Antifungal compound process

1. A process to prepare compound 1 or 1a, salts thereof, or a mixture thereof:

comprising performing a chemical reaction with morpholine amide 2b:

as a reactant, wherein the reaction results in a product compound 1 or 1a, or mixtures thereof;

wherein R 1 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.

2. The process of claim 1 , comprising reacting morpholine amide 2b:

with

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

wherein the reaction results in a product compound 1 or 1a, or a mixture thereof:

wherein R 1 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.

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

4. The process of claim 1 , further comprising performing a reaction to form an amidation product of ester 2:

wherein the reaction results in product morpholine amide 2b:

wherein each R 1 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 4 , comprising reacting ester 2:

with morpholine, wherein the reaction results in a product morpholine amide 2b:

wherein each R 1 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 1 , further comprising:

(i) performing a reaction to displace the morpholino portion of morpholine amide 2b,

to

wherein the reaction of (i) results in a product ketone 3,

(ii) performing a reaction to arylate ketone 3,

to wherein the reaction of (ii) results in a product aryl-pyridine 1-4,

(iii) performing a reaction to form an epoxide of aryl-pyridine 1-4,

wherein the reaction of (iii) results in a product epoxide 5,

(iv) performing a ring-opening reaction to open the ring of epoxide 5,

wherein the reaction of (iv) results in a product amino-alcohol ±1-6,

(v) enriching the enantiomeric purity of amino-alcohol ±1-6,

wherein the enrichment of (v) results in an enantio-enriched amino-alcohol 1-6* or 1-7*,

or a mixture thereof; and

(vi) performing a reaction to form the tetrazole of enantio-enriched amino-alcohol 1-6* or 1-7*,

or a mixture thereof, wherein the reaction of (vi) results in a product compound 1 or 1a,

or a mixture thereof;

wherein each R 1 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.

7. The process of claim 1 , further comprising:

(i) performing a reaction to displace the morpholino portion of morpholine amide 2b,

wherein the reaction of (i) results in a product ketone 3,

(ii) performing a reaction to form an epoxide of ketone 3,

wherein the reaction of (ii) results in a product epoxide 4,

(iii) performing a ring-opening reaction to open the ring of epoxide

wherein the reaction of (iii) results in a product amino-alcohol ±4b,

(iv) enriching the enantiomeric purity of amino-alcohol ±4b,

wherein the enrichment of (iv) results in an enantio-enriched amino-alcohol 4b or 4c:

or a mixture thereof;

(v) performing a reaction to form the tetrazole of enantio-enriched amino-alcohol 4b or 4c:

or a mixture thereof, wherein the reaction of (v) results in a product tetrazole 6 or 6a,

or a mixture thereof; and

(vi) performing a reaction to arylate tetrazole 6 or 6a,

or a mixture thereof, wherein the reaction of (vi) results in a product compound 1 or 1a,

or a mixture thereof;

wherein each R 1 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.

8. The process of claim 7 , further comprising:

(i) combining compound 1 or 1a,

or a mixture thereof, a sulfonic acid

and a crystallization solvent or crystallization solvent mixture;

(ii) diluting the mixture from step (i) with a crystallization co-solvent or crystallization co-solvent mixture; and

(iii) isolating a compound of formula IX or IXa,

or a mixture thereof;

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

9. The process of claim 8 , wherein Z is phenyl, p-tolyl, methyl, or ethyl.

10. The process of claim 8 , wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

11. The process of claim 8 , wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl tert-butylether, hexane, heptane, or toluene, or combinations thereof.

12. The process of claim 1 , further comprising:

(i) performing a reaction to displace the ester portion of ester 2,

wherein the reaction of (i) results in a product morpholine amide 2b,

(ii) performing a reaction to displace the morpholino portion of morpholine amide 2b,

wherein the reaction of (ii) results in a product ketone 3,

(iii) performing a reaction to form an epoxide of ketone 3,

wherein the reaction of (iii) results in a product epoxide 4,

(iv) performing a ring-opening reaction to open the ring of epoxide 4,

wherein the reaction of (iv) results in amino-alcohol ±4b,

(v) enriching the enantiomeric purity of amino-alcohol ±4b,

wherein the enrichment of (v) results in an enantio-enriched amino-alcohol 4b or 4c:

or a mixture thereof;

(vi) performing a reaction to arylate the enantio-enriched amino-alcohol 4b or 4c,

or a mixture thereof, wherein the reaction of (vi) results in a product enantio-enriched amino-alcohol 1-6* or 1-7*,

or a mixture thereof;

(vii) performing a reaction to form a salt of enantio-enriched amino-alcohol 1-6* or 1-7*,

or a mixture thereof, wherein reaction of (vii) results in a product XI or Xia,

or a mixture thereof; and

(viii) performing a reaction to form the tetrazole of XI or Xia,

or a mixture thereof, wherein the reaction of (viii) results in a product compound 1 or 1a,

or a mixture thereof;

wherein each R 1 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.

13. The process of claim 12 , wherein the salt is selected from the group consisting of maleic acid salt, malonic acid salt, succinic acid salt, fumaric acid salt, malic acid salt, tartaric acid salt, dibenzoyltartaric acid salt, di-p-toluoyltartaric acid salt, and mandelic acid salt.

14. The process of claim 12 , wherein the salt is tartaric acid salt, di-p-toluoyltartaric acid salt, or malic acid salt.

15. The process of claim 12 , wherein the salt is L-tartaric acid salt or D-malic acid salt.

16. The process of claim 12 , wherein the salt is L-tartaric acid salt.