2,6-Lutidine → HCID 67189136, compound

Temperature

0 °C

A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid (210 mg, 0.57 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 329 μL, 0.66 mmol) which produced gas evolution and was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL. In another round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 97 mg, 0.63 mmol), 2,6-lutidine (95 μL, 0.86 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture diluted with methylene chloride (10 mL). The organic layers were then washed with a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was then extracted with methylene chloride (2×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an Isco flash system (12 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 207 mg, 72%) as a light yellow foam: ES-HRMS m/e calcd for C22H28N3O4SClF2 (M+H)+ 504.1530, observed 504.1526; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.65-2.29 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.90 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.0 Hz, 1H, Ar), 7.52 (d, J=2.0 Hz, 1H, Ar), 7.60 (d, Jo=8.3 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).

1. customproduced gas evolution
2. temperaturewarmed to 25° C.
3. stirringstirred for 1 h
4. concentrationAfter this time, the reaction was concentrated in vacuo to about 2 mL
5. customIn another round bottom flask was placed
6. temperatureto warm up to 25° C.
7. stirringstirred for 16 h
8. washThe organic layers were then washed with a saturated aqueous sodium bicarbonate solution (10 mL)
9. extractionThe aqueous layer was then extracted with methylene chloride (2×10 mL)
10. washwashed with a 1 N aqueous hydrochloric acid solution (10 mL)
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customPurification on an Isco flash system (12 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes)

ORD record

ord-d70d7caf88f141f1be09deb7c8eb1ed5

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2