7-chloro-1-(propan-2-yl)-1H-pyrrolo[2,3-c]pyridine synthesis

Yield:-

Reaction Conditions:

Stage #1:7-chloro-1H-pyrrolo[2,3-c]pyridine with sodium hydride in N,N-dimethyl-formamide;mineral oil at 0 - 20;
Stage #2:2-iodo-propane in N,N-dimethyl-formamide;mineral oil at 20; for 6 h;
Stage #3:2-iodo-propane with sodium hydride in N,N-dimethyl-formamide;mineral oil at 20; for 16 h;

Steps:

E
To a 0 ⁰C solution of Compound E-2 (13.98 g, 91.6 mmol, 1 eq.) in DMF (700 mL) was added NaH (5.5 g of a 60% dispersion in mineral oil, 229.2 mmol, 2.5 eq.) in portions. The mixture was allowed to stir at room temperature for 1 hour, then 2-iodopropane (18.3 mL, 183.3 mmol, 2.0 eq.) was added and the resulting mixture was allowed to stir at room temperature for 6 hours. The mixture was then charged with an additional amount of NaH (5 g of a 60% dispersion in mineral oil, 208 mmol, 2.3 eq.) and 2-iodopropane (9 mL, 92 mmol, 1 eq.) and was allowed to stir at room temperature. After 16 hours, the mixture was cooled to 0 ⁰C and MeOH was added. Next, H₂O and ethyl acetate were added and the mixture was stirred. Stirring was stopped and the layers became separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with H₂O twice, followed by saturated aqueous NaCl solution, dried over Na₂SO₄, and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using ethyl acetate and heptane as the eluents to provide Compound E-3: LCMS m/e 195 (M+H); ¹H NMR (400 MHz, Chloroform-^) δppm 1.55 (d, J=6.69 Hz, 6 H), 5.62 - 5.73 (m, 1 H), 6.57 (d, J=3.27 Hz, 1 H), 7.44 (d, J=5.37 Hz, 1 H), 7.46 (d, J=3.22 Hz, 1 H), 7.97 (d, J=5.37 Hz, 1 H).

References:

MERCK SHARP & DOHME CORP.;BANYU PHARMACEUTICAL CO., LTD.;GOTO, Yasuhiro;SAGARA, Takeshi;FAN, Weiming;HAXELL, Thomas, F. N.;JENKS, Matthew, G.;MALASKA, Michael, J.;MOORE, Joseph, A., III;OUVRY, Gilles;PANDI, Bharathi;PEEL, Michael, R.;STEWARD, Kimberly, M. WO2010/42337, 2010, A1 Location in patent:Page/Page column 38; 39; 40