Water → 3-[2-[3-Amino-6-(4-tetrahydropyran-4-ylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenol

HRID 869039Notes

Reaction equation

HRID 869039 reaction equation
[NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CCOC(C)=O.Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:33])=[O:34])=[CH:28][CH:27]=2)=[CH:6][N:7]=1

Participants

9

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 674813674,4,5,5-Tetramethyl-2-(4-tetrahydropyran-4-ylsulfonylphenyl)-1,3,2-dioxaborolaneHCID 86667832HCID 86667832, compound

Product 1

HCID 546711303-[2-[3-Amino-6-(4-tetrahydropyran-4-ylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenolYield 18.7%

Reagents, catalysts & solvents 4

HCID 178418851HCID 178418851, compoundCatalystHCID 313Hydrochloric AcidSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

3-[2-(3-Amino-6-bromo-pyrazin-2-yl)ethynyl]phenol (50 mg, 0.1723 mmol), 4,4,5,5-tetramethyl-2-(4-tetrahydropyran-4-ylsulfonylphenyl)-1,3,2-dioxaborolane (85.70 mg, 0.2068 mmol) and K3PO4 (73.15 mg, 0.3446 mmol) were combined in MeCN (2 mL)/water (0.5 mL) and Pd[P(tBu)3]2 (4.403 mg, 0.008615 mmol) was added. The reaction was heated at 60° C. for 15 hours. The reaction was cooled to ambient temperature and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, dry loaded) followed by purification by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (14 mg, 17% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.30-1.41 (m, 2H), 1.56 (d, 2H), 3.07-3.12 (m, 2H), 3.34-3.40 (m, 2H), 3.71 (dd, J=3.9, 11.4 Hz, 1H), 6.67-6.70 (m, 1H), 6.94 (br s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.07 (t, 1H), 7.70 (d, 2H), 8.05 (d, 2H), 8.55 (s, 1H) and 9.57 (s, 1H) ppm; MS (ES+) 436.1.

Workup

  1. additionwas added
  2. temperatureThe reaction was cooled to ambient temperature
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with EtOAc (×3)
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, dry loaded)
  9. customfollowed by purification by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]
  10. customThe fractions were collected
  11. customfreeze-dried

Sources & evidence

ORD record
ord-9e7dbfd1bfea4bc7b5adc20de8c07f80
Source dataset
uspto-grants-2015_03
Patent number
US08969356B2

Reaction notes

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