Citric Acid → 1-Benzyl 4-tert-butyl 5,6-dimethyl-1,4-diazepane-1,4-dicarboxylate

To a solution of N-Boc-ethylenediamine (5.0 g, 31.2 mmol, 1.0 equiv, 1-2) in diethyl ether (30 mL) was added 3-methyl-3-butene-2-one (2.6 g, 31.2 mmol, 1.0 equiv, 1-1) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then cooled to 0° C. and triethylamine (6.5 mL, 46.8 mmol, 1.5 equiv) and benzyl chloroformate (5.4 mL, 37.4 mmol, 1.2 equiv) were added. The reaction mixture was stirred a further 12 h and partitioned between EtOAc and a 10% aqueous citric acid solution. The layers were separated and the organic was washed with 5% aqueous Na2CO3, then with brine, dried over Na2SO4 and concentrated by rotary evaporation. The residue was dissolved in dioxane (50 mL) and treated with a solution of 4N HCl in dioxane (70 mL, ca. 10 equiv) and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was concentrated directly, dissolved in 1N HCl (100 mL) and extracted with diethyl ether. The aqueous was neutralized with 1N NaOH (150 mL) and subsequently extracted with 3:1 chloroform:ethanol (3×200 mL), dried over MgSO4 and concentrated. The resulting residue was dissolved in DCM (100 mL) and glacial acetic acid (2 mL) was added. After 30 minutes, NaBH(OAc)3 (6.4 g, 30.2 mmol) was added and the reaction was stirred for 1 h. The reaction mixture was concentrated directly; partitioned between saturated NaHCO3 (50 mL) and 3:1 chloroform:ethanol (150 mL) The aqueous layer was extracted with chloroform:ethanol (2×150 mL), dried over MgSO4 and concentrated. The residue was dissolved in DCM (100 mL) and to the solution was added triethylamine (4.2 mL, 30.2 mmol) and Boc2O (5.0 g, 22.7 mmol) and the reaction mixture was stirred 18 hours. To the reaction mixture was added a 10% aqueous citric acid solution. The organic phase was dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (0 to 75% EtOAc in hexanes) to provide 1-3 as an oil. Data for 1-3: LC/MS: m/z (M+Na)=385.2 found; 385.5 required.

1. temperatureThe reaction mixture was then cooled to 0° C.
2. stirringThe reaction mixture was stirred a further 12 h
3. custompartitioned between EtOAc
4. customThe layers were separated
5. washthe organic was washed with 5% aqueous Na2CO3
6. dry with materialwith brine, dried over Na2SO4
7. concentrationconcentrated by rotary evaporation
8. dissolutionThe residue was dissolved in dioxane (50 mL)
9. stirringthe reaction mixture was stirred for 2 h at ambient temperature
10. concentrationThe reaction mixture was concentrated directly
11. dissolutiondissolved in 1N HCl (100 mL)
12. extractionextracted with diethyl ether
13. extractionsubsequently extracted with 3:1 chloroform
14. dry with materialethanol (3×200 mL), dried over MgSO4
15. concentrationconcentrated
16. dissolutionThe resulting residue was dissolved in DCM (100 mL)
17. additionglacial acetic acid (2 mL) was added
18. waitAfter 30 minutes
19. stirringthe reaction was stirred for 1 h
20. concentrationThe reaction mixture was concentrated directly
21. custompartitioned between saturated NaHCO3 (50 mL) and 3:1 chloroform
22. extractionethanol (150 mL) The aqueous layer was extracted with chloroform
23. dry with materialethanol (2×150 mL), dried over MgSO4
24. concentrationconcentrated
25. dissolutionThe residue was dissolved in DCM (100 mL) and to the solution
26. stirringthe reaction mixture was stirred 18 hours
27. dry with materialThe organic phase was dried over MgSO4
28. concentrationconcentrated
29. customThe residue was purified by column chromatography on silica gel (0 to 75% EtOAc in hexanes)

ORD 기록

ord-852c7dc9638c42a7aa5fbdf6abe08d53

출처 데이터셋

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08362009B2