Hydrochloric Acid → HCID 58094849, compound

Temperature

60 °C

To a solution of N-allyl-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (8.60 g, 27.5 mmol) in DCM (309 mL, 4820 mmol) was added phosphorus pentachloride (6.54 g, 31.4 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.51 mL, 2.00 mmol) and the mixture was heated to 60° C. for 2 hrs. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (33.9 mL, 311 mmol) was slowly added. The resulting mixture was heated at 60° C. for 2.5 hrs. To the reaction mixture was added 4 M hydrochloric acid in 1,4-dioxane (200 mL, 783 mmol) and the mixture was stirred at 60° C. overnight. After cooling to room temperature, the suspension was filtered through a Celite pad and the solid residue was washed with 1,4-dioxane. The filtrate was evaporated down and the resulting residue was dissolved in water (300 mL) and extracted with EtOAc (2×150 mL). The water layer was basified by addition of solid NaHCO3 until pH 9, and the aqueous was extracted with EtOAc (3×300 mL). All organics were combined and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 8-25% EtOAc in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 45% MeCN: 50% DCM: 5% EtOAc) to provide 7.12 g of product (76%). LC/MS (FA), ES+ 337. 1H NMR (400 MHz, d6 DMSO) δ: 7.80 (d, J=5.3 Hz, 1H,), 7.68 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.3 Hz, 1H), 7.26 (d, J=5.3 Hz, 1H), 7.13 (d, J=1.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.3 Hz, 1H), 5.47-5.58 (m, 1H), 4.98-5.02 (m, 1H), 4.75-4.82 (m, 1H), 4.19-4.23 (m, 2H).

1. temperatureThe reaction was cooled to room temperature
2. temperatureThe resulting mixture was heated at 60° C. for 2.5 hrs
3. temperatureAfter cooling to room temperature
4. filtrationthe suspension was filtered through a Celite pad
5. washthe solid residue was washed with 1,4-dioxane
6. customThe filtrate was evaporated down
7. dissolutionthe resulting residue was dissolved in water (300 mL)
8. extractionextracted with EtOAc (2×150 mL)
9. additionThe water layer was basified by addition of solid NaHCO3 until pH 9
10. extractionthe aqueous was extracted with EtOAc (3×300 mL)
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe residue was purified by column chromatography (SiO2, elution with 8-25% EtOAc in DCM)
15. customto give crude product which
16. customwas further purified by column chromatography (SiO2, elution with 45% MeCN: 50% DCM: 5% EtOAc)

ORD record

ord-5661e1b943bf4d3e9b8abad12334351d

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796314B2