Lithium Hexamethyldisilazide → HCID 58465935, compound

Temperature

0 °C

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, 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. Step 2: To a solution of (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) in DCM (3 ml) boron tribromide (0.085 ml, 0.900 mmol) was added dropwise at room temperature and the mixture was stirred for 3 hrs at RT. The reaction was quenched by addition of MeOH (˜1 ml), stirred for 10 min, then neutralized by addition of 25% NH4OH. The homogeneous mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with brine and concentrated in vacuo to give after trituration with DCM off white solid. The solid was redissolved in 3 ml of DMF, cesium carbonate (195 mg, 0.600 mmol) and potassium iodide (14.94 mg, 0.090 mmol) were added and then 3-bromomethyll-3-methyloxetane (0.054 ml, 0.330 mmol) was added dropwise. The mixture was stirred at RT for 4 hrs. The mixture was diluted with water (10 ml) and extracted with EtOAc. The combined organic layers was washed twice with water, then with brine and concentrated in vacuo. The residue was purified by chromatography [10-80% DCM/MeOH/NH4OH (90:10:1) in DCM] to afford (S)-7′-(4,4-difluoropiperidin-1-yl)-4′-fluoro-2′-((3-methyloxetan-3-yl)methoxy)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine

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)]

ORD record

ord-c2852e127f5f401c8d5fbe1291fdaee2

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012446B2