Preparation of cyclosporin derivatives

1 . A process for the preparation of a compound of Formula 1a or a pharmaceutically acceptable salt thereof,

wherein

R a is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl;

R 1 and R 2 are independently selected from H, C 1 to C 6 alkyl, or wherein R 1 and R 2 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring;

R 3 and R 4 are independently selected from H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, benzyl, carbonyl, carboxyl, sulfonyl; or wherein R 3 and R 4 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring;

R 5 and R 6 are independently selected from H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or wherein R 5 and R 6 are joined together to form a C 3 to C 6 cycloalkyl or heterocycloalkyl ring;

wherein the process comprises a step of reacting a compound of Formula 2a with an amino alcohol in the presence of a copper salt and a trialkylsilyl halide;

wherein the compound of Formula 2a is:

wherein R a is selected from ethyl, 1-hydroxyethyl, isopropyl, and n-propyl; and

wherein R b is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and

wherein the amino alcohol is of Formula 3:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined for Formula 1a.

2 . The process according to claim 1 , wherein the process is for the preparation of a compound of Formula 1b or a pharmaceutically acceptable salt thereof,

wherein the process comprises a step of reacting a compound of Formula 2b with an amino alcohol in the presence of a copper salt and a trialkylsilyl halide;

wherein the compound of Formula 2b is:

3 . The process according to claim 1 wherein R b is a heteroaryl or substituted heteroaryl substituent, optionally selected from pyridine, pyrimidine, pyrazine, thiazole, oxazole, benzothiazole, and benzimidazole.

4 . The process according to claim 1 wherein the compound of Formula 2a is:

and wherein R a is selected from ethyl, 1-hydroxyethyl, isopropyl, and n-propyl.

5 . The process according to claim 2 , wherein the compound of Formula 2b is:

and wherein R a is selected from ethyl, 1-hydroxyethyl, isopropyl, and n-propyl.

6 . The process according to claim 1 , wherein R 1 and R 2 are both hydrogen.

7 . The process according to claim 1 , wherein R a is ethyl.

8 . The process according to claim 1 , wherein at least one of R 3 and R 4 is methyl, or wherein are R 3 and R 4 is both methyl.

9 . The process according to claim 1 , wherein at least one of R 5 and R 6 is hydrogen, or wherein both R 5 and R 6 are hydrogen.

10 . The process according to claim 1 , wherein the amino alcohol is dimethylaminoethanol.

11 . The process according to claim 1 wherein the compound of Formula 2a is reacted with the amino alcohol in the presence of between 1.8 to 2.4 equivalents of trialkylsilyl halide.

12 . The process of claim 1 , wherein the trialkylsilyl halide is trimethylsilyl chloride.

13 . The process of claim 1 , wherein the compound of Formula 2a is reacted with 4.3 equivalents of the amino alcohol in the presence of 2.4 equivalents of trimethylsilyl chloride and 3.6 equivalents of copper triflate.

14 . A process for the preparation of Compound 1 or a pharmaceutically acceptable salt thereof:

wherein the process comprises a step of reacting Compound 2

with dimethylaminoethanol, in the presence of a copper salt and a trialkylsilyl halide.

15 . The process of claim 14 , wherein Compound 2 is reacted with 3 to 5 equivalents of dimethylaminoethanol.

16 . The process according to claim 14 , wherein the trialkylsilyl halide is trimethylsilyl chloride.

17 . The process according to claim 14 , wherein Compound 2 is reacted with dimethylaminoethanol in the presence of 1.8 to 2.4 equivalents of the trialkylsilyl halide, optionally trimethylsilyl chloride.

18 . The process according to claim 14 , wherein Compound 2 is reacted with 4.3 equivalents of the dimethylaminoethanol in the presence of 2.4 equivalents of trimethylsilyl chloride and 3.6 equivalents of copper triflate.

19 . The process according to claim 1 , wherein the reaction is conducted in the absence of molecular sieves.

20 . A process for the preparation of Compound 1 or a salt thereof, wherein the process comprises the steps of:

a) reacting cyclosporin A with a disulfide compound optionally pyridyl disulfide, in the presence of a base; and

b) reacting a product of step a) with dimethylaminoethanol, in the presence of a copper salt, optionally copper triflate, and a trialkylsilyl halide, optionally trimethylsilyl chloride.

21 . The process according to claim 2 , wherein the compound of Formula 2b is reacted with the amino alcohol in the presence of between 1.8 to 2.4 equivalents of trialkylsilyl halide.