Diisopropylethylamine → 1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-one

HRID 906241Notes

Reaction equation

HRID 906241 reaction equation
O[C:2]1[C:3](=[O:21])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:6][N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:64][C:65]([F:74])([F:73])[C:66]1[CH:67]=[CH:68][C:69]([SH:72])=[N:70][CH:71]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([S:72][C:69]3[CH:68]=[CH:67][C:66]([C:65]([F:64])([F:73])[F:74])=[CH:71][N:70]=3)[C:3]2=[O:21])=[CH:9][C:10]=1[CH3:20]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 178428036HCID 178428036, compoundHCID 178506226HCID 178506226, compound

Product 1

HCID 251690711-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-oneYield 14.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 3-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one (100 mg, 0.344 mmol), PyBOP (314 mg, 0.603 mmol) and EtN(iPr)2 (0.180 mL, 1.033 mmol) in DMF (6 mL) was stirred at RT for 3 hours prior to addition of 5-(trifluoromethyl)pyridine-2-thiol (74.1 mg, 0.413 mmol). After stirring for 3 days, The reaction was diluted with aq. saturated NaHCO3 (15 ml) prior to extraction with EtOAc (20 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 30×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 30 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). After concentration, the residue in EtOAc (30 ml) was converted to the free base by washing with aq. saturated NaHCO3 (30 ml). The EtOAc layer was dried over Na2SO4 and concentrated. To yield 1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-3-(5-(trifluoromethyl)pyridin-2-ylthio)pyrazin-2(1H)-one (22.76 mg, 14%) as off-white solid. MS (M+1=452). 1H NMR (500 MHz, chloroform-d) δ ppm 8.88 (1H, s), 7.89-7.99 (2H, m), 7.16-7.24 (3H, m), 7.07 (1H, d, J=4.40 Hz), 6.90 (1H, d, J=8.52 Hz), 3.84 (2H, s), 2.30 (3H, s), 1.39 (6H, s).

Workup

  1. stirringAfter stirring for 3 days
  2. extractionto extraction with EtOAc (20 ml)
  3. dry with materialThe EtOAc layer was dried over Na2SO4
  4. concentrationconcentrated
  5. customThe crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 30×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 30 min.
  6. concentrationAfter concentration
  7. washby washing with aq. saturated NaHCO3 (30 ml)
  8. dry with materialThe EtOAc layer was dried over Na2SO4
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-6ef063fc3c6e4788ba2295726cb5d20a
Source dataset
uspto-grants-2011_09
Patent number
US08012984B2

Reaction notes

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