WO2002038574A1

WO2002038574A1 - Diamido alkoxides as polymerisation initiators

Info

Publication number: WO2002038574A1
Application number: PCT/GB2001/004969
Authority: WO
Inventors: Vernon Charles Gibson; Edward Leslie Marshall; Andrew Peter Dove
Original assignee: Imperial College Innovations Ltd
Current assignee: Ip2ipo Innovations Ltd
Priority date: 2000-11-10
Filing date: 2001-11-08
Publication date: 2002-05-16
Anticipated expiration: 2003-05-10
Also published as: DE60117039D1; EP1332148B1; DE60117039T2; JP2004513175A; US20050004384A1; EP1332148A1; ATE316974T1; GB0027530D0; US7026496B2; AU2002214141A1

Abstract

The present invention relates to a complex having the formula (I) wherein M is selected from Sn(II), Sn(IV), Al(III) and Mg(II); each of R?1 and R2¿ is independently hydrocarbyl; R3 is H or hydrocarbyl; and X is a linker group. A further aspect of the invention relates to the use of said complex as a polymerisation initiator, particularly in the polymerisation of lactides.

Description

DIAMIDO ALKOXIDES AS POLYMERISATION INITIATORS

The present invention relates to a series of discrete, well-defined coordination complexes. More specifically, the invention relates to complexes that are useful as polymerisation initiators, and in particular, in lactide polymerisation.

Over recent years, there has been an increasing interest in the design of polymers for in vivo applications such as sutures, artificial tissue networks and drug delivery agents. For these applications it is desirable for the polymer to be non-toxic, biocompatible and resorbable. One of the most promising classes of polymer in this field are the pofy(lactide)s [J.C. Middleton, AJ. Tipton, Biomaterials, 2000, 21, 2335].

Initiators for lactide polymerisation are typically based on alkoxide or alkanoate complexes of metals such as Al, Mg, Sn, Zn and the rare earths. Tin(II) catalysts such as Sn(ethylhexanoate) are generally preferred in the commercial production of poly(lactide)s [E.E. Schmitt and R.A. Rohistina, US Patent 3297033, 1967 (Chem. Abstr. 1967, 66, P38656u); E.E. Schmitt and R.A. Rohistina, US Patent 3463158, 1969 (Chem. Abstr. 1969, 71, P92382t); H.R. Kricheldorf, I. Kreiser-Saunders and C. Boettcher, Polymer, 1995, 36, 1253, and references therein] for medical or pharmaceutical applications due to the low toxicity of Sn(II) compared to other metal ions. Indeed, Sn(ethylhexanoate)₂ is a permitted food additive in many countries.

To date, the ring opening polymerisation of cyclic ethers and esters are usually carried out with the aid of so-called "coordinate catalysts" which are ill-defined with regard to their exact mechanism and structure. In the polymerisation of lactide, the exact structure and detailed mode of reaction of the above-mentioned tin carboxylates, M(O₂CR)₂, are not fully understood. Indeed, some evidence suggests that the active species in the polymerisation of lactides using tin octanoates may actually be a hydrolysis product, present only as a minor component. A number of systems that initiate the living ring-opening polymerisation of lactide have been disclosed in the art. By way of example, systems based on aluminium [P. Dubois, C. Jacobs, R. Jerome, P. Teyssie, Macromolecules 1991, 24, 2266; P.A. Cameron, D. Jhurry, N.C. Gibson, AJ.P. White, DJ. Williams, S. Williams, Macromol. Rapid. Commun. 1999, 20, 616; Ν. Spassky, M. Wisniewski, C. Pluta, A. LeBorgne, Macromol. Chem. Phys. 1996, 197, 2627], and more recently, magnesium [M.H. Chisholm, Ν.W. Eilerts, J. Chem. Soc, Chem. Commun., 1996, 853] and zinc [M. Cheng, A.B. Attygalle, E.B. Lobkovsky, G.W. Coates, J. Am. Chem. Soc. 1999, 121, 11583], have all been described.

Another important advance in modern polymer synthesis is the control achievable over the tacticity of polymers derived from prochiral monomers or monomers bearing stereogenic centres. This is most dramatically exemplified by the family of propylenes obtained using / ra-metallocene polymerisation catalysts, leading to materials with new and markedly different properties.

By comparison, relatively little research has been directed towards poly(lactide)s derived from the polymerisation of rac- and rneso-lactides, which are the cyclic diesters of lactic acid. These are gaining increasing attention due to their medicinal, pharmaceutical and agricultural applications as well as uses as environmentally benign packaging materials.

rac-lactide meso-lactide

Unsurprisingly, the physical properties of the poly(lactide)s are also strongly dependent upon their tacticity. For example, isotactic poly(R-R-lactide) is a semi- crystalline thermoplastic of high mechanical strength and toughness (Tg ~ 57°C, Tm ~ 174°C), while syndiotactic poly(R,S-lactide) has a lower softening temperature (Tg ~ 45°C, Tm ~ 152°C) and has found applications in controlled drug release. Atactic poly(lactide), usually obtained upon polymerisation of rαc-(R, R/S,S)-lactide is an amorphous polymer with a glass transition temperature near room temperature.

In recent years there have been a number of studies on the stereoselective polymerisation of lactide monomers using single-site catalysts. Spassky and co- workers have described the selective polymerisation of one of the enantiomers of rαc-lactide (essentially a kinetic resolution) to isotactic poly(lactide) using a resolved tetradentate Schiff base complex of aluminium [Spassky et al, ibid]. Baker and Smith have shown that a racemic mixture of a similar complex can be used to polymerise both enantiomers of rαc-lactide to the isotactic stereocomplex which has the added advantage of possessing a melting point approximately 50°C higher than the homochiral polymers [C. P. Radano, G.L. Baker, M.R. Smith III, J. Am. Chem. Soc. 2000, 122, 1552]. Moreover, studies on meso-lactide have revealed that syndiotactic poly(lactide) can also be obtained [Cheng et al, ibid]. The aluminium catalyst systems, however, tend to give low rates of propagation, and more highly active catalysts would be beneficial for the commercial production of such materials. A significant development was the recent introduction of a zinc catalyst bearing β- diketiminate ligands which acts as a highly efficient catalyst for the polymerisation of rαc-lactide to heterotactic poly(lactide) via a chain end control mechanism [Cheng et al, ibid].

The present invention seeks to provide alternative, well-defined, single-site metal complexes that are suitable for use as polymerisation initiators. More specifically, the invention seeks to provide well-defined complexes that are suitable for initiating the polymerisation of lactide.

In a broad aspect, the present invention provides a series of well-defined metal complexes.

More specifically, the invention provides a complex having the formula I

I wherein M is selected from Sn(II), Sn(IV), A1(III) and Mg(II); each of R¹ and R² is independently hydrocarbyl; R is H or hydrocarbyl; and X is a linker group.

Preferably, each of R¹, R² and R³ is independently hydrocarbyl.

As used herein, the term "hydrocarbyl" refers to a group comprising at least C and H that may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo-, alkoxy-, nitro-, an alkyl group, or a cyclic group. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain heteroatoms. Suitable heteroatoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen, oxygen, phosphorus and silicon.

In a preferred aspect of the invention, the linker group X comprises a d-₄ carbon backbone, or a heteroatom-containing Cμ carbon backbone. Preferably, the linker group X is a C₂ or C₃ carbon backbone.

In a further preferred aspect of the invention, each of R and R is independently selected from alkyl, cycloalkyl, haloalkyl, aryl, haloaryl or heteroaryl; and R³ is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl or haloaryl. As used herein, the term "alkyl" refers to a saturated carbon-containing chain which may be straight or branched, and substituted (mono- or poly-) or ^substituted.

Suitable substituents include those which do not have any significant adverse effect on the activity of the complex as a polymerisation initiator.

Preferably, the alkyl group is a Cι-₂₀ alkyl group, more preferably a Cj.io alkyl group.

Accordingly, the term "haloalkyl" refers to an alkyl group substituted by at least one halogen, for example, chlorine, bromine, fluorine or iodine.

As used herein, the term "aryl" refers to an aromatic, substituted (mono- or poly-) or unsubstituted. Again, suitable substituents include those which do not have any significant adverse effect on the activity of the complex as a polymerisation initiator.

Accordingly, the term "haloaryl" refers to an aryl group substituted by a halogen, for example, chlorine, bromine, fluorine or iodine.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group.

As used herein, the term "heteroaryl" refers to an aromatic heterocycle comprising one or more heteroatoms. Preferred heteroaryl groups include pyrrole, pyrimidine, pyrazine, pyridine, quinoline and furan.

In a preferred aspect, the linker group X is conjugated.

In one preferred aspect of the invention, the linker group X comprises a vinylene or an arylene group.

In a preferred aspect, the complex of the invention has the formula II,

wherein each of R⁴, R⁵ and R⁶ is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl and heteroaryl, and R^1"3 and M are as defined hereinbefore.

In a more preferred aspect of the invention, each of R⁴, R⁵ and R⁶ is independently selected from H, methyl, t-butyl, phenyl and trifluoromethyl. Even more preferably, R⁵ is H and R⁴ and R⁶ are alkyl, more preferably methyl.

The skilled person will appreciate that where the metal is A1(III), the complex will have an overall charge of 1+, and where the metal is Sn (IN), the ligand will be dianionic and the complex will have an overall charge of 1+. Accordingly, when the metal is Sn(II) or Mg(II), the complex is neutral.

In one particularly preferred aspect, M is Sn(II).

In another particularly preferred aspect, M is Mg(II).

In one particularly preferred embodiment, the complex of the invention has the formula III

wherein Ar is o-diisopropylphenyl.

In contrast to the ill-defined tin "coordinate catalysts" of the prior art, the present invention provides a tin complex with a well-defined structure that is suitable for use as a polymerisation initiator.

The complex of formula III is prepared according to the scheme shown in Figure 1. Treatment of SnCl₂ with [HC{C(Me)NAr}₂]Li in diethylether followed by crystallisation from pentane affords [HC{C(Me)NAr}₂]SnCl, Ilia as a yellow crystalline solid. This is converted to III by treatment with LiOPr¹ followed by re- crystallisation from pentane. Crystals of III suitable for an X-ray structure determination were grown from pentane; the structure is shown in Figure 2. Further details of the X-ray structure may be found in the accompanying examples.

The complex of formula III has non-crystallographic C_s symmetry with the three- coordinate tin atom adopting a tripodal geometry with inter-bond angles in the range 83.6(2) - 94 J (2)°, the most acute being associated with the bite of the chelating N,N' ligand. The Sn-N and Sn-O distances are unexceptional, and there is the expected pattern of delocalisation within the β-diketiminate ligand. The six-membered chelate ring has a boat conformation with C(2) and Sn lying 0J2 and 0.87 A "above" the N(l), C(l), C(3), N(3) plane; the isopropoxide oxygen atom lies 0.74 A "below" this plane. As a consequence of the folded chelate ring conformation, and retention of near trigonal planar geometries at the two nitrogen centres, the C(12) and C(27) isopropyl groups are drawn together, and those associated with C(15) and C(24) are folded away exposing the non-coordinated "face" containing the stereochemically active lone pair on the tin atom; the shortest intermolecular approach to the tin centre

A further aspect of the present invention relates to the use of the above-described complexes as polymerisation initiators.

As used herein, the term "polymerisation initiator" refers to an agent used to start the polymerisation of a monomer.

In a preferred aspect, the invention relates to the use of the complexes described herein as initiators in the polymerisation of lactide. The term "lactide" encompasses rαc-lactide, meso-lactide and the resolved L and D forms of lactide.

In particular, the complexes of the invention may be used as initiators in the "living polymerisation" of lactide. As used herein, the term "living polymerisation" refers to a polymerisation in which there is no termination step, i.e. the initiator complex is associated with the end of the propagating polymer chain and is not released.

Even more preferably, the lactide is in the form of rαc-lactide. As used herein, the term "rαc-lactide" refers to a racemic mixture of L (S,S) and D (R,R) lactide.

By way of example, the polymerisation of rαc-lactide was initially investigated using complex III in CH₂C1₂ at ambient temperature. Under these conditions it was found that 100 equivalents of monomer required 96 hours for complete conversion (>99% by 1H NMR). The resultant polymer has a molecular weight close to that calculated from the monomer nitiator ratio (observed Mi = 17,100; calculated Mi = 14,400) and exhibits a narrow polydispersity (MJM_n = 1.11), characteristics of a living process. The polymerisation was then repeated at 60°C in toluene affording 85% conversion after 4 hours, again resulting in a narrow molecular weight distribution product (M_w/M_n = 1.05). The activity of the tin catalyst is lower than that observed for the related zinc system [Cheng et al, ibid] which may be in part due to the lower electrophilicity of the tin centre, and partly a consequence of the stereochemically active lone pair which may disfavour monomer binding. The living characteristics of the polymerisation are confirmed by the linear increase in M_n with conversion giving in each case a low polydispersity product (Figure 3).

In order to confirm that the initiator is indeed the wo-propoxide complex III, a 1H NMR study was carried out in which increasing amounts of lactide were added to III in CDCI₃. The t^'sO-propoxide methine septet resonance at the end of the propagating chain is shifted slightly to higher frequency (0.005ppm) relative to the unconsumed initiator (54.01). New resonances for the β-diketiminate ligand substituents are also observed for the propagating species. As the number of monomer equivalents is increased, the intensities of the signals attributable to the propagating species increase relative to those of unconsumed III. Due to the overlapping nature of the resonances, accurate integration has not been possible, but the addition of 5 equivalents of monomer leads to an approximately 1 :1 mixture of initiator: propagating species. This indicates a favourable kp/ki ratio (the rate constant of propagation to rate constant of initiation) which is desirable for minimising the polydispersity.

The 1H NMR spectrum of the poly(lactide) derived from III (Figure 4) differs from the spectrum predicted from a Bernouillian analysis of totally random poly(rac- lactide), with the rmr and mrm tetrads much more intense than expected. These observations are consistent with a heterotactic-biased product since the rmr microstructure can only arise from two consecutive D-L or L-D interchanges; each rmr tetrad is accompanied by two mrm tetrads in agreement with the NMR integration. This represents the first example of tacticity bias arising from the polymerisation of rαc-lactide using a tin catalyst.

As used herein, the term "heterotactic" refers to a polymer in which the adjacent monomer units alternate in the form [-L-D-L-D-L-D...]. A true heterotactic polymer is one in which the monomer units alternate perfectly in this fashion. A polymer exhibiting a "heterotactic bias" therefore refers to a polymer in which there is a bias towards heterotacticity, compared to an "atactic" polymer in which there is no regular arrangement of monomer units along the chain.

In another particularly preferred embodiment, the complex of the invention has the formula IN

IN wherein Ar is o-diisopropylphenyl.

In one preferred embodiment, the complex of the invention has the formula N

N wherein R^1"3 and M are as defined hereinabove, and wherein each of R⁷ and R⁸ is independently selected from H, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl and heteroaryl.

Preferably, each of R⁷ and R⁸ is independently selected from H and alkyl, more preferably, H and methyl.

In one particularly preferred embodiment, R⁷ is H and R⁸ is methyl.

Even more preferably, the complex has the formula NI

VI wherein Ar is ø-diisopropylphenyl.

In a further preferred aspect, the complex of the invention comprises a dimer of a complex as described herein.

Preferably, the dimer has the formula Nil

Nil

In a particularly preferred embodiment of the invention, the complex has the formula NIII

NIII The complex of formula VIII is prepared according to either of the two procedures outlined in Figure 5. Reaction of dimethyl magnesium with 2-(2,6-di-wo- propylphenylamino)-4-(2,6-di-wo-propylphenylimino)-2-pentene in toluene affords the bridged methyl dimer, Villa. Alcoholysis proceeds smoothly upon addition of 2 equivalents of 'PrOH in toluene, to give the bridged alkoxide species, NIII.

Alternatively, NIII may be prepared by stirring a toluene solution of

[HC(CMeΝAr) ]Mg¹Pr, NHIb, under a dioxygen atmosphere.

The crystal structure of complex NIII is shown in Figure 6. Both magnesium centres exhibit a distorted tetrahedral geometry (Ν-Mg-Ν = 92°; O-Mg-O = 81°).

Recent studies by the applicant have investigated the synthesis of a range of magnesium alkyl complexes bearing the β-diketiminate ligand [N.C. Gibson, J.A. Segal, AJ.P. White, D.J. Williams, J. Am. Chem. Soc. 2000, 122, 7120]. The present invention discloses that the alkoxide derivatives of these magnesium complexes, as described herein are, in fact, highly effective catalysts for the living polymerisation of lactide.

Yet another aspect of the invention relates to a process for the polymerisation of lactide, said process comprising contacting an initiating amount of a complex according to the invention with lactide monomer in the presence of a suitable solvent.

As used herein, the term "initiating amount" refers to a sufficient amount of an initiator to commence the chemical reaction of polymerisation.

In a preferred aspect, the ratio of lactide monomer to the initiator complex of the invention is between 100:1 and 20000:1.

By way of example, suitable solvents include dichloromethane and toluene. Other solvents suitable for the purposes of the present invention will be familiar to those skilled in the relevant art. A further aspect of the invention relates to an article produced by the process described hereinbefore.

Preferably, the article is a medical article. Typical articles may include sutures, drug delivery devices and medical implants, for example, orthopedic fixation devices.

Yet another aspect of the invention provides a process for preparing a complex of formula I, said process comprising the steps of:

LX X XI I

(i) reacting a compound of formula IX, wherein each of Z' and Z" is

1 9 1 independently H (where -NR and/or -NR is an amino group) or absent (where -NR and/or -NR² is an imino group), with "BuLi to form a compound of formula X; (ii) reacting said compound of formula X with MCl_n to form a compound of formula XI, wherein M is selected from Sn(II), Mg(II), A1(III) and Sn(IN) and n is 2,

2, 3 or 4 respectively;

(ii) reacting said compound of formula XI with LiOR³ to form a complex of formula I; wherein X and R^1"3 are as defined hereinbefore.

Another aspect of the invention relates to a process for preparing a complex of formula XIII, said process comprising the steps of:

(i) reacting a compound of formula IX, wherein each of Z' and Z" is independently H (where -NR¹ and/or -NR² is an amino group) or absent (where -NR¹ and/or -NR² is an imino group), with MgMe₂ to form a compound of formula XII; (ii) reacting said compound of formula XII with R³OH to form a compound of formula XIII; wherein X and R^1"3 are as defined hereinbefore.

A further aspect of the invention provides a process for preparing a complex of formula XIII, said process comprising the steps of:

EX xrv xm

(i) reacting a compound of formula IX, wherein each of Z' and Z" is independently H (where -NR¹ and/or -NR² is an amino group) or absent (where -NR¹ and/or -NR² is an imino group), with (a) ⁿBuLi and (b) R³MgCl to form a compound of formula XIV; (ii) reacting said compound of formula XIV with O to form a complex of formula XIII; wherein X and R ^" are as defined hereinbefore. The present invention will now be described by way of example and with reference to the following figures wherein:

Figure 1 shows the reaction scheme for the preparation of the Sn(II) complex III.

Figure 2 shows the molecular structure of complex III. In more detail, the selected bond lengths (A) and angles (°) in the molecular structure of III are as follows; Sn-O 2.000(5), Sn-N(l) 2.206(4), Sn-N(3) 2.208(4), C(l)-N(l) 1.323(6), C(l)-C(2) 1.404(7), C(2)-C(3) 1.387(7), C(3)-N(3) 1.331(6), O-Sn-N(l) 94.1(2), O-Sn-N(3) 92.5(2), N(l)-Sn-N(3) 83.6(2).

Figure 3 shows M_n of the resulting polymer against the percentage conversion. In particular, Figure 3 confirms the living charactersitics of polymerisation, showing a linear increase in M_n with conversion, giving a low polydispersity product.

Figure 4 shows the 1H NMR spectrum of the poly(lactide) derived from III.

Figure 5 shows the reaction scheme for the preparation of the magnesium (II) complex NIII.

Figure 6 shows the crystal structure of the magnesium (II) complex NIII.

Examples

Synthesis of fΗC(C(Me)ΝAr)₂1SnCi Complex Ilia

To a 75cm³ Et₂O solution of 5.00g ArN=C(Me)CH=C(Me)NHAr (lJ9mmol) at 0°C was added 7.5cm n-BuLi (1.6M in hexanes; 1.20mmol). After stirring at room temperature for 16 hours the mixture was added to a 40cm³ Et₂O suspension of SnCl₂ (2.26g; lJ9mmol) and the reaction was then stirred for 18 hours. Removal of volatiles in vacuo afforded a yellow-orange solid which was recrystallised from cold pentane as pale yellow crystals (3.70g; 0.72mmol; 60%). Spectroscopic Data

Complex Ilia: 1H NMR (250MHz, C₆D₆, 25°C) δ 1.06 (d, 6H, ³J_HH = 6.8Hz,

CHMeMe), 1.18 (d, 6H, ³JHH = 6.9Hz, CH- eMe), 1.22 (d, 6H, ³JHH = 6.8Hz,

CHMe'Me , 1.45 (d, 6H, ³JHH = 6.6Hz, CH e Me'), 1.61 (s, 6H, HC{C(Me)NAr}₂), 3.12 (sept, 2H, ³JHH = 6.8Hz, CHMe₂), 3.95 (sept, 2Η, ³JHH = 6.8Hz, CHMe₂), 5.06

(s, 1Η, HC{C(Me)NAr}₂), 7.15 (m, 6Η, H^ . MS: m/z 572 [M]⁺. Anal. Calc.

(found) for

C, 60.91 (60.77); H, 7.22 (7.32); N, 4.90 (5.07).

Synthesis of rHC(C(Me)NAr>₂lSn(QiPr>. Complex III Lithium z-fo-propoxide (0.4365g, 7.27mmol) in 70cm toluene was added to a rapidly stirred solution of [HC{C(Me)NAr}₂]SnCl (2.081 lg, 3.64mmol) in 50cm³ toluene at 0°C. After 18 hours stirring at ambient temperature volatiles were removed to afford a bright yellow solid which was recrystallised from heptane at -30°C (1.8857g, 3J6mmol, 87%).

Spectroscopic Data

Complex III: 1H NMR (250MHz, C₆D₆, 25°C) δ 0.90 (d, 6H, ³JHH = 6.8Hz, OCHMe₂), 1.14 (d, 3H, ³JHH = 6.8Hz, CHMeMe), 1.24 (d, 3H, ³J_HH = 6.9Hz, CHMeMe), 1.27 (d, 3H, CHMe'Me '), 1.54 (d, 3H, CHMe Me'), 1.59 (s, 6H, HC{C(Me)NAr}₂), 3.25 (sept, 2H, ³JHH = 6.8Hz, CHMe₂), 3.86 (sept, 2Η, ³J_HH = 6.8Hz, CHMe₂), 4.15 (sept, 1Η, ³J_ΗΗ = 6.0Ηz, OCHMe₂), 4.73 (s, 1Η, HC{C(Me)NAr}₂), 7.16 (m, 6Η, U _l). Anal. Calc. (found) for C3₂H4₈N₂OSn: C, 64.55 (64.28); H, 8.13 (8.08); N, 4.70 (4.90).

Crystallo graphic data for Complex III

C₃₂H₄₈N₂OSn, M= 595.4, monoclinic, space group P2_\ln (no. 14), α = 13.205(2), b = 16.680(2), c = 15.527(2) A, β = 107.42(1)°, V= 3263.1(6) A³, Z = 4, E>_c = 1.212 g cm^-3, μ(Mo-Kα) = 8.07 cm^-1, T= 293 K, yellow blocks; 5742 independent measured reflections, E² refinement, Ri = 0.049, wR₂ = 0.112, 4038 independent observed reflections [|E₀| > 4σ(|E₀|), 2Θ < 50°], 326 parameters. Synthesis of [{HC(CMeNAr 9>Mg(OⁱPr)1_?_Complex NIII

Route A

0J5cm³ propan-2-ol (1.96 x 10^"3mol) was added dropwise to a solution of [{HC(CMeΝAr)₂}MgMe]₂ (l.OOlg, 1.067 x 10^"3mol in 50cm³ toluene). The reaction was then stirred for 60minutes at room temperature, during which time a white precipitate formed which was recovered by filtration (0.410g, 0.400 x 10^" mol, 37.5%). Crystals suitable for x-ray diffraction studies were grown from benzene.

Route B

A schlenk tube containing 0.604g (HC^MeNArMMg Pr) (1.215 x 10-³mol) dissolved in 15cm³ toluene under a dinitrogen atmosphere was evacuated and an atmosphere of dioxygen was then introduced. The evacuation/refill cycle was repeated a total of three times. Almost immediately the solution turns cloudy, with more precipitate forming during the time-scale of the reaction.

After 30 minutes stirring a room temperature the solution was filtered to afford a white solid.

Spectroscopic Data

Complex VIII: 1H NMR δ (CDC13, 250MHz): 0J5 (d, 6H, ³J_HH = 6.84Hz, OCHMe2), 0.94 (d, 3H, ³J_HH = 6.58Hz, CHMeMe), 1.02 (d, 3H, ³JHH = 6.58Hz, CHMeMe), 1.03 (d, 3H, ³J_HH = 6.58Hz, CHMe 'Me'), 1.26 (d, 3H, ³J_HH = 6.58Hz, CHMe'Me '), 1.42 (s, 6H, Me_a), 2.89 (sept, ³J_HH = 6.84Hz, CHMeMe), 3.28 (sept, ³J_ΗΗ = 6.84Ηz, CHMe'Me'), 3.63 (sept, ³J_ΗΗ = 6.84Ηz, OCHMe₂), 4.77 (s, 1Η, H_β), 7.11 (m, 6Η, H_aryi). Anal. Calc. for C₇₀H₁₀2N₄Mg₂O₂: C 77.83, H 9.52, N 5.19%. Found C 77.18, H 9.27, N 5.78%.

Crvstallo graphic data for Complex NIII The crystallographic data for Complex NIII is attached in Annex 1. Synthesis of ( ^SnCO'PrX Complex VI

(NN)Sn(O'Pr) was prepared by the synthetic scheme shown below.

2LiO'Pr (NN)SnCI ' > (NN)Sn(O'Pr)

(NN)H

Synthesis of 3-(N-(2.6-di-t O-propylphenyl amino -2-(N-(2,6-di-t θ-propylphenyl imino^propane, (TSTNP)H

86.5g of ArNCHCHNAr (0.230mol) was dissolved in 300cm³ toluene. To this solution a 2.0 M toluene solution of Me₃Al (120cm³, 0.240mol) was added dropwise over 30minutes at room temperature, furnishing a deep red colouration.

The reaction was stirred at 80°C for 16 hours, then chilled in a solid CO₂ / acetone bath at -78°C. The product, [{ArN=C(Me)CH₂NAr}AlMe₂], was then slowly hydrolysed by the addition of 200cm³ degassed, distilled water. The resultant suspension was filtered and the organic layer decanted under nitrogen. The aqueous layer was extracted with 3 x 50cm³ portions of diethyl ether. The ether extracts were combined with the toluene solution and dried over anhydrous MgSO₄. This mixture was then filtered and volatiles removed in vacuo to give a viscous yellow oil, which solidifies under prolonged vacuum.

Spectroscopic Data

(NN H: 1H NMR (C₆D₆, 250MHz, 298K): 7.20-7J 1 (m, 6H) H_/neto and U_para, 5.24 (t, ³J_HH = 4.6Hz, 1H) NH, 3.70 (d, ³J_HH = 4.7Hz, 2H) NCH₂, 3.59 (sept, 2Η) and 2.85 (sept, 2H) CHMe₂, 1.29 (d, 12Η), 1.19 (d, 6H), 1.12 (d, 6H), all CHMe₂, 1.24 (s, 3H) N=C(Me) Synthesis of (NN Li

Handling difficulties associated with the oily nature of (NN)H may be overcome by converting it into its lithium salt, a pale yellow powder, which can be readily recrystallised from hot hydrocarbon solvents (e.g. heptane, toluene).

45.46g (NN)H (0J18mol) was dissolved in 200cm³ Et₂O and chilled in a solid CO₂ / acetone bath at -78°C. To this stirring solution was added 50cm^{3 n}BuLi (2.5M in hexanes, 0J25mol) dropwise over 20 minutes. After stirring at room temperature for

3 hours the reaction mixture was filtered and the precipitate washed with 2 x 50cm³ pentane. Yield: 42.92g 93%.

Spectroscopic Data

(NTSHLi: 1H NMR (d₈-THF, 250MHz, 298K): 7J6-6.91 (m, 3H), 6.72 (m, 2H), 6.27 (m, 1H) H_meto and U_para, 4.57 (s, 2H) NCH₂, 3.49 (sept, 2Η) and 3.04 (sept, 2H) CHMe₂, 1.65 (s, 3Η) N=C(Me),lJ7 (d, 6H), 1.15 (d, 6H), 1.14 (d, 12H), all CHMe₂.

Synthesis of (NN)SnCl

A 50cm³ Et₂O solution of (NN)Li (1.4680g, 3.68 x 10^"3mol) was added to a 30cm³ Et₂O suspension of 0.6983g SnCl₂ (3.68 x 10^"3mol) at -78°C. The mixture was allowed to reach room temperature and then stirred for 2 hours to afford a pale yellow suspension. The reaction was filtered and concentrated in vacuo to give a pale yellow solid. Recrystallisation from Et₂O gave a pale yellow crystalline material. Yield: 1.192g, 59%.

Spectroscopic Data

(NN)SnCl: 1H NMR (C₆D₆, 250MHz, 298K): δ7.22-7.00 (m, 6H) H_meta and R_para, 4.65 (s, br, 2H) NCH₂, 3.89 (br, 2Η) and 3J9 (sept, 2H) CHMe₂, 1.35 (d, 6Η), 1.34 (d, 6H), 1.30 (d, 6H), 1.10 (d, 6H) all CHMe₂, 1.21 (s, 3H) N=C(Me)

Synthesis of (NN^S^O'Pr . Complex VI

1.1427g (NN)SnCl and 0.2765g LuOT ) (2.094 x 10^"3mol and 4.187 x 10^"3mol respectively; 2.00 equivalents) were weighed into a schlenk tube and chilled in a solid CO2 / acetone bath at -78°C. 20cm³ of Et₂O was added and the stirring mixture was allowed to warm to room temperature, affording an orange-brown suspension.

This was stirred for a further 30minutes, filtered and concentrated under reduced pressure to a sticky orange solid. The solid was purified by stirring in 5cm³ pentane at -78°C for lhour. Yield: 0.417g, 35%.

Typical polymerisation procedure

Using [{HC(CMeNAr _z}Mg(OⁱPr ]_?_as an initiator (Complex VHP

200 equivalents of rαc-lactide (0J21g, 0.840 x 10^"3mol, previously recrystallised from ethyl acetate) were dissolved in 2cm³ CH₂C1₂, and this solution was chilled to - 30°C. It was then added to a 2cm³ CH₂C1₂ solution of [{HC(CMeNAr)₂}Mg(OⁱPr)]₂ (0.0043g, 0.419 x 10^"6mol; [M]/[I] - 100) also at -30°C. The reaction mixture was then stirred for the allotted time period, then opened to the atmosphere to destroy the initiator.

The reaction mixture was then reduced in vacuo to afford a sticky white oil, which was analysed by 1H NMR to determine conversion. The oil was purified by dissolving in 2cm³ CH₂C1₂ and then reprecipitating from excess cold MeOH.

Using (NNISn^'Pr) as an initiator (Complex VD

0.0057g (NN)Sn(O^jPr) (1.00 x 10-5mol) and 0.2885g racJactide (2.00x10^"3; 200 equivalents) were weighed into an ampoule and 4cm³ toluene was added. The ampoule was then placed in an oil-bath at 60°C and stirred for 60 minutes. The polymerisation was terminated by opening the ampoule to air. Nolatiles were removed under reduced pressure to yield a cream-coloured foamy solid.

1H ΝMR spectroscopy confirms that the conversion of lactide to poly(lactide) is 40% (i.e. 80 equivalents of monomer consumed in 60minutes). GPC (CHC1₃): Mn = 4.980, Mw = 6110, pdi = 1.23.

Various modifications and variations of the described methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.

Annex 1 Table 1. Crystal data and structure refinement for 1.

Identification code VG0059 Empirical formula C₆₄H₉₆N₁0₂Mg₂ phH Formula weight 1080.18 Temperature 203 (2) k Diffractometer Used Siemens P4/RA Wavelength 1.54178 A Crystal system Monoclinic Space group .. P2jΛι Unit cell dimensions a = 13.5668 (8) A alpha = 90° b = 16.1541 (8) A beta = 98.339 (4) ' c = 14.8933 (7) A gamma = 90°

Volume, Z 3229.5 (3) A³, 2

Density (calculated) l.n i Mg/m³

Absorption Coefficient 0.674 mm^"1

F (000) 1180

Crystal colour/morphology Clear prisms

Crystal size 0.40 x 0.33 x 0.27 mm θ range for data collection 1.06 to 59.99°

Limiting indices -I5 ≤ h < 0, 0 ≤ /c < 18

-16 < 1 ≤ 16

Scan type fij-scans

Reflections collected 5027 Independent reflections 4800 (Ri„_t 0.1057) Observed reflections [ F>4σ (F) ] 4066 Absorption correction None Structure solution method Direct Refinement method Full matrix least-squares on F Data / restraints / parameters 4632/0/353 Goodness of-fit on F² 1.023 Final R indicates [ F>4σ (F) ] Rl = 0.0498, wR2 = 0J298 R indices (all data) Rl = 0.0596, wR2 = 0.1401 Extinction coefficient 0.00024 (3) Largest diff peak and hole 0.330 and -0.369 eA ³ Mean and maximum shift/error 0.000 and 0.000 Table 3. Bond lengths [A] and angles [°] for 1.

Mg-0 1.9803 (14) Mg.0#l 1.9863 (14)

Mg-N(l) 2.114(2) Mg-N(3) 2.126 (2)

Mg-Mg#l 3.0138(12) O-C (30) 1.425(2)

0-Mg#l 1.9863 (14) C(l)-N(l) 1.339(3)

C(l)-C(2) 1.102(3) C(l)-C(4) 1.516(3)

N(l)-C(6) 1.416(3) C(2)-C(3) 1.404(3)

C(3)-N(3) 1.331 (3) C(3) C(5) 1.523 (3)

N(3)-C(18) 1.451(2) C(6) C(7) 1.407(3)

C(6)-C(ll) 1.116(3) C(7) C(8) 1.381 (3)

C (7) - C (12) 1.520(4) C(8) C(9) 1.387(5)

C (9) - C (10) 1.375 (5) C(10) -C(ll) 1.393 (3)

C(ll)-C(15) 1.507(4) C(12)- •C(14) 1.529 (4)

C(12)-C(13) 1.529(3) C(15)- ^■C(17) 1.523(3)

C(15) C(16) 1.530(1) C(18). ^■ C (19) 1.403 (3) C(18) C(23) 1.405(3) C(19)- - C (20) 1.394(3) C(19) C(24) 1.517(3) C (20) ■ •C(21) ^"1.373 (3) C(21) C(22) 1.372(4) C (22) ■ ^■ C (23) 1.401 (3) C(23) C(27) 1.519(3) C (24) ■ ^■ C (26) 1.525 (4)

C (24) - C (25) 1.530 (3) C(27)- - C (29) 1.521 (4) C (27) - C (28) 1.527 (3) C (30) • -C(31) 1.498 (3) C (30) - C (32) 1.511(3)

O-Mg 0#1 81.11(6) O Mg-N (1) 125.90 (7)

0#l-MgN(l) 117.94(6) O-Mg N (3) 123.28 (6)

0#1 Mg-N (3) 120.75 (7) N(l)-MgN(3) 91.40(6)

O-Mg Mg#l 40.63 (4) 0#1-Mg-#1 40.48 (4)

N (1) - Mg-Mg#l 133.95 (5) N (3) -Mg-Mg#l 134.23 (6)

C (30) - O-Mg 133.38 (12) C (30) O Mg#l 127.08 (12)

Mg-0-Mg#l 98.89 (6) N(l)-C(l)-C(2) 124.4 (2)

N(l)-C(l)-C(4) 120.9 (2) C(2)-C(l)-C(4) 114.7(2)

C(l)-N(l)-C(6) 115.0(2) C(1)N(1)-Mg 119.04(13)

C(6)-N(l)-Mg 125.87 (12) C (1) - C (2) - C (3) 130.1 (2)

N (3) - C (3) - C (2) 125.2 (2) N(3)C(3)-C(5) 120.9 (2)

C(2)-C(3)-C(5) 113.9(2) C(3)-N(3)-C(18) 114.7(2)

C(3)-N(3)-Mg 119.05(13) C(18)-N(3)-Mg 126.14(12)

C(7)-C(6)-C(ll) 120.8 (2) C(7)-C(6)-N(l) 118.4(2)

C(ll)-C(6)-N(l) 120.7 (2) C(8)-C(7)-C(6) 118.9(2)

C (8) - C (7) C (12) 119.5(2) C (6) - C (7) - C (12) 121.5(2)

C(7)-C(8)-C(9) 121.0(3) C(10)-C(9)-C(8) 119.7(2)

C(9)-C(10)-C(ll) 122.1 (3) C(10)-C(ll)-C(6) 117.5(2)

C(10)-C(ll)-C(15) 119.6(2) C(6)-C(ll)-C(15) 122.9 (2)

C (7) - C (12) - C (14) 111.5(2) C (7) - C (12) - C (13) 113.7(2)

C (14) - C (12) - C (13) 108.7 (2) C(ll)-C(15)-C(17) 110.6(2)

C(ll)-C(15)-C(16) 113.2(2) C(17)-C(15)-C(16) 109.1 (2)

C(19)-C(18)-C(23) 120.6 (2) C(19)-C(18)-N(3) 121.0(2)

C(23)-C(18)-N(3) 118.4(2) C(20)-C(19)-C(18) 118.4(2)

C(20)-C(19)-C(21) 119.0(2) C (18) - C (19) - C (24) 122.6 (2)

C (21) - C (20) - C (19) 121.6 (2) C (22) - C (21) - C (20) 119.8(2)

C (21) - C (22) - C (23) 121.2(2) C(22)-C(23)-C(18) 118.3 (2)

C (22) - C (23) - C (27) 119.7(2) C(18)-C(23)-C(27) 121.9(2)

C (19) - C (21) - C (26) 110.1(2) C (19) - C (24) - C (25) 113.2(2)

C (26) - C (24) - C (25) 109.6 (2) C (23) - C (27) - C (29) 111.3(2)

C (23) - C (27) - C (28) 113.6(2) C (29) - C (27) - C (28) 110.7(2)

OC(30) -C(31) 111.5(2) O C (30) - C (32) 111.2(2)

C(31)-C(30)C(32) 110.5(2)

Symmetry transformations used to generate equivalent atoms:

Claims

A complex having the formula I

I wherein M is selected from Sn(II), Sn(IV), Al(III) and Mg(II);

1 each of R and R is independently hydrocarbyl; R is H or hydrocarbyl; and X is a linker group.

2. A complex according to claim 1 wherein linker group X comprises a Cj;-₄ carbon backbone, or a heteroatom-containing Cμ carbon backbone.

1 -_}

3. A complex according to claim 1 or claim 2 wherein each of R and R is independently selected from alkyl, cycloalkyl, haloalkyl, aryl, haloaryl or heteroaryl; R³ is H, alkyl, cycloalkyl, haloalkyl, aryl or haloaryl.

4. A complex according to any preceding claim wherein X comprises a vinylene or an arylene group.

5. A complex according to any preceding claim, having the formula II,

II

wherein each of R⁴, R⁵ and R⁶ is independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl and heteroaryl, and R^1"3 and M are as defined in claim 1.

6. A complex according to claim 5 wherein each of R⁴, R⁵ and R⁶ is independently selected from H, methyl, t-butyl, phenyl and trifluoromethyl.

7. A complex according to any preceding claim wherein M is Sn(II).

8. A complex according to any one of claims 1 to 7 having the formula III

III wherein Ar is o-diisopropylphenyl.

9. A complex according to any one of claims 1 to 6 wherein M is Mg(II).

10. A complex according to any one of claim 9 having the formula IV

IN wherein Ar is o-diisopropylphenyl.

11. A complex according to any one of claims 1 to 8 having the formulaN

N wherein R^1"3 and M are as defined in claim 1, and wherein each of R⁷ and R⁸ is independently selected from H, alkyl, cycloalkyl, haloalkyl, aryl, haloaryl and heteroaryl.

12. A complex according to claim 11 wherein R⁷ is H and R⁸ is methyl.

13. A complex according to claim 11 or claim 12 having the formula VI

VI wherein Ar is ø-diisopropylphenyl.

14. A complex comprising a dimer of a complex according to any preceding claim.

15. A dimer according to claim 14 of formula Nil

Nil

16. A dimer according to claim 14 or claim 15 of formula VIII

NIII

wherein Ar is o-diisopropylphenyl.

17. Use of a complex according to any one of claims 1 to 16 as a polymerisation initiator.

18. Use according to claim 17 in the polymerisation of lactide.

19. Use according to claim 18 wherein the lactide is rαc-lactide.

20. A process for the polymerisation of lactide, said process comprising contacting an initiating amount of a complex according to any one of claims 1 to 16 with a lactide monomer in the presence of a suitable solvent.

21. A process according to claim 20 wherein the ratio of lactide monomer to the complex is between 100:1 and 20000:1.

22. An article prepared by a process according to 20 or claim 21.

23. An article according to claim 22 wherein said article is a medical article.

24. A composition comprising lactide monomer and a complex according to any one of claims 1 to 16.

25. A composition comprising poly(lactide) and a complex according to any one of claims 1 to 16.

26. A composition comprising poly(lactide) and a complex according to any one of claims 1 to 16, wherein said complex is deactivated, for example, by the addition ofmethanol.

27. A process for preparing a complex of formula I, said process comprising the steps of:

IX X XI I (i) reacting a compound of formula IX, wherein each of Z' and Z" is independently H (where -NR¹ and/or -NR² is an amino group) or absent (where -NR¹ and/or -NR² is an imino group), with "BuLi to form a compound of formula X;

(ii) reacting said compound of formula X with MCl_n to form a compound of formula XI, wherein M is selected from Sn(II), Mg(II), A1(III) and Sn(IN) and n is 2,

2, 3 or 4 respectively;

(ii) reacting said compound of formula XI with LiOR³ to form a complex of formula I; wherein X and R ^" are as defined in claim 1.

28. A process for preparing a complex of formula XIII, said process comprising the steps of:

(i) reacting a compound of formula IX, wherein each of Z' and Z" is independently H (where -NR¹ and/or -NR² is an amino group) or absent (where -NR¹ and/or -NR² is an imino group), with MgMe₂ to form a compound of formula XII; (ii) reacting said compound of formula XII with R³OH to form a compound of formula XIII; wherein X and R^1"3 are as defined in claim 1.

29. A process for preparing a complex of formula XIII, said process comprising the steps of:

LX XIN XIII

(i) reacting a compound of formula IX, wherein each of Z' and Z" is independently H (where -ΝR¹ and/or -ΝR² is an amino group) or absent (where -ΝR¹ and/or -ΝR² is an imino group), with (a) ⁿBuLi and (b) R³MgCl to form a compound of formula XIN;

(ii) reacting said compound of formula XIN with O₂ to form a complex of formula XIII; wherein X and R^1"3 are as defined in claim 1.