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

HRID 455631Notes

Reaction equation

HRID 455631 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:11][CH:10]=3.[F:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:23]1[C:22]([C:12]2[CH:13]=[C:14]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[CH:32][N:31]=[C:30]([F:29])[CH:35]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:27][CH:26]=[CH:25][N:24]=1

Participants

4

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27833962-Fluoropyridine-4-boronic acidHCID 86658381(S)-3-chloro-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465915(S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 74.5%

Conditions

Temperature
110 °C

Procedure

A vial was charged with (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (104.72 mg, 0.264 mmol), 2-fluoropyridin-4-ylboronic acid (74.4 mg, 0.528 mmol), potassium phosphate (168 mg, 0.792 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (9.34 mg, 0.013 mmol). The vial was flushed with Argon, then dioxane (990 μL) and water (330 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by chromatography (30-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (90 mg) as a light-yellow solid. MS m/z=458.2 [M+H]+.

Workup

  1. customThe vial was flushed with Argon
  2. additiondioxane (990 μL) and water (330 μL) were added
  3. customThe vial was sealed
  4. extractionThe mixture was extracted with EtOAc (3×)
  5. concentrationthe combined organic extracts were concentrated under reduced pressure
  6. customThe residue was purified by chromatography (
  7. addition30-60% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM)

Sources & evidence

ORD record
ord-572a3eb80bd04e3f8636697241dc1a5b
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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