Lithium Hexamethyldisilazide → HCID 58465935, compound

HRID 1472408Notes

Reaction equation

HRID 1472408 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, compoundYield 59%

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-i-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. The vial was sealed and stirred at room temperature 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 was continued for another hour. The mixture was quenched by addition of 2 ml of water and extracted with ethyl acetate. The combined organic layers 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 (130 mg, 0.300 mmol, 59.0% yield) as yellowish foam.

Workup

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

Sources & evidence

ORD record
ord-bdd9fa6f5ba843d3a71f300a7a830fd5
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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