Method for the synthesis of 2′,3′-dideoxy-2′,3′-didehydronucleosides

• US 6,927,291 B2
• Filed: 03/01/2002
• Issued: 08/09/2005
• Est. Priority Date: 03/01/2001
• Status: Expired due to Term

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Pharmasset Ltd (Gilead Sciences Inc.)
• Inventors: Jin, Fuqiang, Confalone, Pasquale N.
• Primary Examiner(s): McKenzie, Thomas C.
• Application Number:
  US10/087,112
• Publication Number:
  US 20020198224A1
• Time in Patent Office: 1,257 Days
• Field of Search: 544/317
• US Class Current: 544/317
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

An efficient synthetic route to antiviral 2′,3′-dideoxy-2′,3′-didehydro-nucleosides, such as 2′,3′-dideoxy and 2′- or 3′-deoxyribo-nucleoside analogs, from available precursors is disclosed, with the option of introducing functionality as needed. In one embodiment, a method for the preparation of β-D and β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleosides is described that includes: activating a compound of structure (1)
wherein B is a pyrimidine or purine base and Y is O, S or CH₂ with an acyl halide of the formula X—C(═O)R¹, X—C(═O)C(R¹)₂OC(═O)R¹ or X—C(═O)OR¹ (wherein X is a halogen, and each R¹ is independently hydrogen, lower alkyl, alkyl, aryl or phenyl); reducing the resulting compound with a reducing agent to form a 2′,3′-dideoxy-2′,3′-didehydro-nucleoside; and optionally deprotecting the nucleoside. The haloacylation of the first step can form the 2′-acyl-3′-halonucleoside, the 3′-acyl-2′-halonucleoside, or a mixture thereof.

Claims

1. A process for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

Q is 2-(R¹CH₂CO₂)phenyl-, R¹CH₂—

, or R¹CH₂C(═

O)OC(R²)₂—

;

X is Cl, Br, or I;

R¹ is H or C₁-C₆ alkyl;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

in a suitable polar aprotic solvent at a temperature from about 0°

C. to 60°

C. to form a compound of Formula (II), a compound of Formula (II*), or a mixture of compounds of Formula (II) and (II*);

wherein R³ is X; and

R⁴ is R¹CH₂C(═

O)O—

;

(2) contacting the compound of Formula (II), the compound of Formula (II*), or the mixture of compounds of Formula (II) and (II*);

with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III);

(3) contacting the compound of Formula (III) with a suitable base to form the compound of Formula (IV).

2. The process of claim 1 for the preparation of a compound of Formula (IV), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide, 2-(acetoxy)-2-methyl-butanoyl bromide,

2-(acetoxy)-2-ethyl-butanoyl bromide, or 2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

3. The process according to claim 1, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a compound of Formula (II-a), a compound of Formula (II*-a), or a mixture of compounds of Formula (II-a) and (II*-a);

(2) contacting the compound of Formula (II-a), the compound of Formula (II*-a), or the mixture of compounds of Formula (II-a) and (II*-a);

with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III-a);

(3) contacting the compound of Formula (III-a) with a suitable base to form the compound of Formula (IV).

4. The process of claim 3 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

5. The process of claim 4 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises a combination of acetonitrile and ethyl acetate;

in step (2), the suitable reducing agent is Zn—

Cu couple;

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate; and

in step (3) the suitable base is sodium methoxide.

6. The process according to claim 5, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent comprising a combination of acetonitrile and ethyl acetate, wherein the ratio of acetonitrile to ethyl acetate is 1;

4;

to form a compound of Formula (II-a), a compound of Formula (II*-a), or a mixture of compounds of Formula (II-a) and (II*-a);

(2) contacting the compound of Formula (II-a), the compound of Formula (II*-a), or the mixture of compounds of Formula (II-a) and (II*-a);

with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4, to form a compound of Formula (III-a);

(3) contacting the compound of Formula (III-a) with sodium methoxide to form the compound of Formula (IV).

7. The process of claim 1 for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

Q is R¹CH₂C(═

O)OC(R²)₂—

;

X is Cl, Br, or I;

R¹ is H, CH₃, CH₂CH₃, or CH₂CH₂CH₃;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

in a suitable polar aprotic solvent to form a compound of Formula (II) or a compound of Formula (II*);

wherein R³ is X; and

R⁴ is R¹CH₂C(═

O)O—

;

(2) contacting the compound of Formula (II) or the compound of Formula (II*) with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III);

(3) contacting the compound of Formula (III) with a suitable base to form the compound of Formula (IV).

8. The process of claim 7 for the preparation of a compound of Formula (IV), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide, 2-(acetoxy)-2-methyl-butanoyl bromide,

2-(acetoxy)-2-ethyl-butanoyl bromide, or 2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises

one polar aprotic solvent or a combination of two or more polar aprotic solvents;

and is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises

one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

9. The process according to claim 7, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a compound of Formula (II-a) or a compound of Formula (II*-a);

(2) contacting the compound of Formula (II-a) or the compound of Formula (II*-a) with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III-a);

(3) contacting the compound of Formula (III-a) with a suitable base to form the compound of Formula (IV).

10. The process of claim 9 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

11. The process of claim 10 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises a combination of acetonitrile and ethyl acetate;

in step (2), the suitable reducing agent is Zn—

Cu couple;

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate; and

in step (3) the suitable base is sodium methoxide.

12. process according to claim 11, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent comprising a combination of acetonitrile and ethyl acetate, wherein the ratio of acetonitrile to ethyl acetate is 1;

4;

to form a compound of Formula (II-a) or a compound of Formula (II*-a);

(2) contacting the compound of Formula (II-a) or the compound of Formula (II*-a);

with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4, to form a compound of Formula (III-a);

(3) contacting the compound of Formula (III-a) with sodium methoxide to form the compound of Formula (IV).

13. The process of claim 1 for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

Q is R¹CH₂C(═

O)OC(R²)₂—

;

X is Cl, Br, or I;

R¹ is H, CH₃, CH₂CH₃, or CH₂CH₂CH₃;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

in a suitable polar aprotic solvent to form a mixture of compounds of Formula (II) and (II*);

wherein R³ is X; and

R⁴ R¹CH₂C(═

O)O—

;

(2) contacting the mixture of compounds of Formula (II) and (II*) with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III);

(3) contacting the compound of Formula (III) with a suitable base to form the compound of Formula (IV).

14. The process of claim 13 for the preparation of a compound of Formula (IV), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide, 2-(acetoxy)-2-methyl-butanoyl bromide,

2-(acetoxy)-2-ethyl-butanoyl bromide, or 2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

15. The process according to claim 13, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a mixture of compounds of Formula (II-a) and (II*-a);

(2) contacting the mixture of compounds of Formula (II-a) and (II*-a) with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III-a);

(3) contacting the compound of Formula (III-a) with a suitable base to form the compound of Formula (IV).

16. The process of claim 15 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

17. The process of claim 16 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises a combination of acetonitrile and ethyl acetate;

in step (2), the suitable reducing agent is Zn—

Cu couple;

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate; and

in step (3) the suitable base is sodium methoxide.

18. The process according to claim 17, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent comprising a combination of acetonitrile and ethyl acetate, wherein the ratio of acetonitrile to ethyl acetate is 1;

4;

to form a mixture of compounds of Formula (II-a) and (II*-a);

(2) contacting the mixture of compounds of Formula (II-a) and (II*-a) with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4, to form a compound of Formula (III-a);

(3) contacting the compound of Formula (III-a) with sodium methoxide to form the compound of Formula (IV).

47. The process of claim 1 or 29 wherein the compound of Formula (IV) is in the form of a β

-D-enantiomer.

53. The process of claim 1 wherein the temperature in step (1) is about 10°

C. to about 40°

C.

54. The process of claim 1 wherein the temperature in step (1) is about 25°

C. to about 40°

C.

19. A process for the preparation of a compound of Formula (III):

wherein;

Q is 2-(R¹CH₂CO₂)phenyl-, R¹CH₂—

, or R¹CH₂C(═

O)OC(R²)₂—

;

R¹ is H or C₁-C₆ alkyl;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

comprising;

(1) contacting a compound of Formula (I);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

Q is 2-(R¹CH₂CO₂)phenyl-, R¹CH₂—

, or R¹CH₂C(═

O)OC(R²)₂—

;

X is Cl, Br, or I;

R¹ is H or C₁-C₆ alkyl;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

in a suitable polar aprotic solvent at a temperature from about 0°

C. to 60°

C. to form a compound of Formula (II), a compound of Formula (II*), or a mixture of compounds of Formula (II) and (II*);

wherein R³ is X; and

R⁴ is R¹CH₂C(═

O)O—

; and

(2) contacting the compound of Formula (II), the compound of Formula (II*), or the mixture of compounds of Formula (II) and (II*);

with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III).

20. The process of claim 19 for the preparation of a compound of Formula (III), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide, 2-(acetoxy)-2-methyl-butanoyl bromide, 2-(acetoxy)-2-ethyl-butanoyl bromide, or 2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn; and

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether.

21. The process according to claim 19, for the preparation of a compound of Formula (III-a):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a compound of Formula (II-a), a compound of Formula (II*-a), or a mixture of compounds of Formula (II-a) and (II*-a);

(2) contacting the compound of Formula (II-a), the compound of Formula (II*-a), or the mixture of compounds of Formula (II-a) and (II*-a);

with a suitable reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (III-a).

22. The process of claim 21 for the preparation of a compound of Formula (III-a), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the suitable reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn; and

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether.

23. The process of claim 22 for the preparation of a compound of Formula (III-a), wherein:

in step (1), the suitable polar aprotic solvent comprises a combination of acetonitrile and ethyl acetate;

in step (2), the suitable reducing agent is Zn—

Cu couple; and

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate.

24. The process according to claim 23, for the preparation of a compound of Formula (III-a):

comprising;

(1) contacting a compound of Formula (I);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent comprising a combination of acetonitrile and ethyl acetate, wherein the ratio of acetonitrile to ethyl acetate is 1;

4;

to form a compound of Formula (II-a), a compound of Formula (II*-a), or a mixture of compounds of Formula (II-a) and (II*-a);

(2) contacting the compound of Formula (II-a), the compound of Formula (II*-a), or the mixture of compounds of Formula (II-a) and (II*-a);

with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4, to form a compound of Formula (III-a).

48. The process of claim 19 or 41 wherein the compound of Formula (III) is in the form of a β

-D-enantiomer.

55. The process of claim 19 wherein the temperature in step (1) is about 10°

C. to about 40°

C.

56. The process of claim 19 wherein the temperature in step (1) is about 25°

C. to about 40°

C.

25. A compound of Formula (II) or (II*):

or a pharmaceutically acceptable salt thereof, wherein;

in Formula II, Q is R¹CH₂—

R¹ is C₁-C₆ alkyl;

R² is independently selected from methyl, ethyl, and propyl;

R³ is Cl, Br, or I; and

R⁴ is R¹CH₂C(═

O)O—

;

or in Formula II, Q is R¹CH₂C(═

O)OC(R²)₂—

;

R¹ is H or C₁-C₆ alkyl;

R² is independently selected from methyl, ethyl, and propyl;

R³ is Cl, Br, or I; and

R⁴ R¹CH₂C(═

O)O—

;

and wherein;

in Formula II*,

Q is R¹CH₂C(═

O)OC(R²)₂—

;

R¹ is H or C₁-C₆ alkyl;

R² is independently selected from methyl, ethyl, and propyl;

R³ is Cl, Br, or I; and

R⁴ is R¹CH₂C(═

O)O—

;

.

49. The compound of claim 25 wherein the compound of Formula (II) or (II*) is in the form of a β

-D-enantiomer.

26. A compound of Formula (II-a) or (II*-a):

or a pharmaceutically acceptable salt thereof.

50. The compound of claim 26 wherein the compound of Formula (II-a) or (II*-a) is in the form of a β

-D-enantiomer.

27. A compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein;

Q is R¹CH₂C(═

O)OC(R²)₂—

;

R¹ is H or C₁-C₆alkyl; and

R² is independently selected from methyl, ethyl, and propyl.

51. The compound of claim 27 wherein the compound of Formula (III) is in the form of a β

-D-enantiomer.

28. A compound of Formula (III-a):

or a pharmaceutically acceptable salt thereof.

52. The compound of claim 28 wherein the compound of Formula (III-a) is in the form of a β

-D-enantiomer.

29. A process for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (IV);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

Q is 2-(R¹CH₂CO₂)phenyl-, R¹CH₂—

, or R¹CH₂C(═

O)OC(R²)₂—

;

X is Cl, Br, or I;

R¹ is H or C₁-C₆ alkyl;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

in a suitable polar aprotic solvent at a temperature from about 0°

C. to 60°

C. to form a compound of Formula (VI), a compound of Formula (VI*), or a mixture of compounds of Formula (VI) and (VI*);

wherein R³ is X; and

R⁴ is R¹CH₂C(═

O)O—

;

(2) contacting the compound of Formula (VI), the compound of Formula (VI*), or the mixture of compounds of Formula (VI) and (VI*);

with a reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (VII);

(3a) contacting the compound of Formula (VII) with an activating agent in the presence of an amine base, to form a compound of Formula (VIII);

wherein LG is a leaving group derived from the activating agent;

(3b) contacting the compound of Formula (VIII) with an aminating agent to form a compound of Formula (III),

(4) contacting the compound of Formula (III) with a suitable base to form the compound of Formula (IV).

30. The process of claim 29 for the preparation of a compound of Formula (IV), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide,

2-(acetoxy)-2-methyl-butanoyl bromide,

2-(acetoxy)-2-ethyl-butanoyl bromide, or

2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents, and is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether;

in step (3a) the activating agent is selected from the group consisting of;

methanesulfonyl chloride, trifluoromethyl sulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,

p-toluene-sulfonyl chloride, triazole/phosphorus oxychloride and triazole/diphenyl chloro-phosphate;

in step (3a) the amine base is selected from the group consisting of;

triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropyl-ethylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dimethyloctylamine, tetramethylethylenediamine, pyridine, N,N-dimethyl-aminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,5-diazabicyclo[4.3.0]non-5-ene;

in step (3a) the leaving group LG is selected from the group consisting of methanesulfonyloxy, trifluoromethyl-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, and triazolyl;

in step (3b) the aminating agent is selected from the group consisting of;

NH₃, ammonium hydroxide, and ammonium carbonate; and

in step (4) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

31. The process according to claim 29, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (V);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a compound of Formula (VI-a), a compound of Formula (VI*-a), or a mixture of compounds of Formula (VI-a) and (VI*-a);

(2) contacting the compound of Formula (VI-a), the compound of Formula (VI*-a), or the mixture of compounds of Formula (VI-a) and (VI*-a);

with a reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (VII-a);

(3a) contacting the compound of Formula (VII-a) with an activating agent selected from the group consisting of;

i) an aryl sulfonyl halide,

ii) an alkyl sulfonyl halide, and

iii) 1,2,4-triazole in the presence of a phosphorus chloride;

in the presence of an amine base, to form a compound of Formula (VIII-a);

wherein LG is a leaving group derived from the activating agent;

(3b) contacting the compound of Formula (VIII-a) with an aminating agent to form a compound of Formula (III-a),

(4) contacting the compound of Formula (III-a) with a suitable base to form the compound of Formula (IV).

32. The process of claim 31 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether;

in step (3a) the activating agent is selected from the group consisting of;

methanesulfonyl chloride, trifluoromethyl sulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,

p-toluene-sulfonyl chloride, triazole/phosphorus oxychloride and triazole/diphenyl chloro-phosphate;

in step (3a) the amine base is selected from the group consisting of;

triethylamine,

tributylamine,

N-methylmorpholine, N,N-diisopropyl-ethylamine,

tetramethylethylenediamine, pyridine,

N,N-dimethyl-aminopyridine,

1,4-diazabicyclo[2.2.2]octane, and

1,8-diazabicyclo[5.4.0]undec-7-ene;

in step (3a) the leaving group LG is selected from the group consisting of methanesulfonyloxy, trifluoromethyl-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, and triazolyl;

in step (3b) the aminating agent is selected from the group;

NH₃, ammonium hydroxide, and ammonium carbonate; and

in step (4) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

33. The process of claim 32 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one solvent which is acetonitrile;

in step (2), the reducing agent is Zn—

Cu couple;

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate;

in step (3a) the activating agent is triazole/phosphorus oxychloride;

in step (3a) the amine base is triethylamine;

in step (3a) the leaving group LG is triazolyl;

in step (3b), the aminating agent is NH₃; and

in step (4) the suitable base is sodium methoxide.

34. The process according to claim 33, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (V);

with 2-acetoxy-2-methyl-propionyl bromide in acetonitrile to form a compound of Formula (VI-a), a compound of Formula (VI*-a), or a mixture of compounds of Formula (VI-a) and (VI*-a);

(2) contacting the compound of Formula (VI-a), the compound of Formula (VI*-a), or the mixture of compounds of Formula (VI-a) and (VI*-a);

with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4, to form a compound of Formula (VII-a);

(3a) contacting the compound of Formula (VII-a) with 1,2,4-triazole/phosphorus oxychloride, in the presence of triethylamine, to form a compound of Formula (VII-a);

(3b) contacting the compound of Formula (VIII-a) with NH₃, to form a compound of Formula (III-a), and

(4) contacting the compound of Formula (III-a) with sodium methoxide to form the compound of Formula (IV).

35. The process of claim 29 for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (V);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

wherein LG is a leaving group derived from the activating agent;

(3b) contacting the compound of Formula (VIII) with an aminating agent to form a compound of Formula (III),

(4) contacting the compound of Formula (III) with a suitable base to form the compound of Formula (IV).

36. The process of claim 35 for the preparation of a compound of Formula (IV), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide,

2-(acetoxy)-2-methyl-butanoyl bromide,

2-(acetoxy)-2-ethyl-butanoyl bromide, or

2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents, and is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether;

in step (3a) the activating agent is selected from the group consisting of;

methanesulfonyl chloride, trifluoromethyl sulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,

p-toluene-sulfonyl chloride, triazole/phosphorus oxychloride and triazole/diphenyl chloro-phosphate;

in step (3a) the amine base is selected from the group consisting of;

triethylamine,

tributylamine,

N-methylmorpholine, N,N-diisopropyl-ethylamine,

N,N-dimethylcyclohexylamine,

N,N-diethylcyclohexylamine,

N,N-dimethyloctylamine, tetramethylethylenediamine,

pyridine, N,N-dimethyl-aminopyridine,

1,4-diazabicyclo[2.2.2]octane,

1,8-diazabicyclo[5.4.0]undec-7-ene, and

1,5-diazabicyclo[4.3.0]non-5-ene;

in step (3a) the leaving group LG is selected from the group consisting of methanesulfonyloxy, trifluoromethyl-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, and triazolyl;

in step (3b) the aminating agent is selected from the group consisting of;

NH₃, ammonium hydroxide, and ammonium carbonate; and

in step (4) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

37. The process according to claim 35, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (V);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a mixture of compounds of Formula (VI-a) and (VI*-a);

(2) contacting the mixture of compounds of Formula (VI-a) and (VI*-a);

with a reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (VII-a);

(3a) contacting the compound of Formula (VII-a) with a activating agent selected from the group consisting of;

i) an aryl sulfonyl halide,

ii) an alkyl sulfonyl halide, and

iii) 1,2,4-triazole in the presence of a phosphorus chloride;

in the presence of an amine base, to form a compound of Formula (VII-a);

wherein LG is a leaving group derived from the activating agent;

(3b) contacting the compound of Formula (VIII-a) with an aminating agent to form a compound of Formula (III-a),

 

and

(4) contacting the compound of Formula (III-a) with a suitable base to form the compound of Formula (IV).

38. The process of claim 37 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether;

in step (3a) the activating agent is selected from the group consisting of;

methanesulfonyl chloride, trifluoromethyl sulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,

p-toluene-sulfonyl chloride, triazole/phosphorus oxychloride and triazole/diphenyl chloro-phosphate;

in step (3a) the amine base is selected from the group consisting of;

triethylamine,

tributylamine,

N-methylmorpholine, N,N-diisopropyl-ethylamine,

tetramethylethylenediamine, pyridine,

N,N-dimethyl-aminopyridine,

1,4-diazabicyclo[2.2.2]octane, and

1,8-diazabicyclo[5.4.0]undec-7-ene;

in step (3a) the leaving group LG is selected from the group consisting of methanesulfonyloxy, trifluoromethyl-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, and triazolyl;

in step (3b) the aminating agent is selected from the group;

NH₃, ammonium hydroxide, and ammonium carbonate; and

in step (4) the suitable base is selected from the group consisting of;

sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, C₃-C₆ alkyl primary amine, ammonium hydroxide, and ammonium C₁-C₆ alkoxide.

39. The process of claim 38 for the preparation of a compound of Formula (IV), wherein:

in step (1), the suitable polar aprotic solvent comprises one solvent which is acetonitrile;

in step (2), the reducing agent is Zn—

Cu couple;

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate;

in step (3a) the activating agent is triazole/phosphorus oxychloride;

in step (3a) the amine base is triethylamine;

in step (3a) the leaving group LG is triazolyl;

in step (3b), the animating agent is NH₃; and

in step (4) the suitable base is sodium methoxide.

40. The process according to claim 39, for the preparation of a compound of Formula (IV):

comprising;

(1) contacting a compound of Formula (V);

with 2-acetoxy-2-methyl-propionyl bromide in acetonitrile to form a mixture of compounds of Formula (VI-a) and (VI*-a);

(2) contacting the mixture of compounds of Formula (VI-a) and (VI*-a);

with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4 to form a compound of Formula (VII-a);

(3a) contacting the compound of Formula (VII-a) with 1,2,4-triazole/phosphorus oxychloride, in the presence of triethylamine, to form a compound of Formula (VIII-a);

(3b) contacting the compound of Formula (VIII-a) with NH₃, to form a compound of Formula (III-a), and

(4) contacting the compound of Formula (III-a) with sodium methoxide to form the compound of Formula (IV).

57. The process of claim 29 wherein the temperature in step (1) is about 10°

C. to about 40°

C.

58. The process of claim 29 wherein the temperature in step (1) is about 25°

C. to about 40°

C.

41. A process for the preparation of a compound of Formula (III):

wherein;

Q is 2-(R¹CH₂CO₂)phenyl-, R¹CH₂—

, or R¹CH₂C(═

O)OC(R²)₂—

;

R¹ is H or C₁-C₆ alkyl;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

comprising;

(1) contacting a compound of Formula (V);

with an acyl halide of Formula Q—

C(═

O)X, wherein;

Q is 2-(R¹CH₂CO₂)phenyl-, R¹CH₂—

, or R¹CH₂C(═

O)OC(R²)₂—

;

X is Cl, Br, or I;

R¹ is H or C₁-C₆ alkyl;

R², at each occurrence, is independently selected from methyl, ethyl, and propyl;

in a suitable polar aprotic solvent at a temperature from about 0°

C. to 60°

C. to form a compound of Formula (VI), a compound of Formula (VI*), or a mixture of compounds of Formula (VI) and (VI*);

wherein R³ is X; and

R⁴ is R¹CH₂C(═

O)O—

;

(2) contacting the compound of Formula (VI), the compound of Formula (VI*), or the mixture of compounds of Formula (VI) and (VI*);

with a reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (VII);

(3a) contacting the compound of Formula (VII) with an activating agent in the presence of an amine base, to form a compound of Formula (VIII);

wherein LG is a leaving group derived from the activating agent;

(3b) contacting the compound of Formula (VIII) with an aminating agent to form a compound of Formula (III).

42. The process of claim 41 for the preparation of a compound of Formula (III), wherein:

in step (1) the acyl halide of Formula Q—

C(═

O)X comprises;

2-acetoxy-2-methyl-propionyl bromide,

2-(acetoxy)-2-methyl-butanoyl bromide,

2-(acetoxy)-2-ethyl-butanoyl bromide, or

2-(acetoxy)-2-methyl-pentanoyl bromide;

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether;

in step (3a) the activating agent is selected from the group consisting of;

methanesulfonyl chloride, trifluoromethyl sulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,

p-toluene-sulfonyl chloride, triazole/phosphorus oxychloride and triazole/diphenyl chloro-phosphate;

in step (3a) the amine base is selected from the group consisting of;

triethylamine,

tributylamine,

N-methylmorpholine, N,N-diisopropyl-ethylamine,

N,N-dimethylcyclohexylamine,

N,N-diethylcyclohexylamine,

N,N-dimethyloctylamine, tetramethylethylenediamine,

pyridine, N,N-dimethyl-aminopyridine,

1,4-diazabicyclo[2.2.2]octane,

1,8-diazabicyclo[5.4.0]undec-7-ene, and

1,5-diazabicyclo[4.3.0]non-5-ene;

in step (3a) the leaving group LG is selected from the group consisting of methanesulfonyloxy, trifluoromethyl-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, and triazolyl;

in step (3b) the aminating agent is selected from the group;

NH₃, ammonium hydroxide, and ammonium carbonate.

43. The process according to claim 41, for the preparation of a compound of Formula (III-a):

comprising;

(1) contacting a compound of Formula (V);

with 2-acetoxy-2-methyl-propionyl bromide in a suitable polar aprotic solvent to form a compound of Formula (VI-a), a compound of Formula (VI*-a), or a mixture of compounds of Formula (VI-a) and (VI*-a);

(2) contacting the compound of Formula (VI-a), the compound of Formula (VI*-a), or the mixture of compounds of Formula (VI-a) and (VI*-a);

with a reducing agent in a suitable polar solvent, in the absence of an acid catalyst, to form a compound of Formula (VII-a);

(3a) contacting the compound of Formula (VII-a) with a activating agent selected from the group consisting of;

i) an aryl sulfonyl halide,

ii) an alkyl sulfonyl halide, and

iii) 1,2,4-triazole in the presence of a phosphorus chloride;

in the presence of an amine base, to form a compound of Formula (VIII-a);

wherein LG is a leaving group derived from the activating agent; and

(3b) contacting the compound of Formula (VIII-a) with an aminating agent to form a compound of Formula (III-a).

44. The process of claim 43 for the preparation of a compound of Formula (III-a), wherein:

in step (1), the suitable polar aprotic solvent comprises one polar aprotic solvent or a combination of two or more polar aprotic solvents; and

is selected from the group consisting of;

methylene chloride, tetrahydrofuran, t-butyl methyl ether, dimethoxy ethane, 2-methoxyethyl ether, dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate, and isopropyl acetate;

in step (2), the reducing agent is selected from the group consisting of;

Fe, Zn—

Cu couple and Zn;

in step (2), the suitable polar solvent comprises one polar solvent or a combination of two or more polar solvents; and

is selected from the group consisting of;

methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, dimethoxy ethane, and 2-methoxyethyl ether; and

in step (3a) the activating agent is selected from the group consisting of;

methanesulfonyl chloride, trifluoromethyl sulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride,

p-toluene-sulfonyl chloride, triazole/phosphorus oxychloride and triazole/diphenyl chloro-phosphate;

in step (3a) the amine base is selected from the group consisting of;

triethylamine,

tributylamine,

N-methylmorpholine, N,N-diisopropyl-ethylamine,

tetramethylethylenediamine, pyridine,

N,N-dimethyl-aminopyridine,

1,4-diazabicyclo[2.2.2]octane, and

1,8-diazabicyclo[5.4.0]undec-7-ene;

in step (3a) the leaving group LG is selected from the group consisting of methanesulfonyloxy, trifluoromethyl-sulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy, and triazolyl; and

in step (3b) the aminating agent is selected from the group;

NH₃, ammonium hydroxide, and ammonium carbonate.

45. The process of claim 44 for the preparation of a compound of Formula (III-a), wherein:

in step (I), the suitable polar aprotic solvent comprises one solvent which is acetonitrile;

in step (2), the reducing agent is Zn—

Cu couple;

in step (2), the suitable polar solvent comprises a combination of methanol and ethyl acetate;

in step (3a) the activating agent is triazole/phosphorus oxychloride;

in step (3a) the amine base is triethylamine;

in step (3a) the leaving group LG is triazolyl; and

in step (3b), the animating agent is NH₃.

46. The process according to claim 45, for the preparation of a compound of Formula (III-a):

comprising;

(1) contacting a compound of Formula (V);

with 2-acetoxy-2-methyl-propionyl bromide in acetonitrile to form a compound of Formula (VI-a), a compound of Formula (VI*-a), or a mixture of compounds of Formula (VI-a) and (VI*-a);

(2) contacting the compound of Formula (VI-a), the compound of Formula (VI*-a), or the mixture of compounds of Formula (VI-a) and (VI*-a);

with Zn—

Cu couple in a suitable polar solvent comprising a combination of methanol and ethyl acetate, wherein the ratio of methanol to ethyl acetate is in the range of 1;

2 to 1;

4, to form a compound of Formula (VII-a);

(3a) contacting the compound of Formula (VII-a) with 1,2,4-triazole/phosphorus oxychloride, in the presence of triethylamine, to form a compound of Formula (VIII-a);

 

and

(3b) contacting the compound of Formula (VIII-a) with NH₃, to form a compound of Formula (III-a).

59. The process of claim 41 wherein the temperature in step (1) is about 10°

C. to about 40°

C.

60. The process of claim 41 wherein the temperature in step (1) is about 25°

C. to about 40°

C.