反应详情

A stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (200 g, 529 mol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (200 mL) and DMF (1.5 L) was cooled to −78° C., and a 0.5 M solution of potassium bis(trimethylsilyl)amide in THF (1.27 L) was added. After the above solution had stirred for about one hour, the free base of 2-picolyl chloride was generated by extracting the corresponding hydrochloride salt (217 g, 1.32 mol) from saturated sodium bicarbonate solution with methylene chloride. The combined organic extracts were dried (MgSO4), concentrated, immediately dissolved in DMF (100 mL), and then added dropwise to the enolate containing solution. The reaction was stirred for 4 hours at −78° C., then slowly warmed to room temperature and stirred overnight. The toluene and THF were removed under reduced pressure. The residue was extracted from water (1.5 L) with ethyl acetate (3×1 L), the combined extracts were then washed with water (1.5 L), dried (MgSO4) and then concentrated in vacuo to give 240 g of crude product of part A which carried on to the next step: +APcI MS (M+H)+470, (M−tBu+H) 436; 1H NMR=400 MHz (methanol-d4) δ: 8.4 (arom, m, 1H), 7.65-7.2 (arom, m, 7H), 6.94 (arom, m, 1H), 5.18 (CbzNCHH, m, 1H), 5.05 (CbzNCHH, m, 1H), 2.54 (m, 1H), 1.41 (Boc, s, 9H).

1. dry with materialThe combined organic extracts were dried (MgSO4)
2. concentrationconcentrated
3. dissolutionimmediately dissolved in DMF (100 mL)
4. additionadded dropwise to the enolate containing solution
5. stirringThe reaction was stirred for 4 hours at −78° C.
6. stirringstirred overnight
7. customThe toluene and THF were removed under reduced pressure
8. extractionThe residue was extracted from water (1.5 L) with ethyl acetate (3×1 L)
9. washthe combined extracts were then washed with water (1.5 L)
10. dry with materialdried (MgSO4)
11. concentrationconcentrated in vacuo