Methyl iodide → Methyl 1-Boc-2-Methylazetidine-2-carboxylate

Temperature

-78 °C

To a solution of diisopropylamine (1.05 equiv; 5.9 mmol, 0.6 g, 0.83 mL) in anhydrous tetrahydrofuran (15 mL) was added n-butyl lithium (1.05 equiv; 5.9 mmol, 2.36 mL of a 2.5M solution in hexanes) and the resulting light yellow solution was warmed to 0° C. for 10 min. It was then cooled back to −78° C. and N-(tert-butoxycarbonyl)-azetidine-2(S)-carboxylic acid, methyl ester (5.63 mmol, 1.21 g) in dry tetrahydrofuran (3.0 mL) was added dropwise and stirring was continued for 45 min. After this time, hexamethylphosphoramide (2.0 equiv; 11.3 mmol, 2.02 g, 1.96 mL) was added and the reaction mixture was stirred for 0.5 h. At this point, iodomethane (5.0 equiv; 28.2 mmol, 3.99 g, 1.75 mL) was added (−78° C.), the cooling bath was removed, and stirring was continued overnight (16 h) at ambient temperature. Addition of saturated ammonium chloride solution, extraction with ethyl acetate, washing of the combined organic layer with water (2×) and brine, drying (MgSO4), and concentration yielded crude material which was purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes) to provide N-(tert-butyloxycarbonyl)-2(R,S)-methylazetidine-2-carboxylic acid, methyl ester (0.9 g, 70% yield).

1. stirringthe reaction mixture was stirred for 0.5 h
2. customthe cooling bath was removed
3. stirringstirring
4. waitwas continued overnight
5. custom(16 h)
6. customat ambient temperature
7. additionAddition of saturated ammonium chloride solution, extraction with ethyl acetate
8. washwashing of the combined organic layer with water (2×) and brine
9. customdrying
10. concentration(MgSO4), and concentration
11. customyielded crude material which
12. customwas purified by Biotage flash-coloumn chromatography (15% ethyl acetate, 85% hexanes)

ORD record

ord-09c6d7e2c9834dc283d0a18312d2c08b

Source dataset

uspto-grants-2003_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06645939B1