Diethyl Malonate → 5-Bromo-2-methyl-3-nitropyridine

To a suspension of NaH 55% in oil (300 mg, 6.87 mmol) in 6 ml DMF was added dropwise diethyl malonate (Aldrich, Buchs, Switzerland, 1.0 g, 6.24 mmol). The reaction mixture was stirred for 20 min at rt before adding 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 1.19 g, 5.0 mmol). The reaction mixture was stirred for 30 min at rt and for 1 h at 40° C. The reaction mixture was quenched with 10% aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine (4×), dried over Na2SO4, filtered and evaporated. The residue was stirred in concentrated HCl (20 ml) for 13 h at 100° C. After cooling, the reaction mixture was basified with 10 M aqueous NaOH and extracted with EtOAc (2×). The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0% to 15%) to give the title compound as a yellow solid. (HPLC: tR 2.84 (Method A).

1. stirringThe reaction mixture was stirred for 30 min at rt and for 1 h at 40° C
2. customThe reaction mixture was quenched with 10% aqueous NH4Cl
3. extractionextracted with EtOAc (2×)
4. washThe combined organic layers were washed with brine (4×)
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. customevaporated
8. stirringThe residue was stirred in concentrated HCl (20 ml) for 13 h at 100° C
9. temperatureAfter cooling
10. extractionextracted with EtOAc (2×)
11. washThe organic layers were washed with brine
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. customevaporated
15. customThe residue was dry
16. custompurified by MPLC (heptane/EtOAc 0% to 15%)

ORD record

ord-3d292053d77d4dec9350919fac6a5b59

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08476294B2