Synthesis of bicycle toxin conjugates, and intermediates thereof
AssigneeBicycleTx Limited
InventorsDarren Limb, William Moss, David Witty, Jie Zhang, Jinguang Lin, William Nesbit
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Abstract
The present invention relates methods of preparing Bicycle toxin conjugates, and intermediates thereof.
Claims27
A method of synthesizing Glutaryl-Val-Cit-PAB-MMAE (gvcMMAE):
- or a salt thereof, comprising adding glutaric anhydride into a solution comprising vcMMAE:
- in a solvent comprising N,N-dimethylacetamide (DMA) and tetrahydrofuran (THF) to afford a reaction mixture.
The method of any one of the preceding claims, wherein the solvent further comprises methyl tert-butyl ether (MTBE)
The method of any one of the preceding claims, comprising reacting vcMMAE with from about 1 to about 1.1 equivalents of glutaric anhydride;
- optionally wherein glutaric anhydride is about 1.1 equivalent, and vcMMAE is about 1 equivalent.
The method of any one of the preceding claims, wherein the reaction mixture comprises from about 1.3 to about 1.5 equivalents of triethylamine (TEA);
- optionally wherein the method comprises adding about 1.3 equivalent TEA into the reaction mixture.
The method of any one of the preceding claims, wherein the reaction between vcMMAE and glutaric anhydride is carried out at a temperature of from about −5° C. to about 25° C.
The method of any one of the preceding claims, where the reaction between vcMMAE and glutaric anhydride is carried out at a temperature of from about 15° C. to about 25° C.
The method of any one of the preceding claims, comprising stirring the reaction mixture during said reaction.
The method of any one of the preceding claims, wherein the reaction mixture is stirred for about 1 hour at about −5° C. to about 25° C. for the reaction to complete, optionally thereby affording a mixture comprising primarily gvcMMAE, or a gvcMMAE mixture.
The method of any one of the preceding claims, comprising quenching the reaction between vcMMAE and glutaric anhydride with water (H2O).
The method of any one of the preceding claims, wherein quenching the reaction comprises adding from about 0.002 to about 0.01 kg/kg water (H2O).
The method of any one of the preceding claims, wherein the gvcMMAE mixture is warmed up to about 15° C. to about 25° C.;
- optionally wherein the gvcMMAE mixture is warmed up until it is a clear solution.
The method of any one of the preceding claims, wherein the gvcMMAE mixture is added into a mixture of THF and methyl tert-butyl ether (MTBE) to afford gvcMMAE as a precipitate.
Dependencies are inferred from the claim text.