Triethylamine → N-(4-(1-(4-methoxybenzyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2241193Notes

Reaction equation

HRID 2241193 reaction equation
[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][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](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]#[CH:53])[CH2:47][CH2:46]1.C(N(CC)CC)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][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]([C:53]#[C:52][CH2:51][N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[N:9]2)=[CH:5][CH:4]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 135140911-Methyl-4-(prop-2-yn-1-yl)piperazine2×HCID 68512093HCID 68512093, compound

Product 1

HCID 68518374N-(4-(1-(4-methoxybenzyl)-3-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 39.4%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 178418397HCID 178418397, compoundCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.036 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.072 mmol; obtained from Example 7, Step D), copper(I)iodide (0.3 mg, 0.002 mmol), triethylamine (0.25 mL, 1.8 mmol), and THF (0.5 mL) was sparged with N2 for 2 minutes, then tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) was added. The sealed reaction was heated to 50° C. for 18 hours. Additional 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.07 mmol), copper(I)iodide (0.3 mg, 0.002 mmol), and tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) were added and heating was continued at 80° C. for 5 hours. After cooling to room temperature, the entire reaction mixture was loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (10 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.30 (d, J=6 Hz, 1H), 8.25 (s, 1H), 7.77 (m, 1H), 7.45 (m, 2H), 7.34 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.82 (d, J=9 Hz, 2H), 6.25 (d, J=6 Hz, 1H), 5.60 (s, 2H), 3.76 (s, 3H), 3.55 (s, 2H), 2.68 (m, 4H), 2.39 (m, 4H), 2.23 (s, 3H), 1.81 (m, 2H), 1.62 (m, 2H).

Workup

  1. customwas sparged with N2 for 2 minutes
  2. customThe sealed reaction
  3. temperatureheating
  4. temperatureAfter cooling to room temperature
  5. customthe entire reaction mixture
  6. washeluting with 10% MeOH (containing 7N NH3) in CHCl3

Sources & evidence

ORD record
ord-9a03502216c54164b5219e24c3e0d88b
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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