Hydrochloric Acid → HCID 86666578, compound

Temperature

5 °C

Prepare lithium diisopropyl amide (LDA) as follows: Charge diisopropylamine (316.8 g, 2.5 equiv) and methyl tert-butyl ether (1.25 L) to a reactor and cool the reaction vessel to −10° C. to 0° C. Add n-butyl lithium in hexane (748 g, 2.2 equiv) while maintaining the temperature between −10° C. and 0° C. Stir the mixture for 30-60 min. In a separate vessel, add methyl tert-butyl ether (1.8 L), dibromomethane (471.6 g, 2.2 equiv) and methyl tetrahydro-2H-pyran-4-carboxylate (180 g) and cool to −90° C. to −70° C. Slowly add the LDA solution while maintaining the temperature between −90° C. and −70° C. After 30-90 min, transfer the reaction mixture to a solution of 1 N HCl (5.58 kg) maintained at 0-10° C. Upon completion of the addition, allow the mixture to warm to 15° C. to 25° C. and stir at this temperature for 15-20 min. Separate and discard the aqueous layer. Wash the organic layer with water (1.8 L) until the water layer registers a pH of 6-7, and concentrate the organic layer in vacuo to ˜2.2-2.5 volumes below 35° C. Add n-heptanes (720 mL), cool to −10° C. to −5° C. and stir for 1-2 h. Filter, rinse the filter cake with cold heptanes (90 mL) and dry under vacuum to give 2,2-dibromo-1-(tetrahydro-2H-pyran-4-yl)ethanone as a pale yellow solid (203.6 g, 55%). 1H NMR (400 MHz, CDCl3) δ 5.87 (s, 1H), 4.02 (m, 2H), 3.48 (m, 2H), 3.34 (m, 1H), 1.86 (m, 4H).

1. temperaturecool the reaction vessel to −10° C. to 0° C
2. temperaturecool to −90° C. to −70° C
3. temperaturewhile maintaining the temperature between −90° C. and −70° C
4. waitAfter 30-90 min
5. additionUpon completion of the addition
6. temperatureto warm to 15° C. to 25° C.
7. stirringstir at this temperature for 15-20 min
8. customSeparate
9. washWash the organic layer with water (1.8 L) until the water layer
10. concentrationconcentrate the organic layer in vacuo to ˜2.2-2.5 volumes below 35° C
11. temperatureAdd n-heptanes (720 mL), cool to −10° C. to −5° C.
12. stirringstir for 1-2 h
13. filtrationFilter
14. washrinse the filter cake with cold heptanes (90 mL)
15. customdry under vacuum

ORD record

ord-25a8f2c4ae0d4ba19404440145e2a7d3

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08436002B2