Water → HCID 71743244, compound

HRID 1915762Notes

Reaction equation

HRID 1915762 reaction equation
O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[F-].[K+].O>CS(C)=O>[CH3:16][N:15]1[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]1

Participants

6

Reactant 4

HCID 962WaterHCID 522689Potassium FluorideHCID 2723901PiperonylamineHCID 123448365-chloro-1-methyl-4-nitro-1H-pyrazole

Product 1

HCID 71743244HCID 71743244, compoundYield 109.8%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).

Workup

  1. extractionextracted into EtOAc (3×100 mL)
  2. customThe combined organic layers were passed through a phase separation cartridge
  3. concentrationconcentrated under reduced pressure
  4. customPurification via silica gel column chromatography (0-5% MeOH/DCM)

Sources & evidence

ORD record
ord-cf6b76093dcc4b59afec91d52a1fd41c
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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