Formaldehyde → 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-hydroxy-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]propan-1-one

HRID 710664Notes

Reaction equation

HRID 710664 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH2:18][N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:38]=[O:39].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:29])[CH:18]([N:19]4[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:27])([F:26])[F:28])=[N:20]4)[CH2:38][OH:39])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 25517Ammonium ChlorideHCID 2724682Lithium diisopropylamideHCID 733351261-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone

Product 1

HCID 733359171-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-hydroxy-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]propan-1-oneYield 55%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a mixture of 1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]ethanone (0.100 g, 0.25 mmol) in THF (3 mL) at −78° C. was added LDA (0.15 mL, 0.3 mmol, 2 M in THF). After stirring for 10 min at −78° C., dry paraformaldehyde (0.025 g, 0.82 mmol, suspended in THF) was added. The mixture was then warmed to rt for 8 min, followed by the addition of sat. NH4Cl. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to yield the desired product (0.056 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.42 (m, 2H), 7.18 (dd, J=8.4, 8.4 Hz, 2H), 6.36 (s, 1H), 5.41 (t, J=5.6 Hz, 1H), 4.36 (m, 1H), 4.20 (m, 1H), 3.69 (m, 1H), 3.26 (m, 1H), 2.76 (m, 2H), 2.31 (s, 3H), 1.92 (m, 2H); MS: (ES) m/z calculated for C20H19F4N5O2 [M+H]+ 438.1, found 438.1.

Workup

  1. temperatureThe mixture was then warmed to rt for 8 min
  2. customThe mixture was partitioned between EtOAc (50 mL) and brine (30 mL)
  3. customThe organic layer was separated
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-0d7cd4dde4d04e4d9e27e9d6e86a8b4e
Source dataset
uspto-grants-2015_11
Patent number
US09181241B2

Reaction notes

Loading…