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B. Preparation of [1-(t-butoxycarbonyl)azetidin-3-yl]methyl}(iodo)zinc (C71). Zinc powder (116.5 g, 1.78 mol) was suspended in dimethylacetamide (300 mL) under argon. A mixture of trimethylsilyl chloride and 1,2-dibromoethane (7:5 v/v, 34.5 mL) was added and the mixture was stirred for 20 mins. A solution of C70 (426.8 g, 1.437 mol) in dimethylacetamide (650 mL) was added under water cooling and the reaction mixture was stirred overnight. The concentration of the resulting solution of compound C71 was about 1 mol/L and this was used in the next step.; C. Preparation of t-butyl 3-[(6-methylpyridin-3-yl)methyl]azetidine-1-carboxylate (C72). 5-Bromo-2-methylpyridine (25 g, 0.145 mol) was dissolved in dimethylacetamide (150 mL) and the solution was degassed. To the solution was added tetrakis(triphenylphosphine)palladium(0) (5 g, 4.4 mmol), copper iodide (1.7 g, 8.7 mmol) and the 1 mol/L solution of compound C71 (170 mL) under an atmosphere of argon. The reaction mixture was stirred at 50 C. for 12 h; during this time, partial decomposition of the catalyst was observed and additional amounts of tetrakis(triphenylphosphine)palladium(0) (5 g, 4.4 mmol) and copper iodide (0.9 g, 4.7 mmol) were added. The reaction mixture was stirred at 50 C. for 48 h, cooled and poured into a mixture of a saturated aqueous solution of ammonium chloride (600 mL) and diethyl ether (600 mL). The resulting mixture was stirred for 30 mins and filtered through a layer of Celite to remove insoluble impurities. The organic layer was separated and the aqueous layer was extracted with diethyl ether (4*300 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (Eluant: EtOAc) to afford compound C72. Yield: 27.9 g, 0.106 mol, 73%.
A 2.5 M solution of n-butyllithium in pentane (6.97 ml, 17.44 mmol) was added dropwise to a solution of DIPEA (3.29 ml, 23.25 mmol) in THF (50 ml). The mixture was stirred at 0 C for 30 min., cooled down to -78 C and then a solution of 5-bromo- 2-methylpyridine (2.0 g, 11.63 mmol) in THF (50 ml) was added. The mixture was stirred at -78 C for a further 2h. and then DMF (8.5 g, 116.26 mmol) was added dropwise. The mixture was stirred at -78 C for 2 h, at 0 C for 30 min. and finally allowed to warm to RT. MeOH (25 ml) and sodium borohydride (0.439 g, 11.6 mmol) were added and the mixture was stirred at RT for a further 30 min. A saturated solution of ammonium chloride was added and the organic layer was separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried(Na2S04), filtered and the solvents evaporated in vacuo to yield intermediate 51 (2.8 g, 87%) as a colourless oil.
87%
Example A51 2-(5-Bromo-pyridin-2-yl)-ethanol A 2.5 M solution of n-butyllithium in pentane (6.97 ml, 17.44 mmol) was added dropwise to a solution of DIPEA (3.29 ml, 23.25 mmol) in THF (50 ml). The mixture was stirred at 0 C. for 30 min., cooled down to -78 C. and then a solution of 5-bromo-2-methylpyridine (2.0 g, 11.63 mmol) in THF (50 ml) was added. The mixture was stirred at -78 C. for a further 2 h. and then DMF (8.5 g, 116.26 mmol) was added dropwise. The mixture was stirred at -78 C. for 2 h, at 0 C. for 30 min. and finally allowed to warm to RT. MeOH (25 ml) and sodium borohydride (0.439 g, 11.6 mmol) were added and the mixture was stirred at RT for a further 30 min. A saturated solution of ammonium chloride was added and the organic layer was separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield intermediate 51 (2.8 g, 87%) as a colourless oil.
35%
A two-necked round-bottommed flask equipped with thermometer was charged with anh. THF (2.0 mL) and cooled to -78 C. Then, LDA (2 M in THF/heptane/ethylbenzene, 1.74 mL, 1.5 eq.) was added dropwise at -78 C. The resulting mixture was stirred for 15 min and then solution of 5-bromo-2-methylpyridine (0.4 g, 1.0 eq.) in anh. THF (4.0 mL) was dropped in slowly at -78 C and the reaction mixture was stirred for 1.5 h at -78 C. Afterwards, DMF (1.8 mL, 10.0 eq.) was added dropwise and stirring was continued for 1 h at -78 C. Subsequently, the mixture was allowed to warm to RT and MeOH (4.5 mL) was added followed by NaBH4 (0.089 g, 1.0 eq.). During NaBH4 addition generation of heat was observed, temperature increased to 30 C. The reaction was continued for 30 min at RT and then quenched with saturated NH4Cl aq. solu- tion. The resulting mixture was extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The residue was purified by two consecutive FCC (SiHP; DCM:MeOH) and (SiHP; hexane:EtOAc) to give the product (0.204 g, 35% yield) as a yellowish oil. ESI-MS: 202.0 [M+H]+.
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