Diisopropylethylamine → N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl) methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

HRID 529790Notes

Reaction equation

HRID 529790 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36](=[O:44])[N:35]([CH3:34])[CH3:45])[CH2:43][CH2:42]3)=[O:28])[N:9]=2)[CH:7]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 46743104N,N-Dimethyl-2-(piperazin-1-yl)acetamide hydrochlorideHCID 118522370{3-(5-Chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid

Product 1

HCID 118522567N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl) methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (4 mL) was added N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride (72 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 73.4 mg (64%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=616.3, RT=2.41 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 9.09 (dd, 1H, J=1.6, 7.2 Hz), 8.66-8.64 (m, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=2.8 Hz), 7.57 (dd, 1H, J=2.8, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.4, 7.2 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.29 (s, 2H), 3.84-3.77 (m, 4H), 3.75 (s, 2H), 3.08 (s, 3H), 3.06-2.96 (m, 7H).

Workup

  1. concentrationconcentrated under vacuum
  2. customThe crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005)
  3. waitmobile phase, water with 0.05% FA and MeCN (27.0% up to 36.0% in 10 min
  4. waitup to 95.0% in 1 min
  5. customin 1 min
  6. waitdown to 27.0% in 2 min)

Sources & evidence

ORD record
ord-8727ae61714549d690cb240a0b617388
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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