| 34.9% |
Stage #1: 2,3-dichloro-pyridine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78℃; for 0.25h;
Stage #3: With water In tetrahydrofuran; hexane at 20℃; |
41
To a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) [C.A.S. 2402-77-9] in dryTHF (200 ml) cooled at -78°C under a nitrogen atmosphere, n-butyllithium (37.165 ml, 74 mmol, 2 M in hexanes) was dropwise added. The resulting reaction mixture was stirred at -78 0C for 20 min. Then dry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min stirring at - 78°C, the mixture was allowed to warm to room temperature, quenched with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The crude residue was purified by short open column chromatography (DCM as eluent). The desired product fractions were collected and evaporated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM/heptane up to 50% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D41 (4.15 g, 34.9%) as a white solid.GCMS = RT (min): 7.9. |
| 34.9% |
Stage #1: 2,3-dichloro-pyridine With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.333333h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexanes at -78℃; for 0.25h; |
36
To a solution of 2,3-dichloropyridine [C.A.S. 2402-77-9] (10 g, 67.57 mmol) in dry THF (200 ml) cooled at -78 0C under a nitrogen atmosphere, was added dropwise n- butyllithium (37.165 ml, 74 mmol, 2 M in hexanes). The resulting reaction mixture was stirred at -78 0C for 20 min. Then dry DMF (6.28 ml, 81.087 mmol) was added dropwise. After 15 min. stirring at -78 0C, the mixture was allowed to warm to r.t., quenched with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by short open column chromatography (DCM as eluent). The desired product fractions were collected and concentrated in vacuo to give a residue that was further purified by column chromatography (silica gel; DCM/heptane up to 50% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D36 (4.15 g, 34.9%) as a white solid. |
|
Stage #1: 2,3-dichloro-pyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 2h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78℃; for 0.5h; |
38.1
Step 1. 2,3-dichloroisonicotinaldehydeN,N-Diisopropylamine (1.14 mL, 8.11 mmol) was dissolved in THF in a 1-neck round-bottom flask (15.00 mL, 184.9 mmol). The solution was then cooled at -78° C. and 1.60 M of n-butyllithium in hexane (4.64 mL, 7.43 mmol) was added. The reaction was allowed to warm at 0° C. and was re-cooled to -78° C. Into the reaction was added 2,3-dichloropyridine (1.00 g, 6.76 mmol) in THF (5.00 mL, 61.6 mmol). The reaction was then stirred at -78° C. for 2 h and DMF (1.046 mL, 13.51 mmol) was added and was stirred at -78° C. for 30 min and was allowed to warm to 0° C. TLC analysis (20% EtOAc/hexanes) showed no starting material present. LCMS analysis showed M+1+CH3OH peak. NMR analysis showed an aldehyde proton, although most of the product had solidified and the NMR is more indicative of the composition of the non-crystallized material. The reaction was chromatographed on silica gel using 25% EtOAc/hexanes to give the product. 1H NMR (CDCl3): δ 10.49 (s, 1H), 8.49 (d, 1H), 7.67 (d, 1H). |
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