Diisopropylethylamine → Methyl 1-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-3-(1H-pyrazol-5-yl)pyridin-2-yl)pyrrolidine-3-carboxylate

HRID 73811Notes

Reaction equation

HRID 73811 reaction equation
CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:43][O:44][C:45]([CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:46]>CC(O)C>[Cl:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:14]2[CH:29]=[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)[C:11]([N:49]3[CH2:50][CH2:51][CH:47]([C:45]([O:44][CH3:43])=[O:46])[CH2:48]3)=[N:12][CH:13]=2)=[O:16])=[CH:19][CH:20]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 19261352Methyl pyrrolidine-3-carboxylate hydrochlorideHCID 867026376-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 72545853Methyl 1-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-3-(1H-pyrazol-5-yl)pyridin-2-yl)pyrrolidine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
130 °C

Procedure

DIPEA (181 μL, 1.035 mmol) was added to a mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 36.1, 100 mg, 0.207 mmol), methyl-3-pyrrolidine carboxylate hydrochloride (44.5 mg, 0.269 mmol) and iPrOH (414 μL). in MW vial, which was flushed with argon, sealed and stirred at 130° C. for 24 h. The RM was diluted with EtOAc, treated with brine and extracted with EtOAc. 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 (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc) followed by preparative TLC (Silica gel, eluent EtOAc). Additional lyophilization from 1,4-dioxane afforded the title compound as a white light solid. UPLC-MS (Condition 6) tR=1.09 min, m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.06-3.20 (m, 1H) 3.23-3.48 (m, 4H) 3.61 (s, 3H) 6.35-6.48 (m, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.79-7.90 (m, 1H) 7.89 (d, J=8.80 Hz, 2H) 8.03-8.13 (m, 1H) 8.70-8.83 (m, 1H) 10.26 (s, 1H).

Workup

  1. customin MW vial, which was flushed with argon
  2. customsealed
  3. additionThe RM was diluted with EtOAc
  4. additiontreated with brine
  5. extractionextracted with EtOAc
  6. dry with materialThe combined extracts were dried over Na2SO4
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give the crude product which
  9. customwas purified by flash chromatography (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc)

Sources & evidence

ORD record
ord-6525b030c6d24d4088b89a5ea6541c12
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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