Synthesis of cyclosporin analogs

A method of preparing an isomeric mixture of cyclosporin A analogs modified at the 1-amino acid residue, wherein the synthetic pathway comprises the steps of:

• a) protecting the β-alcohol of cyclosporin A by forming a first intermediate acetyl cyclosporin A;
• b) oxidizing the acetyl cyclosporin A to produce a second intermediate acetyl cyclosporin A aldehyde;
• c) converting an intermediate acetyl cyclosporin A aldehyde to a mixture of (E) and (Z)-isomers of acetyl-1,3-diene by reacting the intermediate with a phosphorus ylide via a Wittig reaction, optionally in the presence of a lithium halide;
• and
• d) preparing a mixture of (E) and (Z)-isomers of ISATX247 by treating the mixture of (E) and (Z)-isomers of acetyl-1,3-diene with a base.

A method of producing an E-isomer enriched mixture of cyclosporin A analogs modified at the 1-amino acid residue, wherein the stereoselective synthesis of the E-isomer enriched material comprises the steps of:

• a) reacting an acetyl cyclosporin A aldehyde with a reagent selected from the group consisting of γ-(trialkylsilylallyl) boronate esters and E-γ-(trialkylsilylallyl) dialkylboranes to form a β-trialkylsilyl alcohol;
• b) treating the β-trialkylsilyl alcohol with acid to form acetyl-(E)-1,3-diene;
• and
• c) treating the acetyl-(E)-1,3-diene with base to form the (E)-isomer of ISATX247.

A method of producing a Z-isomer enriched mixture of cyclosporin A analogs modified at the 1-amino acid residue, wherein the stereoselective synthesis of the Z-isomer enriched material comprises the steps of:

• a) reacting an acetyl cyclosporin A aldehyde with a reagent selected from the group consisting of γ-(trialkylsilylallyl) boronate esters and E-γ-(trialkylsilylallyl) dialkylboranes to form a β-trialkylsilyl alcohol;
• b) treating the β-trialkylsilyl alcohol with base to form acetyl-(Z)-1,3-diene;
• and
• c) treating the acetyl-(Z)-1,3-diene with base to form the (Z)-isomer of ISATX247.

A method of producing a Z-isomer enriched mixture of cyclosporin A analogs modified at the 1-amino acid residue, wherein the stereoselective synthesis of the Z-isomer enriched material comprises the steps of:

• a) reacting an acetyl cyclosporin A aldehyde with [3-(diphenylphosphino)allyl] titanium to form a titanium-containing intermediate;
• b) allowing the titanium-containing intermediate to proceed to an erythro-α-adduct;
• c) converting the erythro-α-adduct to a β-oxidophosphonium salt by treatment of iodomethane;
• d) converting the β-oxidophosphonium salt to an acetyl-(Z)-1,3-diene;
• and
• e) treating the acetyl-(Z)-1,3-diene with base to form the (Z)-isomer of ISATX247.

A mixture of (E) and (Z)-isomers prepared by a process comprising the steps of:

• a) protecting the β-alcohol of cyclosporin A to form acetyl cyclosporin A;
• b) brominating the η-carbon of the side chain of the 1-amino acid residue of acetyl cyclosproin A to produce a first intermediate acetyl-η-bromocyclosporin A;
• c) heating the first intermediate acetyl-η-bromocyclosporin A with a reagent selected from the group consisting of triphenyl phosphine and trialkyl phosphine to produce an intermediate selected from the group consisting of triphenyl- and trialkyl phosphonium bromides of acetyl cyclosporin A;
• d) preparing a mixture of (E) and (Z)-isomers of acetyl-1,3-diene by stirring the ylide generated from the triphenyl- or trialkyl salt (second intermediate triphenylphosphonium bromide) of acetyl cyclosporin A with formaldehyde;
• and
• e) preparing the mixture of (E) and (Z)-isomers of ISATX247 by treating the mixture of (E) and (Z)-isomers of acetyl-1,3-diene with a base.

A method for the stereoselective synthesis of the Z-isomer of ISATX247 comprising the steps of:

• a) reacting a trimethylsilyl (TMS) cyclosporin A aldehyde with E-γ-(trialkylsilylallyl) borane to form a β-trialkylsilyl alcohol;
• b) treating the β-trialkylsilyl alcohol with base to form TMS-(Z)-1,3-diene;
• and
• c) deprotecting the TMS-(Z)-1,3-diene to form the Z-isomer of ISATX247.

A method of preparing an isomeric mixture of cyclosporin A analogs modified at the 1-amino acid residue, the method comprising a synthetic pathway that prepares an (E)-isomer and a (Z)-isomer of ISATX247 such that the (E)-isomer and the (Z)-isomer are present in the mixture in a predetermined ratio, wherein the synthetic pathway comprises the steps of:

• a) protecting the β alcohol of the 1 amino acid of cyclosporin A;
• b) oxidizing the protected cyclosporin A to produce a protected cyclosporin A aldehyde;
• c) converting the protected cyclosporin A aldehyde to a mixture of E- and Z-isomers of protected 1,3 diene by reacting the protected cyclosporin A aldehyde with a phosporus ylide via a Wittig reaction, optionally in the presence of a lithium halide;
• and
• d) preparing a mixture of E- and Z-isomers by deprotecting the protected 1,3 diene.

A method of preparing a predetermined isomeric mixture of cyclosporin A analogs modified at the 1-amino acid residue, the method comprising:

• a) preparing a first material enriched in an (E)-isomer of ISATX247;
• b) preparing a second material enriched in a (Z)-isomer of ISATX247;
• and
• c) mixing the first and second materials in a ratio designed to give the desired isomeric composition.

A method for the preparation of cyclosporin A aldehyde comprising the steps of:

• a) protecting the β alcohol of cyclosporin A by forming acetyl cyclosporin A;
• b) converting the acetyl cyclosporin A to the acetyl cyclosporin A epoxide with a monopersulfate, preferably oxone, in the presence of a ketone, preferably an activated ketone, preferably acetoxyacetone or diacetoxyacetone, at a pH over 7;
• and
• c) cleaving the epoxide with periodic acid or perodate salt under acidic conditions.

A method for the stereoselective synthesis of the E-isomer of ISATX247 comprising the steps of:

• a) reacting an acetyl cyclosporin A aldehyde with E-γ-(trialkylsilylallyl) borane to form a β-trialkylsilyl alcohol;
• b) treating the β-trialkylsilyl alcohol with acid to form acetyl-(E)-1,3-diene;
• and
• c) treating the acetyl-(E)-1,3-diene with a base to form the E-isomer of ISATX247.

A method for the stereoselective synthesis of the Z-isomer of ISATX247 comprising the steps of:

• a) treating an acetyl cyclosporine A aldehyde with a 3-(dimethylamino)propyltriphenylphosphonium halide in the presence of a first base to form an acetyl-(Z)-octenyldimethylamine;
• b) treating the acetyl-(Z)-octenyldimethylamine with an oxidizing reagent to form an acetyl-(Z)-octenyldimethylamine oxide;
• c) heating the acetyl-(Z)-octenyldimethylamine oxide in a Cope elimination to form an acetyl-(Z)-1,3-diene;
• and
• d) treating the acetyl-(Z)-1,3-diene with a second base to form the (Z)-isomer of ISATX247.