Diisopropylamine → HCID 22660212, compound

Temperature

0 °C

A solution of diisopropylamine (1.05 mL, 7.5 mmol) in THF (5 mL) was cooled to −10° C. and a solution of n-butyl lithium (2.9 mL, 7.25 mmol) in hexanes was added dropwise while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. The solution was cooled to −70° C. and a solution of methyl cyclobutane carboxylate (0.57 g, 5 mmol) in THF (2 mL) was added dropwise maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 30 min at −50 to −60° C. Then, a solution of 4-(1-methyltetrazol-5-yl)benzyl chloride (0.94 g, 4.5 mmol) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight at which point TLC analysis indicated the absence of 4-(1-methyltetrazol-5-yl)benzyl chloride (Note: the product and 4-(1-methyltetrazol-5-yl)benzyl chloride has the same Rf value, however they were differentiated by spraying with PMA). The mixture was poured into a mixture of water (70 mL) and ethyl acetate (70 mL). An emulsion formed and was filtered through celite. The resulting two layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with 1:2 ethyl acetate:hexane to give methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.42 g, 32%) as a syrup. HR MS: obs. mass, 301.1668. Calcd mass, 301.1664.

1. temperaturewhile maintaining the temperature below 0° C
2. additionAfter addition
3. temperatureThe solution was cooled to −70° C.
4. temperaturemaintaining the internal temperature between −60 to −70° C
5. additionAfter addition
6. stirringthe reaction mixture was stirred for 30 min at −50 to −60° C
7. stirringthe reaction mixture was stirred for 1 h at −60 to −70° C
8. temperatureto warm to room temperature
9. stirringstirred overnight at which point TLC analysis
10. customAn emulsion formed
11. filtrationwas filtered through celite
12. customThe resulting two layers were separated
13. extractionthe aqueous layer was extracted with ethyl acetate (2×50 mL)
14. washThe combined extracts were washed with saturated brine
15. dry with materialdried over anhydrous magnesium sulfate
16. filtrationAfter filtration
17. concentrationthe solution was concentrated under vacuum
18. customthe residue was purified by silica gel chromatography
19. washeluting with 1:2 ethyl acetate

ORD record

ord-0c5473aafd0d4f0eac780fb946e4ec18

Source dataset

uspto-grants-2002_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06455550B1