IP Library › Granted Patent US 6,927,291

Granted Patent B2

US 6,927,291 · App. 10/087,112 · Granted Aug 9, 2005

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

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Quick Facts

Patent No.: US 6,927,291
App. No.: 10/087,112
Granted: Aug 9, 2005
Kind: B2

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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 CH 2 with an acyl halide of the formula X—C(═O)R 1 , X—C(═O)C(R 1 ) 2 OC(═O)R 1 or X—C(═O)OR 1 (wherein X is a halogen, and each R 1 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 (459)

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-(R 1 CH 2 CO 2 )phenyl-, R 1 CH 2 —, or R 1 CH 2 C(═O)OC(R 2 ) 2 —;

X is Cl, Br, or I;

R 1 is H or C 1 -C 6 alkyl;

R 2 , 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 R 3 is X; and R 4 is R 1 CH 2 C(═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, C 3 -C 6 alkyl primary amine, ammonium hydroxide, and ammonium C 1 -C 6 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 (2), the suitable reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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 R 1 CH 2 C(═O)OC(R 2 ) 2 —;

X is Cl, Br, or I;

R 1 is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 ;

R 2 , 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 R 3 is X; and R 4 is R 1 CH 2 C(═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

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 (2), the suitable reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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):

(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 R 1 CH 2 C(═O)OC(R 2 ) 2 —;

X is Cl, Br, or I;

R 1 is H, CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 ;

R 2 , 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 R 3 is X; and R 4 R 1 CH 2 C(═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 (2), the suitable reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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 (2), the suitable reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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).

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

wherein:

Q is 2-(R 1 CH 2 CO 2 )phenyl-, R 1 CH 2 —, or R 1 CH 2 C(═O)OC(R 2 ) 2 —;

R 1 is H or C 1 -C 6 alkyl;

R 2 , 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-(R 1 CH 2 CO 2 )phenyl-, R 1 CH 2 —, or R 1 CH 2 C(═O)OC(R 2 ) 2 —;

X is Cl, Br, or I;

R 1 is H or C 1 -C 6 alkyl;

R 2 , 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 R 3 is X; and R 4 is R 1 CH 2 C(═O)O—; and

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 (2), the suitable reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn; and

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):

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

in step (2), the suitable reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn; and

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):

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

or a pharmaceutically acceptable salt thereof, wherein:

in Formula II, Q is R 1 CH 2 —

R 1 is C 1 -C 6 alkyl;

R 2 is independently selected from methyl, ethyl, and propyl;

R 3 is Cl, Br, or I; and

R 4 is R 1 CH 2 C(═O)O—;

or in Formula II, Q is R 1 CH 2 C(═O)OC(R 2 ) 2 —;

R 1 is H or C 1 -C 6 alkyl;

R 2 is independently selected from methyl, ethyl, and propyl;

R 3 is Cl, Br, or I; and

R 4 R 1 CH 2 C(═O)O—;

and wherein:

in Formula II*,

Q is R 1 CH 2 C(═O)OC(R 2 ) 2 —;

R 1 is H or C 1 -C 6 alkyl;

R 2 is independently selected from methyl, ethyl, and propyl;

R 3 is Cl, Br, or I; and

R 4 is R 1 CH 2 C(═O)O—;.

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

or a pharmaceutically acceptable salt thereof.

27. A compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

Q is R 1 CH 2 C(═O)OC(R 2 ) 2 —;

R 1 is H or C 1 -C 6 alkyl; and

R 2 is independently selected from methyl, ethyl, and propyl.

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

or a pharmaceutically acceptable salt thereof.

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-(R 1 CH 2 CO 2 )phenyl-, R 1 CH 2 —, or R 1 CH 2 C(═O)OC(R 2 ) 2 —;

X is Cl, Br, or I;

R 1 is H or C 1 -C 6 alkyl;

R 2 , 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 R 3 is X; and R 4 is R 1 CH 2 C(═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 (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: NH 3 , 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, C 3 -C 6 alkyl primary amine, ammonium hydroxide, and ammonium C 1 -C 6 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 (2), the reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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: NH 3 , ammonium hydroxide, and ammonium carbonate; and

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 NH 3 ; 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 NH 3 , 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 (2), the reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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: NH 3 , ammonium hydroxide, and ammonium carbonate; and

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 (2), the reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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: NH 3 , ammonium hydroxide, and ammonium carbonate; and

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 NH 3 ; 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 NH 3 , 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).

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

wherein:

Q is 2-(R 1 CH 2 CO 2 )phenyl-, R 1 CH 2 —, or R 1 CH 2 C(═O)OC(R 2 ) 2 —;

R 1 is H or C 1 -C 6 alkyl;

R 2 , 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-(R 1 CH 2 CO 2 )phenyl-, R 1 CH 2 —, or R 1 CH 2 C(═O)OC(R 2 ) 2 —;

X is Cl, Br, or I;

R 1 is H or C 1 -C 6 alkyl;

R 2 , 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 R 3 is X; and R 4 is R 1 CH 2 C(═O)O—;

(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 (2), the reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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: NH 3 , 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):

(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 (2), the reducing agent is selected from the group consisting of: Fe, Zn—Cu couple and Zn;

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: NH 3 , 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 NH 3 .

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):

(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 NH 3 , to form a compound of Formula (III-a).

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

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

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

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.

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

52. The compound of claim 28 wherein the compound of Formula (III-a) 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.

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.

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.

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.

Assignments (3)

CERTIFICATE OF CONVERSION FROM A CORPORATION TO LIMITED LIABILITY CORPORATION Recorded Mar 7, 2013

From: PHARMASSET, INC.

To: GILEAD PHARMASSET LLC

Reel/Frame 029940/0476 →

CERTIFICATE OF DOMESTICATION: INCORPORATION IN DELAWARE Recorded Mar 30, 2005

From: PHARMASSET, LTD.

To: PHARMASSET, INC.

Reel/Frame 015972/0603 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 23, 2002

From: JIN, FUQIANG; CONFALONE, PASQUALE N.

To: PHARMASSET, LTD.

Reel/Frame 013107/0111 →