Processes for preparing gonadotropin releasing hormone receptor antagonists

1. A method for preparing a compound having Formula II:

or a pharmaceutically acceptable salt thereof, wherein

B is (CR 13 R 14 ) k —D,

D is optionally substituted quinoxaline, wherein the substituents are selected from one or more of —V—H, —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ′) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl;

k is 0, 1, 2, or 3;

R 13 and R 14 are, independently at each occurrence, H or optionally substituted alkyl, wherein the substituents are selected from one or more of —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl,

A is optionally substituted phenyl, wherein the substituents are selected from one or more of —V—H, —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2;

R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroalkyl being optionally substituted,

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S, optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m , R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl, alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S; and R 24 is H, or OH;

R 2 , R 3 , and R 4 are H; and

R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 , are, independently, H or optionally substituted alkyl, wherein the substituents are selected from one or more of —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl;

which comprises reacting a compound having Formula I:

wherein A and R 1 -R 12 are as defined above;

with a compound having formula:

L g —(CR 13 R 14 ) k —D

wherein D, k and R 13 and R 14 are as defined above, and L g is halogen or OSO 2 R 32 , wherein R 32 is

an optionally substituted alkyl, wherein the substitutents are selected from one or more of —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, or

an optionally substituted aryl, wherein the substituents are selected from one or more of —V—H, —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2; R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionally substituted,

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m , R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl, alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S; and R 24 is H, or OH, or

an optionally substituted fluoroalkyl, wherein the substituents are selected from one or more of C 1 -C 6 alkyl including straight and branched chain aliphatic groups having from 1 to 6 carbons;

in an organic solvent in the presence of a base; and optionally converting the compound of Formula II to a pharmaceutically acceptable salt.

2. The method of claim 1 , wherein R 1 is H or C 1 -C 3 alkyl.

3. The method of claim 1 , wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 , are, independently, H or C 1 -C 4 alkyl.

4. The method of claim 1 , wherein the compound of Formula I has the formula:

wherein A is optionally substituted phenyl and R 9 is H or C 1 -C 4 alkyl.

5. The method of claim 4 , wherein the compound of Formula I is prepared by a process comprising reacting a compound having formula

with a compound having formula

wherein L g is as defined in claim 1 , and R 9 is as defined in claim 4 , and Boc is tertiary butyloxycarbonyl, and removing the Boc protecting group.

6. The method of claim 5 , wherein L g is Br or triflate.

7. The method of claim 5 , wherein the reaction of the compounds of Formula V and VI is carried Out in toluene-THF in the presence of Pd 2 (dba) 3 and CyMAP ligand with solid lithium hexamethyldisilazide.

8. The method of claim 5 , wherein the compound of formula

is prepared by a process comprising chlorinating a compound having formula

with N-chlorosuccinimide in methanol, and reacting the resulting N-chloride with potassium carbonate.

9. The method of claim 8 , wherein the compound having formula

is prepared by a process comprising reacting a compound having formula

with thionyl chloride to form an imidoyl chloride, and reacting said imidoyl chloride with aqueous ammonia.

10. The method of claim 9 , wherein the compound having formula

is prepared by a process comprising reacting a compound of formula

with a compound of formula

wherein L g ′ is a halogen.

11. The method of claim 10 , wherein Lg′ is Br.

12. The method of claim 10 , wherein the reaction of the compounds of formula

is carried out under Schotten-Bauman conditions with NaHCO 3 .

13. The method of claim 1 , wherein R 13 and R 14 are, independently at each occurrence, H or C 1 -C 3 alkyl.

14. The method of claim 1 , wherein A is phenyl substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2;

R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, aryl, or heteroalkyl, wherein

each alkyl, alkenyl, alkynyl, or heteroalkyl may be optionally substituted, wherein the substituents are selected from one or more of —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, or

each aryl may be optionally substituted, wherein the substitutents are selected from one or more of —V—H, —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2;

R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 1 -C 7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionally substituted,

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m , R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl, alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S; and R 24 is H, or OH,

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m ,

R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl,

alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group; and

R 24 is H, or OH.

15. The method of claim 1 , wherein A is para t-butyl phenyl.

16. The method of claim 1 , wherein D is (quinoxalin-6-yl)methyl.

17. The method of claim 1 , wherein L g is Br.

18. The method of claim 1 , wherein L g —(CR 13 R 14 ) k —D is 6-bromomethyl-quinoxaline.

19. The method of claim 18 , wherein the 6-bromomethyl-quinoxaline is prepared by a process comprising brominating 6-methylquinoxaline.

20. The method of claim 18 , wherein the bromination is achieved using N-bromosuccinimide and azobisisobutyronitrile in carbon tetrachloride at reflux.

21. The method of claim 19 , wherein the 6-methylquinoxaline is prepared by a process comprising reacting 4-methylphenylene-1,2-diamine with glyoxal.

22. The method of claim 1 , wherein the organic solvent comprises at least one of acetone, acetonitrile, dimethylsulfoxide, and tetrahydrofuran.

23. The method of claim 1 , wherein the base comprises potassium carbonate or N,N-diisopropylethylamine.

24. The method of claim 1 , wherein the base comprises potassium carbonate and the organic solvent comprises acetone.

25. The method of claim 23 , wherein 2 equivalents of potassium carbonate are used.

26. The method of claim 1 , wherein 1 equivalent of L g —(CR 13 R 14 ) k —D is used.

27. A method for preparing a compound of Formula IV:

or a pharmaceutically acceptable salt thereof

wherein

R 1 is H or alkyl;

R 9 and R 10 , are, independently, H or optionally substituted alkyl, wherein the substituents are selected from one or more of —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO—R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl; and

R 31 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2;

R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, or heteroalkyl may be optionally substituted, wherein the substituents are selected from one or more of —V-halogen, —V—N3, —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, V—CON(R′) 2 , —C(OH)(CF) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, or

each aryl may be optionally substituted, wherein the substitutents are selected from one or more of —V—H, —V-halogen, —V—N 2 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2;

R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 , alkenyl, C 2 -C 7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionally substituted,

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m , R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl, alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S; and

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m ,

R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl,

alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group; and

R 24 is H, or OH;

D is optionally substituted quinoxaline, wherein the substituents are selected from one or more of —V—H, —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl;

L g is halogen or OSO 2 R 32 , wherein R 32 is alkyl, or fluoroalkyl, that may be optionally substituted, wherein the substituents are selected from one or more of —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, or aryl that may be optionally substituted, wherein the substitutents are selected from one or more of —V—H, —V-halogen, —V—N 3 , —V—NO 2 , —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, NR 22 R 23 , CR 24 (CF 3 ) 2 , JR 22 , or C(═O)R 22 , wherein J is O or SO m , wherein m is 0, 1, or 2;

R 22 and R 23 are, independently, H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionally substituted,

alternatively, R 22 and R 23 , taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S optionally substituted with R 20 —E—R 21 , wherein E is O, N, NR 21 , or SO m , R 20 and R 21 are, independently, H, C 1 -C 3 alkyl, or heteroalkyl, alternatively, R 20 and R 21 , taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, having from 3-8 ring members and the heteroatoms are selected from O, N and S; and R 24 is H, or OH;

k is 0, 1,2, or 3; and

R 13 and R 14 are, independently at each occurrence, H or optionally substituted alkyl, wherein the substituents are selected from one or more of —V-halogen, —V—N 3 , —V—NO, —V—CN, —V—OR′, —V—SR′, —V—SO 2 R′, —V—SO 2 N(R′) 2 , —V—N(R′) 2 , —V—COR′, —V—CO 2 R′, —V—NR′CO 2 R′, —V—NR′COR′, —V—NR′CONR′, —V—CON(R′) 2 , —C(OH)(CF 3 ) 2 , —CH(CF 3 ) 2 , or —C(CF 3 ′) 3 , wherein each R′ is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (C 1 -C 6 )-alkyl, and

which comprises reacting a compound having Formula III:

with a compound having formula:

L g —(CR 13 R 14 ) k —D

wherein L g , R 13 , R 14 , k and D are as defined above, in an organic solvent in the presence of base; and optionally converting the compound of Formula IV to a pharmaceutically acceptable salt.

28. The method of claim 27 , wherein R 1 is H or O, C 1 -C 3 alkyl.

29. The method of claim 27 , wherein R 9 and R 10 , are, independently, H or C 1 -C 4 alkyl.

30. The method of claim 27 , wherein R 13 and R 14 are, independently at each occurrence, H or C 1 -C 3 alkyl.

31. The method of claim 27 , wherein L g —(CR 13 R 14 ) k —D is 6-bromomethyl-quinoxaline.

32. The method of claim 27 , wherein L g is Br.

33. The method of claim 31 , wherein the 6-bromomethyl-quinoxaline is prepared by a process which comprises brominating 6-methylquinoxaline.

34. The method of claim 33 , wherein the bromination is achieved using N-bromosuccinimide and azobisisobutyronitrile in carbon tetrachloride at reflux.

35. The method of claim 33 , wherein 6-methylquinoxaline is prepared by a process which comprises reacting 4-methylphenylene-1,2-di amine with glyoxal.

36. The method of claim 27 , wherein the base comprises potassium carbonate and N,N-diisopropylethyl amine.

37. The method of claim 27 , wherein the organic solvent comprises at least one of acetone, acetonitrile, dimethylsulfoxide, and tetrahydrofuran.

38. The method of claim 27 , wherein the base comprises potassium carbonate and the organic solvent comprises acetone.

39. The method of claim 36 , wherein 2 equivalents of potassium carbonate are used.

40. The method of claim 27 , wherein 1 equivalent of L g —(CR 13 R 14 ) k —D is used.

41. The method of claim 27 , wherein the compound of Formula III is prepared by a process which comprises reacting a compound having formula

with a compound having formula

and deprotecting.

42. The method of claim 41 , wherein L g is Br.

43. The method of claim 41 , wherein the reaction is carried out in toluene-THF in the presence of Pd 2 (dba) 3 and CyMAP ligand with solid lithium hexamethyldisilazide.

44. The method of claim 41 , wherein the compound having formula

is prepared by a process which comprises chlorinating a compound having formula

with N-chlorosuccinimide in methanol, and reacting the resulting N-chloride with potassium carbonate.

45. The method of claim 44 , wherein the compound having formula

is prepared by a process which comprises reacting a compound having formula

with thionyl chloride to form an imidoyl chloride, and reacting the imidoyl chloride with aqueous ammonia.

46. The method of claim 45 , wherein the compound having formula

is prepared by a process which comprises reacting a compound of formula

with a compound of formula

wherein L g is a halogen.

47. The method of claim 46 , wherein

are combined under Schotten-Bauman conditions with NaHCO 3 .

48. The method of claim 46 , wherein L g ′ is Br.

49. The method of claim 27 , wherein R 31 is t-butyl.

50. The method of claim 1 , wherein the compound of Formula II is converted to a salt by a process comprising adding 2 equivalents of ethereal HCl to a solution of the compound having Formula II in ethanol.

51. The method of claim 27 , wherein the compound of Formula IV is converted to a salt by a process comprising adding 2 equivalents of ethereal HCl to a solution of the compound having Formula IV in ethanol.