PROCESSES FOR PREPARING FLUOROKETOLIDES
Processes and intermediates for preparing fluoroketolide compounds are described herein.
1 . A process for preparing a fluoroketolide of formula (I)
the process comprising contacting a compound of the formula
with a fluorinating agent and an amine base; wherein
R 1 is H or acyl, or le is a monosaccharide, such as methylamino or dimethylamino containing monosaccharide;
V is CH 2 —N(R), C═Q or C═NQ 1 ; where Q is O or (NR, H); where R is hydrogen or optionally substituted alkyl; and Q 1 is hydroxy or a derivative thereof or amino or a derivative thereof; and
W 1 is hydroxy or a derivative thereof; and W 2 is H, or hydroxy or a derivative thereof; or W 1 and W 2 are taken together with the attached carbon atoms to form an oxygen and/or nitrogen containing heterocycle, each of which is optionally substituted.
2 . The process of claim 1 wherein the base is a cyclic amine base, a non-aromatic amine base, or an amine base with a conjugate acid pKa of at least about 11, or a combination of the foregoing.
3 . The process of claim 1 wherein the base is sterically hindered.
4 . The process of claim 1 wherein the base is a diamine.
5 . The process of claim 1 wherein the base includes at least one nitrogen that does not have a hydrogen.
6 . The process of claim 1 wherein the base includes at least one C=N group.
7 . The process of claim 1 wherein the base is DBN or DBU, or a combination thereof.
8 . The process of claim 1 wherein the fluorinating agent is selected from the group consisting of NFSi, Selectfluor, and F-TEDA, and combinations thereof
9 . The process of claim 1 wherein the compound of formula (I) is
or a salt thereof.
10 . The process of claim 1 wherein the compound of formula (I) is
or a salt thereof.
11 . The process of claim 1 wherein the compound of formula (I) is solithromycin or a salt thereof.
12 . The process of claim 1 wherein the starting compound is of the formula
or a salt thereof.
13 . The process of claim 1 claim 8 wherein the starting compound is of the formula
or a salt thereof.
14 . A process for preparing a compound of formula (I), the process comprising or further comprising contacting a compound of the formula (DM)
or a salt thereof, with a methylating agent; wherein:
R 1a is H or acyl;
V is CH 2 —N(R), C═Q or C═NQ 1 ; where Q is O or (NR, H); where R is hydrogen or optionally substituted alkyl; and Q 1 is hydroxy or a derivative thereof or amino or a derivative thereof;
W 1 is hydroxy or a derivative thereof; and W 2 is H, or hydroxy or a derivative thereof; or W 1 and W 2 are taken together with the attached carbon atoms to form an oxygen and/or nitrogen containing heterocycle, each of which is optionally substituted.
15 . The process of claim 14 wherein the compound of formula (DM) is
or a salt thereof.
16 . The process of claim 14 wherein the compound of formula (DM) is
or a salt thereof.
17 . A composition comprising solithromycin that is substantially free of desfluoro solithromycin or N-desmethyl solithromycin, or both.
18 . The composition of claim 17 wherein the composition is substantially free of N desmethyl solithromycin.
19 . The composition of claim 17 wherein the composition is substantially free of desfluoro solithromycin.