Thiophene → Methyl thieno[3,4-c]pyridine-6-carboxylate

Temperature

0 °C

3,4-Thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) is dissolved in CH2Cl2 (40 ml) and chilled to 0° C. Methyl (acetylamino)(dimethoxyphosphoryl)acetate (1.88 g, 7.85 mmol) is dissolved in CH2Cl2 (30 ml) and combined with DBU (1.1 ml, 7.85 mmol). This solution is added dropwise to the chilled thiophene solution after stirring for 5 min. The reaction mixture is stirred at 0° C. for 1 h and then overnight at rt. The volatiles are removed in vacuo and the crude material is chromatographed over 68 g slurry-packed silica eluting with 70% EtOAc/hexane. The appropriate fractions are combined and concentrated to yield 2.09 g of the carbinol intermediate as a white foam. The intermediate is dissolved in CHCl3 (50 ml) and treated with DBU (1.32 ml, 8.8 mmol) and trifluoracetic anhydride (1.24 ml, 8.8 mmol) in a drop-wise fashion. The reaction is stirred overnight at rt and is then quenched with saturated NaHCO3 solution (50 ml). The layers are separated, and the aqueous layer is extracted with CHCl3 (2×50 ml). The combined organics are dried over MgSO4, filtered, and concentrated to a yellow oil. This oil is chromatographed over 50 g slurry-packed silica, eluting with 90% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.2 g (88%) of methyl thieno[3,4-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 193 (M+).

1. stirringThe reaction mixture is stirred at 0° C. for 1 h
2. customovernight
3. customat rt
4. customThe volatiles are removed in vacuo
5. customthe crude material is chromatographed over 68 g slurry-packed silica eluting with 70% EtOAc/hexane
6. concentrationconcentrated
7. customto yield 2.09 g of the carbinol intermediate as a white foam
8. stirringThe reaction is stirred overnight at rt
9. customis then quenched with saturated NaHCO3 solution (50 ml)
10. customThe layers are separated
11. extractionthe aqueous layer is extracted with CHCl3 (2×50 ml)
12. dry with materialThe combined organics are dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated to a yellow oil
15. customThis oil is chromatographed over 50 g slurry-packed silica
16. washeluting with 90% EtOAc/hexane
17. concentrationconcentrated

ORD record

ord-c7e883ca7fda4ff09107b64b748facbf

Source dataset

uspto-grants-2005_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06911543B2