Antifungal compound process

1. A process to prepare a compound of Formula 5 or 5:

the method comprising:

(a) reacting a compound of Formula 6:

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

wherein R 4 is H, —(C═O)-phenyl, or —(C═O)-haloalkyl-substituted phenyl; and

R 5 is H or methyl;

to provide a compound of Formula 7 or 7*, or mixture thereof; and

(b) conversion of a compound of Formula 7 or 7*, or mixture thereof, to a compound of Formula 5 ;

wherein R 2 is —OCF 3 or —OCH 2 CF 3 ; and

R 3 is halo,

2. The process of claim 1 , further comprising:

(a) amidation of ester 9;

to afford morpholine amide 10; and

(b) arylation of morpholine amide 10 to afford ketone 6;

wherein R 3 is halo,

3. The process of claim 2 , wherein step (b) comprises reacting morpholine amide 10,

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

R 3 is halo,

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

5. The process of claim 1 , further comprising reducing a compound of Formula 7 or 7*, or mixture thereof:

to afford a compound of Formula 11 or 11*, or mixture thereof:

wherein R 3 is halo,

6. The process of claim 5 , further comprising:

(a) arylating a compound of Formula 11;

to afford a compound of Formula 12; and

(b) forming the tetrazole of a compound of Formula 12, to afford a compound of Formula 5;

wherein R 2 is —OCF 3 or —OCH 2 CF 3 ; and

R 3 is halo.

7. The process of claim 5 , further comprising:

(a) forming the tetrazole of a compound of Formula 11;

to afford a compound of Formula 13; and

(b) arylating a compound of Formula 13 to afford a compound of Formula 5;

wherein R 2 is —OCF 3 or —OCH 2 CF 3 ; and

R 3 is halo.

8. 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 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.

9. The process of claim 8 , further comprising reslurrying the enantio-enriched chiral salt mixture in a slurrying solvent or slurrying solvent mixture.

10. The process of claim 8 , wherein the suitable solvent or solvent mixture is (a) acetonitrile or (b) a mixture of acetonitrile and methanol.

11. The process of claim 9 , wherein the slurrying solvent or slurrying solvent mixture is (a) acetonitrile or (b) a mixture of acetonitrile and methanol.

12. The process of claim 10 , wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.

13. The process of claim 11 , wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.

14. The process of claim 8 , 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.

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

16. The process of claim 15 , wherein the mole percent of the chiral catalyst is about 0.5-50; about 0.5-25; about 1-10; or about 5.

17. The process of claim 1 , wherein the number of equivalents of nitromethane is about 1-25; about 5-15; or about 10.

18. A process to prepare a compound 5:

the method comprising:

(a) production of ketone 6, by one of two methods:

(i) amidation of ester 9,

with

to afford ketone 6,

wherein X is halogen;

or

(ii) reacting ester 9,

with morpholine to afford morpholine amide 10,

and

(iii) arylation of morpholine amide 10,

with

to afford ketone 6,

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

(b) reacting a ketone 6,

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

to afford compounds 7

(c) reduction of compound 7

to afford compound 11,

(e)(i) arylating compound 11

to afford compound 12,

and

(ii) forming the tetrazole of compound 12,

to afford compound 5

wherein R 2 is —OCF 3 or —OCH 2 CF 3 ; and

R 3 is halo,

R 4 is H —(C═O)-phenyl, or —(C═O)-haloalkyl-substituted phenyl; and

R 5 is H or methyl.

19. The process of claim 1 , further comprising reducing a compound of Formula 7:

to afford a compound of Formula 11:

11;

wherein R3 is halo,