Acetonitrile → Methyl 4-amino-6'-cyclopropyl-3-fluoro-5-methoxy-[2,3'-bipyridine]-6-carboxylate

HRID 407260Notes

Reaction equation

HRID 407260 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[CH:16]1([C:19]2[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=2)[CH2:18][CH2:17]1.[F-].[Cs+].C(#N)C>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:5]=[C:6]([C:22]2[CH:23]=[N:24][C:19]([CH:16]3[CH2:18][CH2:17]3)=[CH:20][CH:21]=2)[C:7]=1[F:8]

Participants

9

Reactant 4

HCID 6342AcetonitrileHCID 25953Cesium fluorideHCID 53338917(6-Cyclopropylpyridin-3-yl)boronic acidHCID 86675409Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate

Product 1

HCID 71150560Methyl 4-amino-6'-cyclopropyl-3-fluoro-5-methoxy-[2,3'-bipyridine]-6-carboxylateYield 32.2%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
85 °C

Procedure

To a tube, methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (500 mg, 2.131 mmol) (˜90% pure), (6-cyclopropylpyridin-3-yl)boronic acid (417 mg, 2.56 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.107 mmol), and Cesium Fluoride (647 mg, 4.26 mmol) were charged as solids. The tube was sealed and charged with inert atmosphere. The solids were then diluted with Dioxane (5.7 ml) and Water (1.4 ml). The resulting suspension was heated to 85° C. for 18 hrs. The reaction solution was poured in to a brine solution. The aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The product was purified (flash chromatography: silica, 5-50% EtOAc in Hex 16 CV; C18 5-100% ACN in H2O 16 CV) to yield methyl 4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate (0.218 g, 0.687 mmol, 32.2% yield). ESIMS for m/z 318 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 0.99 (tt, J=7.6, 2.7 Hz, 4H), 2.17 (tt, J=7.8, 5.1 Hz, 1H), 3.77 (s, 3H), 3.86 (s, 3H), 6.55 (s, 2H), 7.42 (d, J=8.9 Hz, 1H), 8.00 (ddd, J=8.2, 2.3, 1.2 Hz, 1H), 8.77 (t, J=2.0 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.19.

Workup

  1. customThe tube was sealed
  2. additioncharged with inert atmosphere
  3. extractionThe aqueous phase was extracted with EtOAc (3×25 mL)
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe product was purified (flash chromatography

Sources & evidence

ORD record
ord-4b29f5cf3c394e72b1decf1c90a53a27
Source dataset
uspto-grants-2014_06
Patent number
US08754229B2

Reaction notes

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