Tetrahydrofuran → Methyl 1-(((1(R)-(3-(((2-tetrahydropyranyl)oxy)methyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetate

Temperature

-45 °C

The diol of Step 14 (17.9 g, 46.6 mmol) was dissolved in CH3CN (40 mL) and DMF (10 mL) and cooled to -42° C. under nitrogen. Diisopropyl-ethylamine (8.5 mL, 48.9 mmol) was added followed by methanesulfonyl chloride (3.6 mL, 46.6 mmol) dropwise. The solution was stirred 1.5 hr with a mechanical stirring while maintaining the temperature between -42° and -35° C.; then it was cooled to -45° C. The thiol of Step 9 (7.84 g, 48.9 mmol) was added followed by dropwise addition of DMF (15 mL). Potassium tert-butoxide in THF (56 mL, 1.75M, 97.9 mmol) was added to the reaction mixture over 20 minutes using a syringe pump. Stirring was continued for 5 hr with slow warming from -35° C. to -22° C., giving a very thick translucid gel. The reaction was quenched with saturated aq. NH4Cl (250 mL) and EtOAc (300 mL). The product was extracted with EtOAc, washed with H2O and brine, and dried over MgSO4. Purification by flash chromatography (20% to 30% EtOAc in hexanes) gave 16.8 g (68%) of the title compound.

1. stirringa mechanical stirring
2. temperaturewhile maintaining the temperature between -42° and -35° C.
3. stirringStirring
4. waitwas continued for 5 hr
5. temperaturewith slow warming from -35° C. to -22° C.
6. customgiving a very thick translucid gel
7. customThe reaction was quenched with saturated aq. NH4Cl (250 mL) and EtOAc (300 mL)
8. extractionThe product was extracted with EtOAc
9. washwashed with H2O and brine
10. dry with materialdried over MgSO4
11. customPurification by flash chromatography (20% to 30% EtOAc in hexanes)

ORD record

ord-3258a0357c92465a864976b03b6510fb

Source dataset

uspto-grants-1995_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05472964