Antifungal compound process

1. A process to prepare a compound of Formula 5 or 5*, or mixture thereof:

the method comprising at least the initial two steps:

(a) reacting a compound of ketone 6,

with nitromethane in the presence of a chiral catalyst of Formula 3,

to yield compounds of Formula 7 or 7*,

or mixtures thereof; and

(b) reducing compounds of Formula 7 or 7*,

or mixtures thereof to yield compounds of Formula 11 or 11*,

or mixtures thereof;

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;

each R 3 is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.

2. The process of claim 1 , further comprising:

(a) reacting ester 9,

with morpholine

to yield morpholine amide 10

and

(b) arylating of morpholine amide 10,

yield ketone 6,

wherein M is Mg, MgX, Li, or AlX 2 ; and X is halogen, alkyl, or aryl; and

each R 3 is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.

3. The process of claim 2 , wherein M is Mg or MgX, and X is halogen.

4. The process of claim 1 , further comprising:

(a) alkynylating compounds of Formula 11 or 11*,

or mixture thereof with an ethynyl moiety R 2 ,

to yield a compound of Formula 12 or 12*,

or mixture thereof; and

(b) forming the tetrazole of compounds of Formula 12 or 12*,

or mixtures thereof, to yield compounds of Formula 18 or 18*,

or mixture thereof;

wherein each R 2 is independently ethynyl, substituted ethynyl, or

and

each R 3 is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.

5. The process of claim 1 , further comprising:

(a) forming the tetrazole of compounds of Formula 11 or 11*,

or mixture thereof,

to yield compounds of Formula 13 or 13*,

or mixtures thereof; and

(b) alkynylating compounds of Formula 13 or 13*,

or mixtures thereof, with an ethynyl moiety R 2 , to yield compounds of Formula 18 or 18*,

or mixtures thereof;

wherein each R 2 is independently ethynyl, substituted ethynyl, or

and

each R 3 is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.

6. The process of claim 4 , the process further comprising coupling the compound of Formula 18 or 18*, or mixture thereof, wherein R 2 is ethynyl, with

wherein Y is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl,

to afford of compound of Formula 5 or 5*, or a mixture thereof:

7. The process of claim 5 , the process further comprising coupling the compound of Formula 18 or 18*, or mixture thereof, wherein R 2 is ethynyl, with

wherein Y is halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl,

to afford of compound of Formula 5 or 5*, or a mixture thereof:

8. The process of claim 4 , the process further comprising:

(a) coupling the compound of Formula 18 or 18*, wherein R 2 is ethynyl, with

(b) alkylating the product from step a. with

to yield compounds of Formula 5 or 5*, or a mixture thereof:

wherein each Y is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.

9. The process of claim 5 , the process further comprising:

(a) coupling the compound of Formula 18 or 18*, wherein R 2 is ethynyl, with

(b) alkylating the product from step a. with

to yield compounds of Formula 5 or 5*, or a mixture thereof:

wherein each Y is independently halo, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, —O(C═O)—O-alkyl, —O(C═O)—O-substituted alkyl, —O(C═O)—O-aryl, —O(C═O)—O-substituted aryl, —O(SO 2 )-alkyl, —O(SO 2 )-substituted alkyl, —O(SO 2 )-aryl, or —O(SO 2 )-substituted aryl.

10. The process of claim 4 , further comprising:

(a) combining a compound of Formula 5 or 5*, or a mixture thereof, a sulfonic acid

and a crystallization solvent or crystallization solvent mixture; and

(b) isolating a compound of formula 14 or 14*, or a mixture thereof;

wherein each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

11. The process of claim 5 , further comprising:

(a) combining a compound of Formula 5 or 5*, or a mixture thereof, a sulfonic acid

and a crystallization solvent or crystallization solvent mixture; and

(b) isolating a compound of formula 14 or 14*, or a mixture thereof;

wherein each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

12. The process of claim 1 , further comprising enriching the enantiomeric purity of an enantiomeric compound mixture of Formula 7 and 7* and/or enriching the enantiomeric purity of an enantiomeric compound mixture of Formula 11 and 11*, comprising:

(i) crystallizing said enantiomeric compound mixture with a chiral acid in a solvent or solvent mixture, wherein:

the 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 12 , 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 solvent or solvent mixture is (a) acetonitrile or (b) a mixture of acetonitrile and isopropanol.

15. The process of claim 13 , wherein the slurrying solvent or slurrying solvent mixture is (a) acetonitrile or (b) a mixture of acetonitrile and isopropanol.

16. The process of claim 14 , wherein the mixture of acetonitrile and isopropanol comprises 80-90% acetonitrile and 10-20% isopropanol.

17. The process of claim 15 , wherein the mixture of acetonitrile and isopropanol comprises 80-90% acetonitrile and 10-20% isopropanol.

18. 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.

19. The process of claim 13 , 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.

20. The process of claim 1 , wherein the chiral catalyst is

21. The process of claim 20 , wherein the mole percent of the chiral catalyst is 0.5-50.

22. The process of claim 20 , wherein the mole percent of the chiral catalyst is 0.5-25.

23. The process of claim 20 , wherein the mole percent of the chiral catalyst is 1-10.

24. The process of claim 20 , wherein the mole percent of the chiral catalyst is 5.

25. The process of claim 1 , wherein the number of equivalents of nitromethane is 1-25.

26. The process of claim 1 , wherein the number of equivalents of nitromethane is 5-15.

27. The process of claim 1 , wherein the number of equivalents of nitromethane is 10.