Hydrochloric Acid → N-(4-(Chlorodifluoromethoxy)phenyl)-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

HRID 924130Notes

Reaction equation

HRID 924130 reaction equation
Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:28][CH2:29][C@@H:30]1[CH2:34][NH:33][CH2:32][C@H:31]1[OH:35].Cl.CCN(C(C)C)C(C)C>CC(O)C.O>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)[C:2]([N:33]3[CH2:34][C@@H:30]([CH2:29][OH:28])[C@H:31]([OH:35])[CH2:32]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 11217244(3s,4s)-4-(Hydroxymethyl)pyrrolidin-3-olHCID 899064746-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide

Product 1

HCID 89908027N-(4-(Chlorodifluoromethoxy)phenyl)-6-(trans-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent

Procedure

A suspension of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Stage 247.1, 80 mg, 0.195 mmol), trans-4-(hydroxymethyl)pyrrolidin-3-ol (+/−), hydrochloride (80 mg, 0.521 mmol) in a mixture of DIPEA (136 μL, 0.778 mmol) and iPrOH (389 μL) was subjected to MW irradiation at 140° C. for 1.5 h. The RM was treated with water (10 mL) and extracted with EtOAc. The combined extracts were washed with sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product that was purified by preparative SFC (Column DEAP, from 22% to 27% in 10 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.86 min, m/z=492.1 [M+H]+, m/z=536.2 [M+ formic acid-H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04-2.14 (m, 1H) 2.89 (dd, J=11.13, 3.91 Hz, 1H) 3.10 (dd, J=11.13, 5.26 Hz, 1H) 3.20-3.29 (m, 2H) 3.34-3.48 (m, 2H) 3.92-4.01 (m, 1H) 4.63 (t, J=5.26 Hz, 1H) 4.98 (d, J=4.40 Hz, 1H) 7.35 (d, J=9.05 Hz, 2H) 7.81-7.90 (m, 2H) 8.10 (d, J=2.45 Hz, 1H) 8.80 (d, J=2.32 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).

Workup

  1. customwas subjected to MW irradiation at 140° C. for 1.5 h
  2. extractionextracted with EtOAc
  3. washThe combined extracts were washed with sat. NaHCO3 and brine
  4. dry with materialdried over Na2SO4
  5. customthe solvent was evaporated off under reduced pressure
  6. customto give a crude product that
  7. customwas purified by preparative SFC (Column DEAP, from 22% to 27% in 10 min)

Sources & evidence

ORD record
ord-d11ab0292ace4be9922474c0199cf41c
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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