Process for the deprotection of protected thiols
View Patent ↗The synthesis of peptides comprising disulphide bridges is challenging since it is difficult to ensure that the correct cysteine residues combine to form the desired disulphide bridges. The present invention describes novel protection techniques useful in the preparation of peptides. Described is a process for the deprotection of an Acm-, MBzl- and/or tBu-protected thiol which comprises reacting said protected thiol with an acid in the presence of an oxidising agent at a temperature sufficient to effect deprotection and generation of disulphide bonds.
1. A process the for the preparation of a compound comprising at least two disulphide bonds from a precursor having at least two pairs of thiol groups, each pair of thiol groups being protected with different thiol-protecting groups selected from acetamidomethyl (Acm), 4-methylbenzyl (MBzl) and t-butyl (tBu), said process comprising:
(i) reaction of the precursor with an acid in the presence of an oxidising agent at a first temperature sufficient to effect deprotection of tBu protected thiols and disulphide bond formation for a first pair of protected thiol groups;
(ii) raising the temperature of the reaction mixture from step (i) to a second temperature sufficient to effect deprotection of Acm and/or MBzl protected thiols and disulphide bond formation for a second pair of protected thiol groups.
2. A process as claimed in claim 1 wherein said acid is trifluoroacetic acid (TFA).
3. A process as claimed in either one of claim 1 wherein said oxidising agent is dimethyl sulphoxide (DMSO).
4. A process as claimed in any one of claim 1 wherein deprotection is effected using a TFA/DMSO mixture comprising 1 to 20% DMSO.
5. A process as claimed in any one of claim 1 wherein said protected thiol is present in a peptide.
6. A process as claimed in claim 5 wherein said peptide comprises at least two tBu protected thiols and/or at least two Acm or MBzl protected thiols.
7. A process as claimed in any of claim 1 wherein tBu protected thiols are deprotected at room temperature in step (i).
8. A process as claimed in any one of claim 1 wherein Acm or MBzl protected thiols are deprotected at temperatures of 30-50° C., in step (ii).
9. A process as claimed in claim 8 wherein Acm or MBzl protected thiols are deprotected at temperatures of 50-70° C., in step (ii).