Hydrochloric Acid → PF-4191834

HRID 501501Notes

Reaction equation

HRID 501501 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Si](C(C)C)(C(C)C)[S:18][C:19]1[CH:20]=[C:21]([C:25]2([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)(C)C.CC(C)([O-])C.[K+].C1COCC1.Cl>CC(O)C.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>[CH3:13][N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:18][C:19]3[CH:20]=[C:21]([C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=[N:11]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 125810925-(4-Bromophenyl)-1-methyl-1H-pyrazoleHCID 23665647Potassium tert-butoxideHCID 566014104-(3-(triisopropylsilylthio)phenyl)tetrahydro-2H-pyran-4-carboxamide

Product 1

HCID 24986635PF-4191834Yield 85.9%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 3776IsopropanolSolvent

Procedure

A mixture of 5-(4-bromophenyl)-1-methyl-1H-pyrazole (0.50 g, 2.10 mmols,), 4-{3-[(tri-isopropylsilyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxamide (0.83 g, 2.10 mmols), Tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.10 equivalents), bis[(2-diphenyl-phosphino)]phenyl ether (113 mg, 0.10 equivalents), and 1.0 M potassium tert-butoxide in THF (6.3 mmols, 3 equivalents) in iPrOH (15 mL) that contained 5% water was heated for 4 hours at 90 degrees Celcius in an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and 7 mL of 1N HCl was added. The product was precipitated by the addition of water (30 mL). The precipitate was collected by suction filtration and washed with water (2×20 mL) and cold ethyl ether (4×20 mL). The tan brown solid was dissolved in a small volume of methylene chloride containing 1% methanol and applied to a 140 g cartridge of silica gel. The cartridge was eluted with an acetone:hexane gradient. The appropriate fractions were concentrated and triturated with methanol to produce a white solid (710 mg) as product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.84 (m, 3H) 2.40 (d, J=13.54 Hz, 3H) 3.43-3.51 (m, 1H) 3.72 (d, J=11.34 Hz, 3H) 3.84 (s, 3H) 6.40 (d, J=1.46 Hz, 1H) 7.02 (s, 1H) 7.22-7.30 (m, 2H) 7.34 (d, J=8.05 Hz, 1H) 7.38-7.43 (m, 2H) 7.45-7.52 (m, 3H). HRMS calc M+H, 394.1589, found 394.1630.

Workup

  1. temperaturewas heated for 4 hours at 90 degrees Celcius in an atmosphere of nitrogen
  2. customThe product was precipitated by the addition of water (30 mL)
  3. filtrationThe precipitate was collected by suction filtration
  4. washwashed with water (2×20 mL) and cold ethyl ether (4×20 mL)
  5. dissolutionThe tan brown solid was dissolved in a small volume of methylene chloride containing 1% methanol
  6. washThe cartridge was eluted with an acetone
  7. concentrationThe appropriate fractions were concentrated
  8. customtriturated with methanol

Sources & evidence

ORD record
ord-28570f8f84ea42e2a1109607d498fa07
Source dataset
uspto-grants-2010_08
Patent number
US07772269B2

Reaction notes

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