2,6-Lutidine → (αR)-3-Chloro-α-(cyclopentylmethyl)-N-[1-(ethylsulfonyl)-1H-pyrazol-3-yl]-4-(methylsulfonyl)benzeneacetamide

Temperature

0 °C

Triphenylphosphine (216 mg, 0.83 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (166 mg, 0.94 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 182 mg, 0.55 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 30 min. The mixture was chilled to 0° C. and 1-ethanesulfonyl-1H-pyrazol-3-ylamine (88 mg, 0.50 mmol) was added followed by 2,6-lutidine (192 μL, 1.65 mmol). The mixture was continued to stir at 0° C. for 30 min and then at 25° C. for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-ethanesulfonyl-1H-pyrazol-3-yl)-propionamide (112 mg, 46%) as a white foam: ESI-LRMS m/e calcd for C20H26ClN3O5S2 [M+] 487.1. found 488.2 [M+H+], 396.1 [M−SO2CH2CH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.18 (m, 2H, CH2), 1.22 (t, J=7.3 Hz, 1H, CH3), 1.40-1.89 (m, 8H, 4×CH2), 2.12-2.23 (m, 1H, CH), 3.29 (s, 3H, SO2CH3), 3.38 (q, J=7.3 Hz, 2H, SO2CH2), 3.67 (t, J=7.5 Hz, 1H, CH), 6.99 (d, J=2.7 Hz, 1H, Ar), 7.45 (d, Jo=8.1, 1H, Ar), 7.56 (d, Jm=1.3 Hz, 1H, Ar), 7.89 (d, J=2.7 Hz, 1H, Ar), 8.06 (d, Jo=8.1 Hz, 1H, Ar), 8.74 (s, 1H, NH).

1. dissolutionwas completely dissolved
2. stirringit was stirred at 0° C. for 15 min
3. temperaturewarmed to 25° C.
4. stirringstirred for 30 min
5. temperatureThe mixture was chilled to 0° C.
6. stirringto stir at 0° C. for 30 min
7. washwashed with water (3×20 mL) and saturated aqueous brine solution (2×20 mL)
8. dry with materialThe organic layer was dried over magnesium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes)

ORD record

ord-915debb688df49daac22a4af4a1dccb7

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2