Dichloromethane → HCID 67189667, compound

Temperature

0 °C

A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in PCT WO 2003/095438 A1, Example 9, 290 mg, 0.96 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, 550 μL, 1.09 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 30 min 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 (prepared in Example 80, 163 mg, 1.05 mmol), 2,6-lutidine (158 μL, 1.43 mmol) and methylene chloride (10 mL) was 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. 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 (1×20 mL) and the aqueous layers were than extracted with methylene chloride (2×10 mL). The combined organic layers were then washed with a 1 N aqueous hydrochloric acid solution (1×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide (339 mg, 81%) as a white foam (reaction of a set of racemic diastereomers, 4 compounds) ES-HRMS m/e calcd for C21H27N3O3C12 (M+H)+ 440.1502, observed 440.1500; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-1.03 (3×bs, 6H, 2×CH3), 1.14-2.28 (7×m, 8H, 4×CH2), 3.04-3.30 (m, 2H, OCH2), 3.77-4.05 (m, 4H, ArCH and NCH2 and OCH), 4.62, 4.63 (2×s, 1H, OH), 6.42, 6.43 (2×d, J=2.3 Hz, 1H, Ar), 7.30, 7.33 (2×m, 1H, Ar), 7.47-7.50 (m, 1H, Ar), 7.54-7.60 (m, 2H, Ar), 10.62, 10.68 (2×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 (1×20 mL)
7. extractionthan extracted with methylene chloride (2×10 mL)
8. washThe combined organic layers were then washed with a 1 N aqueous hydrochloric acid solution (1×20 mL)
9. dry with materialdried over sodium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customPurification on an AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 65% ethyl acetate/hexanes)

ORD record

ord-7164ff7586a848f89425c6ae7889eb43

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935699B2