Hexamethylphosphoramide → Tert-butyl4-(3-methyl-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-ylcarbamate

Temperature

-78 °C

To a stirred solution of 2,6-dimethyl-N-phenylbenzamide (compound 4403), which may be synthesized as described in Example 9) (30 g, 0.13 mol, 1 eq) and HMPA (26 g, 0.16 mol, 1.2 eq) in anhydrous THF (300 mL) at −78° C. under an argon atmosphere, n-butyllithium (100 mL, 2.5 M, 0.25 mol, 2.5 eq) was added carefully over 1 h and the reaction temperature was kept below −60° C. during addition. The resulting mixture was stirred at −78° C. for 1 h, and then (S)-methyl 2-(tert-butoxycarbonylamino)-propanoate (compound 4803) (35 g, 0.173 mol, 1.3 eq) was quickly added (the reaction temperature rose to −50° C. during addition). The mixture was stirred at −50° C. for 10 min, quenched with water (300 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (500 mL×2), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a semi-solid oil. The crude product was slurried in ethyl acetate (500 mL) and stirred for 10 min. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min. The solid was collected by filtration and further dried in vacuo to afford the desired product, tert-butyl4-(3-methyl-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-ylcarbamate (compound 4703) (4.61 g, 9% yield) as a white solid.

1. customat −78° C.
2. additionthe reaction temperature was kept below −60° C. during addition
3. additionrose to −50° C. during addition)
4. stirringThe mixture was stirred at −50° C. for 10 min
5. customquenched with water (300 mL)
6. extractionextracted with ethyl acetate (2×100 mL)
7. washThe organic layer was washed with water (500 mL×2)
8. dry with materialdried over anhydrous MgSO4
9. filtrationfiltered
10. concentrationThe filtrate was concentrated in vacuo
11. customto afford the crude product as a semi-solid oil
12. stirringstirred for 10 min
13. customThe solid was removed by filtration
14. concentrationthe filtrate was concentrated in vacuo
15. stirringThe oil residue was stirred in a mixture of ethyl acetate (30 mL) and isopropyl alcohol (200 mL) at room temperature for 10 min
16. filtrationThe solid was collected by filtration
17. customfurther dried in vacuo

ORD record

ord-890713d840ec4f5b9c8de254610a632e

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569323B2