Hydrochloric Acid → 1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid

HRID 1632037Notes

Reaction equation

HRID 1632037 reaction equation
[CH2:1]1[CH:4]([C:5]([OH:7])=[O:6])[NH:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([CH2:25][C:26]3[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=3)[C:18]=2[F:33])[CH:14]=[CH:15][CH:16]=1.Cl>CCOC(C)=O.O.CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N:3]4[CH2:2][CH2:1][CH:4]4[C:5]([OH:7])=[O:6])=[N:30][CH:31]=3)[C:18]=2[F:33])[CH:14]=[CH:15][CH:16]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 17288Azetidinecarboxylic AcidHCID 24758Sodium hydrideHCID 577037115-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine

Product 1

HCID 577038011-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acidYield 6%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A vial was charged with D,L-azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and DMF (1 mL). Then NaH (60% dispersion in mineral oil, 33 mg, 0.84 mmol) was added slowly (gas evolution). After 2 min. of stirring at room temperature was added 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456). The heterogeneous white reaction mixture was stirred and heated at 120° C. After overnight stirring the reaction mixture was cooled to rt and was diluted in EtOAc (5 mL). The mixture was poured into a reparatory funnel with 0.5M HCl (1 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane in methanol (9:1) to produce 7.7 mg (6% yield) of 1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (P-446) as a cream solid.

Workup

  1. stirringThe heterogeneous white reaction mixture was stirred
  2. temperatureheated at 120° C
  3. stirringAfter overnight stirring the reaction mixture
  4. temperaturewas cooled to rt
  5. extractionThe aqueous layer was extracted with EtOAc (3×5 mL)
  6. washThe combined organic layers were washed with brine (15 mL)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in-vacuo
  9. customThe crude was purified by silica gel column chromatography
  10. washeluted with dichloromethane in methanol (9:1)

Sources & evidence

ORD record
ord-7e61a772342b4ff5be2062e1d6ab0f48
Source dataset
uspto-grants-2014_07
Patent number
US08791267B2

Reaction notes

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