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

HRID 710663Notes

Reaction equation

HRID 710663 reaction equation
[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].[Li+].CC([N-]C(C)C)C.[CH2:39]=[O:40]>C1COCC1>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH:8]([CH2:39][OH:40])[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 2724682Lithium diisopropylamideHCID 733351252-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone

Product 1

HCID 733359162-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-hydroxy-propan-1-oneYield 56%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a mixture of 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.100 g, 0.23 mmol) in THF (3 ml) at −78° C. was added LDA (0.15 mL, 0.3 mmol, 2 M in THF). After stirred for 10 min at −78° C., dry paraformaldehyde (0.020 g, 0.66 mmol, suspended in THF) was added. The mixture was then warmed to rt for 8 min, quenched with 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 (0.060 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.43 (dd, J=8.4, 4.6 Hz, 2H), 7.17 (dd, J=8.8, 8.4 Hz, 2H), 5.40 (t, J=5.4 Hz, 1H), 4.90 (s, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 3.71 (m, 1H), 3.29 (m, 1H), 2.79 (m, 2H), 2.28 (s, 3H), 1.95 (m, 2H); MS: (ES) m/z calculated for C20H18ClF4N5O2 [M+H]+ 472.1, found 472.1.

Workup

  1. temperatureThe mixture was then warmed to rt for 8 min
  2. customquenched with sat. NH4Cl
  3. customThe mixture was partitioned between EtOAc (50 mL) and brine (30 mL)
  4. customThe organic layer was separated
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-18851c1a347140449008ed28ff00ab74
Source dataset
uspto-grants-2015_11
Patent number
US09181241B2

Reaction notes

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