Tetrabutylammonium Fluoride Trihydrate → (S)-5-amino-4'-fluoro-2'-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-7'-ol

HRID 455661Notes

Reaction equation

HRID 455661 reaction equation
O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:22][C:23]1[CH2:44][O:43][CH2:42][C@:25]2([C:38]3[CH:37]=[C:36](Br)[CH:35]=[C:34]([F:40])[C:33]=3[O:32][C:31]3[C:26]2=[CH:27][C:28]([OH:41])=[CH:29][CH:30]=3)[N:24]=1.C[Si](C)(C)[C:47]#[C:48][C:49]1([CH3:53])[CH2:52][O:51][CH2:50]1>C1COCC1.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.[Cu]I>[NH2:22][C:23]1[CH2:44][O:43][CH2:42][C@:25]2([C:38]3[CH:37]=[C:36]([C:47]#[C:48][C:49]4([CH3:53])[CH2:52][O:51][CH2:50]4)[CH:35]=[C:34]([F:40])[C:33]=3[O:32][C:31]3[C:26]2=[CH:27][C:28]([OH:41])=[CH:29][CH:30]=3)[N:24]=1

Participants

7

Reactant 3

HCID 11726816Tetrabutylammonium Fluoride TrihydrateHCID 58547788Trimethyl((3-methyloxetan-3-yl)ethynyl)silaneHCID 67437656(S)-5-amino-2'-bromo-4'-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-7'-ol

Product 1

HCID 86761970(S)-5-amino-4'-fluoro-2'-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-7'-ol

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A microwave vial was charged with tetrabutylammonium fluoride trihydrate (0.301 g, 0.952 mmol), Pd(PPh3)4 (0.073 g, 0.063 mmol), and copper(I) iodide (12.3 mg, 0.065 mmol). The (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (0.241 g, 0.64 mmol) was added as a solution in THF (2.7 mL). Argon was blown through the vessel, and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.161 g, 0.951 mmol) was added. The vessel was sealed and heated in an 80° C. oil bath for 1.5 h. The mixture was cooled and concentrated, diluted with water (15 mL), and the aqueous phase was extracted with 5% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL), dried over sodium sulfate and concentrated to afford (S)-5-amino-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol, which was used in the next step without further purification.

Workup

  1. additionwas added
  2. customThe vessel was sealed
  3. temperatureThe mixture was cooled
  4. concentrationconcentrated
  5. additiondiluted with water (15 mL)
  6. extractionthe aqueous phase was extracted with 5% MeOH-DCM (3×25 mL)
  7. washwashed with dilute brine (7 mL)
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-12676260b9ed4468a3e726879e7fa52b
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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