1,4-Dioxane → 2-[4-(4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)piperidin-1-yl]ethanol

HRID 2090443Notes

Reaction equation

HRID 2090443 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:45]=[N:44]2)[CH2:39][CH2:38]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:46]4[CH:45]=[N:44][N:43]([CH:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][OH:34])[CH2:42][CH2:41]5)[CH:47]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 594023174-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amineHCID 594023251-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine

Product 1

HCID 594022822-[4-(4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1H-pyrazol-1-yl)piperidin-1-yl]ethanolYield 23.5%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (12 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was concentrated. The residue was treated with methanol. After solid was filtered off the filtrate was concentrated. The resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution and stirred at r.t. overnight. Then it was purified with RP-HPLC (pH=10) to afford the desired product (2.5 mg). LCMS (M+H)+:m/z=532.3.

Workup

  1. temperatureAfter cooling it
  2. concentrationwas concentrated
  3. additionThe residue was treated with methanol
  4. filtrationAfter solid was filtered off the filtrate
  5. concentrationwas concentrated
  6. dissolutionThe resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution
  7. stirringstirred at r.t. overnight
  8. customThen it was purified with RP-HPLC (pH=10)

Sources & evidence

ORD record
ord-3bae28515e4d46ffa3636b6e883199ed
Source dataset
uspto-grants-2013_05
Patent number
US08436008B2

Reaction notes

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