Preparation of imidazo[1,2-a]pyridine-6-carbaldehyde_Industrial additives

Preparation background and overview of imidazo[1,2-a]pyridine-6-carbaldehyde

Imidazo[1,2-a]pyridine-6-carboxaldehyde can be used as a pharmaceutical synthesis intermediate. It can use 1H-imidazo[1,2-a]pyridine-6-carboxylic acid as the reaction raw material and ethyl chloroformate. The intermediate thioester is prepared by reacting ester and ethyl mercaptan, which is further reacted with triethylsilane.

Preparation of imidazo[1,2-a]pyridine-6-carbaldehyde

Preparation of imidazo[1,2-a]pyridine-6-carbaldehyde:

1) Dissolve 1H-imidazo[1,2-a]pyridine-6-carboxylic acid (2.0 g, 5.1 mmol) in anhydrous DCM (30 ml) and cool to 0°C. Ethyl chloroformate (130 mL, 13.6 mmol) and TEA (4.31 mL, 30.8 mmol) were added to the solution and stirred for 1 hour while the temperature was allowed to warm to ambient. Ethyl mercaptan (2.0 mL, 27 mmol) was added and the solution was stirred overnight. The material was partially converted so TEA (2.0 mL, 14 mmol) and ethyl chloroformate (7.8 mL, 82 mmol) were added and allowed to stir for 15 min followed by more ethyl mercaptan (80 mL, 1.1 mol) ). The solution was stirred for 2 hours and then poured into saturated aqueous NaHCO₃ solution. The DCM layer was removed and the aqueous portion was extracted with EtOAc (4 x 70 ml). The combined organic fractions of 3-(pyrrolidin-2-yl)pyridine were dried over Na₂SO₄, filtered and concentrated under vacuum. The product was purified (SGC using an acetone:hexane gradient from 1:4 to 3:1) to yield the thioester intermediate (0.2 g). ¹HNMR(CDCl₃)δ8.82(s, 1H), 7.67-7.57(m, 4H), 3.07(glycidol q, 2H), 1.32(t , 3H).

2) Dissolve the thioester from step 1 (0.H g, 0.53 mmol) in acetone (1.0 mL) and add 10% palladium on carbon (0.027 g), followed by triethylsilane ( 0.089 ml, 0.558 mmol). The mixture was stirred for 1 hour and another portion of triethylsilane (0.089 mL, 0.558 mmol) was added. After 1.5 hours, the reaction was passed through a syringe filter and purified (SGC using an acetone:hexane gradient from 3:17 to 3:1) to yield the title compound imidazo[1,2-a]pyridine-6 -Formaldehyde (0.049 g). MS(ESI+)m/z147(M+H)⁺.¹HNMR(CDCl₃)δ9.90(s, 1H), 8.66(s, 1H), 7.70(d, 2H), 7.66-7.60(m, 2H).

References

[1]CN200580048246.5 macrolide