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

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

Procedure: A solution of (R)-1-t-butyloxycarbonyl-2-azetidinemethanol (36.5 g, 0.195 mol) in 195 mL of dichloromethane was treated with triethylamine (35.6 ml, 0.255 mol) and then p-toluenesulfonyl chloride (48.5 g, 0.254 mol). The resulting mixture was stirred at room temperature for 16 hours. A 10% solution of sodium hydroxide was added rapidly and the mixture stirred for one hour. After phase separation, the aqueous phase was extracted with additional dichloromethane, combined with the organic phase, washed with NaHCO3 solution and brine, then dried (MgSO4), filtered, and concentrated in vacuo to give 63.1 g of (R)-1-t-butyloxycarbonyl-2-toluensulfonyloxymethylazetidine (94.8%). Next, a solution of 2-chloro-5-hydroxypyridine (from Step 1g below, 24 g, 0.185 mol) in DMF (690 mL) was treated with ground KOH (17.95 g, 0.295 mol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added (2R)-1-t-butyloxycarbonyl)-2-toluensulfonyloxymethylazetidine (63.1 g) dissolved in DMF (395 mL) and the mixture was stirred for 16 hours at 80° C. The mixture was concentrated in vacuo to remove the DMF and the resultant residue was diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give 58.5 g of unpurified product. This material was chromatographed (silica gel, 25% EtOAc in hexane) to give 43.2 g of 5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethyloxy)-2-chloropyridine as a clear oil (74%). A solution of 5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)-2-chloropyridine (30 g, 0.1 mol) in 450 mL of dichloromethane at 0° C. was treated with 225 mL of trifluoroacetic acid dropwise over a 30 minute period. After two hours, the bulk of the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with 1.0 M K2CO3 and brine, dried (Na2SO4) and concentrated in vacuo to give 19.1 g of a yellow oil. Flash silica gel chromatography (90:10 CHCl3 :MeOH then 90:10:0.5 CHCl3 :MeOH:NH4OH) gave 16.5 g of the title compound (83% yield): MS (CI/NH3) m/z: 199 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 2.21-2.43 (m, 2H), 3.42-3.50 (m, 1H), 3.69-3.78 (m, 1H), 3.98-4.07 (m, 2H), 4.25-4.34 (m, 1H), 7.22 (d, J=1.7 Hz, 2H), 8.07 (dd, 1.7, 2.0 Hz, 1H). the mixture stirred for one hour After phase separation the aqueous phase was extracted with additional dichloromethane washed with NaHCO3 solution and brine dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg, 3.0 mmol; 38% yield). MS (DCl/NH3): 266 (M+1)+, 283 (M+18)+. to warm to room temperature stir for 1 hour the solid was removed by filtration the organic phase was concentrated The residue was dissolved in dichloromethane (40 mL) washed with water (20 mL) concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg, 3.0 mmol; 38% yield). MS (DCl/NH3): 266 (M+1)+, 283 (M+18)+. to warm to room temperature stir for 1 hour the solid was removed by filtration the organic phase was concentrated The residue was dissolved in dichloromethane (40 mL) washed with water (20 mL) concentrated

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

Procedure: Disopropyl azodicarboxylate (0.717 g) was added to a solution of tert-butyl 6-benzyloxycarbonylamino-3-bromo-2-hydroxybenzoate (Intermediate 48, 1.25 g), tert-butyl (R)-2-hydroxymethylazetidine-1-carboxylate (0.665 g) and triphenylphosphine (0.93 g) in anhydrous THF (20 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The solution was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give tert-butyl (R)-2-(3-benzyloxycarbonylamino-6-bromo-2-tert-butoxycarbonylphenoxymethyl)-azetidine-1-carboxylate (1.74 g) as a colourless gum. The solution was concentrated in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20%

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

Procedure: An ice cooled solution of the compound from step 41a (0.151 g, 0.81 mmol) was allowed to react with 2-methyl-3-hydroxypyridine (0.092 g, 0.85 mmol) under the conditions of Example 2a, except that DEAD was replaced by di-t-butyl azodicarbonate, to yield the title compound (0.125 g, 55%). MS (DCI/NH3) m/e: 279 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.11 (dd J=4.6, 1.3 Hz, 1H), 7.20-7.10 (m, 2H), 4.54-4.53 (m, 1H), 4.36-4.35 (m, 1H), 4.09 (dd, J=10.0, 2.6 Hz, 1H), 3.95-3.88 (m, 2H), 2.55 (s, 3H), 2.42-2.30 (m, 2H), 1.40 (s, 9H).

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

Procedure: Commercially available (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (1.8 g, 9.61 mmol) in pyridine was treated with p-toluenesulfonyl chloride (1.83 g, 9.61 mmol). The reaction mixture was stirred at room temperature for 20 h then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water (3×75 mL) and then dried (MgSO4), filtered, and concentrated in vacuo to afford the titled compound. MS (DCI) m/z 342 (M+H)+. extracted with ethyl acetate The ethyl acetate layer was washed with water (3×75 mL) dried (MgSO4) filtered concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg. 3.0 mmol; 38% yield). MS (DCI/NH3): 266 (M+1)+, 283 (M+18)+. to warm to room temperature stir for 1 hour the solid was removed by filtration the organic phase was concentrated The residue was dissolved in dichloromethane (40 mL) washed with water (20 mL) concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg. 3.0 mmol; 38% yield). MS (DCI/NH3): 266 (M+1)+, 283 (M+18)+. to warm to room temperature stir for 1 hour the solid was removed by filtration the organic phase was concentrated The residue was dissolved in dichloromethane (40 mL) washed with water (20 mL) concentrated

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

Procedure: A solution of (R)-1-t-butyloxycarbonyl-2-azetidinemethanol (36.5 g, 0.195 mol) in 195 mL of dichloromethane was treated with triethylamine (35.6 ml, 0.255 mol) and then p-toluenesulfonyl chloride (48.5 g, 0.254 mol). The resulting mixture was stirred at room temperature for 16 hours. A 10% solution of sodium hydroxide was added rapidly and the mixture stirred for one hour. After phase separation, the aqueous phase was extracted with additional dichloromethane, combined with the organic phase, washed with NaHCO3 solution and brine, then dried (MgSO4), filtered, and concentrated in vacuo to give 63.1 g of (R)-1-t-butyloxycarbonyl-2-toluensulfonyloxymethylazetidine (94.8%). Next, a solution of 2-chloro-5-hydroxypyridine (from Step 1g below, 24 g, 0.185 mol) in DMF (690 mL) was treated with ground KOH (17.95 g, 0.295 mol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added (2R)-1-t-butyloxycarbonyl)-2-toluensulfonyloxymethylazetidine (63.1 g) dissolved in DMF (395 mL) and the mixture was stirred for 16 hours at 80° C. The mixture was concentrated in vacuo to remove the DMF and the resultant residue was diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give 58.5 g of unpurified product. This material was chromatographed (silica gel, 25% EtOAc in hexane) to give 43.2 g of 5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethyloxy)-2-chloropyridine as a clear oil (74%). A solution of 5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)-2-chloropyridine (30 g, 0.1 mol) in 450 mL of dichloromethane at 0° C. was treated with 225 mL of trifluoroacetic acid dropwise over a 30 minute period. After two hours, the bulk of the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with 1.0 M K2CO3 and brine, dried (Na2SO4) and concentrated in vacuo to give 19.1 g of a yellow oil. Flash silica gel chromatography (90:10 CHCl3 :MeOH then 90:10:0.5 CHCl3 :MeOH:NH4OH) gave 16.5 g of the title compound (83% yield): MS (CI/NH3) m/z: 199 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 2.21-2.43 (m, 2H), 3.42-3.50 (m, 1H), 3.69-3.78 (m, 1H), 3.98-4.07 (m, 2H), 4.25-4.34 (m, 1H), 7.22 (d, J=1.7 Hz, 2H), 8.07 (dd, 1.7, 2.0 Hz, 1H). the mixture stirred for one hour After phase separation the aqueous phase was extracted with additional dichloromethane washed with NaHCO3 solution and brine dried (MgSO4) filtered concentrated in vacuo

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

Procedure: A 2.25 g (1.2 mmol) sample of (R)-1-t-butoxycarbonyl-2-azetidinemethanol (prepared as in Example 1b above, except replacing the N-BOC-L-proline thereof with N-BOC-S-azetidinecarboxylic acid) and 2.25 g (18 mmol) of 3-nitrophenol (Aldrich) were added to a complex of TPP and DEAD (prepared as in Example 1 above, 18.1 mmol of each)in 80 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform:hexane to give 1.5 g (40%) of the title compound. the solvents were removed under vacuum the residue was chromatographed on silica gel eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform

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

Procedure: A 2.25 g (1.2 mmol) sample of (R)-1-t-butoxycarbonyl-2-azetidinemethanol (prepared as in Example 1b above, except replacing the N-BOC-L-proline thereof with N-BOC-S-azetidinecarboxylic acid) and 2.25 g (18 mmol) of 3-nitrophenol (Aldrich) were added to a complex of TPP and DEAD (prepared as in Example 1 above, 18.1 mmol of each)in 80 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform:hexane to give 1.5 g (40%) of the title compound. the solvents were removed under vacuum the residue was chromatographed on silica gel eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform

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

Procedure: A 2.25 g (1.2 mmol) sample of (R)-1-t-butoxycarbonyl-2-azetidinemethanol (prepared as in Example 1b above, except replacing the N-BOC-L-proline thereof with N-BOC-S-azetidinecarboxylic acid) and 2.25 g (18 mmol) of 3-nitrophenol (Aldrich) were added to a complex of TPP and DEAD (prepared as in Example 1 above, 18.1 mmol of each)in 80 mL of THF. The reaction was stirred for 16 hr, the solvents were removed under vacuum, and the residue was chromatographed on silica gel, eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform:hexane to give 1.5 g (40%) of the title compound. the solvents were removed under vacuum the residue was chromatographed on silica gel eluting with a gradient of 1:1, 1:2, 1:3, 1:4 chloroform