Trifluoroacetic acid → HCID 178480858, compound

HRID 2241197Notes

Reaction equation

HRID 2241197 reaction equation
COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH2:41][CH2:42][N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)[C:11]=12

Participants

3

Reactant 2

HCID 6422Trifluoroacetic acidHCID 68515156HCID 68515156, compound

Product 1

HCID 178480858HCID 178480858, compoundYield 34.7%

Conditions

Temperature
70 °C

Procedure

A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (4 mg, 0.006 mmol) and TFA (0.5 mL) was heated to 70° C. for 18 hours. The mixture was concentrated in vacuo, using toluene (2×5 mL) to azeotrope residual TFA. The residue was partitioned between EtOAc (5 mL) and a 1:1 water/saturated aqueous NaHCO3 (5 mL) mixture. The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×2 mL). The combined organic phases were concentrated in vacuo. The residue was loaded on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was further purified on a Waters SepPak silica gel column (2 g silica), eluting with DCM, 5% MeOH/DCM, then 5% MeOH (containing 7N NH3) in DCM to elute the product. The product was obtained as a waxy solid (1.2 mg, 34%). LCMS (ESI+): 93% purity, 220 nm, m/z 576 (M+1) detected; 1H NMR (400 MHz, MeOD-d3) δ 8.27 (d, J=6 Hz, 1H), 7.84 (m, 1H), 7.55 (m, 2H), 7.43 (m, 1H), 7.37 (t, J=9 Hz, 1H), 7.07 (t, J=9 Hz, 2H), 6.29 (d, J=6 Hz, 1H), 3.65 (m, 1H, overlaps MeOD), 3.57 (m, 1H), 2.94 (m, 2H), 2.64 (m, 8H), 2.37 (s, 3H), 1.64 (m, 4H).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. customThe residue was partitioned between EtOAc (5 mL)
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (2×2 mL)
  5. concentrationThe combined organic phases were concentrated in vacuo
  6. washeluting with 10% MeOH (containing 7N NH3) in CHCl3
  7. customThe product was further purified on a Waters SepPak silica gel column (2 g silica)
  8. washeluting with DCM, 5% MeOH/DCM
  9. wash5% MeOH (containing 7N NH3) in DCM to elute the product

Sources & evidence

ORD record
ord-1e0c307ac36e43da985bd2302d6d5543
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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