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 1472375Notes

Reaction equation

HRID 1472375 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)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (546.36 mg, 1.435 mmol), 2-fluoropyridin-3-ylboronic acid (303 mg, 2.153 mmol), potassium phosphate (914 mg, 4.31 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (50.8 mg, 0.072 mmol). The vial was flushed with Argon, and then dioxane (5383 μL) and water (1794 μL) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, concentrated under reduced pressure. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-3-chloro-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (510.4 mg, 95% purity) as an off-white solid. Step 2: 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-c9183654bd0d49db9409d483d4a54c69
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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