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0 °C

To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenesulfonic acid (650 mg, 1.11 mol) in DCM (7 mL) and DMF (cat.) was added thionyl chloride (1.32 g, 11.1 mol, 10 eq.) and heated to reflux for 1.5 h with stirring. The reaction mixture was concentrated to dryness and the residue was diluted with 1,2-dichloroethane, co-evaporated (3×2 mL) and dried under high vacuum. Meanwhile a mixture of D-alanine methyl ester (622 mg, 4.44 mol, 4.0 eq.), MeCN (1.2 mL) and 2M Na2CO3 (6 mL) was stirred for 30 min and then cooled to 0° C. with an ice-water bath. A solution of the above sulfonyl chloride in MeCN (6 mL) then was added dropwise to the chilled aqueous mixture over 15 min with vigorously stirring. After complete addition, the ice-water bath was removed and the reaction slurry was stirred vigorously another 15 min. The reaction mixture was transferred into a separatory funnel with MeCN and the organic layer was collected. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with water/brine (1:1), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting product was purified by chromatography (silica, Hex/EtOAc, 1:1) to afford (R)-methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (709 mg, 95%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.18 (s, 1H), 7.13-7.15 (d, 1H), 6.76-6.80 (t, 2H), 6.46-6.48 (m, 2H), 6.36-6.39 (m, 2H), 5.37 (d, 1H), 4.06 (s, 2H), 3.93-4.03 (m, 1H), 3.73 (s, 3H), 3.60 (s, 3H), 1.46 (s, 6H), 1.39-1.41 (d, 3H).

1. temperatureheated
2. temperatureto reflux for 1.5 h
3. concentrationThe reaction mixture was concentrated to dryness
4. additionthe residue was diluted with 1,2-dichloroethane
5. customdried under high vacuum
6. stirringwas stirred for 30 min
7. stirringwith vigorously stirring
8. additionAfter complete addition
9. customthe ice-water bath was removed
10. stirringthe reaction slurry was stirred vigorously another 15 min
11. customThe reaction mixture was transferred into a separatory funnel with MeCN
12. customthe organic layer was collected
13. extractionThe aqueous layer was extracted with DCM (2×10 mL)
14. washThe combined organic layers were washed with water/brine (1:1)
15. dry with materialdried over MgSO4
16. filtrationfiltered
17. concentrationconcentrated under reduced pressure
18. customThe resulting product was purified by chromatography (silica, Hex/EtOAc, 1:1)