taken up in dichloromethane (50 mL), treated with triethylamine (8.7 mL, 62 mmol), cooled to 0° C., treated dropwise with methanesulfonyl chloride (4.4 mL, 57 mmol), stirred overnight at ambient temperature, treated with sodium bicarbonate solution (50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 10:1, 5:1, 2:1 and 3:2 hexane:ethyl acetate to provide 10.7 g (78%). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9 H) 2.27 (m, 2 H) 3.05 (s, 3 H) 3.82 (m, 2 H) 4.28 (dd, J=10.85, 2.71 Hz, 1 H) 4.43 (m, 1 H) 4.54 (dd, J=10.85, 4.07 Hz, 1 H). the layers were separated The aqueous layer was extracted with dichloromethane (50 mL) The combined organic layers were dried (MgSO4) filtered concentrated chromatographed on silica gel eluting with a gradient of 10:1, 5:1, 2:1 and 3:2 hexane ethyl acetate to provide 10.7 g (78%)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-BOC-2-(S)-azetidinylmethanol (868 mg, 4.64 mmol) and 3-hydroxy-5-nitropyridine from Example 132d (500 mg, 3.57 mmol) were coupled according the procedure of Example 17a. Solvent was removed, and the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) to afford the title compound (800 mg, 73%). 1H NMR (CHCl3, 300 MHz) δ 1.45 (s, 9H), 2.56 (m, 2H), 4.52 (m, 4H), 4.82 (m, 1H), 8.25 (t, J=3 Hz, 1H), 8.65 (d, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H). MS (DCI/NH3) m/z 310 (M+H)+. Solvent was removed the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of triphenylphosphine (1.73 g, 6.6 mmol) in THF (26 mL) was added diethyl azodicarboxylate (1.04 mL, 6.6 mmol) at 0° C., and the reaction mixture was stirred for 15 minutes. 1-BOC-2-(S)-azetidinemethanol (1.03 g, 5.5 mmol) and 2-chloro-3-pyridinol (785 mg, 6.0 mmol, Aldrich Chemical Co.) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. Solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane (1:4 to 1:1) to afford the title compound (611 mg). MS (DCI/NH3) m/z 299 (M+H)+. stir overnight Solvent was removed the residue was dissolved in ethyl acetate The solution was washed with saturated aqueous K2CO3 and brine dried over MgSO4 concentrated The residue was chromatographed on a silica gel column eluting with ethyl acetate:hexane (1:4 to 1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A sample of (S)-1-t-butoxycarbonyl-2-azetidinemethanol (1.64 g, 8.18 mmol) and 1.05 g (6.29 mmol) of 6-acetyloxymethyl-3-hydroxypyridine, prepared as described by Deady and Dayhe, Aust. J. Chem., 2565:36 (1983), were reacted with triphenylphosphine (540 mg, 2.06 mmol) and DEAD (0.33 mL, 2.06 mmol) in TBF (25 mL) according to the procedure of Example 2a. The product was stirred in methanol (4 mL) containing KOH (450 mg) at room temperature for 4 hours, then neutralized and concentrated. The residue was purified by chromatography (silica gel; 1:1 ether: hexane and ethyl acetate) to give title compound (240 mg, 41% for two steps). MS (DCI/NH3) m/e: 295 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 1.42 (s, 9H), 2.24-2.48 (m, 2H), 3.84-3.96 (m, 2H), 4.18 (dd, J=2.6, 11 Hz, 1H), 4.40 (m, 1H), 4.53 (m, 1H), 4.82 (s, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.51 (m 1H), 8.31 (d, J=3.0 Hz, 1H). concentrated The residue was purified by chromatography (silica gel; 1:1 ether: hexane and ethyl acetate)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 950 mg (5.1 mmol) sample of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7c above, and 550 mg (4.25 mmol) of 2-chloro-5-hydroxypyridine (Example 1g above) were added to a solution of triphenylphosphine and DEAD (5.1 mmol each) in 20 mL of THF, according to the procedure of Example 12a, to give 1.09 g of 3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-6-chloropyridine: [α]D25 -67.3 (c 1.1, CHCl3); 1H NMR (DMSO-d6, 300 MHz) δ 8.14 (d, J=3.3 Hz, 1H), 7.48 (dd, J=8.8, 3.3 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.47-4.42 (m, 1H), 4.36 (dd, J=11.0, 4.4 Hz, 1H), 4.20 (dd, J=11.0, 3.3 Hz, 1H), 3.77 (t, J=7.7 Hz, 2H), 2.36-2.29 (m, 1H), 2.19-2.12 (m, 1H), 1.36 (s, 9H); MS (CI/NH3) m/z: 299/301 (M+H)+. A portion of this material (1.02 g) was stirred with 10 mL of 4.5 N HCl at room temperature for 30 minutes. The solvent was removed, and the residue was recrystallized from methanol/ether, to afford 340 mg of the title compound: mp 113-115° C.; 1H NMR (D2O, 300 MHz) δ: 8.15 (d, J=3.0 Hz, 1H), 7.57 (dd, J=8.9, 3.0 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 4.98-4.89 (m, 1H), 4.42 (d, J=4.4 Hz, 2H), 4.19-4.02 (m, 2H), 2.68 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z: 299/301 (M+H)+. Anal. Calcd for C9H13N2OCl3 : C, 39.80; H, 4.82; N, 10.32; Found C, 40.12 H, 4.84; N, 10.35.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of triphenylphosphine (2.6 g, 9.94 mmol) and diethyl azodicarboxylate (1.6 mL, 9.94 mmol) in THF (16 mL) was stirred at 0° C. for 15 minutes. 1-t-Butyloxycarbonyl-2-(S)-azetidinemethanol (1.55 g, 8.28 mmol, from step 7c above) and 5,6-dichloro-3-pyridinol (1.5 g, 9.1 mmol) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. The solvent was removed, and the residue was redissolved in methylene chloride. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; ethyl acetate:hexane, 1:5) to afford the 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (1.08 g): MS (CI/NH3) m/z 333 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.85-3.92 (m, 2H), 4.12 (dd, J=2.7, 10.1 Hz, 1H), 4.30-4.40 (m, 1H), 4.48-4.56 (m, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.97 (d, J=2.8 Hz, 1H). To a solution of 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)-pyridine (1.06 g, 3.11 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (10 mL). The solution was allowed to warm to room temperature while stirring for 45 minutes. The volatile components were then removed under vacuum. The residue was treated with saturated K2CO3 solution, then extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; MeOH/CHCl3 /NH4OH, 1:10:0 to 1:10:0.05) to afford the free base of the title compound (475 mg, 64% yield): mp 59-60° C.; MS (CI/NH3) m/z 233 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 2.21-2.44 (m, 2H), 3.45 (m, 1H), 3.73 (dd, J=8.4, 15.8 Hz, 1H), 3.98-4.08 (m, 2H), 4.28 (m, 1H), 7.37 (d, J=2.8 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H). The base (336 mg) was slurried in ether and converted to the hydrochloride salt by treatment with saturated HCl in ether. Recrystallization from methanol/ether gave the title compound (317 mg, 81% yield): mp 181-182° C.; MS (CI/NH3) m/z 233 (M+H)+ ; 1H NMR (D2O, 300 MHz) δ 2.65-2.74 (m, 2H), 4.03-4.21 (m, 2H), 4.44 (d, J=4.4 Hz, 1H), 4.95 (m, 1H), 7.79 (d, J=2.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H). Anal. Calcd. for C9H11N2OCl2.1.0 HCl: C, 40.10; H, 4.11; N, 10.39. Found: C, 39.89; H, 4.08; N, 10.25. The solvent was removed the residue was redissolved in methylene chloride The solution was washed with saturated aqueous K2CO3 and brine dried over MgSO4 concentrated The residue was chromatographed (silica gel; ethyl acetate:hexane, 1:5)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mnol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+. The 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated with with 4 M HCl in dioxane to give the free base of the title compound. This was converted to the dihydrochloride salt and recrystallized from methanol/ether to provide the title compound: mp 163-165° C.; [α]25D -5.1 (c 0.57, methanol); 1H NMR (D2O, 300 MHz) δ 8.36 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z 243/246 (M+H)+, 260/262 (M+NH4)+. Anal. calcd for C9H13N2OBrCl2 : C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17; N, 8.89. (1.51 g, 10.2 mmol, Step 10c above) were added the mixture was stirred for 40 hours at room temperature The volatile components were removed under vacuum the residue was triturated with hexane The separated hexane fraction was concentrated the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (2S)-1-t-butyloxycarbonyl-2-azetidinemethanol (22.6 g, 0.121 mol) in 40 mL of pyridine was treated with p-toluenesulfonyl chloride (27.6 g, 0.145 mol). The resulting mixture was stirred at room temperature for 16 hours, diluted with CH2Cl2 and washed sequentially with 1 N aqueous HCl, H2O, saturated aqueous K2CO3, and brine. The organic phase was dried (Na2SO4) and concentrated. Purification by chromatography (silica gel; Hexane/EtOAc, 80:20) afforded 32.8 g of a white solid which was recrystallized from CH2Cl2 /hexane to afford the title compound as thin white needles: mp 59-60° C.; 1H NMR (CDCl3, 300 MHz) δ 1.37 (s, 9H), 2.15-3.28 (m, 2H), 2.44 (s, 3H), 3.74-3.81 (m, 2H), 4.13 (dd, J=3.1, 10.2 Hz, 1H), 4.23-4.34 (m, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H); MS (CI/NH3) m/z: 242 (M+H)+. washed sequentially with 1 N aqueous HCl, H2O, saturated aqueous K2CO3, and brine The organic phase was dried (Na2SO4) concentrated Purification by chromatography (silica gel; Hexane/EtOAc, 80:20)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triphenylphosphine (6.3 g, 24 mmol) was dissolved in THF (100 mL), cooled to 0° C. and treated with diethylazodicarboxylate (3.8 mL, 24 mmol) for 15 min. Then the compound of 196d (3 g, 16 mmol) followed by 1-BOC-2-(S)-azetidinemethanol (3.4 g, 18 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After 3 days, the solvent was evaporated and the crude residue was chromatographed (silica gel; hexanes/EtOAc, 4:1) to provide an oil. The product was contaminated with a byproduct related to the DEAD reagent and was taken forward as is; the subsequent allowed isolation of the byproduct and revealed ~35 wt % contamination therefor the calculated yield was 70% (4.0 g, 11.2 mmol): TLC Rf 0.6 (1:1 hexanes/EtOAc); MS (CI/NH3) m/z 357 (M+H)+. was added to warm slowly to ambient temperature the solvent was evaporated the crude residue was chromatographed (silica gel; hexanes/EtOAc, 4:1) to provide an oil

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diethyl azodicarboxylate (1.52 mL, 9.6 mmol) in THF (56 mL) was added triphenylphosphine (2.52 g, 9.6 mmol) at 0° C., and the reaction mixture was stirred for half an hour. 1-BOC-2-(S)-azetidinemethanol (1.44 g, 7.7 mmol) and 5-bromo-6-chloropyridine-3-ol (1.4 g, 6.4 mmol; prepared according to V. Koch and S. Schnatterer, Synthesis 1990, 499-501)) were then added. The reaction mixture was slowly warmed up to room temperature overnight. Solvent was removed, and the residue was chromatographed on a silica gel column, eluting with CHCl3 :MeOH 100:1 to afford the title compound. MS (CI/NH3) m/z 377/379 (M+H)+. Solvent was removed the residue was chromatographed on a silica gel column eluting with CHCl3 :MeOH 100:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mmol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for for 10 minutes. Samples of 1-BOC-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol), prepared as described above, and 5-bromo-3-hydroxypyridine (1.505 g, 10.2 mmol) were added, and the reaction rnixture was stirred for 40 hours at room temperature. The volatiles were removed under vacuum, and the residue was triturated with hexane. The hexane was removed, and the residue was chromatographed on a silica gel column, eluting with hexane:Et2O 10:1 to 10:2 to afford the title compound as a colorless oil (1.669 g). MS (CI/NH3) m/z 344 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H). were added the reaction rnixture was stirred for 40 hours at room temperature The volatiles were removed under vacuum the residue was triturated with hexane The hexane was removed the residue was chromatographed on a silica gel column eluting with hexane:Et2O 10:1 to 10:2

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid (10.42 g, 49.4 mmol) was introduced into a 500-mL pear-shaped flask, and tetrahydrofuran (200 mL) was added to dissolve the compound. Then, a tetrahydrofuran solution of 10 M borane-dimethyl sulfide complex salt (9.87 mL, 98.7 mmol) was slowly added at 0° C., and the mixture was heated to reflux for 2 hours while stirring. The reaction solution was left to cool, and then was concentrated under reduced pressure. Ice water (100 mL) was poured thereto, and the mixture was extracted with ethyl acetate (200 mL×2). The extract was washed with saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After filtering the extract, the filtrate was concentrated under reduced pressure to obtain the title compound (8.03 g, 42.9 mmol, 87%) as an oily matter. to dissolve the compound the mixture was heated to reflux for 2 hours The reaction solution was left to cool was concentrated under reduced pressure Ice water (100 mL) was poured the mixture was extracted with ethyl acetate (200 mL×2) The extract was washed with saturated brine (200 mL) dried over anhydrous sodium sulfate After filtering the extract the filtrate was concentrated under reduced pressure