Lithium Hexamethyldisilazide → HCID 58465935, compound

HRID 455668Notes

Reaction equation

HRID 455668 reaction equation
Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:26][C:27]1([F:33])[CH2:32][CH2:31][N:30]([C:2]2[CH:15]=[C:14]3[C:5]([O:6][C:7]4[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=4[C@:13]43[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1

Participants

5

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 27583514,4-Difluoropiperidine hydrochlorideHCID 58465878HCID 58465878, compound

Product 1

HCID 58465935HCID 58465935, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A vial was charged with (S)-7′-bromo-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (200 mg, 0.509 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), 4,4-difluoropiperidine hydrochloride (160 mg, 1.017 mmol) and 1 ml of THF. The mixture was cooled to 0° C. and LHMDS (1M in THF) (2035 μL, 2.035 mmol) was added, and the vial was sealed and stirred at RT for 2 hr. At this point more chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-t-butylether adduct (18.53 mg, 0.025 mmol), (18.53 mg, 0.025 mmol) was added followed by LHMDS solution (1 ml) and stirring continued for another hour. The mixture was quenched by addition of 2 ml of water and extracted with EtOAc. The combined organic fractions were concentrated and purified by chromatography [5-50% DCM/MeOH/NH4OH (90:10:1)] to afford (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine as yellowish foam.

Workup

  1. customthe vial was sealed
  2. stirringstirring
  3. waitcontinued for another hour
  4. customThe mixture was quenched by addition of 2 ml of water
  5. extractionextracted with EtOAc
  6. concentrationThe combined organic fractions were concentrated
  7. custompurified by chromatography [5-50% DCM/MeOH/NH4OH (90:10:1)]

Sources & evidence

ORD record
ord-498c1d1ec03f4046a359d850f0264bd1
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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