INTRODUCTION

[0001] The present invention relates to the use of compounds in the polymerisation of cyclic esters and cyclic amides. More specifically, the invention relates to the use of ansa- metallocene compounds in the polymerisation of cyclic esters and cyclic amides.

BACKGROUND OF THE INVENTION

[0002] Poly(lactic acids) (PLAs) have been studied intensively over the past few decades due to the promise they have shown as potential alternatives to petroleum-based polymers for uses a plastics, fibres and coatings. Moreover, since PLAs are both biodegradable and biocompatible, they are of equal value to the field of medicine, wherein their versatile physical properties make them suitable for in vivo applications (e.g. as media for controlled drug delivery devices).

[0003] Lactic acid forms PLA upon polycondensation. However, the fact that this reaction is in equilibrium, and the difficulties in completely removing water, makes it difficult to obtain PLAs of high molecular weight. With this in mind, ring opening polymerisation (ROP) of lactides is the most efficient route to PLAs with controlled molecular weights and narrow molecular weight distributions.

[0004] Metal complexes useful for initiating ring opening polymerisation of lactides are known.

[0005] Wenshan Ren et al, Inorganic Chemistry Communications, 30, (2013), 26-28 report that benzyl thorium metallocenes [n ⁵ -1 ,3-(Me ₃ C)2C5H3]2 Th(CH ₂ Ph)2 (1 ) and [n ⁵ -1 ,2,4-(Me ₃ C) ₃ C5H2]2 Th(CH ₂ Ph)2 (2) can initiate the ring opening polymerisation of racemic-lactide (rac-LA) under mild conditions. Complete conversion of 500 equiv of lactide occurs within 5h at 40°C in dichloromethane at [rac-LA]=1 .0 mol L ^~ \ and the molecular weight distribution is very narrow (ca.1.15) over the entire monomer-to-initiator range, indicating a single-site catalyst system.

[0006] Yalan Ning et al, Organometallics 2008, 27, 5632-5640 report four neutral zirconocene bis(ester enolate) and non-zirconocene bis(alkoxy) complexes employed for ring-opening polymerisations and chain transfer polymerisations of L-lactide ( .-LA) and ε-caprolactone (ε- CL).

[0007] In spite of the above, due to the high value that industry places on such materials, there remains a need for catalysts/initiators capable of effectively polymerising cyclic esters (such as lactides) and cyclic amides. [0008] The present invention was devised with the foregoing in mind.

SUMMARY OF THE INVENTION

[0009] According to a first aspect of the present invention there is provided a use of a compound according to formula I defined herein in the polymerisation of cyclic esters or cyclic amides.

[0010] According to another aspect of the present invention, there is provided a process for polymerising one or more cyclic esters or cyclic amides comprising the step of polymerising one or more cyclic esters or cyclic amides in the presence of a compound of formula I defined herein.

[0011] According to another aspect of the present invention, there is provided a polymer obtainable, obtained or directly obtained by a polymerisation process defined herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0012] The term "alkyl" as used herein includes reference to a straight or branched chain alkyl moieties, typically having 1 , 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert- butyl), pentyl, hexyl and the like. In particular, an alkyl may have 1 , 2, 3 or 4 carbon atoms.

[0013] The term "alkenyl" as used herein include reference to straight or branched chain alkenyl moieties, typically having 1 , 2, 3, 4, 5 or 6 carbon atoms. The term includes reference to alkenyl moieties containing 1 , 2 or 3 carbon-carbon double bonds (C=C). This term includes reference to groups such as ethenyl (vinyl), propenyl (allyl), butenyl, pentenyl and hexenyl, as well as both the c/ ^' s and trans isomers thereof.

[0014] The term "alkynyl" as used herein include reference to straight or branched chain alkynyl moieties, typically having 1 , 2, 3, 4, 5 or 6 carbon atoms. The term includes reference to alkynyl moieties containing 1 , 2 or 3 carbon-carbon triple bonds (C≡C). This term includes reference to groups such as ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0015] The term "alkoxy" as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1 , 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, alkoxy has 1 , 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like. [0016] The term "aryl" as used herein includes reference to an aromatic ring system comprising 6, 7, 8, 9 or 10 ring carbon atoms. Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic. This term includes reference to groups such as phenyl, naphthyl and the like. Unless otherwise specification, aryl groups may be substituted by one or more substituents.

[0017] The term "aryloxy" as used herein refers to -O-aryl, wherein aryl has any of the definitions discussed herein. Also encompassed by this term are aryloxy groups in having an alkylene chain situated between the O and aryl groups..

[0018] The term "halogen" or "halo" as used herein includes reference to F, CI, Br or I. In a particular, halogen may be F or CI, of which CI is more common.

[0019] The term "substituted" as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1 , 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents. The term "optionally substituted" as used herein means substituted or unsubstituted.

[0020] It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefinic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled person.

[0021] The terms "cyclic esters" and "cyclic amides" as used herein refer to heterocycles containing at least one ester or amide moiety. It will be understood that lactides, lactones and lactams are encompassed by these terms.

Polymerisation of cyclic esters and cyclic amides

[0022] As discussed hereinbefore, the present invention provides a use of a compound according to formula I shown below in the polymerisation of cyclic esters or cyclic amides:

(I)

wherein:

Ri and R2 are each independently (1 -2C)alkyl;

R ₃ and R ₄ are each independently hydrogen or (1 -4C)alkyl, or R ₃ and R ₄ are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl, heteroaryl, carbocyclic and heterocyclic, wherein each aryl, heteroaryl, carbocyclic and heterocyclic group is optionally substituted with one or more groups selected from (1 - 6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, halo, amino, nitro, cyano, (1 - 6C)alkylamino, [(1 -6C)alkyl] ₂ amino and -S(0) ₂ (1 -6C)alkyl;

R ₅ and R ₆ are each independently hydrogen or (1 -4C)alkyl, or R ₅ and R ₆ are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl, heteroaryl, carbocyclic and heterocyclic, wherein each aryl, heteroaryl, carbocyclic and heterocyclic group is optionally substituted with one or more groups selected from (1 - 6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, halo, amino, nitro, cyano, (1 - 6C)alkylamino, [(1 -6C)alkyl] ₂ amino and -S(0) ₂ (1 -6C)alkyl;

R _a and Rb are independently selected from (1 -6C)alkyl, (1 -6C)alkoxy, (2- 6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkylamino, [(1 -6C)alkyl] ₂ amino, aryl, halo, amino, nitro and cyano;

X is selected from zirconium or hafnium; and

each Y group is independently selected from halo, hydride, a phosphonated, sulfonated or borate anion, or a (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl or aryloxy group which is optionally substituted with one or more groups selected from (1 -6C)alkyl, halo, nitro, amino, phenyl, (1 -6C)alkoxy, -C(0)NR _x R _y , or Si[(1 - 4C)alkyl] ₃ ; and

wherein R _x and R _y are independently (1 -4C)alkyl.

[0023] In an embodiment:

i) when R ₃ and R4 are hydrogen or (1 -4C)alkyl, R ₅ and Re are not linked to form a fused 6-membered aromatic ring that is substituted with four methyl groups; and ii) when R ₅ and Re are hydrogen or (1 -4C)alkyl, R ₃ and R4 are not linked to form a fused 6-membered aromatic ring that is substituted with four methyl groups.

[0024] Having regard to the proviso outlined above, it will be understood that the particular motifs not covered are as follows:

[0025] The present invention also provides a process of polymerising one or more cyclic esters or cyclic amides comprising polymerising one or more cyclic esters or cyclic amides in the presence of a compound of formula I defined herein.

[0026] It will be appreciated that the structural formula I presented above is intended to show the substituent groups in a clear manner. A more representative illustration of the spatial arrangement of the groups is shown in the alternative representation below:

[0027] It will also be appreciated that when substituents R ₃ and R ₄ are not identical to substituents R ₅ and R ₆ respectively, the compounds of the present invention may be present as meso or rac isomers, and the present invention includes both such isomeric forms. A person skilled in the art will appreciate that a mixture of isomers of the compound of formula I may be used for polymerisation, or the isomers may be separated and used individually (using techniques well known in the art, such as, for example, fractional crystallization).

[0028] If the structure of a compound of formula I is such that rac and meso isomers do exist, the compound may be present in the rac form only, or in the meso form only.

[0029] The compounds of formula I are effective initiators/catalysts in the polymerisation of cyclic esters and amides (e.g. lactides and lactams), with the resulting polymers exhibiting low polydispersity idences, thus making them highly desirable to industry.

[0030] In an embodiment, F and FU are each independently hydrogen or linear (1 -4C)alkyl, or Ri and R2 are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl, heteroaryl, carbocyclic and heterocyclic, wherein each aryl, heteroaryl, carbocyclic and heterocyclic group is optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1 -6C)alkoxy and halo.

[0031] Suitably, R3 and R4 are each independently hydrogen or linear (1 -4C)alkyl, or Ri and R2 are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted with one or more groups selected from (1 - 6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy and halo.

[0032] More suitably, R3 and R4 are each independently hydrogen or linear (1 -4C)alkyl, or Ri and R2 are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1 -4C)alkoxy, aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted with one or more groups selected from (1 -4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1 -4C)alkoxy and halo.

[0033] Even more suitably, wherein R ₃ and R4 are each independently hydrogen or linear (1 - 4C)alkyl, or Ri and R2 are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring.

[0034] Most suitably, R ₃ and R ₄ are each hydrogen.

[0035] In another embodiment, R ₅ and R ₆ are each independently hydrogen or linear (1 - 4C)alkyl, or Ri and R ₂ are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl, heteroaryl, carbocyclic and heterocyclic, wherein each aryl, heteroaryl, carbocyclic and heterocyclic group is optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy and halo.

[0036] Suitably, R ₅ and R ₆ are each independently hydrogen or linear (1 -4C)alkyl, or Ri and R ₂ are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted with one or more groups selected from (1 - 6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy and halo.

[0037] More suitably, R ₅ and R ₆ are each independently hydrogen or linear (1 -4C)alkyl, or Ri and R ₂ are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring optionally substituted with one or more groups selected from (1 -4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1 -4C)alkoxy, aryl or heteroaryl, wherein each aryl or heteroaryl group is optionally substituted with one or more groups selected from (1 -4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1 -4C)alkoxy and halo.

[0038] Even more suitably, wherein R ₅ and R ₆ are each independently hydrogen or linear (1 - 4C)alkyl, or Ri and R ₂ are linked such that, when taken in combination with the atoms to which they are attached, they form a 6-membered fused aromatic ring.

[0039] Most suitably, R ₅ and R ₆ are each hydrogen.

[0040] In a particularly suitable embodiment, R3, R4, R5, and Re are hydrogen.

[0041] In another embodiment, Ri and R ₂ are each independently (1 -2C)alkyl. Suitably, Ri and R ₂ are both methyl.

[0042] In another embodiment, X is Zr.

[0043] In another embodiment, each Y is independently selected from halo, hydride, a phosphonated, sulfonated or borate anion, or a (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 - 6C)alkoxy, aryl or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 -4C)alkyl.

[0044] Suitably, each Y is independently selected from halo, hydride, or a (1 -6C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 -4C)alkyl.

[0045] More suitably, each Y is independently selected from halo, or a (1 -6C)alkoxy, or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 - 4C)alkyl. [0046] Even more suitably, each Y is independently selected from CI, Br, I or a group -OR ₇ , wherein R ₇ is a phenyl group optionally substituted with one or more R ₈ , wherein each R ₈ is independently (1 -4C)alkyl. For example the group -OR? may have the following structure:

[0047] In a particular embodiment, both Y groups are CI, or one Y is CI and the other Y is a group -OR ₇ having the structure shown above.

[0048] In another embodiment, R _a and Rb are each independently (1 -6C)alkyl or (2-6C)alkenyl. Suitably, R _a and Rb are each independently (1 -4C)alkyl. More suitably, R _a and Rb are each methyl.

[0049] In another embodiment, the compound of formula I has a structure according to formula la, lb or Ic shown below:

wherein

X, Y, R _a and Rb have any of the definitions set out hereinbefore;

Ri and R ₂ are independently selected from (1 -2C)alkyl;

R ₃ , R4, R5 and R ₆ are each independently selected from hydrogen, (1 -4C)alkyl, (2- 4C)alkenyl and (2-4C)alkynyl; and

each R ₉ , R10 and R is independently selected from (1 -6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1 -6C)alkoxy, aryl, heteroaryl, carbocyclic and heterocyclic, wherein each aryl, heteroaryl, carbocyclic and heterocyclic group is optionally substituted with one or more groups selected from (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, halo, amino, nitro, cyano, (1 -6C)alkylamino, [(1 -6C)alkyl] ₂ amino and -S(0) ₂ (1 -6C)alkyl.

[0050] In another embodiment, the compound of formula I has a structure according to formula la, lb or lc, wherein

X is Zr;

each Y is independently selected from halo, or a (1 -6C)alkoxy, or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 -4C)alkyl;

R _a and Rb are each independently (1 -2C)alkyl;

Ri and R ₂ are independently selected from (1 -2C)alkyl

R ₃ , R4, R5 and R ₆ are each independently selected from hydrogen or (1 -4C)alkyl; and each R ₉ , R10 and R is independently selected from (1 -6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1 -6C)alkoxy, aryl, heteroaryl, carbocyclic and heterocyclic, wherein each aryl, heteroaryl, carbocyclic and heterocyclic group is optionally substituted with one or more groups selected from halo, (1 -4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl.

[0051] In another embodiment, the compound of formula I has a structure according to formula la' shown below:

(la') wherein

Ri and R ₂ are each independently (1 -2C)alkyl;

X is Zr or Hf;

R _a and Rb are each independently (1 -6C)alkyl or (2-6C)alkenyl; and

each Y is independently selected from halo, hydride, or a (1 -6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1 -6C)alkoxy, aryl or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 -4C)alkyl.

[0052] Suitably, the compound of formula I has a structure according to formula la' wherein Ri and R ₂ are each independently (1 -2C)alkyl

X is Zr

R _a and Rb are each independently (1 -3C)alkyl; and

each Y is independently selected from halo, or a (1 -6C)alkoxy, or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 -4C)alkyl.

[0053] In another embodiment, the compound of formula I has a structure according to formula la" shown below:

(la")

wherein

Ri and R ₂ are each independently (1 -2C)alkyl

X is Hf or Zr

R _a and Rb are each independently (1 -6C)alkyl or (2-6C)alkenyl; and

each Y is independently selected from halo, hydride, or a (1 -6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1 -6C)alkoxy, aryl or aryloxy group which is optionally substituted with one or more groups selected from halo and (1 -4C)alkyl. [0054] Suitably, the compound of formula I has a structure according to formula la" wherein Ri and R ₂ are each independently (1 -2C)alkyl

X is Zr

R _a and Rb are each independently (1 -3C)alkyl; and

each Y is independently selected from CI, Br, I or (1 -4C)alkyl.

[0055] In a particular embodiment, the compound of formula I is selected from any of the structures appearing below:

[0056] In another embodiment, the compound of formula I is used with a suitable activator. Suitable activators are well known in the art and include alcohols Particularly suitable activators include linear alcohol, tert-butanol, phenol, and benzyl alcohol.

[0057] In another embodiment, the cyclic amides and cyclic esters have a structure according to the general formula II below:

(II)

wherein

Q is selected from O or NR _Z , wherein R _z is selected from H, (1 -6C)alkyl, (2-6C)alkenyl or (2-6C)alkynyl; and

Ring A is a 3-16 membered heterocycle containing 1 or 2 ring heteroatoms in total, wherein the heterocycle may be optionally substituted with one or more suitable substituents selected from oxo, (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl and heteroaryl.

[0058] It will be understood that the one or more cyclic esters and cyclic amides may be identical (e.g. all caprolactone) or different (e.g. a mixture of different cyclic esters and/or cyclic amides). Accordingly, the compounds of the invention may be used for the homopolymerisation or copolymerisation of cyclic esters and cyclic amides.

[0059] Suitably, the cyclic amides and cyclic esters are selected from lactides, lactones (e.g. caprolactone), and lactams.

[0060] It will be appreciated by one of skill in the art that there are three stereoisomers of lactide, shown below, all of which are encompassed by the invention :

D- lactide {R,R) L- lactide (S,S) meso- lactide {R,S)

[0061 ] Suitably, the lactide is L-lactide.

[0062] It will also be appreciated that the term lactam encompasses β-lactams (4 ring members), γ-lactams (5 ring members), δ-lactams (6 ring members) and ε-lactams (7 ring members).

[0063] It will also be appreciated that the term lactone encompasses a-acetolactone, β- propiolactone, γ-butyrolactone, and δ-valerolactone, ω-pentadecalactone and ε-decalactone.

[0064] In an embodiment, ring A is a 3-8 membered heterocycle containing 1 or 2 ring heteroatoms in total, wherein the heterocycle may be optionally substituted with one or more suitable substituents selected from oxo, (1 -6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1 -6C)alkoxy, aryl and heteroaryl.

Synthesis of compounds

[0065] The compounds of formula I may be synthesised by any suitable process known in the art. Particular examples of processes for preparing compounds of formula I are set out in the accompanying examples.

[0066] Suitably, compounds of formula I may be prepared by:

(i) reacting a compound of formula A:

(wherein Ri , R ₂ , R3, R4, R5, Re, Ra and Rb are each as defined hereinbefore and M is Li, Na or K)

with a compound of the formula B:

X(Y') ₄

B

(wherein X is as defined hereinbefore and Y' is halo (particularly chloro or bromo)) in the presence of a suitable solvent to form a compound of formula C:

and optionally thereafter:

(ii) reacting the compound of formula C above with MY" (wherein M is as defined above and Y" is a group Y as defined herein other than halo), in the presence of a suitable solvent to form the compound of the formula D shown below

D

Suitably, M is Li in step (i) of the process defined above.

[0067] Suitably, the compound of formula B is provided as a solvate. In particular, the compound of formula B may be provided as X(Y') ₄ .THFp, where p is an integer (e.g. 2).

[0068] Any suitable solvent may be used for step (i) of the process defined above. A particularly suitable solvent is toluene or THF.

[0069] If a compound of formula (I) in which Y is other than halo is required, then the compound of formula C above may be further reacted in the manner defined in step (ii) to provide a compound of formula D.

[0070] Any suitable solvent may be used for step (ii) of the process defined above. A suitable solvent may be, for example, diethyl ether, toluene, THF, dicloromethane, chloroform, hexane DMF, benzene etc.

[0071] Compounds of formula A may be generally prepared by

i) Reacting a compound of formula E

E

(wherein M is lithium, sodium, or potassium; and Ri and R ₂ are as defined hereinbefore) with one equivalent of a compound having formula F shown below: Si(Ra)(Rb)(CI) ₂

F

(wherein R _a and Rb are as defined hereinbefore)

to form the compound of the formula G shown below:

G ii) Reacting the compound of formula G with a compound of formula H shown below:

H

(wherein R ₃ , R4, R5 and R ₆ are as defined hereinbefore, and M is lithium, sodium or potassium).

[0072] Compounds of formulae E and H can be readily synthesized by techniques well known in the art.

[0073] Any suitable solvent may be used for step (i) of the above process. A particularly suitable solvent is THF.

[0074] Similarly, any suitable solvent may be used for step (ii) of the above process. A suitable solvent may be, for example, toluene, THF, DMF etc.

[0075] A person of skill in the art will be able to select suitable reaction conditions (e.g. temperature, pressures, reaction times, agitation etc.) for such a synthesis. EXAMPLES

[0076] Particular examples of the invention will now be described, for illustrative purposes only, with references to the accompanying figures, in which:

Fig. 1 shows polymerisation plots of lactide conversion in function of time using SB(Cp,l*)ZrCl2 (square), SB(Cp,l ^* )HfCI ₂ (circle) and SB(Cp,l ^* )ZrCI(0-2,6-Me2-C ₆ H ₃ ) (triangle). Data points are an average of the results for each temperature.

Fig. 2 shows MALDI-TOF mass spectrum of PLA produced from SB(Cp,l ^* )ZrCI ₂ and (S,S)-LA. Polymerisation conditions: 80 °C, [LA] ₀ :[ SB(Cp,l ^* )ZrCI ₂ ] of 20:1 , [LA] ₀ = 0.5 M, c/i-chloroform.

Fig. 3 shows Polymerisation plots of lactide conversion in function of time using SB(Cp,l ^* )ZrCI ₂ (square), SB(Cp,l ^* )HfCI ₂ (circle) and SB(Cp,r)ZrCI(0-2,6-Me2-C ₆ H ₃ ) (triangle). Data points are an average of the results for each temperature.

Fig. 4 shows an Eyring-Polanyi plot for the polymerisation of (S,S)-lactide with SB(Cp, )ZrCI ₂ . Data points are an average of the results for each temperature, error bars are calculated to one standard deviation.

Fig. 5 shows a double logarithmic plot of variation of concentration of SB(Cp, )ZrCI ₂ with k _obs for (S,S)-lactide.

Example 1 a - Synthesis of SB(Cp,l*)ZrCI ₂

in£S ^* )Si¾te ₂ Ci S8{CpJ ⁴ )ZrCi ₂

[0077] Toluene (40 ml) was added to a LiCp (246 mg, 3.41 mmol) and lnd ^* SiMe ₂ CI (1 g, 3.41 mmol) in a Schlenk tube, dissolved in -5 °C THF (50 ml.) and left to stir for two hours. "BuLi (4.7 mL, 1 .6 M in hexanes, 7.51 mmol) was added, dropwise, over 30 minutes and the reaction left to stir for 12 hours. The solvent was removed in vacuo and the residue washed with pentane (3 x 40 mL) and dried to afford a grey powder. One equivalent of ZrCU (796 mg, 3.41 mmol) was added and the mixture dissolved in benzene and left to stir for sixty hours. The solution changed colour from green, to orange and finally red/brown. The solvent was removed under vacuum and the product extracted with pentane (3 x 40 mL) and filtered through Celite. The filtrate was concentrated in vacuo and stored at -34 °C. This yielded SB(Cp,l ^* )ZrCl2 as an orange/brown precipitate in 23% yield (365 mg, 0.76 mmol). Orange crystals, suitable for single crystal X-ray diffraction, were grown from a concentrated solution in hexanes at -34 °C.

¹ H NMR (cie-benzene): δ 6.59 (2H, dm, CpH), 5.60 (2H, dm, CpH), 2.52 (3H, s, ArMe), 2.48 (3H, s, ArMe), 2.26 (3H, s, ArMe), 2.15 (3H, s, ArMe), 2.05 (3H, s, ArMe), 1.97 (3H, s, ArMe), 0.72 (3H, s, SiMe), 0.64 (3H, s, SiMe).

¹³ C{ ¹ H} NMR (^benzene): δ 135.65 (Ar), 135.13 (Ar), 134.86 (Ar), 131 .1 1 (Ar), 131 .50 (Ar), 131 .15 (Ar), 129.16 (Ar), 126.35 (Ar), 125.92 (ArSi), , 1 15.87 (CpH), 106.49 (CpH), 84.01 (CpSi), 21 .69 (ArMe), 17.91 (ArMe), 17.64 (ArMe), 17.16 (ArMe), 16.92 (ArMe), 15.97 (ArMe), 5.59 (SiMe), 3.26 (SiMe).

MS (El): Predicted: m/z 482.0372. Observed: m/z 482.0371 . IR (KBr) (cm ¹ ): 2961 , 2925, 1543, 1260, 1029, 809, 668.

CHN Analysis (%): Expected: C 54.74, H 5.85, Found: C 54.85, H 5.94.

Example 1 b - Synthesis of SB(Cp,l ^* )HfCI ₂

SB(Cp,l*}Li ₂ SB(Cp,r)HfC¾

24% yield

[0078] SB(Cp,l ^* )Li ₂ (1 g, 2.99 mmol) and HfCU (958 mg, 2.99 mmol) were added to a Schlenk tube. Benzene (100 mL) was added and the reaction was left to stir for 60 hours. The solution changed colour from brown to yellow. The solvent was the removed under vacuum and the product was extracted with pentane (3 x 40 mL) and filtered through Celite. The filtrate was concentrated in vacuo and stored at -34 °C yielding SB(Cp,l ^* )HfCl2 as yellow crystals, suitable for single crystal X-ray diffraction, in 24% yield (360 mg, 0.632 mmol).

¹ H NMR (cie-benzene): δ 6.54 (3H, dm, CpH), 5.53 (3H, dm, CpH), 2.57 (3H, s, ArMe), 2.56 (3H, s, ArMe), 2.25 (3H, s, ArMe), 2.20 (3H, s, ArMe), 2.09 (3H, s, ArMe), 2.03 (3H, s, ArMe), 0.65 (3H, s, SiMe), 0.57 (3H, s, SiMe). ¹³ C{ ¹ H} NMR (^benzene): δ 134.55 (Ar), 134.18 (Ar), 133.51 (Ar), 131 .73 (Ar), 131 .05 (Ar), 129.64 (Ar), 126.23 (Ar), 125.18 (Ar), 124.38 (Ar), 1 13.33 (C _P H), 107.32 (C _P H), 82.33 (C _p Si), 21 .53 (ArMe), 17.68 (ArMe), 17.37 (ArMe), 16.77 (ArMe), 16.64 (ArMe), 15.51 (ArMe), 5.00 (SiMe), 3.00 (SiMe).

MS (El): Predicted: m/z 570.0785. Observed: m/z 570.0701 . IR (KBr) (cm ¹ ): 2960, 2923, 1542, 1262, 1028, 812, 670.

CHN Analysis (%): Expected: C 46.36, H 4.95, Found: C 46.52, H 5.04.

Example 1 c - Synthesis of SB(Cp,l ^* )ZrCI(0-Me2-C ₆ H ₃ )

[0079] SB(Cp,l ^* )ZrCI ₂ (100 mg, 0.207 mmol) and 2,6-dimethyl potassium phenoxide (66 mg, 0.414 mmol) were added to a Schlenk tube, dissolved in benzene (20 mL), and left to stir for sixteen hours. The solvent was removed in vacuo and the product extracted with pentane (2 x 20 mL). The ¹ H NMR spectra showed resonances corresponding to a mixture of two isomers. Thin, yellow crystals of isomer (a), suitable for single crystal X-ray diffraction were obtained when the solution was concentrated and stored in a -34 °C freezer. Purity was 94% by ¹ H NMR spectroscopy and crystals were obtained in 15% yield (16 mg, 0.028 mmol).

Isomer (a):

Ή NMR ( /e-benzene): δ 7.06 (2H, dd, Ar _phe nH), 6.82 (1 H, t, Ar _phe nH), 6.26 (1 H, m, CpH),

6.13 (1 H, m, CpH), 5.93 (1 H, m, CpH), 5.61 (1 H, m, CpH), 2.34 (3H, s, ArMe), 2.24 (3H, s, ArMe), 2.22 (6H, s, Ar _phe nMe), 2.19 (3H, s ,ArMe), 2.18 (3H, s, ArMe), 2.15 (3H, s, ArMe), 1.99 (3H, s, ArMe), 0.81 (3H, s, SiMe), 0.75 (3H, s, SiMe).

Isomer (b):

¹ H NMR (de-benzene): δ 6.88 (2H, dd, Ar _phe nH), 6.69 (1 H, t, Ar _phe nH), 6.51 (1 H, m, CpH), 6.02 (1 H, m, CpH), 5.88 (1 H, m, CpH), 5.80 (1 H, m, CpH), 2.61 (3H, s, ArMe), 2.42 (6H, s, Ar _P henMe), 2.40 (3H, s, ArMe), 2.08 (3H, s, ArMe), 1.99 (3H, s, ArMe), 1 .64 (3H, s, ArMe), 1.48 (3H, s, ArMe), 0.64 (3H, s, SiMe), 0.61 (3H, s, SiMe). Example 2 - lactide polymerisation

[0080] Polymerisations were carried out in Young's tap NMR tubes containing 40 mg, 0.278 mmol of either L-lactide or rac-lactide in a solution with an amount of initiator to correspond to an initiator/lactide ratio of 50:1 . The reaction was followed by ¹ H NMR spectroscopy comparing the integration values of the methine signals of PLA and LA. All polymerisations were worked up by decanting into -5 °C pentane (10 mL), removing the pentane, washing the resultant polymer with diethyl ether (10 mL) and drying under vacuum for 18 hours.

[0081] Polymerisation studies were carried out using SB(Cp,l ^* )ZrCI ₂ and SB(Cp,l ^* )HfCI ₂ in the presence of two equivalents of benzyl alcohol as a co-initiator, which is postulated to form the bis(benzyl alkoxide) in situ and a mixture of mono(alkoxide) complexes SB(Cp,l ^* )ZrCI(0-2,6- Me2-C ₆ H ₃ ) without a co-initiator.

[0082] In order to compare the activities of these complexes, all initial polymerisation studies were carried out at 80 °C in c/i -chloroform, with an S,S-LA: initiator ratio of 50:1 , ensuring that [S,S-LA]= 0.5 M.

Table 1. Rate constants and GPC data for ring-opening polymerisation of S,S-LA with selected initiators.

Initiator fobs (h- ¹ ) i.exp (gmor ¹ ) PDI (Mw/Mn)

SB(Cp,l ^* )ZrCI ₂ 0.231 7 4071 1 .1 0

SB(Cp,l ^* )HfCI ₂ 0.2262 3826 1 .1 1

SB(Cp,l ^* )ZrCI(OR) 0.2081 1 8032 1 .30

[0083] The results shown in Table 1 and Fig. 1 demonstrate that SB(Cp,l ^* )ZrCI ₂ displays the highest activity with 88% conversion in seven hours {k _obs = 0.231 7 ± 0.0058 h ¹ ), closely followed by SB(Cp,l ^* )HfCI ₂ with 81 % conversion in six hours (Aobs = 0.2262 ± 0.01 47 IT ¹ ) while SB(Cp,r)ZrCI(0-2,6-Me ₂ -C ₆ H3) was slower with 66 % conversion in 5 hours (k _ob s = 0.2081 ± 0.0055 h ^"1 ). The values of 1 .1 0 and 1 .1 1 for SB(Cp,l ^* )ZrCI ₂ and SB(Cp,l ^* )HfCI ₂ show that polymerisation is well controlled for these. The value reported for SB(Cp,l ^* )ZrCI(0-2,6-Me ₂ - C ₆ H ₃ ) is slightly higher but is still considered controlled; the higher value could be attributed to the mixture of isomers used in the polymerisation. [0084] The MALDI-TOF mass spectrum of the polymer produced when (S,S)- LA was polymerised with SB(Cp, )ZrCI ₂ and benzyl alcohol shows a series of peaks which are m/z = 72 apart (Fig. 2).

[0085] Fig. 3 shows a plot of ln([LA] ₀ /[LA] _t ) against time using SB(Cp,l ^* )ZrCI ₂ and SB(Cp,l ^* )ZrCI ₂ with 2 equivalents of benzyl alcohol, and SB(Cp,l ^* )ZrCI(0-2,6-Me ₂ -C ₃ H ₆ ) in the absence of a co-initiator, at 80 °C with an initial rac-lactide concentration of 0.5 M.

Table 2. Rate constants and GPC data for ring opening polymerisation of rac-LA with selected initiators.

Initiator fcbs (h- ¹ ) /Wn.ex (gmor ¹ ) PDI (MJMn)

SB(Cp,r)ZrCI ₂ 0.3948 17826 1.07

SB(Cp,l ^* )HfCI ₂ 0.0258 - -

SB(Cp,l ^* )ZrCI(OR) 0.2617 15981 1.18

[0086] Table 2 shows that SB(Cp,l ^* )ZrCI ₂ catalyses rac-LA the fastest, k _obs = 0.3948 h ¹ , shortly followed by SB(Cp,r)ZrCI(0-2,6-Me ₂ -C ₃ H ₆ ), k _obs = 0.2617 h ¹ . The PDI value of 1 .07 for SB(Cp,l ^* )ZrCI ₂ is very low when compared with literature. SB(Cp,r)ZrCI(0-2,6-Me ₂ -C ₃ H ₆ ) shows slightly less control, compared to SB(Cp, )ZrCI ₂ and SB(Cp, )HfCI ₂ , over the molecular weight with a PDI of 1.18 (which is still considered controlled).

[0087] The effect of temperature on the rate constant and GPC data for ring-opening polymerisation of S,S-Lactide with SB(Cp, )ZrCI ₂ was also investigated. The results are outlined in Table 3 below:

Table 3. Rate constants and GPC data for ring-opening polymerisation of S,S-Lactide with

SB(Cp, )ZrCI ₂ at variable temperatures initiators.

Temp/ °C /Cobs/ h ^_1 Mi, exp/ gmol ^"1 PDI (Kv/Mn)

60 0.0731 - -

70 0.1252 3190 1 .08

80 0.2317 3870 1 .1 1

90 0.3033 5046 1 .13 [0088] A plot of ln(k _obs /T) against 1/T (Fig. 4) gives a linear plot with gradient of -AHVR and an intercept of AS*/R + ln(ke/h). The lactide: initiator ratio was kept at 50:1 maintaining an initial (S,S)-lactide concentration of 0.5 M. The value of ΔΗ* obtained from this study is -49 ± 4 kJmol ^"1 , the value obtained for AS* was -188 ± 9 Jmol ¹ K ^~1 again this is well within the values in the literature, with the negative sign indicating the transition state has a higher degree of order than the starting material, as is to be expected for a coordination-insertion mechanism.

[0089] A further study was undertaken to investigate how the zirconium concentration affected the overall polymerisation rate. A constant concentration of 0.5 M of (S,S)-lactide was used and lactide:initiator ratios of 10:1 , 25:1 , 50:1 and 100:1 were used ([Zr]= 0.05, 0.02, 0.01 and 0.005 M respectively).

[0090] The double logarithmic plot of ln[Zr] against ln[ ₀ bs] (Fig. 5) reveals a straight line plot with slope of 0.9. As expected for a first order rate law the rate, k _obs , increases with increasing initiator concentration as there are more active species present to polymerise the monomer.

[0091] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.