Water → N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

HRID 525730Notes

Reaction equation

HRID 525730 reaction equation
Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:17]1[C:36]([C:37]2[NH:41][N:40]=[CH:39][CH:38]=2)=[CH:35][C:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([Cl:34])([F:33])[F:32])=[CH:26][CH:25]=2)=[O:22])=[CH:19][N:18]=1.O>CC(O)C>[Cl:34][C:31]([F:32])([F:33])[O:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:35]=[C:36]([C:37]3[NH:41][N:40]=[CH:39][CH:38]=3)[C:17]([N:5]3[CH2:6][CH:3]([OH:2])[CH2:4]3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1

Participants

6

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 27592903-Hydroxyazetidine hydrochlorideHCID 722015896-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 89908255N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
140 °C

Procedure

3-Hydroxyazetidine hydrochloride (53.2 mg, 0.486 mmol) and DIPEA (0.170 mL, 0.972 mmol) were added to a suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.243 mmol) in iPrOH (0.5 mL) and the RM was heated at 140° C. for 3 h. The RM was treated with water, extracted with EtOAc, and the combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give. the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1) to give the title product as a yellow foam. HPLC (Condition 7) tR=5.518 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=436 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.49-3.57 (m, 2H) 3.87-3.99 (m, 2H) 4.32-4.44 (m, 1H) 5.53 (br.s, 1H) 6.40 (br.s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.81-7.91 (m, 3H) 8.06 (d, J=2.35 Hz, 1H) 8.70 (br.s, 1H) 10.23 (s, 1H) 13.01 (s, 1H).

Workup

  1. extractionextracted with EtOAc
  2. dry with materialthe combined extracts were dried over Na2SO4
  3. customthe solvent was evaporated off under reduced pressure
  4. customto give
  5. customthe crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1)

Sources & evidence

ORD record
ord-a1b26e148438417a8898cfd5125d4982
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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