Diisopropylethylamine → 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone

HRID 390565Notes

Reaction equation

HRID 390565 reaction equation
CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH2:39][C:40]([OH:42])=O)[N:31]=1.Cl.Cl.[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1.CCN(C(C)C)C(C)C>>[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][N:58]([C:40](=[O:42])[CH2:39][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[C:30]([C:26]4[NH:25][CH:29]=[CH:28][N:27]=4)=[N:31]3)[CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1

Participants

5

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 671041171-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazine dihydrochlorideHCID 1361746462-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid

Product 1

HCID 1361746481-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone

Procedure

(Protocol A—the HBTU coupling procedure) A solution of [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid (0.30 M, 0.40 mL, 0.12 mmol) was transferred to a vial. 1-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazine dihydrochloride (48 mg, 0.14 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (55 mg, 0.14 mmol) and i-Pr2NEt (0.30 mL) were added to the vial and the mixture was stirred at ambient temperature. After 30 minutes, LC/MS analysis indicated formation of desired product and complete consumption of the carboxylic acid starting material. The mixture was diluted with EtOAc, washed with water (1×) and brine (1×), dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6; H, J=8.4, 1.6 Hz), 8.66 (dd, 0.4; H, J=8.0, 1.6 Hz), 8.57-8.55 (m, 1H), 7.29-7.26 (m, 1H), 7.22-7.16 (m, 1H), 7.09-7.05 (m, 2H), 6.50-6.45 (m, 2H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 4.07-4.01 (m, 2H), 3.81-3.69 (m, 4H), 3.17-3.13 (m, 1.6H), 3.08-3.02 (m, 2.4H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 484.4.

Workup

  1. customformation of desired product and complete consumption of the carboxylic acid starting material
  2. additionThe mixture was diluted with EtOAc
  3. washwashed with water (1×) and brine (1×)
  4. dry with materialdried over Na2SO4
  5. customevaporated
  6. customThe residue was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-e7fbef6815124b7abf400ce945ed71ee
Source dataset
uspto-grants-2013_02
Patent number
US08383630B2

Reaction notes

Loading…