Antifungal compound process
The present invention relates to a process for preparing a compound of 5 or 5*, or a mixture thereof, that is useful as an antifungal agent. In particular, the invention seeks to provide new methodology for preparing compounds 7, 7* and 11, 11* and substituted derivatives thereof.
1. A process to prepare a compound of Formula 1 or 1*, or mixture thereof:
the process comprising reacting a compound of Formula 2:
with nitromethane in the presence of a chiral catalyst of Formula 3:
wherein R 4 is H, optionally substituted alkyl, (C═O)-optionally substituted alkyl, (C═O)-optionally substituted aryl; and R 5 is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted aryl;
to provide a compound of Formula 1 or 1*, or mixture thereof;
wherein each R is independently halo,
2. The process of claim 1 , further comprising enriching the enantiomeric purity of an enantiomeric compound mixture of Formula 1 and 1*, comprising:
(i) crystallizing said enantiomeric compound mixture with a chiral acid in a suitable solvent or solvent mixture, wherein:
the suitable solvent or solvent mixture is selected from acetonitrile, isopropanol, ethanol, water, methanol, or combinations thereof;
(ii) isolating the enantio-enriched chiral salt mixture; and
(iii) free-basing the enantio-enriched chiral salt mixture to provide the enantio-enriched compound mixture.
3. The process of claim 2 , further comprising reslurrying the enantio-enriched chiral salt mixture in a slurrying solvent or slurrying solvent mixture.
4. The process of claim 3 , wherein the slurrying solvent or slurrying solvent mixture is (a) acetonitrile or (b) a mixture of acetonitrile and methanol.
5. The process of claim 4 , wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.
6. The process of claim 4 , wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.
7. The process of claim 2 , wherein the chiral acid is selected from the group consisting of tartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid, camphorsulfonic acid, ascorbic acid, and di-p-toluoyltartaric acid.
8. The process of claim 1 , wherein the chiral catalyst is
9. The process of claim 8 , wherein the mole percent of the chiral catalyst is selected from about 0.5-50, about 0.5-25, about 1-10, and about 5.
10. The process of claim 1 , wherein the number of equivalents of nitromethane is selected from about 1-25, about 5-15, and about 10.
11. The process of claim 1 , further comprising reducing a compound of Formula 1 or 1*, or mixture thereof:
to afford a compound of Formula 4 or 4*, or mixture thereof:
wherein each R is independently halo,
12. The process of claim 11 , further comprising enriching the enantiomeric purity of an enantiomeric compound mixture of Formula 1 and 1* and/or enriching the enantiomeric purity of an enantiomeric compound mixture of Formula 4 and 4*, comprising:
(i) crystallizing said enantiomeric compound mixture with a chiral acid in a suitable solvent or solvent mixture, wherein:
the suitable solvent or solvent mixture is selected from acetonitrile, isopropanol, ethanol, water, methanol, or combinations thereof;
(ii) isolating the enantio-enriched chiral salt mixture; and
(iii) free-basing the enantio-enriched chiral salt mixture to provide the enantio-enriched compound mixture.
13. The process of claim 11 , further comprising reslurrying the enantio-enriched chiral salt mixture in a slurrying solvent or slurrying solvent mixture.
14. The process of claim 12 , wherein the slurrying solvent or slurrying solvent mixture is (a) acetonitrile or (b) a mixture of acetonitrile and methanol.
15. The process of claim 13 , wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.
16. The process of claim 14 , wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.
17. The process of claim 12 , wherein the chiral acid is selected from the group consisting of tartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid, camphorsulfonic acid, ascorbic acid, and di-p-toluoyltartaric acid.