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WO2021260392A1 - Polymère - Google Patents

Polymère Download PDF

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Publication number
WO2021260392A1
WO2021260392A1 PCT/GB2021/051623 GB2021051623W WO2021260392A1 WO 2021260392 A1 WO2021260392 A1 WO 2021260392A1 GB 2021051623 W GB2021051623 W GB 2021051623W WO 2021260392 A1 WO2021260392 A1 WO 2021260392A1
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Prior art keywords
optionally substituted
polymer
formula
alkynyl
alkyl
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PCT/GB2021/051623
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English (en)
Inventor
Rongjun Chen
Li Yu
Yuying Tang
Xinyu Lu
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Ip2ipo Innovations Ltd
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Imperial College Innovations Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/685—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen
    • C08G63/6852—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
    • C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
    • C08G65/2612—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aromatic or arylaliphatic hydroxyl groups

Definitions

  • the present disclosure is concerned with polymers.
  • the disclosure is concerned with a method of producing polymers, as well as the polymers per se.
  • Highly organized biomacromolecules play a crucial role in nature.
  • DNA stores huge genetic information for the development, functioning, growth and reproduction of all known living organisms and many viruses, via perfectly defining the sequential arrangements of four different nitrogen-containing nucleobase monomer units 1, 2 (adenine [A], thymine [T], cytosine [C] and guanine [G]), and the refined sequence regulations of diverse peptides direct the folding of chains into precise tertiary three-dimensional structures, endowing proteins with various highly specific activities 3 .
  • Solid-phase iterative peptide synthesis is arguably the first most successful example, opening up a new era of artificial sequence-control polymers 7-9 . Nevertheless, the coupling, filtration and washing process is typically time-consuming 10, 11 and the insoluble solid supports are often expensive 12 . Moreover, the solid-phase coupling reaction rates are restricted by monomer diffusion into the solid support, ultimately resulting in poor yields 13 . Overall, the solid-phase iterative synthesis is difficult to scale up, limiting the potential for numerous real-world applications 12, 14 .
  • a dizinc catalyst was able to switch between distinct polymerization cycles and show a high monomer selectivity among mixtures of several different monomers, such as lactones, epoxides and anhydrides.
  • the monomers with significantly faster rates of insertion into the zinc intermediate were consumed first to form the first block and monomers with lower insertion rates were then polymerized to constitute subsequent blocks. It opened up a new way of chemoselective polymerization for synthesis of block copolyesters with predictable compositions and sequences. Nevertheless, owing to the kinetic nature of monomers, this kind of block copolyesters are typically amenable only to some fixed sequence.
  • a method of producing a polymer comprising contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer, wherein the plurality of monomers are a plurality of molecules of formula (I): , wherein X 1 is CO, CR 1 R 2 , SO or SO 2 ; X 2 is O, NR 3 or S; X 3 is CR 4 R 5 or CO; each X 4 is independently CR 6 R 7 , NR 8 , CO, O, S, SO or SO 2 ; n is 0 or an integer which is at least 1; R 1 and R 2 are each independently H, a halogen, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cyclo
  • the method allows a novel quantitative one-pot iterative living ring- opening polymerization (QOIL-ROP) approach for the scalable production of well- defined sequence-controlled functional polymers with desirable biocompatibility via successive sequential addition of monomers without intermediate purification.
  • QOIL-ROP quantitative one-pot iterative living ring- opening polymerization
  • the method can be used to produce polymers with relatively narrow molecular weight distributions (MWDs) and extraordinary agreement between the theoretical and experimental molecular weights.
  • Various properties, including the physicochemical properties and biodegradation behaviours of resultant polymers can be tuned by precisely controlling monomer types, monomer sequences and chain length. The biological activity of the polymers could also be tuned. This strategy offers new perspectives for integration of structural versatility and further functional diversity into both water-soluble and water-insoluble sequence-controlled artificial polymers.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • the alkyl may be a primary, secondary, or tertiary hydrocarbon.
  • C 1-30 alkyls include for example methyl, ethyl, n-propyl (1-propyl), isopropyl (2-propyl, 1-methylethyl), butyl, pentyl, hexyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • the or each alkyl may be an optionally substituted C 1-30 alkyl, an optionally substituted C 1-20 alkyl, an optionally substituted C 1-12 alkyl, an optionally substituted C 1-6 alkyl or an optionally substituted C 1-3 alkyl.
  • An alkyl group can be unsubstituted or substituted.
  • a substituted alkyl may be substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N3, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optional
  • the optionally substituted alkyl may be a halogenated alkyl, i.e. an alkyl substituted with one or more halogens.
  • a halogenated alkyl may be substituted with one or more further substituents.
  • alkenyl refers to olefinically unsaturated hydrocarbon groups which can be unbranched or branched. Accordingly, an alkenyl may contain one or more double bonds between adjacent carbon atoms.
  • C2-C30 alkenyl includes for example vinyl, allyl, propenyl, butenyl, pentenyl and hexenyl.
  • the or each alkenyl may be an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-12 alkenyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-3 alkenyl.
  • An alkenyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N 3 , an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H
  • the optionally substituted alkenyl may be a halogenated alkenyl, i.e. an alkenyl substituted with one or more halogens.
  • a halogenated alkenyl may be substituted with one or more further substituents.
  • alkynyl refers to acetylenically unsaturated hydrocarbon groups which can be unbranched or branched. Accordingly, an alkynyl may contain one or more triple bonds between adjacent carbon atoms. An alkynyl group may further contain one or more double bonds between adjacent carbon atoms.
  • the C 2 -C 30 alkynyl includes for example propargyl, propynyl, butynyl, pentynyl and hexynyl.
  • the or each alkynyl may be an optionally substituted C 2-30 alkynyl, an optionally substituted C 2-20 alkynyl, an optionally substituted C 2-12 alkynyl, an optionally substituted C 2-6 alkynyl or an optionally substituted C 2-3 alkynyl.
  • An alkynyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N3, an optionally substituted C 2-30 alkenyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloal
  • the optionally substituted alkynyl may be a halogenated alkynyl, i.e. an alkynyl substituted with one or more halogens.
  • a halogenated alkynyl may be substituted with one or more further substituents.
  • “Aryl” refers to an aromatic 6 to 20 membered hydrocarbon group. Examples of a C 6 - C 20 aryl group include, but are not limited to, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, tetrahydronaphthyl and indanyl.
  • the or each aryl may be an optionally substituted C 6-12 aryl.
  • An aryl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N3, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl,
  • the optionally substituted aryl may be a halogenated aryl, i.e. an aryl substituted with one or more halogens.
  • a halogenated aryl may be substituted with one or more further substituents.
  • the term “bicycle” or “bicyclic” as used herein can refer to a molecule that features two fused rings, which are a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl, a heteroaryl, or a heterocycle. In one embodiment, the rings are fused across a bond between two atoms. The bicyclic moiety formed therefrom shares a bond between the rings.
  • the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of the rings to form a bridgehead.
  • a “bridge” is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound.
  • the bicyclic molecule is a “spiro” or “spirocyclic” moiety.
  • the spirocyclic group may be a cycloalkyl, a cycloalkenyl, a cycloalkynyl, a heteroaryl, or a heterocycle which is bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety.
  • the spirocyclic group is a cycloalkyl, a cycloalkenyl or a cycloalkynyl and is bound to another cycloalkyl, cycloalkenyl or cycloalkynyl.
  • the spirocyclic group is a cycloalkyl, a cycloalkenyl or a cycloalkynyl and is bound to a heterocycle.
  • the spirocyclic group is a heterocycle and is bound to another heterocycle.
  • the spirocyclic group is a heterocycle and is bound to a cycloalkyl, a cycloalkenyl or a cycloalkynyl.
  • Cycloalkyl refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 20 membered ring system.
  • the or each cycloalkyl may be an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-12 cycloalkyl or an optionally substituted C3-6 cycloalkyl.
  • a cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • a cycloalkyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N3, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11
  • the optionally substituted cycloalkyl may be a halogenated cycloalkyl, i.e. a cycloalkyl substituted with one or more halogens.
  • a halogenated cycloalkyl may be substituted with one or more further substituents.
  • Cycloalkenyl refers to a non-aromatic, olefinically unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 20 membered ring system. Accordingly, a cycloalkenyl may contain one or more double bonds between adjacent carbon atoms in the ring.
  • the or each cycloalkenyl may be an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-12 cycloalkenyl or an optionally substituted C 3-6 cycloalkenyl.
  • a cycloalkenyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N 3 , an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or
  • the optionally substituted cycloalkenyl may be a halogenated cycloalkenyl, i.e. a cycloalkenyl substituted with one or more halogens.
  • a halogenated cycloalkenyl may be substituted with one or more further substituents.
  • Cycloalkynyl refers to a non-aromatic, acetylenically unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 20 membered ring system. Accordingly, a cycloalkynyl may contain one or more triple bonds between adjacent carbon atoms in a ring.
  • a cycloalkenyl may also contain one or more double bonds between adjacent carbon atoms in a ring.
  • the or each cycloalkynyl may be an optionally substituted C 3-20 cycloalkynyl, an optionally substituted C 3-12 cycloalkynyl or an optionally substituted C 3- 6 cycloalkynyl.
  • a cycloalkynyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N3, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 al
  • the optionally substituted cycloalkynyl may be a halogenated cycloalkynyl, i.e. a cycloalkynyl substituted with one or more halogens.
  • a halogenated cycloalkynyl may be substituted with one or more further substituents.
  • “Heteroaryl” refers to a monocyclic or bicyclic aromatic 5 to 20 membered ring system in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorous.
  • the heteroaryl may be an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 5 to 10 membered heteroaryl.
  • Examples of 5 to 20 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline.
  • Bicyclic heteroaryl groups include for example those where a phenyl, pyridine, pyrimidine, pyrazine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring.
  • a heteroaryl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N 3 , an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkyny
  • the optionally substituted heteroaryl may be a halogenated heteroaryl, i.e. a heteroaryl substituted with one or more halogens.
  • a halogenated heteroaryl may be substituted with one or more further substituents.
  • “Heterocycle” or “heterocyclyl” refers to 3 to 20 membered monocyclic, bicyclic, polycyclic or bridged molecules in which at least one ring atom is a heteroatom. The or each heteroatom may be independently selected from the group consisting of oxygen, sulfur, nitrogen and phosphorous.
  • a heterocycle may be saturated or partially saturated.
  • a heterocyclic group may be an optionally substituted 3 to 20 membered heterocycle or an optionally substituted 3 to 12 membered heterocycle.
  • Exemplary 3 to 20 membered heterocycle groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6- tetrahydropyridine-1-yl, tetrahydropyran, pyran, morpholine, piperazine, thiane, thiine, piperazine, azepane, diazepane, and oxazine.
  • a heterocycle group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 , CONR 11 R 12 , CN, N 3 , an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl or an optionally substituted 3 to 20 membered heterocycle, wherein R 11 is a protecting group and R 12 is H, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl
  • the optionally substituted heterocycle may be a halogenated heterocycle, i.e. a heterocycle substituted with one or more halogens.
  • a halogenated heterocycle may be substituted with one or more further substituents.
  • a “protecting group” may be understood to be a substituent configured to prevent the adjacent group from reacting in a polymerisation reaction. Suitable protecting groups are known in the art.
  • the or each protecting group may be selected from the group consisting of an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, COOR 13 , fluorenylmethoxycarbonyl (Fmoc), tosyl (Ts), benzyl, Si(R 13 ) 3 , 4,4’-dimethoxytrityl (DMTr) and tetrahydropyranyl (THP), where R 13 is an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl or an optionally substituted C6-12 aryl.
  • R 13 is an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl or an optionally substituted C6-12 aryl.
  • the C 1-30 alkyl may be a methyl, an ethyl, an isopropyl or a tert-butyl.
  • the C6-12 aryl may be phenyl.
  • the or each protecting group may be tert-butyl, BOC, Fmoc, Ts, benzyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS/TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), DMTr or THP.
  • the ring may be an optionally substituted C 3-20 cycloalkyl ring, an optionally substituted C 3-20 cycloalkenyl ring, an optionally substituted C 3-20 cycloalkynyl ring, an optionally substituted C 6-20 aryl ring, an optionally substituted 5 to 20 membered heteroaryl ring or an optionally substituted 3 to 20 membered heterocycle ring.
  • the pair of substituents may be attached to the same atom. Alternatively, the pair of substituents may be attached to adjacent atoms.
  • the initiator may have a molecular weight between 10 and 20,000 Da, between 20 and 10,000 Da, between 40 and 10,000 Da, between 60 and 5,000 Da, between 80 and 3,000 Da or between 100 and 2,000 Da.
  • the initiator may be a microinitiator.
  • An initiator may be considered to be a microinitiator if it has a molecular weight of less than 2,000 Da, less than 1,500 Da or less than 1,000 Da, more preferably less than 750 Da or less than 500 Da, and most preferably less than 250 Da, less than 200 Da or less than 150 Da.
  • the initiator may be a macroinitiator.
  • An initiator may be considered to be a macroinitiator if it has a molecular weight of at least 2,000 Da.
  • a macroinitiator may have a molecular weight of between 2,000 and 20,000 Da, between 2,500 and 10,000 Da or between 3,000 and 5,000 Da.
  • the initiator may be an alcohol or an amine.
  • the alcohol may be a primary alcohol.
  • the amine may be ammonia, a primary amine, a secondary amine or a tertiary amine.
  • the initiator is benzyl alcohol.
  • the alcohol may be polyethylene glycol (PEG).
  • PEG may be a microinitiator or a macroinitiator.
  • PEG may have a molecular weight between 50 and 10,000 Da, between 100 and 10,000 Da, between 200 and 5,000 Da, between 300 and 3,000 Da or between 400 and 2,000 Da.
  • the molecular weight may be the number average molecular weight (M n ). It may be appreciated that the ratio of the initiator to the plurality of monomers may vary depending upon the desired degree of polymerisation (DPn).
  • the molar ratio of the initiator to the plurality of monomers may be between 1:1 and 1:1000, between 1:1 and 1:500, between 1:1 and 1:250, between 1:1 and 1:100, between 1:1 and 1:50 or between 1:1 and 1:40. In some embodiments, the molar ratio of the initiator to the plurality of monomers is between 1:1 and 1:20, between 1:1 and 1:10 or between 1:2 and 1:6.
  • the molar ratio of the initiator to the plurality of monomers is between 1:2.5 and 1:30, between 1:5 and 1:20 or between 1:7.5 and 1:15. In further alternative embodiments, the molar ratio of the initiator to the plurality of monomers is between 1:5 and 1:40, between 1:10 and 1:30 or between 1:15 and 1:25.
  • the method may comprise contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur and, to thereby obtain a modified polymer, wherein the further plurality of monomers are a plurality of molecules of formula (I).
  • the further plurality of monomers may be the same as the first plurality of monomers.
  • the further plurality of monomers may be different to the first plurality of monomers.
  • the method may comprise contacting the modified polymer with a yet further plurality of monomers, to cause a further polymerisation reaction to occur and, to obtain a further modified polymer, wherein the further plurality of monomers are a plurality of molecules of formula (I).
  • the further plurality of monomers may be the same as one or more of the plurality of monomers used in the preceding steps.
  • the further plurality of monomers may be different to the plurality of monomers used in the preceding steps. It may be appreciated that the ratio of the polymer or the modified polymer to the further plurality of monomers may vary depending upon the desired DP n .
  • the molar ratio of the polymer or the modified polymer to the plurality of monomers may be between 1:1 and 1:1000, between 1:1 and 1:500, between 1:1 and 1:250, between 1:1 and 1:100, between 1:1 and 1:50 or between 1:1 and 1:40. In some embodiments, the molar ratio of the polymer or the modified polymer to the plurality of monomers is between 1:1 and 1:20, between 1:1 and 1:10 or between 1:2 and 1:6. In alternative embodiments, the molar ratio of the polymer or the modified polymer to the plurality of monomers is between 1:2.5 and 1:30, between 1:5 and 1:20 or between 1:7.5 and 1:15.
  • the molar ratio of the polymer or the modified polymer to the plurality of monomers is between 1:5 and 1:40, between 1:10 and 1:30 or between 1:15 and 1:25.
  • the method may comprise: (a) contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer; and (b) contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur, and to thereby obtain a modified polymer, wherein each of the plurality of monomers are a plurality of molecules of formula (I) and may be the same or different to the plurality of monomers used in the other step.
  • the method may not comprise any further polymerisation reactions.
  • the method comprises: (a) contacting a plurality of monomers with an initiator, to cause a first polymerisation reaction to occur, and thereby obtaining a polymer; (b) contacting the polymer with a further plurality of monomers, to cause a second polymerisation reaction to occur, and to thereby obtain a modified polymer; and (c) contacting the modified polymer with a further plurality of monomers, to cause a further polymerisation reaction to occur, and to thereby obtain a further modified polymer, wherein each of the plurality of monomers are a plurality of molecules of formula (I) and may be the same or different to the plurality of monomers used in the other steps.
  • Step (c) may be repeated.
  • step (c) could be repeated at least 1 time, at least 2 times, at least 3 times, at least 4 times or at least 5 times.
  • step (c) could be repeated between 1 and 100 times, between 1 and 50 times, between 1 and 25 times, between 1 and 10 times, between 1 and 5 times or between 1 and 2 times.
  • the plurality of monomers used in any polymerisation reaction may all have the same chemical formula. Accordingly, the polymerisation reaction may be a ring opening polymerisation (ROP) reaction. Alternatively, or additionally, the plurality of monomers used in any polymerisation reaction may comprise a first molecule of formula (I) and a second molecule of formula (I), wherein the first and second molecules are different.
  • the plurality of monomers used in any of the polymerisation reactions may comprise a plurality of first molecules of formula (I) and a plurality of second molecules of formula (I). Accordingly, the polymerisation reaction may be called a ring opening copolymerisation (ROCOP) reaction.
  • the plurality of monomers and the initiator or polymer may be contacted in the presence of the catalyst.
  • the catalyst may be an organocatalyst or an organometallic catalyst.
  • the catalyst may be tin(II) 2-ethylhexanoate (Sn(Oct)2), t-Bu-P4 or a salt thereof.
  • the molar ratio of the catalyst to the initiator or polymer may be between 1:100 and 100:1, between 1:75 and 75:1, between 1:50 and 50:1, between 1:25 and 25:1, between 1:10 and 10:1, between 1:5 and 5:1 or between 1:2 and 2:1. In some embodiments, the molar ratio of the catalyst to the initiator or polymer is about 1:1.
  • the plurality of monomers and the initiator or polymer may be contacted at a temperature between 0 and 500 °C, between 5 and 400 °C or between 10 and 300 °C, more preferably between 15 and 200 °C, between 20 and 160 °C or between 25 and 140 °C, and most preferably between 30 and 120 °C or between 35 and 115 °C.
  • the plurality of monomers and the initiator or polymer are contacted at a temperature between 50 and 200 °C, between 60 and 180 °C, between 70 and 160 °C or between 80 and 140 °C, and most preferably between 90 and 130 °C, between 100 and 120 °C or between 105 and 115 °C.
  • the plurality of monomers and the initiator or polymer are contacted at a temperature between 10 and 100 °C, between 15 and 80 °C or between 20 and 60 °C, and most preferably between 30 and 50 °C or between 35 and 45 °C.
  • the plurality of monomers and the initiator or polymer may be contacted under an inert atmosphere.
  • the plurality of monomers and the initiator or polymer may be contacted under a nitrogen or argon atmosphere.
  • the method may comprise removing the protecting groups.
  • the method may comprise removing the protecting groups after a desired number of polymerisation reactions have been conducted. Suitable methods for removing protecting groups are known in the art.
  • the method may comprise purifying the polymer.
  • the method may comprise purifying the polymer after a desired number of polymerisation reactions have been conducted.
  • the method may comprise purifying the polymer after the protecting groups have been removed.
  • the method may comprise purifying the polymer before the protecting groups have been removed. Suitable purification techniques are known in the art.
  • purifying the polymer may comprise dissolving the polymer in a first solvent and precipitating it into a second solvent.
  • first solvent may comprise dichloromethane (DCM).
  • the second solvent may comprise hexane or methanol.
  • the first solvent may comprise dimethyl sulphoxide (DMSO).
  • DMSO dimethyl sulphoxide
  • the second solvent may comprise diethyl ether.
  • the second solvent may be cold. Accordingly, the second solvent may be at a temperature of less than 20 °C, less than 15 °C, less than 10 °C, less than 5 °C or less than 0°C.
  • the second solvent may be at a temperature between -150 and 20 °C, between -100 and 10 °C, between -80 and 5 °C or between -50 and 0 °C.
  • purifying the polymer may comprise using a flash column method. The method may not comprise a purification step between subsequent polymerisation reactions. The inventors have found that purification is not required between subsequent polymerisation reactions. This enables the polymer to be produced more quickly and in a higher yield.
  • the plurality of monomers comprise a compound of formula (I) which is an ester or anhydride.
  • the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ia):
  • the plurality of monomers may comprise an ester-ether or an anhydride-ether cyclic monomer.
  • at least one X 4 may be O or S.
  • the plurality of monomers may comprise an ester-amide, anhydride-amide, ester-sulphoamide or anhydride- sulphoamide cyclic monomer.
  • an adjacent pair of X 4 groups may be CO and NR 8 or SO 2 and NR 8 .
  • each of X 4 may be CR 6 R 7 or NR 8 .
  • X 3 is CR 4 R 5 .
  • the compound of formula (I) is preferably an ester.
  • R 4 and R 5 may independently be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 4 and R 5 are independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl. More preferably, R 4 and R 5 are H, a halogen or methyl.
  • R 4 and R 5 are both H.
  • the plurality of monomers comprise a compound of formula (I) which is an ether.
  • the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ib):
  • R 1 and R 2 may independently be H, a halogen, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl or an optionally substituted C 2-30 alkynyl.
  • R 1 and R 2 are independently H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl or an optionally substituted C 2-20 alkynyl.
  • R 1 and R 2 may independently be H, a halogen, an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl or an optionally substituted C 2-12 alkynyl.
  • R 1 and R 2 may independently be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 1 and R 1 are independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl. More preferably, R 1 and R 2 are H, a halogen or methyl. In some embodiments, R 1 and R 2 may be H.
  • X 3 is CR 4 R 5 .
  • R 4 and R 5 may independently be H, a halogen, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl or an optionally substituted C 2-30 alkynyl.
  • R 4 and R 5 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl or an optionally substituted C 2-20 alkynyl.
  • the plurality of monomers comprise a compound of formula (I) which is an amide. Accordingly, the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ic):
  • R 3 may be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 3 is independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl. More preferably, R 3 is H, a halogen or methyl. In some embodiments, R 3 is H.
  • X 3 is CR 4 R 5 .
  • R 4 and R 5 may independently be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 4 and R 5 are independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl. More preferably, R 4 and R 5 are H, a halogen or methyl.
  • the plurality of monomers comprise a compound of formula (I) which is a sulphoamide.
  • the plurality of monomers may comprise a compound or a plurality of compounds of formula (Id):
  • R 3 may be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 3 is independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl. More preferably, R 3 is H, a halogen or methyl.
  • R 3 is H.
  • X 3 is CR 4 R 5 .
  • R 4 and R 5 may independently be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 4 and R 5 are independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl. More preferably, R 4 and R 5 are H, a halogen or methyl.
  • n may be 0 or an integer between 1 and 20, or more preferably between 1 and 10. Accordingly, n may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • n is an integer between 2 and 8, between 3 and 6 and most preferably n is 4.
  • the plurality of monomers may comprise a compound or a plurality of compounds of formula (Ie): , wherein X 1 to X 4 are as defined above; and X 5 to X 7 are each independently CR 6 R 7 , NR 8 , CO, O, S, SO or SO 2 .
  • X 1 is CO and X 2 is O.
  • X 1 is CR 1 R 2 and X 2 is O.
  • X 1 is CO and X 2 is NR 3 .
  • X 1 may be SO 2 and X 2 may be NR 3 .
  • X 1 is CO and X 2 is O. In an alternative preferred embodiment, X 1 is CR 1 R 2 and X 2 is O.
  • R 4 and R 5 are H, a halogen or methyl.
  • X 3 is CH 2 .
  • Each of X 4 to X 7 may independently be CR 6 R 7 or NR 8 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 , NR 9 R 10 , CN or N3.
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 or NR 9 R 10 .
  • Each of X 4 to X 7 may independently be CHR 7 or NR 8 .
  • Each of X 4 to X 7 may independently be CH2, CHNR 9 R 10 , CHOR 10 , CHN3 or NR 8 .
  • R 10 may be H, an optionally substituted C1-15 alkyl or a protecting group.
  • R 10 may be H, an optionally substituted C 1-6 alkyl or a protecting group.
  • R 10 may be H, a C 1-3 alkyl or a protecting group.
  • R 10 is H, methyl or tert-butyldimethylsilyl.
  • X 4 is CR 6 R 7 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 , NR 9 R 10 , CN or N3.
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 or NR 9 R 10 .
  • X 4 may be CH 2 .
  • X 5 is CR 6 R 7 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 , NR 9 R 10 , CN or N 3 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 or NR 9 R 10 .
  • X 5 may be CH2, CHNR 9 R 10 or CHOR 10 .
  • R 10 may be H, an optionally substituted C1-15 alkyl or a protecting group.
  • R 10 may be H, an optionally substituted C 1-6 alkyl or a protecting group.
  • R 10 may be H, a C 1- 3 alkyl or a protecting group.
  • R 10 is H, methyl or tert- butyldimethylsilyl.
  • X 5 is NR 8 .
  • X 6 is CR 6 R 7 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 , NR 9 R 10 , CN or N 3 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 or NR 9 R 10 .
  • X 6 may be CH2. In some embodiments, X 7 is CR 6 R 7 .
  • R 6 and R 7 may independently be H, a halogen, an optionally substituted C1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, OR 10 , NR 9 R 10 , CN or N 3 .
  • R 6 and R 7 may independently be H, OR 10 , NR 9 R 10 , CN or N 3 .
  • R 6 and R 7 may independently be H or N 3 .
  • X 7 may be CHR 7 .
  • X 7 may be CH 2 or CHN 3 .
  • the or each protecting group may be tert-butoxycarbonyl (Boc) protecting group.
  • the plurality of monomers may comprise a compound or a plurality of compounds of one or more of formula (If) to (Ik):
  • the compound of formula (Ig) may be a compound of formula (Igi):
  • the compound of formula (Ih) may be a compound of formula (Ihi) or (Ihii) and is preferably a compound of formula (Ihiii) or a compound of formula (Ihiv):
  • the compound of formula (Ij) may be a compound of formula (Iji):
  • the compound of formula (Ik) may be a compound of formula (Iki):
  • n is 0 or an integer between 1 and 5, between 3 and 6 or n is 0 or an integer between 1 and 3, and most preferably n is 0.
  • the plurality of monomers may comprise a compound or a plurality of compounds of formula (Il): ( )
  • X 1 is CO and X 2 is O.
  • X 1 is CR 1 R 2 and X 2 is O.
  • X 1 is CO and X 2 is NR 3 .
  • X 1 may be SO 2 and X 2 may be NR 3 .
  • X 1 is CR 1 R 2 and X 2 is O.
  • X 3 is CR 4 R 5 .
  • the compound may be a compound of formula (Ili):
  • R 1 and R 2 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl or an optionally substituted C 2-20 alkynyl.
  • R 1 and R 2 are independently H, a halogen, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl.
  • R 1 and R 2 are H, a halogen or methyl.
  • R 1 and R 2 may be H.
  • the compound may be a compound of formula (Ilii):
  • R 4 and R 5 may independently be H, a halogen, an optionally substituted C 1-20 alkyl, an optionally substituted C 2-20 alkenyl or an optionally substituted C 2-20 alkynyl.
  • R 4 may be an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl or an optionally substituted C 2-12 alkynyl.
  • R 4 is a C 1-12 alkyl, a C 2-12 alkenyl or a C 2-12 alkynyl.
  • R 4 is an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 4 may be an optionally substituted C 1-3 alkyl, an optionally substituted C 2-3 alkenyl or an optionally substituted C 2-3 alkynyl.
  • the alkyl, alkenyl or alkynyl may be substituted with NR 11 R 12 , OR 12 , SR 12 , SSR 12 , COOR 11 or CONR 11 R 12 .
  • the alkyl, alkenyl or alkynyl is substituted with OR 12 , SR 12 , COOR 11 or CONR 11 R 12 .
  • R 12 may be H, an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl or an optionally substituted C 2-12 alkynyl.
  • R 12 is H, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 12 is H.
  • R 12 may be an optionally substituted C 1-3 alkyl, an optionally substituted C 2-3 alkenyl or an optionally substituted C 2-3 alkynyl. Accordingly, R 12 may be –CH 2 CH 2 COOR 11 .
  • the or each protecting group may be tert- butoxycarbonyl (Boc) protecting group or tert-butyl.
  • R 5 may be H, a halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 5 is H, a halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 2-3 alkenyl or an optionally substituted C 2-3 alkynyl.
  • R 5 is H, a halogen or methyl.
  • the compound of formula (Il) may be a compound of any one of formula (Iliii) to (Ilxii):
  • the method may comprise removing one or more protecting groups.
  • the method may comprise removing the protecting groups after the final time the polymer has been contacted with a plurality of monomers. Accordingly, the method may comprise removing the protecting groups after the desired number of polymerisation reactions have been conducted.
  • the method may comprise producing the plurality of monomers.
  • Producing a plurality of monomers may comprise contacting a compound of formula (II) with an oxidant, wherein the compound of formula (II) is: , wherein X 1 , X 3 and X 4 are as defined above and n is an integer of at least 1.
  • the compound of formula (II) may be a compound of formula (IIa): , wherein X 5 to X 7 are also as defined above.
  • the compound of formula (IIa) may be a compound of formula (IIb) to (IIe):
  • the compound of formula (IIc) may be a compound of formula (IIci):
  • the compound of formula (IId) may be a compound of formula (IIdi) or (IIdii), and is preferably a compound of formula (IIdiii), or a compound of formula (IIdiv).
  • the compound of formula (IIe) may be a compound of formula (IIei):
  • the oxidant may be a peroxy compound, a metal oxide, a metalloid oxide or a monooxygenase.
  • the oxidant may be meta-chloroperoxybenzoic acid (mCPBA), cobalt (II,III) oxide (Co 3 O4 ) , iron (III) oxide (Fe 2 O 3 ), antimony (III) oxide (Sb 2 O 3 ), manganese dioxide (MnO 2 ), chromium (III) oxide (Cr 2 O 3 ), cobalt (II) oxide (CoO), tin (IV) oxide (SnO 2 ) or cyclopentadecanone monooxygenase.
  • mCPBA meta-chloroperoxybenzoic acid
  • cobalt (II,III) oxide Co 3 O4
  • iron (III) oxide Fe 2 O 3
  • antimony (III) oxide Sb 2 O 3
  • manganese dioxide MnO 2
  • Cr 2 O 3 chromium oxide
  • tin (IV) oxide SnO 2
  • the molar ratio of the oxidising agent to the compound of formula (II) may be between 100:1 and 1:100, between 50:1 and 1:50 or between 25:1 and 1:25, more preferably is between 15:1 and 1:10, between 10:1 and 1:5 or between 7:1 and 1:2, and most preferably is between 5:1 and 1:1 or between 4:1 and 2:1. In some embodiments, the molar ratio of the oxidising agent to the compound of formula (II) is about 3:1.
  • the oxidising agent and the compound of formula (II) may be contacted at a temperature between 10 and 250 °C, more preferably between 20 and 150 °C or between 30 and 100°C, and most preferably between 40 and 90 °C, between 50 and 80°C or between 60 and 70 °C.
  • the method may comprise recrystallizing the compound of formula (I). The inventors have found that a recrystallization step is sufficient to obtain the compounds in the required purity.
  • X 1 to X 4 , R 1 to R 7 , R 10 and n may be as defined in relation to the first aspect.
  • the terms “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “cycloalkyl”, “cycloalkenyl”, “cycloalkynyl”, “heteroaryl”, “heterocycle”, “heterocyclyl” and “protecting group” may be as defined in relation to the first aspect expect R 11 may be H, a protecting group, an optionally substituted C 1-30 alkyl, an optionally substituted C 2-30 alkenyl, an optionally substituted C 2-30 alkynyl, an optionally substituted C 6-20 aryl, an optionally substituted C 3-20 cycloalkyl, an optionally substituted C 3-20 cycloalkenyl, an optionally substituted C 3-20 cycloalkynyl, an optionally substituted 5 to 20 membered heteroaryl, an optionally substituted 3 to 20 member
  • R 8 , R 9 and R 11 may differ between the first and second aspects. These groups are defined as being a protecting group in the monomer of the first aspect. However, the or each protecting group can be removed after polymerisation. Accordingly, the polymer of the second aspect does not have to contain the protecting groups, and may comprise alternative groups in these positions.
  • R 8 and R 9 may be H or a protecting group.
  • the protecting group may be Boc.
  • R 11 may be H or a protecting group.
  • the protecting group may be Boc.
  • m may be an integer of at least 2, at least 5, at least 10, at least 20, at least 30, at least 40 or at least 50.
  • m may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 20 and 100, between 30 and 75 or between 40 and 60.
  • the polymer may have a molecular weight of at least 250 Da, at least 500 Da, at least 1,000 Da, at least 2,000 Da, at least 3,000 Da, at least 4,000 Da, at least 5,000 Da, at least 6,000 Da, at least 7,000 Da, at least 8,000 Da, at least 9,000 Da or at least 10,000 Da.
  • the polymer may have a molecular weight between 250 and 10,000,000 Da, between 500 and 1,000,000 Da, between 1,000 and 500,000 Da, between 2,000 and 100,ooo Da, between 3,000 and 50,000 Da, between 4,000 and 25,000 Da, between 5,000 and 20,000 Da, between 6,000 and 15,000 Da, between 7,000 and 14,000 Da, between 8,000 and 13,000 Da or between 9,000 and 12,000 Da or between 10,000 and 11,000 Da.
  • the molecular weight may be the number average molecular weight (Mn).
  • the molecular weight may be calculated by nuclear magnetic resonance (NMR) analysis using an initiator as the reference.
  • R 14 is an optionally substituted C1-20 alkyl, an optionally substituted C 2-20 alkenyl, an optionally substituted C 2-20 alkynyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 cycloalkenyl, an optionally substituted C 3-12 cycloalkynyl, an optionally substituted 5 to 12 membered heteroaryl or an optionally substituted 3 to 12 membered heterocycle.
  • R 14 is an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl or an optionally substituted C 2-12 alkynyl.
  • R 14 is an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl. Even more preferably, R 14 is an optionally substituted C 1-3 alkyl, an optionally substituted C 2-3 alkenyl or an optionally substituted C 2-3 alkynyl, and most preferably is an optionally substituted methyl.
  • the alkyl, alkenyl or alkynyl may be substituted with a C 6-20 aryl, a C 3-20 cycloalkyl, a C 3-20 cycloalkenyl, a C 3-20 cycloalkynyl, a 5 to 20 membered heteroaryl or a 3 to 20 membered heterocycle.
  • the alkyl, alkenyl or alkynyl is substituted with a C 6-12 aryl, a C 3-12 cycloalkyl, a C 3-12 cycloalkenyl, a C 3-12 cycloalkynyl, a 5 to 12 membered heteroaryl or a 3 to 12 membered heterocycle.
  • R 14 is In alternative embodiments, R 14 is R 15 (OCH 2 CH 2 ) p -.
  • p may be an integer of between 2 and 500, between 5 and 300, between 10 and 200, between 20 and 150 or between 30 and 125.
  • p may be an integer between 2 and 100, between 4 and 50, between 6 and 40, between 8 and 30 or between 9 and 20.
  • p may be an integer between 2 and 200, between 5 and 100, between 10 and 75, between 20 and 60 or between 30 and 50.
  • p may be an integer between 50 and 200, between 75 and 150, or between 100 and 125.
  • R 15 is H, an optionally substituted C 1-15 alkyl, an optionally substituted C2-15 alkenyl or an optionally substituted C2-15 alkynyl.
  • R 15 may be H, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 15 may be H, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl.
  • R 15 may be H or methyl.
  • R 15 is X 1 to X 4 , n and m may be as defined above.
  • X 8 is O.
  • the polymer may be a homopolymer or a copolymer.
  • the copolymer may be a block copolymer, a statistical copolymer, a random copolymer or a combination thereof. It may be appreciated that a mer is a repeating unit within a polymer. It may be appreciated that in embodiments where the polymer is a homopolymer, X 1 to X 4 and n will be the same for all of the mers in the polymer. Alternatively, in embodiments where the polymer is a copolymer, the polymer will comprise at least two mers, wherein at least one of X 1 to X 4 and/or n is different between the at least two mers.
  • the polymer may comprise one or more mers of formula (IVa): Alternatively, or additionally, the polymer may comprise one or more mers of formula (IVb): Alternatively, or additionally, the polymer may comprise one or more mers of formula (IVc): Alternatively, or additionally, the polymer may comprise one or more mers of formula (IVd): n may be as defined in relation to the first aspect. Accordingly, in embodiments where n is 4, the polymer may comprise one or more mers of formula (IVe): , wherein X 5 to X 7 are independently CR 6 R 7 , NR 8 , CO, O, S, SO or SO 2 .
  • the polymer may comprise one or more mers of formula (IVf), (IVg), (IVh), (IVj) and/or (IVk): It may be appreciated that the mer of formula (IVf) may be referred to as PCL. As explained above, the polymer is not polycaprolactone. However, as also explained above, one or more of the mers of the polymer may be of formula (IVf). In this embodiment, the polymer may be a copolymer. Accordingly, it may comprise further mers which are not of formula (IVf). One or more mers of formula (IVg) may be mers of formula (IVgi) or (IVgii): It may be appreciated that a mer of formula (IVgi) may be referred to as P t BOOC. One or more mers of formula (IVh) may be mers of one of formula (IVhi) to (IVhvi):
  • a mer of formula (IVhiii) may be referred to as P t BOC and a mer of formula (IVhv) may be identified as P t BMOOC.
  • One or more mers of formula (IVj) may be mers of one of formula (IVji) and (IVjii):
  • a mer of formula (IVji) may be referred to as P t BOO.
  • One mer of formula (IVk) may be mer of formula (IVki): It may be appreciated that the mer of formula (IVki) can alternatively be referred to as PN 3 CL.
  • the polymer may be a compound of formula (IIIa): R 14 -X 8 -A m1 -b-(-B m2 -stat-C m6 -)-b-A m3 -b-(-B m4 -stat-C m7 -)-b-A m5 -H (IIIa) , wherein A is a mer of formula (IVg); B is a mer of formula (IVf); C is a mer of formula (IVh); and each of m1 to m7 is 0 or an integer of at least 1, at least one of m1, m3, m5, m6 and m7 is an integer of at least 1, and the sum of m1 to m7 is an integer of at least 2.
  • b when provided between adjacent sections of a polymeric formula, indicates that the adjacent sections are arranged sequentially. Accordingly, the polymer, or the relevant portion thereof, may be viewed as a block copolymer. It may be appreciated that stat, when provided between adjacent sections of a polymeric formula, indicates that the adjacent sections are provided together in a statistical arrangement. Accordingly, the polymer, or the relevant portion thereof, may be viewed as a statistical copolymer. It may be appreciated that the sum of m1 to m7 is m, and may be as defined above. In some embodiments, m6 and/or m7 may be an integer of at least 1.
  • m1 to m5 may each be 0 or an integer of at least 1, at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16 or at least 18.
  • m1 to m5 may each be 0 or an integer between 1 and 100, between 1 and 50, between 2 and 25, between 3 and 15, between 3 and 10 or between 4 and 6.
  • m6 and m7 may each be 0 or an integer of at least 1 or at least 2.
  • m6 and m7 may each be 0 or an integer between 1 and 100, between 1 and 50, between 1 and 25, between 1 and 10, between 1 and 5 or between 2 and 3.
  • m1, m3 and m5 are all 6, m2 and m4 are both 4 and m6 and m7 are both 2.
  • the polymer may be a polymer of formula (IIIai): R 14 -X 8 -Am1-H (IIIai) , wherein m1 is an integer of at least 2.
  • m1 is equal to m, and may be as defined above.
  • m1 may be an integer of at least 2, at least 5, at least 10, at least 20, at least 30, at least 40 or at least 50.
  • m1 may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 20 and 100, between 30 and 75 or between 40 and 60.
  • m1 may be an integer between 20 and 50.
  • m1 may be 24, 30 or 50.
  • the polymer may be a compound of formula (IIIaii): R 14 -X 8 -Am1-b-Bm2-b-Am3-b-Bm4-b-Am5-H (IIIaii)
  • m1 to m5 may each be 0 or an integer of at least 1, at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16 or at least 18, wherein at least one of m1, m3 and m5, is an integer of at least 1.
  • m1 to m5 may each be 0 or an integer between 1 and 100, between 4 and 50, between 6 and 25, between 8 and 20 or between 10 and 18, wherein at least one of m1, m3 and m5, is an integer of at least 1.
  • m1 to m5 are each 6.
  • m1, m2 and m4 are 6, m3 is 12 and m5 is 0.
  • m1 is 18, m2 is 12 and m3 to m5 are 0.
  • m1, m3 and m5 may be 4 and m2 and m4 may be 6.
  • the polymer may comprise one or more mers of formula (IVl):
  • the one or more mers of formula (IVl) may be mers of formula (IVli):
  • the one or more mers of formula (IVl) may be mers of one or more of formulae (IVlii) to (IVlxi):
  • R 12 may be H, an optionally substituted C 1-12 alkyl, an optionally substituted C 2-12 alkenyl or an optionally substituted C 2-12 alkynyl.
  • R 12 is H, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 12 is H.
  • R 12 is an optionally substituted C 1-3 alkyl, an optionally substituted C 2-3 alkenyl or an optionally substituted C 2-3 alkynyl. Accordingly, R 12 may be –CH 2 CH 2 COOR 11 .
  • R 11 may be a protecting group, H, a C 1-12 alkyl, a C 2-12 alkenyl or a C 2-12 alkynyl.
  • R 11 is a protecting group, H, a C 1-6 alkyl, a C 2-6 alkenyl or a C 2-6 alkynyl.
  • R 11 is a protecting group or H.
  • the protecting group may be tert- butoxycarbonyl (Boc) protecting group or tert-butyl.
  • the polymer may be a compound of formula (IIIb): R 14 -X 8 -Dm8-b-Em9-H (IIIb) ,wherein D is a mer of formula (IVlxi); E is a mer of formula (IVliv); and each m8 and m9 are each an integer of at least 1.
  • m may be an integer of at least 2, at least 5, at least 10, at least 20, at least 30, at least 40 or at least 50.
  • m may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 20 and 100, between 30 and 75 or between 40 and 60.
  • the polymer may be a compound of formula (IIIc): (IIIc) Accordingly, in some embodiments, the polymer may be a polymer of formula (IIIbi): R 15 -(-OCH 2 CH 2 -)p-X 8 -Fm-H (IIIci) , where F is a mer of formula (IVf), formula (IVgi), formula (IVhiii), formula (IVhv), formula (IVji), formula (IVki) or formula (IVlii).
  • R 15 is H, an optionally substituted C 1-15 alkyl, an optionally substituted C 2-15 alkenyl or an optionally substituted C 2-15 alkynyl.
  • R 15 may be H, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6 alkenyl or an optionally substituted C 2-6 alkynyl.
  • R 15 may be H, a C 1-3 alkyl, a C 2-3 alkenyl or a C 2-3 alkynyl.
  • R 15 may be H or methyl.
  • m may be an integer between 2 and 1,000, between 5 and 750, between 10 and 500, between 15 and 400 or between 20 and 300. In other embodiments, R 15 is .
  • X 1 to X 4 , n and m may be as defined above.
  • R 15 may be a mer of formula (IVlii). Each m may be an integer between 2 and 50, between 2 and 30, between 2 and 20, between 3 and 10 or between 4 and 6.
  • the polymer may be a polymer of any one of formula (101) to (147):
  • a use of the polymer of the second aspect as an antimicrobial agent to store information or in nanoscience or nanotechnology, wherein the use as an antimicrobial agent excludes use in a therapeutic application.
  • the charge, multifunctionality, hydrophobicity-hydrophilicity balance, sequence and/or molecular weight of the polymer of the second aspect can be manipulated to provide a polymer with antimicrobial properties. Accordingly, the polymer could be used in an antimicrobial application.
  • the polymers of the second aspect maybe used to store information.
  • information can be written, read and erased at the molecular level by controlling synthetic polymer chains.
  • Different building blocks with specific molecular weights and functionality can be defined as o-bit and 1-bit and detected by NMR, size exclusion chromatography (SEC) and/or other techniques.
  • SEC size exclusion chromatography
  • Another possibility is that if the synthetic polymer chains consist of different types of building blocks, much more information could be stored, like DNA.
  • the digital information encoded can then be deciphered.
  • the novel polyesters are readily biodegradable.
  • the information encrypted in the polyester chains can be erased by specific enzymes in water and/ or directly by water.
  • the polymer of the second aspect can also be used in the field of nanoscience and nanotechnology since the controllable sequences, degradability, multifunctionalities and stimuli-responsiveness can precisely control folding and self-assembly behaviour of polymer molecules, leading to formation of various self-assembled soft matter systems.
  • a fibre comprising the polymer of the second aspect.
  • a fibre made from the sequence-controlled multifunctional polymers of the second aspect could be useful for not only drug delivery and tissue engineering, but also other applications including membrane separation and purification.
  • a medicament or a vaccine comprising the polymer of the second aspect.
  • the polymer could be used to provide targeted delivery of a small-molecule drug and/or a macromolecular drug including a peptide, a protein and/or a nucleic acid. Accordingly, the polymer could be used in a drug delivery or gene therapy application. In particular, this can be achieved by precisely controlling the chain length, the functionality, the distribution of positive and/or negative charges and/or the distribution of hydrophobic and/or hydrophilic segments of the polymer.
  • the polymers can also be used as vaccine adjuvants for example by mixing vaccines with the polymers. They can also be used for applications in vaccine delivery formulations.
  • the polymer of the second aspect for use in therapy.
  • the polymer of the second aspect for use in drug delivery, gene therapy, tissue engineering, medical imaging and/or sensing and/or in treating a microbial infection.
  • PCL and PEG are widely used in drug delivery and tissue engineering. When it comes to tissue engineering, PCL and PEG suffer from some shortcomings such as slow degradation rate and low cell adhesion. These could be addressed by designing specific polymers with specific monomer types, monomer sequences and multifunctionality. Since the method of the first aspect allows the production of the polymer of the second aspect with controllable sequences, functionalities and degradability, a suitable polymer can be produced which overcomes the limitations of PCL and PEG.
  • the microbial infection may be a bacterial infection or a viral infection.
  • imaging and/or sensing moieties can be built into the polymers.
  • the resulting polymers, and also particles or vesicles developed from them, can be useful for medical imaging and/or sensing.
  • Figures la-ig show the structure of pentablock polyesters, with protected functional groups, synthesized via a quantitative one-pot iterative living ring-opening polymerization (QOIL-ROP) without intermediate purification.
  • tBOOC tert-butyl 7-oxo-1,4- oxazepane-4-carboxylate
  • Figure if shows the structure of the pentablock copolyester with variableDP n 4 or 6, identified as A 4 B 6 A 4 B 6 A 4 .
  • Figures 2a-2g show the structure of the pentablock polyesters of Figures ta-ig after deprotection;
  • Figure 3 shows a schematic representation of synthesis of sequence-controlled pentablock functional polyesters. All pentablock polyesters were prepared in toluene at 110 °C with benzyl alcohol as an initiator and with Sn(0ct) 2 as a catalyst via QOIL-ROP by consecutive sequential addition of monomers without intermediate purification. During the cycles, chain extensions were confirmed by NMR and SEC. The sequence- controlled pentablock polyesters were obtained after 5 successive chain extensions. Finally, the Boc protecting group was cleaved to generate water-soluble sequence- controlled pentablock functional polyesters;
  • Figures 4a-4g show synthesis and characterization of the sequence-controlled polyesters with protected functional groups shown in Figures la and lg, i.e. A6A6A6A6A6 and A 6 B 4 C 2 A 6 B 4 C 2 A 6 , respectively.
  • Figure 4a shows 1 H NMR traces (400MHz) for synthesis of A6A6A6A6A6 in deuterated chloroform (CDCl 3 ). Values to the left of each spectrum indicate a monomer conversion >98% for all chain extensions; values to the right indicate the number of sequential monomer additions.
  • Figure 4b shows molecular weight distributions for successive block extensions of A6A6A6A6A6 determined by SEC.
  • the y-axis ‘w (log M)’ label represents the differential logarithmic molecular weight.
  • Figure 4c shows evolution of theoretical (black line) and experimental molecular weights M n (squares) and M w (triangles) determined by SEC and dispersities M w /M n (circles) versus the number of cycles for synthesis of A 6 A 6 A 6 A 6 A 6.
  • n,th [Monomer]o x p x M Monomer /[Initiator] 0 + M intiator , p was the monomer conversion.
  • Figure 4d shows 1 H NMR spectra for consecutive block formations of A 6 B 4 C 2 A 6 B 4 C 2 A 6 in CDCl 3 .
  • Figure 4e shows molecular weight distributions of synthesis of A 6 B 4 C 2 A 6 B 4 C 2 A 6 determined by SEC.
  • Figure 4f shows evolution of theoretical (black line) and experimental molecular weights M n (squares) and w (triangles) determined by SEC and dispersities (circles) versus the number of cycles for preparation of A 6 B 4 C 2 A 6 B 4 C 2 A 6 ;
  • Figures 5a-5d show scale-up synthesis of the sequence-controlled pentablock copolyester with protected functional groups shown in Figure id, i.e. A 6 B 6 A 6 A 6 6 6 .
  • Figure 5a shows 1 H NMR spectra for consecutive block formations of A 6 B 6 A 6 A 6 B 6 , in CDCI 3 .
  • Figure 5b shows molecular weight distributions of synthesis of A 6 B 6 A 6 A 6 B 6 , determined by SEC.
  • Figure 5c shows evolution of theoretical (black line) and experimental molecular weights n (squares) and w (triangles) determined by SEC and dispersities (circles) versus the number of cycles for preparation of A 6 B 6 A 6 A 6 B 6
  • Figure 5d shows the total amount of obtained product (after precipitation purification);
  • Figures 6a and 6b show the kinetics of ROP of the A block.
  • Figure 6a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time.
  • Figure 6b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the Sn(0ct) 2 -catalyzed ROP of A block in toluene at 110 °C.
  • [Monomer] 0 0.75 M
  • Figures 7a and 7b show the kinetics of ROP of the B block.
  • Figure 7a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time.
  • Figure 7b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the Sn(0ct) 2 -catalyzed ROP of B block in toluene at 110 °C.
  • [Monomer] 0 0.75 M
  • Figures 8a and 8b show the kinetics of ROP of the BC block.
  • Figure 8a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time.
  • Figure 8b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the Sn(0ct) 2 -catalyzed ROP of BC block in toluene at 110 °C.
  • Figures 9a-9d show physicochemical and biodegradation properties of sequence- controlled pentablock polyesters.
  • Figure 9a shows the differential scanning calorimetry (DSC) traces of the seven synthesized sequence-controlled polyesters with protected functional groups, along with their corresponding T g values listed.
  • Figure 9b shows enzymatic biodegradation of water-soluble sequence-controlled, functional, deprotected polyesters as a function of time at 37 °C in deuterium oxide (D 2 0).
  • Figures 9c and 9d show hydrolysis of water-soluble sequence-controlled, functional, deprotected polyesters as a function of time at 37 °C at pH 5 (c) and 7.4 (d) in D 2 0. The degradation degrees were determined by 1 H NMR;
  • FIG. 10 shows the synthetic route for obtaining monomers tert-butyl 7-oxo-i,4- oxazepane-4-carboxylate (tBOOC, A), tert-butyl (7-oxooxepan-4-yl)carbamate (tBOC, C), tert-butyl N-methyl-N-(7-oxooxepan-4-yl) carbamate (tBMOOC) and 5-(tert- Butyldimethylsiloxy)Oxepane-2-One (tBOO);
  • Figure 11 shows the thermogravimetric analysis (TGA) traces of the seven synthesized sequence-controlled pentablock polyesters with protected functional groups along with their corresponding T d values listed;
  • TGA thermogravimetric analysis
  • Figure 12 shows the 1 H NMR spectra of (a) e-decalactone (DL) monomer and (b) the reaction mixture by bulk polymerization in CDCl 3 .
  • the monomer conversion was 94-7%;
  • Figure 13 shows the 1 H NMR spectra of (a) tert-butyl 7-oxooxepane-4-carboxylate (tBOCO) monomer and (b) the reaction mixture in CDCl 3 .
  • the monomer conversion was 90%
  • Figure 14 shows 1 H NMR traces for synthesis of the pentablock A 10 A 10 A 10 A 10 A 10 homopolyester in CDCl 3 .
  • the monomer conversion in each cycle was >98%. Values to the left of each spectrum indicate a monomer conversion >98% for all chain extensions; values to the right indicate the number of sequential monomer additions.
  • the molecular weight of pentablock A 10 A 10 A 10 A 10 A 10 homopolyester was 10,858 Da calculated by 1 H NMR;
  • the monomer conversion was 99.2%;
  • Figure 16 shows the SEC trace of the reaction mixture corresponding to Figure 15;
  • Figure 18 shows the SEC trace of the reaction mixture corresponding to Figure 17;
  • Figure 20 shows the SEC trace of the reaction mixture corresponding to Figure 19;
  • the monomer conversion was 98.5%
  • Figure 22 shows the SEC trace of the reaction mixture corresponding to Figure 21;
  • Figure 24 shows the SEC trace of the reaction mixture corresponding to Figure 23;
  • Figure 26 shows the SEC trace of the reaction mixture corresponding to Figure 25;
  • Figure 28 shows the SEC trace of the reaction mixture corresponding to Figure 27;
  • Figure 30 shows the SEC trace of the reaction mixture corresponding to Figure 29;
  • Figure 32 shows the SEC trace of the reaction mixture corresponding to Figure 31;
  • Figure 34 shows the SEC trace of the reaction mixture corresponding to Figure 33;
  • Figure 36 shows the SEC trace of the reaction mixture corresponding to Figure 35;
  • Figure 38 shows the SEC trace of the reaction mixture corresponding to Figure 37;
  • Figures 39a-39i show the structures of quasi pentablock polyethers synthesized via the QOIL-ROP method without intermediate purification;
  • Figures 40a and 40b shows the structures of the polyethers shown in Figures 39h and 391 after deprotection
  • Figure 41 shows a schematic representation of synthesis of sequence-controlled pentablock functional polyethers. All pentablock polyethers were prepared in toluene at 40 °C with benzyl alcohol as an initiator and t-Bu-P 4 as a catalyst via QOIL-ROP by consecutive sequential addition of monomers without intermediate purification. During the cycles, chain extensions were confirmed by NMR and SEC. The pentablock polyethers were obtained after 5 successive chain extensions.
  • Figures 42a and 42b show the kinetics of ROP of the D block;
  • Figure 42a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time;
  • Figure 42b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of D block in toluene at 40 °C.
  • [Monomer] 0 5.7 M
  • [Catalyst] 100:1:1;
  • Figures 43a and 43b show the kinetics of ROP of the E block;
  • Figure 43a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time;
  • Figure 43b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of E block in toluene at 40 °C.
  • [Monomer] 0
  • Figures 44a and 44b show the kinetics of ROP of the F block;
  • Figure 44a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time;
  • Figure 44b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of F block in toluene at 40 °C.
  • [Monomer] 0
  • Figures 45a and 45b show the kinetics of ROP of the G block.
  • Figure 45a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time.
  • Figure 45b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of G block in toluene at 40 °C.
  • [Monomer] 0
  • Figures 46a and 46b show the kinetics of ROP of the H block;
  • Figure 46a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time;
  • Figure 46b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of H block in toluene at 40 °C.
  • [Monomer] 0
  • Figures 47a and 47b show the kinetics of ROP of the I block;
  • Figure 47a shows plots of conversion and in ([ ] 0 /[ ]) as a function of time;
  • Figure 47b shows experimental molecular weights and dispersities (measured by SEC) as a function of conversion for the t-Bu-P4-catalyzed ROP of I block in toluene at 40 °C.
  • [Monomer] 0
  • Figure 48a shows 1 H NMR traces (400MHz) for synthesis of D 20 D 20 D 20 D 20 D 20 D 20 using the BO monomer 1,2-epoxybutane (D) in deuterated chloroform (CDCl 3 ), with benzyl alcohol as an initiator. Values to the left of each spectrum indicate a monomer conversion >99% for all chain extensions; values to the right indicate the number of sequential monomer additions; Figure 48b shows molecular weight distributions for successive block extensions of D 6 D 6 D 6 D 6 D 6 D 6 determined by SEC.
  • the y-axis ‘w (log M)’ label represents the differential logarithmic molecular weight
  • Figure 48c shows evolution of theoretical (black line) and experimental molecular weights n (squares) and M w (triangles) determined by SEC and dispersities w / n (circles) versus the number of cycles for synthesis of D 6 D 6 D 6 D 6 D 6 .
  • M n,t h [Monomer] 0 x p x M Monomer /[Initiator] 0 + M initiator , P was the monomer conversion;
  • the monomer conversion was 99%;
  • Figure 50 shows hemolysis of red blood cells (RBCs) after 1 h of incubation with the sequence-controlled co-polyether L 10O F 5O , synthesized using benzyl alcohol as an initiator, as a function of pH and polymer concentration.
  • Example 1 Synthesis of sequence-controlled multiblock polyesters
  • a number of members of the lactone monomer family were used, in order to form functional sequence-controlled multiblock polyesters.
  • the inventors assign coding letters A, B and C to tert-butyl 7-oxo-i,4-oxazepane-4-carboxylate, e- caprolactone and tert-butyl (7-oxooxepan-4-yl) carbamate monomers, respectively.
  • Monomers A and C were generated by Baeyer-Villiger oxidation reactions of the commercially available corresponding cyclohexanone derivatives in the presence of m- CPBA with only one-step preparation and easy purification by recrystallization, as shown in Fig. 10.
  • Monomer B was obtained from a commercial supplier.
  • the quasi pentablock A6A6A6A6A6A6 polyester (Fig. la) with protected functional groups in backbones and a number-average degree of polymerization(DP n) of 6 for each block was first designed and synthesized using tert-butyl 7-oxo-i,4-oxazepane-4-carboxylate (monomer A) as the building block to demonstrate this new approach.
  • NMR spectroscopy confirmed a very near quantitative monomer conversion (>99%) and the complete consumption of the monomer in this first step (Fig. 4a), the second aliquot of dehydrated and degassed monomer in toluene was subsequently fed into the reactor via a gas-tight syringe under the aforementioned conditions without purification of the first block. As the subsequently fed monomer can react again with the living propagating polymer block chain, the new chain extension was attained through repeated additions of monomers. 1 H NMR analysis confirmed a very near quantitative monomer conversion (>98%) (Fig. 4a).
  • This consecutive polymerization- sampling-extension process was conducted successfully five times to yield the final quasi pentablock polyester with a GPC M n of 5,423 Da.
  • This method enabled an unprecedented realization of both the relatively narrow MWDs and the great agreement between theoretical and experimental molecular weights (Table 1) during successive monomer addition cycles.
  • Table 1 Characterization data for the synthesis of the quasi pentablock A 6 A 6 A 6 A 6 A 6 polyester including monomer conversions, molecular weights and dispersities
  • the quasi pentablock A 4 A 6 A 4 A 6 A 4 polyester (Fig. lb) with variable DP n (4 or 6 for each block) was synthesized to demonstrate a precise control of the molecular weight (or chain length) of each block, which can enable a remarkable manipulation of polymer chemical structure, self-assembly and micro- and macroscopic properties.
  • the experimental molecular weights of intermediate and final polyesters were in good agreement with the corresponding theoretical values.
  • the quantitative monomer conversion (>98%) and precise DP n control during block formation in each cycle were confirmed by 1 H NMR and SEC.
  • Table 2 Characterization data for the synthesis of the quasi pentablock A 4 A 6 A 4 A 6 A 4 polvester including monomer conversions, molecular weights and dispersities
  • the sequence-controlled pentablock copolyesters with three different patterns, A 6 B 6 A 6 B 6 A 6 , A 6 B 6 A 6 A 6 B 6 , and A 6 A 6 A 6 B 6 B 6 , (Fig. 1c-1e) were then synthesized under the optimized conditions, in order to demonstrate that diverse levels of polyester structural complexity can be readily achieved.
  • the hydrophobic e-caprolactone (Monomer B) segments were introduced to the relatively hydrophilic A block, conferring the tunable range of physicochemical properties of final amphiphilic functional sequence- controlled pentablock copolyesters with high-order architecture, thereby unlocking their potential for widespread applications of the third to seventh aspects described above.
  • Table 2 Characterization data for the synthesis of the A6B6A6B6A6 including monomer conversions, molecular weights and dispersities
  • Table 4 Characterization data for the synthesis of the A6A6A6B6B6 including monomer conversions, molecular weights and dispersities
  • the sequence-controlled pentablock A 6 B 6 A 6 B 6 6 6 6 copolyester (Fig. id and 3) was chosen to demonstrate scale-up synthesis on a multigram scale (-56 g) (Fig. 5d). This is advantageous over the reported solid-phase peptide synthesis 7 , or liquid-phase molecular-sieving polyether synthesis 37 and even iterative exponential growth approaches ⁇ , which are typically limited to production at milligram level.
  • Table 5 Characterization data for the synthesis of the A6B6A6A6A6 including monomer conversions, molecular weights and dispersities
  • the inventors decided to synthesize another sequence-controlled pentablock Az,B 6 A,,B 6 A,, copolyester (Fig. if) to further demonstrate the notable precise regulation of the molecular weight (or chain length) of each block of the copolyester through this technique.
  • the final copolyester had an M n of 3,273 Da and a relatively narrow MWD (f) ⁇ 1.33).
  • the quantitative conversions (>98%) and the good agreement between theoretical and experimental molecular weights were confirmed by 1 H NMR and SEC throughout each chain extension cycle with the desired variable DP n .
  • Table 7 Characterization data for the synthesis of the A6 B4 C2 A6B4,C2A6including monomer conversions, molecular weights and dispersities
  • the chain propagation rate constants ( k p ) of A, B and BC blocks were calculated to be 9.0 x to -3 min -1 , 9.1 x 10- 3 min -1 and 9.2 x to -3 min -1 , respectively, as determined from the plots of monomer conversion versus reaction time. Thanks to the similar chain propagation rates, the extent of the undesirable transesterification reactions can be furthest minimized even if monomers were configured in any optional desired sequence 41 ’ 42 . In addition, the molecular weights of A, B and BC blocks, respectively, increased linearly with the monomer conversion (Figs. 6b, 7b and 8b), indicating that the monomers were converted to the resulting polyesters proportionally, which further confirmed the controlled polymerization nature 43 ’ 44 .
  • Full monomer conversion is usually not recommended throughout polymerization due to the accumulation of different side reactions, such as the chain transfer and termination in reversible addition-fragmentation chain transfer (RAFT) and atom- transfer radical polymerization (ATRP) 18 , and transesterification in ROP of lactones 33 .
  • side reactions such as the chain transfer and termination in reversible addition-fragmentation chain transfer (RAFT) and atom- transfer radical polymerization (ATRP) 18 , and transesterification in ROP of lactones 33 .
  • the extent of transesterification side reactions must be understood since it could scramble the sequence-controlled polyester structure. However, this is not a problem for synthesis of polyesters through the new QOIL-ROP approach since transesterification could be avoided.
  • the NMR spectra of all the crude sequence- controlled pentablock copolyesters only showed major carbonyl peaks of each block and their junctions.
  • sequence-controlled copolyesters showed that T g and T d values were dependent on the monomer type, monomer sequence and polyester molecular weight, tunable over the range of -45.4 to -35.4 °C and 212 to 2.2.7 °C, respectively. These sequence-controlled polyesters with longer chains and more orderly packed structures displayed higher T g probably due to their more rigid chains 51 .
  • sequence-controlled pentablock polyesters can be achieved through the simple and widely used reaction with trifluoroacetic acid (TFA) (molar ratio of TFA:Boc group in excess of 35:1) under a nitrogen atmosphere and at room temperature.
  • TFA trifluoroacetic acid
  • the peaks at 1.46 ppm attributed to the Boc protons were not observed in the 1 H NMR spectra, showing that all protecting Boc groups were removed and the water-soluble sequence-controlled, multifunctional pentablock polyesters were obtained. Meanwhile, no evident degradation was detected by 1 H NMR, indicating that the polyesters were relatively stable due to the reduced nucleophilicity of the amine groups upon protonation45.
  • sequence-controlled polyesters with a higher level of hydrophilicity were hydrolyzed faster.
  • Example 2 Maximizing conversion To enable multiple cycles to be carried out without purification being conducted between cycles, it is important to maintain a high monomer conversion. Accordingly, the inventors investigated properties of the monomer and initiator which could affect the percentage conversion.
  • the inventors attempted to conduct the polymerization reaction using a lactone substituted with a butyl group in the 2 position (Fig. 12). It will be appreciated that the 2 position is identified as “X 3 ” in the chemical formulae defined above.
  • the monomer conversion rate was 94.7%, lower than for the monomers used in Example 1 which were unsubstituted in the 2 position. The reduction in the conversion rate would appear to be caused by steric hindrance. Accordingly, this suggests that only monomers which are unsubstituted or have small substituents in the 2 position may be used in the polyester reaction.
  • the inventors then used the same method of producing a polymer to produce a polyester with a higher molecular weight. As shown in Fig. 14, the inventors were able to use their method to successfully synthesize a polyester with a molecular weight of 10,858 Da (measured by 1 H NMR).
  • the method developed by the inventors can be used to synthesize high molecular weight polymers.
  • Example 4 Synthesis of polyesters using macroinitiators
  • the inventors then decided to test whether their method could be applied to the synthesis of polyesters using macroinitiators.
  • a summary of the monomer conversion rates is provided in Table 10.
  • the inventors have shown that their QOIL-ROP strategy can also be used to synthesize polyesters using macroinitiators.
  • Mono-functional PEG with molecular weights of 2,000 and 5,000 Da can be used as initiators with quantitative monomer conversions.
  • the inventors then decided to test whether their method could be applied to the synthesis of polyethers.
  • the inventors were able to obtain the quasi pentablock polyethers shown in Figs. 39 to 41.
  • a summary of the monomer conversion rates is provided in Table 11.
  • Table 11 Summary of epoxy monomers used to synthesize quasi pentablock polvethers. monomer conversions rates, polvether molecular weights and dispersities a The M n and ⁇ of polyethers were determined by SEC.
  • the quasi pentablock D 20 D 20 D 20 D 20 D 20 D 20 D 20 polyether (Fig. 39a) and a number-average degree of polymerization ( DP n ) of 20 for each block was first designed and synthesized using 1,2-epoxybutane (monomer D) as the building block to demonstrate this new approach.
  • Each chain extension process was performed via sequential ROP under a nitrogen atmosphere catalyzed by f-Bu-P 4 in toluene. Polymerization temperature in each cycle was maintained at 40 °C and the molar ratio of t-Bu-P 4 to initiating benzyl alcohol
  • the inventors have shown that their QOIL-ROP strategy can also be used to synthesize well-defined, sequence-controlled, multifunctional multiblock polyethers. As with the polyesters, each block of the polyethers reached nearly full monomer conversion. Additionally, narrow MWDs were observed.
  • the inventors then decided to test whether their method could be applied to the synthesis of polyethers using PEG as an initiator.
  • the inventors were able to obtain the polyethers using PEG with different molecular weights as microinitiators or macroinitiators, following the same mono-directional chain extension method described in Example 1 except the replacement of the microinitiator benzyl alcohol with mono-functional PEG.
  • the BO monomer (D) conversion rate was calculated to be 99.0%.
  • a summary of the quantitative monomer conversion rates (>98%) through mono- directional chain extensions using PEG with different molecular weights (500 - 2,000 Da) is provided in Table 13.
  • the inventors then extended the application of their method to the synthesis of polyethers through a bi-directional chain extension using bi-functional PEG as an initiator.
  • Table 13 when the molecular weight of PEG ranged from 400 to 2,000, the BO monomer conversion was quantitative, changing from 98.7% to 98.5%.
  • the inventors have shown that their QOIL-ROP strategy can also be used to synthesize polyethers through the mono-directional or bi-directional chain extension using PEG microinitiators or macroinitiators.
  • PEG with molecular weights of 2,000, 1,000, 750, 600, 500 and 400 Da can be used as initiators with quantitative monomer conversion rates (>98%).
  • Example 7 pH-Dependent cell membrane activity of the co-polvether at different concentrations
  • the inventors then demonstrated that the polymers could be designed to be cell membrane active.
  • the co-polyether L 100 F 5O labelled as polymer 128, was synthesized using benzyl alcohol as an initiator according to the same method as described in Example 5.
  • This polymer consists of one block containing the side chain with the ionizable carboxylic acid groups, which enable the polymer to display pH-responsiveness, and the other block containing relatively long hydrophobic aliphatic chains, which enhance the polymer-cell membrane interaction.
  • Fig. 50 at the concentration of 0.5 mg mL/ 1 , the polymer displayed pH-responsive cell membrane activity. At higher pH ranging from 5.5 and 7.4, the polymer was non-membrane-lytic.
  • the pH-dependent cell membrane activity of the polymers can be manipulated by the type and sequence of monomers, degree of polymerization, charge (e.g., positive vs. negative, and charge density), hydrophobicity-hydrophilicity balance.
  • the new QOIL- ROP method can be used to readily synthesize a library of novel, sequence-controlled, multifunctional polymers including polyesters and polyethers for intracellular delivery of agents of pharmaceutical agents.
  • the polymerization flask was then resealed, and the polymerization was conducted at 110 °C under nitrogen protection with vigorous stirring. Samples of the reaction mixture were carefully removed for NMR and SEC analyses. The sample for NMR was simply diluted with CDCl 3 , while that for SEC analysis was diluted with tetrahydrofuran (THF). After the monomer was totally consumed, the further degassed and dehydrated monomer solution was carefully injected via gas tight syringe and again the solution was allowed to polymerize at no °C with vigorous stirring under a nitrogen atmosphere. For the iterative chain extension, the above polymerization-sampling-extension procedure was repeated as required.
  • THF tetrahydrofuran
  • the amount of monomer to be added to the reactor in each cycle was calculated according to the desired DP n of each building block and the amount of initiator removed from the system was taken into account to calculate the amounts of reagents for the next addition cycle.
  • samples were taken to monitor the polymerization.
  • the final crude product was dissolved in 3 mL of DCM and precipitated dropwise into 60 mL of cold hexane to obtain pure sequence-controlled pentablock polyesters.
  • the sequence-controlled pentablock polyester (200 mg) was azeotropically distilled by toluene in vacuum, dissolved in 2 mL of anhydrous DCM and then 2 ml TFA was added to a round-bottomed flask under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 2 h under nitrogen and subsequently all the solvents were evaporated. Then the polyester was redissolved in DMSO and precipitated in cold diethyl ether three times to yield the final water-soluble, multifunctional, sequence-controlled pentablock polyester.
  • a protocol for synthesis of sequence-controlled pentablock polyethers A three-neck flask charged with a rubber septum, a magnetic stir bar, monomer (20 eq), benzyl alcohol (1 eq) and 10 mL of anhydrous toluene was immersed into an oil bath at 140 °C. Toluene was removed by azeotropic distillation under a nitrogen atmosphere to remove traces of water from the flask. The solution was further degassed using nitrogen sparging for 30 min. t-Bu-P4 (1 eq) was then added by a gas tight syringe under a positive nitrogen pressure. The polymerization was conducted at 40 °C under nitrogen protection with vigorous stirring.
  • Samples were heated from room temperature to 70 °C, at a rate of 10 °C.min -1 under a helium flow and were kept at 70 °C for 2 min to erase the thermal history. Subsequently, the samples were cooled to -90 °C, at a rate of 10 °C-mim 1 and kept at -90 °C for a further 2 min, followed by a heating procedure from -90 to 70 °C, at a rate of 10 °C-min -1 . Each sample was run for three heating-cooling cycles. The T g was determined as the midpoint of the transition recorded from the third heating cycle.
  • Hemolysis assay was employed to examine the membrane- destabilizing activity of the synthesized polymers.
  • the specific polymer stock solution was added into o.1 M phosphate buffer (pH 5.0-7.4) or 0.1 M citric buffer (pH 4.0-5. o) to achieve the polymer buffer solution at the desired polymeric concentrations and pH.
  • Sheep RBCs were washed three times with 300 mosm PH7.4 phosphate-buffered saline and the polymer buffer solution was used to resuspend the RBC pellet.
  • the final cell concentration was controlled to be within the range of 1 - 2 x to 8 RBCs mL -1 , ensuring the absorbance of hemoglobin solution was proportional to the number of lysed RBCs.
  • Negative control (RBCs suspended in buffer only) and positive control (RBCs lysed with deionized water) were prepared with the same cell concentration.
  • the samples were incubated at 37 °C in a shaking water bath (too rpm) for 1 h, and then centrifuged at 3500 rpm for 3 min.
  • the absorbance of the supernant from each sample was measured at 540 nm using a UV-Vis spectrophotometer (Thermo Scientific, UK) and the percentages of hemolysis were calculated. References

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Abstract

L'invention concerne un procédé de production d'un polymère, le procédé comprenant la mise en contact d'une pluralité de monomères avec un initiateur, pour provoquer la formation d'une première réaction de polymérisation, et ainsi l'obtention d'un polymère. Les monomères sont cycliques et la réaction de polymérisation est soit une réaction de polymérisation par ouverture de cycle (POC), soit une réaction de copolymérisation par ouverture de cycle (COPOC). L'invention concerne également les polymères per se et leurs utilisations.
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CN115010913A (zh) * 2022-06-17 2022-09-06 广东工业大学 一种pH/还原双重响应聚合物胶束及其制备方法与应用
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