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

HRID 1773800Notes

Reaction equation

HRID 1773800 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:28]B(O)O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]([CH3:28])=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 139377Methylboronic AcidHCID 67958487(4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone

Product 1

HCID 67959973(4-fluoro-phenyl)-(3-methyl-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanoneYield 41.6%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 10340Sodium CarbonateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 0.014 mmol) was added to a stirred solution of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.13 g, 0.27 mmol), methylboronic acid (0.122 g, 2.04 mmol) and saturated solution of Na2CO3 (2 mL) in 1,4-dioxane (4 mL) under N2. The mixture was stirred at 100° C. for 21 hours and then the mixture was diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 70/30). 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 (4-fluoro-phenyl)-(3-methyl-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (41 mg, 39% yield). C21H20FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 2.00 (br. s., 3H), 3.98 (br. s., 2H), 4.22 (br. s., 2H), 4.73 (br. s., 2H), 5.02 (s, 2H), 6.96 (t, J=7.4 Hz, 1H), 7.02 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 7.29 (dd, J=8.7, 7.3 Hz, 2H), 7.49 (dd, J=8.8, 5.3 Hz, 2H).

Workup

  1. extractionextracted with DCM
  2. customThe organic layer was separated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customthe solvents evaporated in vacuo
  6. customThe crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 70/30)
  7. customThe desired fractions were collected
  8. customthe solvents evaporated in vacuo
  9. 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-c1cbb4ebbd954e638e42ad875d98b035
Source dataset
uspto-grants-2016_02
Patent number
US09255103B2

Reaction notes

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