Triethylamine → (S)-N-(1-(4-chlorophenyl)-5-isopropyl-1H-pyrazol-4-yl)-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

HRID 1754377Notes

Reaction equation

HRID 1754377 reaction equation
[CH3:1][C:2]1[N:3]([CH:13]([CH2:19]C=C)[C:14]([O:16]CC)=O)[C:4](C=C)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH:34]([CH3:36])[CH3:35])=[C:32]([NH2:37])[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:33]([CH:34]([CH3:35])[CH3:36])=[C:32]([NH:37][C:14](=[O:16])[C@@H:13]([N:3]3[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]3[CH3:1])[CH3:19])[CH:31]=[N:30]2)=[CH:27][CH:28]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 664259211-(4-chlorophenyl)-5-(propan-2-yl)-1H-pyrazol-4-amineHCID 86724377Ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]pent-4-enoate

Product 1

HCID 76902964(S)-N-(1-(4-chlorophenyl)-5-isopropyl-1H-pyrazol-4-yl)-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)propanamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of the acid intermediate from step d (23.6 mg, 0.1 mmol) and 1-(4-chlorophenyl)-5-isopropyl-1H-pyrazol-4-amine (16.6 mg, 0.064 mmol) in DMF (0.5 mL) was added Et3N (20 μL, 0.13 mmol) and HATU (31.6 mg, 0.083 mmol). After stirring 35 min, the slurry was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent). The residue was neutralized and salted with HCL to provide the titled compound hydrochloride salt as a colorless solid (12.3 mg). 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=1.6 Hz, 1H), 7.63 (s, 1H), 7.57 (ddd, J=9.7, 5.1, 3.1 Hz, 2H), 7.41 (ddd, J=9.7, 5.0, 3.1 Hz, 2H), 5.38 (q, J=7.0 Hz, 1H), 3.03 (hept, J=7.0 Hz, 1H), 2.65 (s, 3H), 1.91 (d, J=7.0 Hz, 3H), 1.23 (d, J=7.1 Hz, 3H), 1.22 (d, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C20H22ClF3N5O [M+H]+ 440.1, found 439.9. Retention time on chiral HPLC: 5.9 min (RegisPack cat#783104, 25 cm×4.6 mm, 5 micron; eluent: 0.1% diethylamine/IPA, 1.0 ml/min). The er is determined to be 20:1 with the (R)-enantiomer having a retentime of 3.4 min. Absolute configuration of the (R)-enantiomer was confirmed by an independent synthesis from methyl (L)-lactate.

Workup

  1. concentrationthe slurry was concentrated under reduced pressure
  2. customthe residue was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent)

Sources & evidence

ORD record
ord-bdb8a8c065664c3c9dfc983bc7495534
Source dataset
uspto-grants-2015_10
Patent number
US09169248B2

Reaction notes

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