Reaction #41435

Reaction equation

2,2-difluoropropanoic acid

HATU

DIPEA

2,2-difluoropropanoic acid

HATU

DIPEA

(1R,28)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine

(1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine

→

crude product

N-((1R,2S)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide

Solvents

Water

NMP

NMP

NMP

Conditions

Workup

1. 1
   Otherwas stirrred at r.t. for another h
2. 2
   Extractionthe mixture was extracted with EtOAc (2×50 mL)
3. 3
   Washthe organic phase was washed with 10% NaHSO4 (aq), brine
4. 4
   Dryingdried over MgSO4
5. 5
   Filtrationfiltered
6. 6
   Otherevaporated

Procedure

(1R,28)-1-(1-(4-chlorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (126a) (256 mg, 0.63 mmol) dissolved in NMP (3.5 mL) was added to a solution of 2,2-difluoropropanoic acid (111 mg, 1.00 mmol), HATU (382 mg, 1.00 mmol) and DIPEA (0.438 mL, 2.51 mmol) in NMP (1.5 mL). The reaction mixture was stirred at r.t. for 2 h. Additional 2,2-difluoropropanoic acid (80 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (0.25 mL, 1.4 mmol) in NMP (1.5 mL) was added. The reaction mixture was stirrred at r.t. for another h. Water (50 mL) was added, the mixture was extracted with EtOAc (2×50 mL), the organic phase was washed with 10% NaHSO4 (aq), brine, dried over MgSO4, filtered and evaporated to give a crude product that was purified by HPLC. The fractions containing the product was combined and freeze dried. Yield 197 mg (62%).

Source