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

HRID 455703Notes

Reaction equation

HRID 455703 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12][N:11]=1.Br[C:20]1[CH:21]=[C:22]2[C@:33]3([CH2:38][CH2:37][O:36][C:35]([NH2:39])=[N:34]3)[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:40]4[C:41]([F:46])=[N:42][CH:43]=[CH:44][CH:45]=4)[CH:31]=3)[O:26][C:23]2=[N:24][CH:25]=1.O>O1CCOCC1.CO.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>[F:46][C:41]1[C:40]([C:30]2[CH:31]=[C:32]3[C@@:33]4([CH2:38][CH2:37][O:36][C:35]([NH2:39])=[N:34]4)[C:22]4[C:23](=[N:24][CH:25]=[C:20]([C:14]5[CH:13]=[CH:12][N:11]=[C:10]([F:9])[CH:15]=5)[CH:21]=4)[O:26][C:27]3=[CH:28][CH:29]=2)=[CH:45][CH:44]=[CH:43][N:42]=1

Participants

8

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 27833962-Fluoropyridine-4-boronic acidHCID 58465877(S)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

Product 1

HCID 58465905(S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amineYield 73.4%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
90 °C

Procedure

In a microwave vial, potassium phosphate (0.084 g, 0.394 mmol), PdCl2(AmPhos)2 (8.38 mg, 0.012 mmol), and 2-fluoropyridin-4-ylboronic acid (0.024 g, 0.171 mmol) were loaded. The (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.058 g, 0.131 mmol) was added as a solution in dioxane (2.5 mL). Water (1 mL) was added and argon gas was blown through the vessel, which was sealed and heated in a 90° C. oil bath for 1.5 h. The residue was taken up in 5% MeOH/DCM (60 mL) and the organic layer was extracted with dilute brine (2×6 mL), then was dried over sodium sulfate and concentrated. The residue was purified by chromatography (4.5-5.5% MeOH/DCM) to afford (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (Example 60A; 44 mg). MS (m/z) 458 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm: 8.57 (d, 1H, J=2.5 Hz), 8.32 (d, 1H, J=5.3 Hz), 8.22 (d, 1H, J=4.7 Hz), 8.07 (d, 1H, J=2.3 Hz), 7.88 (m, 1H), 7.55 (m, 2H), 7.43 (m, 2H), 7.30 (m, 1H), 7.17 (s, 1H), 4.39 (br, 2H), 4.18 (m, 2H), 2.02 (m, 1H), 1.90 (m, 1H).

Workup

  1. customwas sealed
  2. extractionthe organic layer was extracted with dilute brine (2×6 mL)
  3. dry with materialwas dried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by chromatography (4.5-5.5% MeOH/DCM)

Sources & evidence

ORD record
ord-3707998e826a48e3a4ec53e2d7f0ce56
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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