Sodium Bicarbonate → ethyl 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoate

HRID 1398565Notes

Reaction equation

HRID 1398565 reaction equation
I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[OH:19][C:20]([CH3:32])([C:26]#[C:27][Si](C)(C)C)[C:21]([O:23][CH2:24][CH3:25])=[O:22].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:27]#[C:26][C:20]([OH:19])([CH3:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=3)[C:6]([CH3:18])=[N:7]2)[CH:16]=[CH:15][N:14]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 2724141Tetrabutylammonium FluorideHCID 681816364-(6-Iodo-3-methylindazol-1-yl)pyrimidin-2-amineHCID 86669592Ethyl 2-hydroxy-2-methyl-4-(trimethylsilyl)but-3-ynoate

Product 1

HCID 68181861ethyl 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoate

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

To a solution of 4-(6-iodo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (170 mg, 0.38 mmol) in dry THF (3 mL) was introduced bis(triphenylphosphine)palladium(II) chloride (27 mg, 0.04 mmol), ethyl 2-hydroxy-2-methyl-4-(trimethylsilyl)but-3-ynoate (164 mg, 0.76 mmol) and TBAF (0.46 mL of a 1M solution in THF, 0.46 mmol). The solution was warmed to 50° C. for 1.5 hr. After cooling, sodium bicarbonate (4 mL of saturated aqueous NaHCO3) was introduced and the solution extracted with EtOAc (3×10 mL extractions). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel flash column chromatography (DCM containing a 1-10% gradient of methanol) furnished the title compound as an orange oil: 1H NMR (250 MHz, Chloroform-d) delta 1.39 (3H, t, J=7.1 Hz), 1.83 (3 H, s), 2.60 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.29 (1H, s), 7.34 (1H, dd, J=8.2, 1.3 Hz), 7.60 (1H, dd, J=8.2, 0.7 Hz), 8.29 (1H, d, J=5.7 Hz), 8.83 (1H, s); LC-MS: m/z=+366.05 (M+H)+.

Workup

  1. temperatureAfter cooling
  2. extractionthe solution extracted with EtOAc (3×10 mL extractions)
  3. washThe combined organic extracts were washed with brine (10 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification by silica gel flash column chromatography (DCM containing a 1-10% gradient of methanol)

Sources & evidence

ORD record
ord-040cfa0717a0435cb3202b61b89e3dcc
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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