Benzonitrile, 4-bromo- → tert-Butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

Temperature

-20 °C

To a dried and cleaned 10 L cryo reactor was added 4-bromobenzonitrile (321 g; 1.74 mol; 2.5 eq) and THF (995 mL; 5.0 vol). The stirred mixture was inerted under a nitrogen atmosphere and cooled (Tj −20° C.). To the cooled mixture at Tj −13° C. Turbo Grignard reagent (Turbo Grignard Reagent from Chemetall equal to iPrMgCl/LiCl 14% w/w in THF; 1.81 L; 2.5 eq) was charged under the nitrogen atmosphere while maintaining the temperature below approx −10° C. during 1 h 14 min. The reaction intermediate was left at approx 0° C. for 3 h giving a conversion of >97% (analytical sample quenched with 15% w/w aq NH4Cl). The mixture was cooled to Ti −20° C. and a solution of tert-butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (191 g; 0.70 mol; 1.0 eq) in THF 496 mL; 2.6 vol) was charged to the reactor for 28 min at approx-10° C. to −6° C. (exothermal reaction). The vessel was rinsed with THF (221 mL; 1.3 L), the reaction mixture warmed to 20° C. and left overnight affording a conversion (HPLC) of approx 90%. The mixture was cooled to 0° C. (Tj-10) and a solution of potassium sodium tartrate (Rochelle salt) (153 g; 1.05 eq) in water (10 vol) was drop wise added during 30 min keeping the temperature at 0 to 10° C. giving an orange coloured slurry. Tj was set to 40° C. and stirring was stopped at Ti 30° C. and the phases allowed to separate. The red coloured organic layer was recovered and the yellow slurry-like water phase was extracted twice at Tj 30° C. with iPrOAc (2×1.91 L; 2×10 vol). The organic layers were combined (7.5 L) and washed at Tj 30° C. three times with a brine-water mixture (3+3 vol; 5+5 vol; 3+3 vol). The washed organic layer was concentrated in vacuo at Tj 60° C. to approx 1.5 L volume and diluted (iPrOAc) to 2 L. The product solution was taken to the next step (example 3, method 2) without further purification.

1. customTo a dried
2. customat Tj −13° C
3. temperaturewhile maintaining the temperature below approx −10° C. during 1 h 14 min
4. customgiving
5. customa conversion of >97% (analytical sample quenched with 15% w/w aq NH4Cl)
6. temperatureThe mixture was cooled to Ti −20° C.
7. addition2.6 vol) was charged to the reactor for 28 min at approx-10° C. to −6° C. (exothermal reaction)
8. washThe vessel was rinsed with THF (221 mL; 1.3 L)
9. temperaturethe reaction mixture warmed to 20° C.
10. waitleft overnight
11. customaffording a conversion (HPLC) of approx 90%
12. temperatureThe mixture was cooled to 0° C. (Tj-10)
13. additionwise added during 30 min
14. customat 0 to 10° C.
15. customgiving an orange coloured slurry
16. customwas set to 40° C.
17. customwas stopped at Ti 30° C.
18. customto separate
19. customThe red coloured organic layer was recovered
20. extractionthe yellow slurry-like water phase was extracted twice at Tj 30° C. with iPrOAc (2×1.91 L; 2×10 vol)
21. washwashed at Tj 30° C. three times with a brine-water mixture (3+3 vol; 5+5 vol; 3+3 vol)
22. concentrationThe washed organic layer was concentrated in vacuo at Tj 60° C. to approx 1.5 L volume
23. additiondiluted (iPrOAc) to 2 L
24. customThe product solution was taken to the next step (example 3, method 2) without further purification

ORD record

ord-fb815580f7f0486eb52d731def7a9be8

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08859556B2