Process for preparing polymers
A process for preparing non-naturally-occurring defined monomer sequence polymers is provided, and in which a high degree of synthetic control is obtained by the use of solvent resistant diafiltration membranes. Also provided is a process for separating non-naturally-occurring defined monomer sequence polymers from synthetic by-products or excess reagents using solvent resistant diafiltration membranes, and a use of a solvent resistant diafiltration membrane in processes for preparing and separating non-naturally-occurring defined monomer sequence polymers.
1. A process for the preparation of a first compound being a non-naturally-occurring defined monomer sequence polymer, the process comprising the steps of:
(i) synthesising the first compound by performing more than one sequential monomeric coupling reaction of monomer units in a first organic solvent, wherein
all of the monomer units coupled in step (i) have an identical backbone moiety,
at least two of the monomer units coupled in step (i) have a pendent side chain moiety, said pendent side chain moieties being distinct from each other, and
at least four of the monomer units coupled in step (i) are distinct from each other; and
(ii) between each coupling reaction, separating a product of the coupling reaction from at least one second compound, which is a reaction by-product of the synthesis of the product and/or an excess of a reagent used for the synthesis of the product;
wherein during step (ii) the product of the coupling reaction and the at least one second compound are dissolved in a second organic solvent and are separated by a process of diafiltration using a membrane that is stable in the organic solvent and which provides a rejection for the product which is greater than the rejection for the second compound.
2. A process for the preparation of a first compound being a defined monomer sequence polymer, the process comprising the steps of:
(i) synthesising the first compound by performing more than one sequential monomeric coupling reaction of monomer units in a first organic solvent, wherein
all of the monomer units coupled in step (i) have an identical backbone moiety,
at least two of the monomer units coupled in step (i) have a pendent side chain moiety, said pendent side chain moieties being distinct from each other, and
at least four of the monomer units coupled in step (i) are distinct from each other; and
(ii) between each coupling reaction, separating a product of the coupling reaction from at least one second compound, which is a reaction by-product of the synthesis of the product and/or an excess of a reagent used for the synthesis of the product;
wherein during step (ii) the product of the coupling reaction and the at least one second compound are dissolved in a second organic solvent and are separated by a process of diafiltration using a membrane that is stable in the organic solvent and which provides a rejection for the product which is greater than the rejection for the second compound, with the proviso that the first compound is not an oligonucleotide, peptide or peptide nucleic acid.
3. The process of claim 1 , wherein all of the monomers collectively forming the first compound are non-naturally-occurring.
4. The process of claim 1 , wherein during synthesis of the first compound, the product is covalently attached to a synthesis support by an initial monomer unit.
5. The process of claim 4 , wherein the synthesis support is a branch point molecule having two or more reactive moieties capable of covalently binding to the initial monomer unit.
6. The process of claim 1 , wherein the first compound has a backbone selected from poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(butylene glycol), poly(ethylene oxide), poly(propylene oxide), poly(butylene oxide), poly(dimethylsiloxane) (PDMS), polybutadiene, polysioprene, polystyrene, nylons and polyesters, poly(ethylene imines) (PEI), poly(propylene imines), poly(L-Lysine) (PLL), poly(amidoamines) (PAA), poly(methyl methacrylate) (PMMA), poly(vinyl benzoic acid), poly(hydroxystyrene), N-substituted glycines, and poly(lactide-co-glycolide) (PLGA).
7. The process of claim 1 , wherein the first compound has a poly(ethylene glycol) backbone.
8. The process of claim 7 , wherein at least one of the monomer units coupled in step (i) has chirality.
9. The process of claim 7 , wherein at least one of the monomer units coupled in step (i) comprises a side chain moiety bound to a chiral carbon atom present within the backbone moiety.
10. The process of claim 7 , wherein at least two of the monomer units coupled in step (i) comprise side chain moieties, each of the side chain moieties being bound to a chiral carbon atom present within the monomer unit's backbone moiety.
11. The process of claim 1 , wherein the more than one sequential monomeric coupling reaction each comprise the steps of:
a) reacting a starting material with an excess of an additional monomer, the additional monomer having one of its reactive terminal protected by a protecting group, and
b) removing the protecting group so as to expose the reactive terminal such that it is ready for reaction with a subsequent additional monomer,
wherein the starting material is either an initial monomer having at least one of its reactive terminals protected, or the polymeric product of the one or more sequential monomeric coupling reactions.
12. The process of claim 11 , wherein the step (ii) is performed after step a) and after step b).
13. The process of claim 1 , wherein at least one or the monomer units coupled during step (i) comprises a side chain moiety comprising an active ingredient.
14. The process of claim 1 , wherein the membrane is an organic solvent resistant diafiltration membrane.
15. The process of claim 13 , wherein the active ingredient is a pharmaceutically active ingredient.