2,6-Lutidine → (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-propionamide

Temperature

25 °C

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 120 mg, 0.36 mmol) was dissolved in methylene chloride (5 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, 210 μL, 0.42 mmol) which produced gas evolution and it was then allowed to warm to 25° C. and stirred 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-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (67 mg, 0.40 mmol), 2,6-lutidine (63 μL, 0.54 mmol) and methylene chloride (5 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 mixture was diluted with methylene chloride (10 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (168 mg, 96%) as a white foam: [α]28589=+10.0° (c=0.43, methylene chloride); ES-HRMS m/e calcd for C23H32N3O4SCl (M+H)+ 482.1875, observed 482.1874; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (d, J=6.1 Hz, 6H, 2×CH3), 1.11 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.09 (m, 1H, CH), 3.34 (s, 3 H, SO2CH3), 3.47 (m, 1H, OCH), 3.64 (t, J=5.5 Hz, 2H, OCH2), 3.91 (m, 1H, ArCHCO), 4.08 (t, J=5.5 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.59 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 7.70 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (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. customtransferred to a separatory funnel
7. washwashed with a saturated aqueous sodium bicarbonate solution (10 mL)
8. dry with materiala 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customPurification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes)

ORD record

ord-08a343081fa84f02b40de340118122d5

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2