1,2-Dimethoxyethane → (4R-cis)-3-[(5H-Dibenzo[a,d]cyclohepten-5-yl)acetyl]-4-methyl-5 phenyl-2-oxazolidinone

Temperature

-20 °C

A solution of acid from Step A (6.0 g, 23.97 mmol) in anhydrous ethylene glycol dimethyl ether (DME) (30 mL) is cooled to -20° C., under nitrogen (N2), and freshly distilled diisopropyl-ethylamine (5.0 mL, 28.77 mmol) is added, followed by slow addition of pivaloyl chloride (3.2 mL, 26.37 mmol). The resulting milky slurry is stirred at -20° C. for 30 minutes. The white solid is filtered, washed with DME (5 mL). The lilt rate of the mixed anhydride is cooled to -78° C. under nitrogen atmosphere. In a separate flask, (4R)-methyl-(5S)-phenyl-2-oxazolidinone (4.7 g, 26.37 mmol) is dissolved in freshly distilled tetrahydrofuran (THF) (53 mL) and cooled to -78° C., under argon (Ar). Several crystals of triphenylmethane (Ph3CH) is added as an indictor. To this solution is added n-butyllithium (n-BuLi) (17.3 mL, 27.81 mmol, 1.6M solution in hexane). The red solution is stirred at -78° C. for 5 minutes, and the solution of mixed anhydride prepared as described above, is added via cannula. The resulting light yellow solution is stirred at -78° C. for 15 minutes and then warmed to room temperature over 2 hours. The reaction is quenched by addition of aqueous ammonium chloride (NH4Cl). The THF is removed in vacuo and the residue is extracted with dichloromethane (CH2Cl2) (3×100 mL). The organic extracts are combined and washed successively with aqueous sodium bicarbonate solution brine (NaHCO3) , dried over MgSO4, and concentrated in vacuc. The resulting yellow solid is recrystallized from hexane-AcOEt/2:1 to give the title compound as a white solid, 6.3 g; mp 172° -173° C., [α]D =+10.1° (c=1.0, CHCl3).

1. filtrationThe white solid is filtered
2. washwashed with DME (5 mL)
3. temperatureThe lilt rate of the mixed anhydride is cooled to -78° C. under nitrogen atmosphere
4. temperaturecooled to -78° C., under argon (Ar)
5. stirringThe red solution is stirred at -78° C. for 5 minutes
6. additionis added via cannula
7. stirringThe resulting light yellow solution is stirred at -78° C. for 15 minutes
8. temperaturewarmed to room temperature over 2 hours
9. customThe reaction is quenched by addition of aqueous ammonium chloride (NH4Cl)
10. customThe THF is removed in vacuo
11. extractionthe residue is extracted with dichloromethane (CH2Cl2) (3×100 mL)
12. washwashed successively with aqueous sodium bicarbonate solution brine (NaHCO3)
13. dry with materialdried over MgSO4
14. concentrationconcentrated in vacuc
15. customThe resulting yellow solid is recrystallized from hexane-AcOEt/2:1

ORD record

ord-8e2e29a14f71414bb008e9e26a4f06ab

Source dataset

uspto-grants-1995_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05380925