Methods and intermediates for preparing macrolactams

1. A method of making compounds of Formula C:

wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8; X 1 and X 2 are each independently selected from the group consisting of Br, Cl and I; and R 5 is CF 3 ; said method comprising:

(1) reacting

 where LG is selected from the group consisting of halogen atoms, —O—SO 2 R 8 , —O—PO(OR 8 ) 2 and a protecting group and each R 8 is independently selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, aryl and heteroaryl groups and each R 8 is independently substituted by 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, halogen, —NH 2 and —OH, and the protecting group is selected from —OSiR 8 and —OR 8 , with a chiral alcohol and

 to produce

 where each R 1 is independently selected from the group consisting of C 1-8 alkyl, aryl and heteroaryl groups, or two R 1 are taken, together with the O—P—O atoms to which they are attached, to form a ring containing 5-19 atoms; and where R 2 and R 3 are each selected from the group consisting of H, C 1-8 alkyl and —O—C 1-8 alkyl groups, or R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a ring containing 5-19 atoms;

(2) reacting

 with a Grignard reagent to produce

 where R 4 is selected from the group consisting of C 1-8 alkyl, aryl, and heteroaryl groups and R 4 is substituted by 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, halogen, —NH 2 or —OH;

(3) halogenating

 to produce

 where X 1 and X 2 are each independently selected from the group consisting of Br, Cl and I; and

(4) reacting

 with triflouroacetic anhydride to produce

 where R 5 is CF 3 .

2. A method of making a compound of Formula B:

or a salt thereof, wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8; and R 7 is selected from the group consisting of acetyl and

and R 6 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and heterocycle groups and R 6 is substituted by 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, halogen, —NH 2 and —OH, and salts thereof; said method comprising:

preparing a compound of Formula C according to the method of claim 1 ; and

converting

 or a salt thereof.

3. The method of claim 1 , wherein

in step (1) is prepared by:

(i) reacting

 where n is as defined in claim 1 and X is a halogen atom, with a magnesium source to produce

and

(ii) reacting

 with

 to produce

 where LG is defined as in claim 1 .

4. The method of claim 3 , wherein X is Br.

5. The method of claim 2 , wherein said converting

 comprises:

(i) de-halogenating

 to produce

(ii) reacting

 with a reagent containing a leaving group to produce

 where LG is said leaving group and is selected from the group consisting of halogen atoms, —O —SO 2 R 8 , —O —PO(OR 8 ) 2 and a protecting group and each R 8 is independently selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and heteroaryl groups and each R 8 is independently substituted by 0, 1, 2, 3,or 4 substituents independently selected from the group consisting of C 1-6 alky, C 2-6 alkenyl, C 2-6 alkynyl, aryl halogen, —NH 2 , and —OH, and the protecting group is slected from —OSiR 8 and —OR 8 ;

(iii) reacting

 with

 to produce

 wherein R 7 is

and

(iv) optionally forming a salt of

6. The method of claim 2 , wherein R 6 is selected from the group consisting of C 2 C 6 alykl groups.

7. The method of claim 2 , wherein R 6 is tert-butyl.

8. The method of claim 1 , wherein LG is Cl.

9. The method of claim 1 , wherein, in step (1), the chiral alcohol is chlorohydrin.

10. The method of claim 1 , wherein, in step (1),

11. The method of claim 5 , wherein step (iv) comprises forming a salt of the compound, wherein the salt is selected from tert-butylamine salt, dibenzylamine salt, and dicyclohexyl amine salt.

12. The method of claim 2 , wherein the compound of Formula B has the following structural formula:

or a salt thereof, said method comprising:

(1) reacting

 with chlorohydrin and

 to produce

(2) reacting

 with a Grignard reagent to produce

(3) brominating

 to produce

(4) reacting

 with trifluoroacetic anhydride to produce

(5) converting

(6) optionally converting

 to a salt thereof.

13. A method of preparing Compound A:

or a pharmaceutically acceptable salt thereof, said method comprising:

(a) producing a compound of Formula B according to claim 12 ,

(b) reacting

 with

 to produce

 where PG is H or a protecting group selected from —OSiR 8 and —OR 8 ;

(c) and further comprising the steps of: