Ammonia → 4-Methoxy-alpha,alpha-dimethylcyclohexa-1,4-diene-1-methanol

Temperature

-30 °C

2-(4-methoxy-phenyl)-propan-2-ol (750 g, 4.5 mol), anhydrous THF (7.5 L) and tert-BuOH (2001.4 g, 27 mol) were added under argon to a 22 L round bottomed flask equipped with an overhead stirrer, thermometer and dropping funnel. The mixture was cooled to −30° C. Gaseous ammonia was bubbled through the reaction mixture for 30 min. Granulated lithium (125 g, 18 mol) was added portion wise to the solution during 1-1.5 hr. The stirring was continued with slow flow of ammonia for 20 rh. The reaction was quenched with a solution of 961 g NH4Cl in 2.7 L water at −20° C. The top layer was separated and evaporated on a rotary evaporator at a bath temperature of 30° C. (all these and subsequent operations are performed under inert atmosphere). The aqueous layer was extracted with MTBE (3×1 L). The concentrate and extract were combined, washed with water and brine, dried over Na2SO4 and evaporated to dryness at a bath temperature of 35° C. The crude oily product was mixed with 725 ml Hexane and filtered. The filtrate was placed in a freezer at −70° C. and left for 24 hr. The solid was decanted and rinsed with Hexane pre-cooled to −70° C. (2×100 mL) with decantation after each rinsing. After drying under vacuum at 20° C., 562 g of the target product was obtained (yield 74%), having an HPLC purity of 89%.

1. customequipped with an overhead stirrer
2. customGaseous ammonia was bubbled through the reaction mixture for 30 min
3. customThe reaction was quenched with a solution of 961 g NH4Cl in 2.7 L water at −20° C
4. customThe top layer was separated
5. customevaporated on a rotary evaporator at a bath temperature of 30° C. (all these and subsequent operations
6. extractionThe aqueous layer was extracted with MTBE (3×1 L)
7. concentrationThe concentrate
8. extractionextract
9. washwashed with water and brine
10. dry with materialdried over Na2SO4
11. customevaporated to dryness at a bath temperature of 35° C
12. additionThe crude oily product was mixed with 725 ml Hexane
13. filtrationfiltered
14. customwas placed in a freezer at −70° C.
15. customThe solid was decanted
16. washrinsed with Hexane
17. temperaturepre-cooled to −70° C. (2×100 mL) with decantation after each rinsing
18. customAfter drying under vacuum at 20° C.

ORD record

ord-3d51ae6bd15e4a7b96d86d4af1da51a3

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08258322B2