反应详情

温度

5 °C

(2R,5R)-2-Hydroxymethyl-5-methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (25 g, 68 mmol) in DCM (823 mL) was cooled to 4° C. (ice bath). 1,8-bis(dimethylamino)naphthalene (72 g, 337 mmol) was added in one portion followed by trimethyl oxonium tetrifluoroborate (50 g, 337 mmol) portionwise over 5 min. The mixture was stirred for 35 min at 5° C., the ice bath removed, then warmed from 5-17° C. over 1 h. After stirring for a further 20 min., saturated aqueous ammonium chloride (300 mL) was added slowly and reaction stirred for 10 min. The organic layer was separated and the aqueous phase extracted with DCM (2×300 mL). The combined organic extracts were washed with 1.0 M HCl (3×1.5 L), saturated sodium bicarbonate solution (3×1.5 L), dried over sodium sulfate, filtered and concentrated. The oil was dissolved in DCM and petrol added until precipitation of 1,8-bis(dimethylamino)naphthalene occurred. Purification by column chromatography (silica gel, 0-0%, 0-100%, EtOAc/petrol) gave an oil which contained 1,8-bis(dimethylamino)naphthalene as a contaminant. The remaining 1,8-bis(dimethylamino)naphthalene was captured during filtration through a SCX-2 column eluting with MeOH, to give the title compound (18 g, 52% over two steps) as a pale yellow oil. 1H NMR (Me-d3-OD): 7.46-7.26 (5H, m), 5.26-5.07 (2H, m), 4.31 (2H, d), 4.04-3.85 (1H, m), 3.79 (1H, d), 3.46 (2H, s), 3.28-3.09 (2H, m), 1.48 (9H, s), 1.15 (3H, dd).

1. customthe ice bath removed
2. temperaturewarmed from 5-17° C. over 1 h
3. stirringAfter stirring for a further 20 min.
4. additionsaturated aqueous ammonium chloride (300 mL) was added slowly
5. customreaction
6. stirringstirred for 10 min
7. customThe organic layer was separated
8. extractionthe aqueous phase extracted with DCM (2×300 mL)
9. washThe combined organic extracts were washed with 1.0 M HCl (3×1.5 L), saturated sodium bicarbonate solution (3×1.5 L)
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated
13. dissolutionThe oil was dissolved in DCM
14. additionpetrol added until precipitation of 1,8-bis(dimethylamino)naphthalene
15. customPurification by column chromatography (silica gel, 0-0%, 0-100%, EtOAc/petrol)
16. customgave an oil which
17. filtrationThe remaining 1,8-bis(dimethylamino)naphthalene was captured during filtration through a SCX-2 column
18. washeluting with MeOH