2-Amino-2-methyl-1-propanol → HCID 46837646, compound

In some embodiments, various compounds of the present invention may be prepared by a novel convergent synthetic approach for the preparation of 2-substituted morpholinols as outlined in Scheme 3. This approach utilizes a nucleophilic addition of Grignard reagents to (35)-3,5,5-trimethylmorpholin-2-one (15). Treatment of methyl (R)-(+)-lactate (13) with trifluoromethanesulfonic anhydride and 2,6-lutidine at 0° C., gives methyl (2R)-2-{[(trifluoromethyl)sulfonyl]oxy}propionate (14) in 77% yield. The alkylation of 2-amino-2-methyl-1-propanol with triflate 14 at −40° C. for 2 h and overnight at room temperature, and subsequent cyclization affords 15. The addition of the appropriate arylmagnesium bromide to 15 provides the desired compounds. The C-3 stereocenter of these compounds is derived from the lactate, rather than created by a synthetic transformation such as the Sharpless hydroxylation used in Scheme 1. In some embodiments, this center was then leveraged to create the second C-2 stereocenter. The resulting stereochemistry at C-2 was a result of either facial selectivity during the Grignard addition anti to the C-3 methyl group and/or a thermodynamic equilibrium of the final product to the S,S-configuration since the resulting product can ring open and close. The ring opened form loses its C-2 stereochemistry, forming a ketone. This route is more convergent than the Sharpless hydroxylation route, and in some embodiments, may be more reliable, requiring far less analytical work.

ORD record

ord-eb23dd7611cb4b6cadb77099f15deae3

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08906908B2