Dimethyl malonate → HCID 117774897, compound

Temperature

130 °C

A vial was charged with 3-chloro-4-fluorophenylacetylene (6 g, 38.8 mmol), dimethyl malonate (4.4 mL, 38.8 mmol) and indium(III) chloride (257 mg, 1.16 mmol). The mixture was stirred at 130° C. for 18 hours, allowed to reach room temperature and used as such. Part of this reaction mixture (4.21 g crude mixture) and 3,5-difluoropicolinimidamide (3.46 g, 22 mmol) in 1,4-dioxane (63 mL) was stirred and heated at 40° C. for 90 minutes. The resulting reaction mixture was concentrated under reduced pressure, phosphorus oxychloride (27.3 mL, 293.81 mmol) was added and this mixture was heated and stirred in an oil bath at 110° C. for 7 hours. The resulting mixture was concentrated under reduced pressure. The obtained residue was treated with sodium bicarbonate (aq sat 150 mL) and stirred for 30 minutes. This was extracted with dichloromethane (3×100 mL). The combined organics were dried on Na2SO4, filtered and concentrated under reduced pressure. The crude was purified using silica gel column chromatography (gradient: Heptane-dichloromethane 60:40 to 40:60). The desired fractions were concentrated under reduced pressure. The obtained crude was purified again using silica column chromatography (gradient: heptane-ethyl acetate 100:0 to 90:10) yielding methyl 6-chloro-4-(3-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-4-methyl-1,4-dihydropyrimidine-5-carboxylate (774 mg) as a yellow solid. This compound (500 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (5 mL) and the solution was purged with nitrogen for 10 minutes. Then, tetramethyltin (322 μl, 2.32 mmol) was added followed by bis(tri-t-butylphosphine)palladium(0) (59.4 mg, 0.12 mmol), the vial was flushed with nitrogen and capped. The mixture was heated by microwave-irradiation at 140° C. for 60 minutes. The mixture was evaporated to dryness in vacuo. The obtained residue was dissolved in diethyl ether and the organic layer was washed with distilled water (3×10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by Prep HPLC (Hypersyl C18 BDS-3 μm, 100×4.6 mm) Mobile phase (NH4OAc 0.5% in water, ACN). The desired fractions were collected, the organic solvent removed in vacuo and the waterlayer extracted with dichloromethane.

1. customto reach room temperature
2. temperatureheated at 40° C. for 90 minutes
3. customThe resulting reaction mixture
4. additionwas added
5. temperaturethis mixture was heated
6. stirringstirred in an oil bath at 110° C. for 7 hours
7. concentrationThe resulting mixture was concentrated under reduced pressure
8. additionThe obtained residue was treated with sodium bicarbonate (aq sat 150 mL)
9. stirringstirred for 30 minutes
10. extractionThis was extracted with dichloromethane (3×100 mL)
11. customThe combined organics were dried on Na2SO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customThe crude was purified
15. concentrationThe desired fractions were concentrated under reduced pressure
16. customThe obtained crude
17. customwas purified again using silica column chromatography (gradient: heptane-ethyl acetate 100:0 to 90:10)

ORD record

ord-2efbb1ebf4444ed18e25a2def29a0e44

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09233933B2