Potassium Phosphate, Tribasic → (S)-7-(2,5-difluorophenyl)-3-(2-fluoropyridin-4-yl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 1472417Notes

Reaction equation

HRID 1472417 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C@@:26]3([N:31]=[C:30]([NH2:32])[CH2:29][O:28][CH2:27]3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23](I)[CH:24]=3)[O:19][C:16]2=[N:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:42][C:43]1[CH:48]=[C:47](B(O)O)[CH:46]=[CH:45][N:44]=1>CC1OCCC1.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].C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:23]1[CH:24]=[C:25]2[C@:26]3([N:31]=[C:30]([NH2:32])[CH2:29][O:28][CH2:27]3)[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:47]4[CH:46]=[CH:45][N:44]=[C:43]([F:42])[CH:48]=4)[CH:14]=3)[O:19][C:20]2=[CH:21][CH:22]=1

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2734335(2,5-Difluorophenyl)boronic acidHCID 27833962-Fluoropyridine-4-boronic acidHCID 58465904(S)-3-bromo-7-iodo-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465923(S)-7-(2,5-difluorophenyl)-3-(2-fluoropyridin-4-yl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 27.9%

Reagents, catalysts & solvents 5

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 73012-MethyltetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A vial was charged with 2,5-difluorophenylboronic acid (0.035 g, 0.222 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.65 mg, 10.59 μmol), (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.100 g, 0.212 mmol), and potassium phosphate (0.450 g, 2.118 mmol). Dioxane (2 mL) and water (1 mL) were added, the vial was flushed with argon, sealed and heated to 80° C. 1 hour. The reaction mixture was cooled to rt and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.50 mg, 10.59 μmol) was added, followed by 2-fluoropyridin-4-ylboronic acid (0.045 g, 0.318 mmol). The reaction mixture was again capped under argon and was heated to 80° C. for and additional hour. The reaction mixture was then diluted with 2-MeTHF, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (95:5 EtOAc/MeOH)/DCM] gave (S)-7-(2,5-difluorophenyl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.028 g, 0.059 mmol, 27.9% yield) as a light yellow solid. [M+H]+=475.0

Workup

  1. customthe vial was flushed with argon
  2. customsealed
  3. custom1 hour
  4. temperatureThe reaction mixture was cooled to rt
  5. customThe reaction mixture was again capped under argon
  6. temperaturewas heated to 80° C. for and additional hour
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customPurification of the crude residue by column chromatography [0-100% (95:5 EtOAc/MeOH)/DCM]

Sources & evidence

ORD record
ord-4dd332c4ebfa459594111528a39b5675
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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