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

HRID 2369607Notes

Reaction equation

HRID 2369607 reaction equation
[Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]3[N:22]=[C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[C:18]3[CH2:17]2)=[O:15])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:1][C:24]1[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:22][N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:34][CH:33]=3)=[O:15])[CH2:17][C:18]=12

Participants

4

Reactant 2

HCID 31398ChlorosuccinimideHCID 679583635-(4-Fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

Product 1

HCID 67958891(3-chloro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanoneYield 48.1%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Conditions

Temperature
80 °C

Procedure

N-chlorosuccinimide (21 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 chloroform (1 mL). The mixture was stirred at 80° C. for 1 hour. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). 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% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% CH3CN) to yield (3-chloro-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-(4-fluoro-phenyl)-methanone (26 mg, 47% yield). C20H17ClFN3O2 1H NMR (500 MHz, CDCl3) δ ppm 4.05 (br. s., 2H), 4.24 (br. s., 2H), 4.75 (br. s., 2H), 5.04 (s, 2H), 6.98 (t, J=7.4 Hz, 1H), 7.03 (d, J=7.8 Hz, 2H), 7.17 (t, J=8.5 Hz, 2H), 7.30 (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; MeOH in DCM 0/100 to 10/90)
  3. customThe desired fractions were collected
  4. customthe solvents evaporated in vacuo
  5. customThe product was repurified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50)
  6. customThe desired fractions were collected
  7. customthe solvents evaporated in vacuo
  8. 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% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% CH3CN)

Sources & evidence

ORD record
ord-26a088ff7dbb444a9643682aa64792a7
Source dataset
uspto-grants-2014_04
Patent number
US08703946B2

Reaction notes

Loading…