Selectfluor → (3-fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone

HRID 2369608Notes

Reaction equation

HRID 2369608 reaction equation
[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[F:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]3[N:35]=[C:36]([CH2:38][O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:37]=[C:31]3[CH2:30]2)=[O:28])=[CH:25][CH:24]=1>CC#N>[F:21][C:37]1[C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:35][N:32]2[CH2:33][CH2:34][N:29]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:47][CH:46]=3)=[O:28])[CH2:30][C:31]=12

Participants

4

Reactant 2

HCID 2724933SelectfluorHCID 679583635-(4-Fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

Product 1

HCID 67958721(3-fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanoneYield 21.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (56 mg, 0.16 mmol) was added to a solution of 5-(4-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (50 mg, 0.14 mmol) in CH3CN (2 mL). The mixture was stirred at 80° C. for 16 hours. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield (3-fluoro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (11 mg, 20% yield). C20H17F2N3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.05 (br. s., 2H), 4.20 (br. s., 2H), 4.79 (br. s., 2H), 5.05 (s, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.02 (d, J=8.1 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 7.29 (dd, J=8.5, 7.4 Hz, 2H), 7.50 (dd, J=8.7, 5.2 Hz, 2H).

Workup

  1. customThen the solvent was evaporated in vacuo
  2. customthe crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 30/70)
  3. customThe desired fractions were collected
  4. customthe solvents evaporated in vacuo
  5. customThe product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH)

Sources & evidence

ORD record
ord-f165385ab73e469cba917b2f89ca18ca
Source dataset
uspto-grants-2014_04
Patent number
US08703946B2

Reaction notes

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