Antifungal compound process

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

comprising converting a compound of formula V or Va, or a mixture thereof:

to compound 1 or 1a, or a mixture thereof;

wherein each R 2 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 reacting a compound of formula IV:

under asymmetric dihydroxylation conditions to provide a compound of formula V or Va, or a mixture thereof:

wherein the asymmetric dihydroxylation conditions comprise:

(i) AD-mix alpha or AD-mix beta; or

(ii) a first oxidant in catalytic amount selected from OsO 4 or K 2 OsO 2 (OH) 4

(iii) a second oxidant in stoichiometric amount selected from K 3 Fe(CN) 6 or N-methylmorpholine-N-oxide;

(iv) a base selected from NaHCO 3 , Na 2 CO 3 , Cs 2 CO 3 , or K 2 CO 3 ; and

(v) a chiral ligand that is selected from (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQD) 2 AQN, (DHQ) 2 AQN, (DHQD) 2 PYR, and (DHQ) 2 PYR; and

each R 2 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 the chiral ligand is selected from the group consisting of (DHQ) 2 PHAL, (DHQD) 2 PHAL, (DHQD) 2 AQN, and (DHQD) 2 PYR.

4. The process of claim 3 , wherein (ii) further comprises methanesulfonamide.

5. The process of claim 1 , further comprising converting a compound of formula VI or VIa, or a mixture thereof:

to a compound of formula VII or VIIa, or a mixture thereof:

wherein each Y is independently —OSO 2 -alkyl, —OSO 2 -substituted alkyl, —OSO 2 -aryl, —OSO 2 -substituted aryl, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, or halogen; and

each R 2 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 2 , wherein the steps of converting compound V or Va into compound 1 or 1a comprises:

(i) activating the primary alcohol of 2-6a or 2-6c,

or a mixture thereof, to provide a compound of formula 2-7a or 2-7c,

or a mixture thereof;

wherein each Y is independently —OSO 2 -alkyl, —OSO 2 -substituted alkyl, —OSO 2 -aryl, —OSO 2 -substituted aryl, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, or halogen;

(ii) ring-closing of a compound of 2-7a or 2-7c,

or a mixture thereof, to provide epoxide 5* or 5b*,

or a mixture thereof;

(iii) ring-opening epoxide 5* or 5b*,

or a mixture thereof, to provide amino-alcohol 1-6* or 1-7*, or

a mixture thereof; and

(iv) forming the tetrazole of amino-alcohol 1-6* or 1-7*,

or a mixture thereof, to provide compound 1 or 1a,

or a mixture thereof.

7. The process of claim 6 , wherein Y is mesylate or tosylate.

8. The process of claim 2 , wherein the steps of converting compound V or Va into compound 1 or 1a comprises:

(i) activating the primary alcohol 2-6b or 2-6d,

or a mixture thereof, to provide a compound of formula 2-7b or 2-7d,

or a mixture thereof;

(ii) ring-closing a compound of 2-7b or 2-7d,

or a mixture thereof, to provide epoxide 4*or 4c*,

or a mixture thereof;

(iii) ring-opening epoxide 4*or 4c*

or a mixture thereof, to provide amino-alcohol 4b or 4c,

or a mixture thereof;

(iv) arylating amino-alcohol 4b or 4c,

or a mixture thereof, to provide aryl-pyridine 1-6* or 1-7*,

or a mixture thereof; and

(v) forming the tetrazole of amino-alcohol 1-6* or 1-7*,

or a mixture thereof, to provide compound 1 or 1a,

or a mixture thereof;

wherein each Y is independently —OSO 2 -alkyl, —OSO 2 -substituted alkyl, —OSO 2 -aryl, —OSO 2 -substituted aryl, —O(C═O)-alkyl, —O(C═O)-substituted alkyl, —O(C═O)-aryl, —O(C═O)-substituted aryl, or halogen; and

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.

9. The process of claim 6 , 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.

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

11. The process of claim 9 , wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

12. The process of claim 9 , wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl tert-butylether, hexane, heptane, or toluene, or combinations thereof.

13. The process of claim 8 , 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.

14. The process of claim 13 , wherein Z is phenyl, p-tolyl, methyl, or ethyl.

15. The process of claim 13 , wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

16. The process of claim 13 , wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl tert-butylether, hexane, heptane, or toluene, or combinations thereof.