Thionyl Chloride → 3-{3'-Chloro-4'-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-biphenyl-4-yl}-propionic acid methyl ester

Temperature

100 °C

Trifluoromethanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 26, Step 1, 100 mg, 0.2 mmol), 4-(2-methoxycarbonylethyl)phenyl boronic acid (53 mg, 0.24 mmol) and chloro-{2′-(dimethylamino)-2-biphenylyl}-(dinorbornylphosphin)-palladium (3 mg, 0.005 mmol) in dioxane (0.8 ml) was treated with water (0.22 ml) and K3PO4 (128 mg, 0.6 mmol) and stirred at 100° C. under argon for 3 h. To reaction mixture were added dioxane (0.5 ml), water (0.022 ml) and chloro-{2′-(dimethylamino)-2-biphenyl}-(dinorbornylphosphin)-palladium (2 mg). The mixture was stirred at 100° C. under argon for 6 h. The reaction mixture was cooled down to r.t., diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in methanol (2 ml) and treated with thionylchloride (56 mg, 0.5 mmol) at 0° C. The reaction solution was stirred at r.t. for 5 h. The mixture was poured on ice-water and sat aq NaHCO3, extracted twice with AcOEt. The combined organic phases were washed with sat aq NaCl, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 3:1) to give the title compound as colorless

1. customTo reaction mixture
2. stirringThe mixture was stirred at 100° C. under argon for 6 h
3. temperatureThe reaction mixture was cooled down to r.t.
4. washwashed with water and brine
5. dry with materialdried over MgSO4
6. concentrationconcentrated in vacuo
7. dissolutionThe crude product was dissolved in methanol (2 ml)
8. stirringThe reaction solution was stirred at r.t. for 5 h
9. additionThe mixture was poured on ice-water
10. extractionextracted twice with AcOEt
11. washThe combined organic phases were washed with sat aq NaCl
12. dry with materialdried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe residue was purified by column chromatography (10 g silica gel, heptane/AcOEt 3:1)

ORD record

ord-498c9aebf0c440e19fba27a050db3683

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08138189B2