HCID 67282962, compound → HCID 67281623, compound

HRID 1187486Notes

Reaction equation

HRID 1187486 reaction equation
C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]([CH3:21])[C:10]=1[CH3:22])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:18])[F:19])[N:11]([CH3:21])[C:10]=1[CH3:22]

Participants

4

Reactant 1

HCID 67282962HCID 67282962, compound

Product 1

HCID 67281623HCID 67281623, compoundYield 52%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

To a suspension of 3-benzyloxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.34 g, 1.04 mmol) in acetonitrile (15 mL), was added thionyl chloride (0.38 mL, 5.19 mmol) at room temperature. A clear solution resulted and the reaction was completed within 10 min. The reaction mixture was evaporated to dryness to give the crude 3-benzyloxy-2-chloromethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil, which was taken up in ethanol (15 mL) to give a clear solution. Sodium borohydride (430 mg, 11.4 mmol) was added to the solution portionwise. The reaction mixture was stirred for another 10 min, and the progress of the reaction was monitored by TLC (methanol/dichloromethane, 1/10 v/v as eluant). There was still some unreacted chloride derivative present at this time. Additional sodium borohydride (360 mg, 9.5 mmol) was added in several portions. The reaction mixture was stirred for another 10 min. The reaction mixture was purified by column chromatography on silica gel (methanol/dichloromethane, 1/20 v/v as eluant) to give 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil (0.20 g, 61% for the two combined steps, HPLC Method 1 (Example 24), RT=15.1 min, HPLC purity (peak percent area): 92% at λ=280 nm). This material, 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.20 g, 0.64 mmol) was taken up in methanol (25 mL) to give a clear solution. To the solution was added Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 90 mg). The hydrogenation reaction was conducted under a hydrogen pressure of 50 psi. The reaction was completed in 30 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was evaporated to give the first crop of 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a solid product (free base, 74 mg, 52% yield), HPLC Method 1 (Example 24), RT=9.9 min, HPLC purity (peak percent area): 96.4% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 6.25 (s, 1H), 3.94 (q, J=11 Hz, 2H), 3.57 (s, 3H), 2.32 (s, 3H). MS-ESI (m/z) 222.2 ([M+1]+, 100%), 202.3, 153.2.

Workup

  1. customto give a clear solution
  2. customThe hydrogenation reaction
  3. customA CELITE™ bed was prepared on a sintered glass
  4. washwashed with 6M HCl (100 mL)
  5. filtrationThe reaction mixture was filtered through the pre-treated CELITE™ bed
  6. customThe filtrate was evaporated

Sources & evidence

ORD record
ord-244f46a73e844108bd72ccf46a9463f9
Source dataset
uspto-grants-2014_03
Patent number
US08673943B2

Reaction notes

Loading…