KOtBu tBuOH → (S)-(4-Fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol

HRID 1404420Notes

Reaction equation

HRID 1404420 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH2:25][C:24]([CH3:26])=[N:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[H][H]>CC([C@@H](N)C(N)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)C.COC1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC(OC)=NC=2OC)=C(OC)N=1.Cl[Ru]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 23676527KOtBu tBuOHHCID 178418361HCID 178418361, compoundHCID 178434106HCID 178434106, compound

Product 1

HCID 56833308(S)-(4-Fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanolYield 82.3%

Reagents, catalysts & solvents 1

HCID 73995191(R)-P-Phos RuCl2 (R)-DaipenCatalyst

Conditions

Temperature
40 °C

Procedure

A stirred mixture of (4-fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (16.66 g, 48 mmol) and [(R)-P-Phos RuCl2 (R)-DAIPEN] (217 mg, 0.192 mmol) at room temperature was subjected to five cycles of pressurizing with nitrogen to 40 psi followed by depressurization. Then 1M KOtBu/tBuOH (576 μL, 0.0.576 mmol) in 9:11-PrOH/H2O (4 mL) was added and the mixture was subjected to five cycles of pressurizing with nitrogen to 40 psi followed by depressurization. The stirred mixture was then subjected to ten cycles of pressurizing with hydrogen to 435 psi followed by depressurization. The mixture was then stirred at 900 rpm under hydrogen (435 psi) at 40° C. for 18 hrs. The mixture was allowed to cool to room temperature and then carefully vented. The resulting precipitate was collected by filtration and washed with cold MeOH (100 mL) to afford (S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol as a white solid (13.8 g). Chiral HPLC indicated a >99% enantiomeric excess of the earlier eluting enantiomer.

Workup

  1. temperatureto cool to room temperature
  2. filtrationThe resulting precipitate was collected by filtration
  3. washwashed with cold MeOH (100 mL)

Sources & evidence

ORD record
ord-baa1c829b40d4e9292106e144dd7bd6f
Source dataset
uspto-grants-2014_12
Patent number
US08912324B2

Reaction notes

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