2-Methoxyethanol → 2-Chloro-3-fluoro-5-(2-methoxyethoxy)pyridine

HRID 81616Notes

Reaction equation

HRID 81616 reaction equation
[Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([O:8][CH2:13][CH2:12][O:11][CH3:10])=[CH:6][N:7]=1

Participants

9

Reactant 4

HCID 80192-MethoxyethanolHCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 404247372-Chloro-3-fluoro-5-hydroxypyridine

Product 1

HCID 866502752-Chloro-3-fluoro-5-(2-methoxyethoxy)pyridine

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of 6-chloro-5-fluoro-pyridin-3-ol (CAS registry 870062-76-3) (800 mg, 5.42 mmol), 2-methoxy-ethanol (454 mg, 0.471 ml, 5.96 mmol) and triphenylphosphine (2.199 g, 8.13 mmol) in THF (40 ml) was added dropwise a solution of DIAD (1.731 g, 8.13 mmol) in THF (20 ml) while keeping the temperature at 0-5° C. The reaction mixture was stirred for 20 h at room temperature, water and brine were added and the mixture was diluted with EtOAc. The aqueous layer was twice extracted with EtOAc, the combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated and yielded after trituration with Et2O and filtration, the title compound as a white solid. The filtrate yielded another batch of the product after purification by prep. NP HPLC using an Alltech Grom Saphir 65 Si 10 μM 250×50 mm column (heptane/EtOAc, gradient 0-1.7 min 15% EtOAc, 1.7-17 min 15-100% EtOAc, 17-24.3 min 100% EtOAc, 24.3-27.8 min 0% EtOAc).

Workup

  1. customat 0-5° C
  2. extractionThe aqueous layer was twice extracted with EtOAc
  3. dry with materialthe combined organic layers were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated
  6. customyielded after trituration
  7. filtrationwith Et2O and filtration
  8. customThe filtrate yielded another batch of the product
  9. customafter purification by prep
  10. customan Alltech Grom Saphir 65 Si 10 μM 250×50 mm column (heptane/EtOAc, gradient 0-1.7 min 15% EtOAc, 1.7-17 min 15-100% EtOAc, 17-24.3 min 100% EtOAc, 24.3-27.8 min 0% EtOAc)

Sources & evidence

ORD record
ord-a5c93617ab814ec286f23560441a6aec
Source dataset
uspto-grants-2014_09
Patent number
US08846658B2

Reaction notes

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