Hexane → HCID 68915228, compound

Temperature

-78 °C

Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF (30 ml) in argon and mixed with a solution of butyl lithium in hexane (2.5M, 5 ml, 12.5 mmol) at −30° C. (bath temperature). The reaction mixture was cooled to −78° C. After this temperature was reached, 4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in dry THF (10 ml), was added in drops within 1 min. The batch was left for 30 min at −78° C. Then, methyl bromoacetate (1 ml, 10.6 mmol), dissolved in dry THF (5 ml), was added in drops within 1 min. The reaction mixture was stirred for 1 h at −78° C. After room temperature was reached, the batch was stirred for a further 4 h. After approx. 2 h the batch became cloudy and a precipitate began to separate out. For work up the batch was carefully mixed with water (1 ml), then a mixture of saturated NaCl solution (30 ml) and 2 N HCl (20 ml) was added. The mixture was stirred for 10 min, the organic phase separated and extracted with saturated NaCl solution (2×10 ml). The combined aqueous phases were washed with ethyl acetate (3×20 ml) and then added to a saturated NaHCO3 solution (approx. 30 ml) for neutralisation. The emulsion formed was strongly basified with 2N NaOH and extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over MgSO4 and then concentrated to low volume. The two possible diastereoisomers of the ketone were isolated from the residue (2.53 g) with yields of 710 g (more non-polar diastereoisomer, 24%) and 260 mg (more polar diastereoisomer with an impurity of approx. 10% of a diester, approx. 8%) by means of chromatographic purification [silica gel 60 G (10 g); cyclohexane/ethyl acetate 2:1 (70 ml), cyclohexane/ethyl acetate 1:1 (70 ml), ethyl acetate (70 ml)]. Since according to all observations made hitherto the di-substituted ketones do not react with tryptophol, a further purification of the more polar compound could be omitted.

1. additionwas added in drops within 1 min
2. additionwas added in drops within 1 min
3. customAfter room temperature
4. stirringthe batch was stirred for a further 4 h
5. waitAfter approx. 2 h the batch became cloudy
6. customto separate out
7. additionFor work up the batch was carefully mixed with water (1 ml)
8. additiona mixture of saturated NaCl solution (30 ml) and 2 N HCl (20 ml)
9. additionwas added
10. stirringThe mixture was stirred for 10 min
11. customthe organic phase separated
12. extractionextracted with saturated NaCl solution (2×10 ml)
13. washThe combined aqueous phases were washed with ethyl acetate (3×20 ml)
14. additionadded to a saturated NaHCO3 solution (approx. 30 ml) for neutralisation
15. customThe emulsion formed
16. extractionextracted with ethyl acetate (3×30 ml)
17. dry with materialThe combined organic phases were dried over MgSO4
18. concentrationconcentrated to low volume

ORD record

ord-3ffe136f7f864d6989ceaf8d396e5e5f

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08293758B2