Water → 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-ol

HRID 1373796Notes

Reaction equation

HRID 1373796 reaction equation
[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].C([Li])CCC.[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]([CH:26]=[O:27])=[C:21]2[CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.CCOCC>[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]([CH:26]([OH:27])[C:3]#[C:2][CH2:1][O:4][CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[C:21]2[CH:20]=[CH:19][CH:18]=1

Participants

7

Reactant 4

HCID 962WaterHCID 98609Tetrahydro-2-(2-propynyloxy)-2H-pyranHCID 221748437-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 866168561-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-olYield 99.4%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a cold (−78° C.) solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (0.5 mL, 3.6 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.05 mL, 1.6 M in hexanes, 3.3 mmol) dropwise. The reaction mixture was allowed to warm to 0° C., then cooled to −78° C. A separate solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (200 mg, 0.73 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. The alkynyllithium solution was added to the aldehyde solution via canula. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added followed by ether. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-ol (301 mg, 99%) as a mixture of diastereomers. 1H NMR (CDCl3) δ 8.00 (d, 1H), 7.79 (m, 2H), 7.17 (m 3H), 6.99 (m, 1H), 5.79 (s, 1H), 4.81–4.74 (m, 1H), 4.39–4.25 (m, 2H), 3.81 (m, 1H), 3.52 (m, 1H), 3.15 (broad, 1H), 1.90–1.48 (m, 6H); 19F NMR (CDCl3) δ −113.01; MS m/z 437 (M+Na+).

Workup

  1. temperaturecooled to −78° C
  2. temperatureto warm to room temperature
  3. washThe organic layer was washed with water and brine
  4. extractionThe aqueous layer was extracted with ether
  5. dry with materialthe combined organics were dried over magnesium sulfate
  6. filtrationFiltration and concentration

Sources & evidence

ORD record
ord-e22493f176a84c758501a2956435ebc8
Source dataset
uspto-grants-2007_01
Patent number
US07163940B2

Reaction notes

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