Phosphorus oxychloride → Ethyl 4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxylate

Temperature

100 °C

Ethyl 4-hydroxy-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxylate (Preparation 3, 150 g, 515 mmol) was added portionwise to phosphorus oxychloride (450 mL, 4.92 mol) and the resulting mixture stirred at 100° C. for 1 hour and then cooled to room temperature. The volatiles were removed in vacuo, and the residue was carefully poured into a vigorously stirred ice/water mixture. Ethyl acetate (500 mL) was added to the mixture. The mixture was adjusted to pH 8, by addition of 10M aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was further extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting oil was poured into a crystallisation dish, where it solidified on standing to give the title compound, 140.69 g, in an 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, 3H), 1.86-1.89 (m, 4H), 2.59 (s, 3H), 2.82-2.84 (m, 2H), 3.08-3.11 (m, 2H), 4.46 (q, 2H).

1. temperaturecooled to room temperature
2. customThe volatiles were removed in vacuo
3. additionthe residue was carefully poured into a vigorously stirred ice/water mixture
4. additionEthyl acetate (500 mL) was added to the mixture
5. additionThe mixture was adjusted to pH 8, by addition of 10M aqueous sodium hydroxide solution
6. customThe layers were separated
7. extractionthe aqueous layer was further extracted with ethyl acetate (3×500 mL)
8. washThe combined organic extracts were washed with brine (300 mL)
9. dry with materialdried over MgSO4
10. concentrationconcentrated in vacuo
11. additionThe resulting oil was poured into a crystallisation dish, where it

ORD record

ord-ccea1d3f9fcc4c90b40ca3fefe9d9618

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809363B2