Pyridine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide

Temperature

0 °C

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 581.7 mg, 1.758 mmol) in methylene chloride (8.6 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (310 mL, 3.554 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 45 min and then slowly warmed to 25° C. over 6 h. The solution was then concentrated in vacuo. The resulting yellow slurry was dissolved in methylene chloride (7 mL) and then cooled to 0° C. To this solution was added a solution of 5-methylsulfanylmethyl-pyrazin-2-ylamine (267.2 mg, 1.721 mmol) and pyridine (174 μL, 2.151 mmol) in methylene chloride (8.6 mL), followed by a methylene chloride rinse (1.7 mL). The pH of the reaction was roughly 3–4, and a second aliquot of pyridine (50 μL, 0.618 mmol) was added to adjust the pH to roughly 5. The reaction mixture was stirred at 0° C. and slowly warmed to 25° C. overnight. The reaction was then quenched with water (10 mL), stirred at 25° C. for 10 min, and concentrated in vacuo. The reaction slurry was partitioned between ethyl acetate (250 mL) and a 1N aqueous hydrochloric acid solution (250 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (250 mL), a saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded the desired chiral 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (679.0 mg, 84%) as a white foam: mp 75.0–76.7° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1180.

1. temperatureslowly warmed to 25° C. over 6 h
2. concentrationThe solution was then concentrated in vacuo
3. dissolutionThe resulting yellow slurry was dissolved in methylene chloride (7 mL)
4. temperaturecooled to 0° C
5. washrinse (1.7 mL)
6. stirringThe reaction mixture was stirred at 0° C.
7. temperatureslowly warmed to 25° C. overnight
8. customThe reaction was then quenched with water (10 mL)
9. stirringstirred at 25° C. for 10 min
10. concentrationconcentrated in vacuo
11. customThe reaction slurry was partitioned between ethyl acetate (250 mL)
12. washThe organic layer was washed with a 1N aqueous hydrochloric acid solution (250 mL)
13. dry with materiala saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo

ORD record

ord-1b02e306e8f84550bba1ed1f9eb96232

Source dataset

uspto-grants-2006_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07132425B2