2,6-Lutidine → 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide

Temperature

0 °C

A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 57, 145 mg, 0.47 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylfomamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 270 μL, 0.54 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 1 h at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (80 mg, 0.52 mmol), 2,6-lutidine (82 μL, 0.71 mmol) and methylene chloride (10 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×15 mL) and a 1 N aqueous hydrochloric acid solution (1×15 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (152 mg, 73%) as a white foam: [α]30589=−20.0° (c=0.13, methylene chloride); ES-HRMS m/e calcd for C23H33N3O4S (M+H)+ 448.2265, observed 448.2260; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.03-1.17 (m, 2H, CH2), 1.36-1.83 (m, 8H, 4×CH2), 2.00-2.17 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.86 (s, 2H, NCH2), 3.82-3.94 (m, 1H, ArCH), 4.65 (s, 1H, OH), 6.45 (d, J=2.1 Hz, 1H, Ar), 7.41-7.47 (m, 2H, Ar), 7.50 (d, J=2.1 Hz, 1H, Ar), 7.84 (d, Jo=8.8 Hz, 1H, Ar), 10.75 (s, 1H, NH). 37022-193 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42-1.59 (m, 1H, CH of CH2), 1.76-2.28 (m, 8H, CH, CH of CH2, and 3×CH2), 3.32 (m, 3 H, SO2CH3), 3.65 (q, J=5.4 Hz, 2H, OCH2), 3.88-4.05 (m, 3H, ArCH and NCH2), 4.82 (t, J=5.3 Hz, 1H, OH), 6.40 (d, J=2.0 Hz, 1H, Ar), 7.53 (d, J=2.0 Hz, 1H, Ar), 7.60 (d, Jo=8.2 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.00 (d, Jo=8.2 Hz, 1H, Ar), 10.83 (s, 1H, NH).

1. customproduced gas evolution and it
2. concentrationAfter this time, the reaction was concentrated in vacuo
3. additionAfter addition
4. temperatureto warm to 25° C.
5. stirringstirred for 16 hours
6. washwashed with a saturated aqueous sodium bicarbonate solution (1×15 mL)
7. dry with materiala 1 N aqueous hydrochloric acid solution (1×15 mL) and then dried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customPurification an AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes)

ORD record

ord-69e5c7b844d54d7f96fb64aff3b00809

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2