Water → 8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine

HRID 335875Notes

Reaction equation

HRID 335875 reaction equation
[F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C:26]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:32]#[C:33][C:34]4([CH3:38])[CH2:37][O:36][CH2:35]4)[CH:24]=3)[O:19][C:15]2=[CH:16][C:17]=1[F:18].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:17]1[CH:16]=[C:15]2[O:19][C:20]3[C:25]([C:26]4([CH2:30][O:29][C:28]([NH2:31])=[N:27]4)[C:14]2=[CH:13][C:12]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[CH:24][C:23]([C:32]#[C:33][C:34]1([CH3:38])[CH2:37][O:36][CH2:35]1)=[CH:22][N:21]=3

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 27832702-Fluoropyridine-3-boronic acidHCID 673834197-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine

Product 1

HCID 584662868-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amineYield 22.1%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of Pd(PPh3)4 (0.077 g, 0.066 mmol), 2-fluoropyridin-3-ylboronic acid (0.19 g, 1.33 mmol), 7-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.30 g, 0.66 mmol), and potassium carbonate (0.46 g, 3.32 mmol) in 4.5 mL dioxane was treated with 1.8 mL water and was heated to 80° C. overnight. The reaction mixture cooled to rt and diluted with EtOAc (50 mL). The layers were separated and the organics were dried over MgSO4, and concentrated in vacuo. Purification of the crude residue by column chromatography [0-80% (9:1 CH2Cl2:MeOH)/CH2Cl2] gave 8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.067 g, 0.146 mmol). Chiral separation provided (4′R)-8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.022 g, 0.048 mmol, peak 1) and (4′S)-8-fluoro-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.022 g, 0.048 mmol, peak 2).

Workup

  1. temperatureThe reaction mixture cooled to rt
  2. customThe layers were separated
  3. dry with materialthe organics were dried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customPurification of the crude residue by column chromatography [0-80% (9:1 CH2Cl2:MeOH)/CH2Cl2]

Sources & evidence

ORD record
ord-a7e865f5302a438ab62d81e7f0d84753
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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