METHOD TO PREPARE BLOCK COPOLYMERS BY THE COMBINATION OF CATIONIC AND ANIONIC POLYMERIZATION

RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application No. 60/790,052, filed on April 7, 2006.

The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Block copolymers containing hard and soft segments are of great interest since they may induce nanodomain arrangements so as to minimize contact energies between different polymer segments yielding phase-separated morphologies. Recently, much attention has been paid to applications of ABA triblock copolymers in drug eluting coronary stent systems. For example, poly(styrene-6-isobutylene-δ- styrene) triblock copolymer has recently been employed as a drug carrier coating material for the TAXUS Express2 Paclitaxel-Eluting Coronary Stent system by Boston Scientific Corp.

Living polymerization is an effective method for the preparation of such block copolymers where neither chain transfer nor termination take place during polymerization. Living polymerization yields polymers with predictable molecular weight on the basis of the [monomer] / [initiator] ratio and narrow molecular weight distribution especially when the rate of initiation is higher than that of propagation. Although each living polymerization system, e.g. anionic, cationic, radical, etc , provides a limited range of polymers, unique polymers not available by a single method are expected to be synthesized by the combination of various polymerization techniques.

Recently, a synthesis of poly(polyisobutylene-Z?-alkyl methacrylate) and poly(alkyl methacrylate-6-isobutylene-δ-alkyl methacrylate) by combining of cationic and anionic polymerization techniques was reported (Feldthusen et al,

Macromolecules (1997) 3O ₅ 6989-93). First, 1,1-diphenyl-l-methoxy or 2,2- diphenylvinyl end-functionalized polyisobutylene was prepared by the reaction of 1,1-diphenylethylene (DPE) and living polyisobutylene. The chain end of the resulting polymer was metallated with alkali metal compounds in tetrahydrofuran at room temperature and the resulting macroanion initiated the polymeπzation of methyl methacrylate. This method has disadvantages. For example, it is inconvenient due to the need of alkali metal since lithiation with alkyllithium (e.g., butyllithium) does not proceed quantitatively.

More recently, the preparation of thiophene cnd-functionalized polyisobutylene and subsequent metallation of the polymer chain end with alkyllithium compound, followed by polymerization of t erf-butyl methacrylate with the generated macroanion was reported (Matinez-Castro el al., Macromolecules (2003) 36, 6985-94). The advantage of this process is a simple and complete metallation. However, a large excess of thiophene must be used in the functionalization of polyisobutylene cation to prevent the coupling reaction between thiophene functionalized polyisobutylene and living polyisobutylene. Moreover, the blocking efficiency is only about 80% even when low molecular weight is targeted.

Very recently, a new efficient method involving the synthesis of DPE end- functionalized polyisobutylene by monoaddition of 1 ,4~bis(l-phenylethehyT)benzene (para-double diphenylethylene, PDDPE) to living polyisobutylene was developed (Cho et al, Am. Chem. Doc, Div. Polym. Sci. (2004), 45(1), 1099-100) and-US 7056985(B2). The resulting macromonomer is metallated with n-butyllithium followed by initiating the polymerization of methacrylate with the generated macrocarbanion. The blocking efficiency is high (> 90%). However, the method requires multi stages that involve syntheses of PDDPF and DPF end-functionalized polyisobutylene, lithiation of terminus, and polymerization of methacrylate.

Because previously described methods of preparing block copolymers by a combination of cationic and anionic polymerization suffer from low blocking efficiency due to poor reactivity of the reagent used and/or the need for multi-step synthetic processes, there is a need for new efficient methods of preparing block copolymers by the combination of cationic and anionic polymeπzation techniques.

SUMMARY OF THE INVENTION

The present invention generally- is directed to a method of preparing of block copolymers by combination of cationic and anionic polymerization techniques.

In one embodiment, the present invention is a method of preparing a compound of formula (III), comprising reacting a compound of formula (I)

with a compound of formula ,

thereby producing the compound of formula (III)

In formulas (I), (II) and (III): R] for each occasion is independently H or an optionally substituted C1-C4 alkyl; R ₂ for each occasion is independently H, X ² , -CH ₂ X ² , -CHX ² ₂ , -CX ² ₃ , -C≡N, or -NO ₂ ; n and m are independently integers not less than 2; X ¹ and X ² are, for each occurrence, independently, a halogen; R ³ is hydrogen, an optionally substituted C1-C4 alkyl, or a C5-C20 aralkyl, having a Cl- C14 alkyl portion; R ⁴ is hydrogen, an optionally substituted C1-C4 alkyl, or -C≡N; R ⁵ is an optionally substituted C1-C20 alkyl or poly(ethylene glycol) of formula -(CH ₂ O) _P -R ⁷ , where p is 1-2000 and R ₇ is hydrogen, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted bicyclic carbocyclic group; R ⁶ is hydrogen, an optionally substituted C1-C20 alkyl or an initiator residue; and M ⁺ is an alkali metal cation.

As used herein, a substituent on a carbon atom that forms an unsaturated carbon-carbon bond and whose attachment to such carbon atom is denoted by the symbol ^/\λ/\Z ^> can be in either cis or trans substituent.

In another embodiment, the present invention is a method of preparing a compound of formula (IIIA), comprising reacting a compound of formula (IA)

with a compound of formu (II)

thereby producing a'compound of formula (IIIA),

-

In formulas (IA) and (IIIA), k is an integer not less than 1 and L is an initiator residue. The remainder of the variables are as defined above with respect to formulas (I) - (III).

In another embodiment, the present invention is a method of preparing a compound of formula (I)

comprising reacting the compound of formula (X)

with an excess of MX ¹ . In formula (X), X ³ is a halogen, provided that X ¹ and X ³ are not the same. M is an alkali metal. The remainder of the variables are as defined above with respect to formulas (I) — (III).

In another embodiment, the present invention is a method of preparing a compound of formula (IA)

comprising reacting the compound of formula (XA)

with an excess of MX ¹ The variables in formula (XA) are as defined above with respect to.formuja (X)

In another embodiment, the present invention is a compound represented by formula (XIII).

The variables in formula (XIII) are as defined above with respect to formula (XA).

In another embodiment, the present invention is a compound of formula (XIV)

The variables in formula (XW) are as defined above with respect to formula (X).

^■ - In one embodiment the present invention is a compound of formulas (XIII) or (XIV), provided that the compound is not of formula (A):

•wherein s is- not less than 2, X ⁿ is a halogen, R ^{1 1} for each occasion is independently H of a C1-C4 alkyl;and R ¹² for each occasion is independently H, a halogen, CH ₂ X ^{1 1} , CHX" _2! -CX ^H 3, -C≡N, -NO ₂ . In another embodiment, the present invention is a comp ^' όuήd of formulas (XIII) or (XIV), provided that the compound is not of formula (B):

The variables in formula (B) are as defined with respect to formula (A).

In one embodiment, the present invention is a method of preparing a compound of formula (IIIB), comprising reacting a compound of formula (IB)

(IB) with a compound of formula (HA)

thereby producing a compound of formula (IIIB)

In formulas (IB), (HA) and (IIIB), nl and ml are each independently an integer not less than 2, q is an integer not less than 1 , and L' is an initiator residue. The remainder of the variables, for each occurrence, is independently selcted from

the values and preferred values defined above with respect to formulas (IA), (II) and

(in).

In another embodiment, the present invention is a compound represented by formula (IIIB):

The present invention provides an efficient method for the preparation of block copolymers, such as those comprised of polyisoolefins and polyacrylates, by coupling reaction which has up to 96% coupling efficiency (see Examples 3.1 and 3.5). The advantages of the inventive method further include facile synthesis and purification process of haloallyl chain end-functionalized polyisoolefins. Compared to multi-step synthesis in prior methods, and the methods disclosed herein provide for convenient characterization of each block segment because polyisolefϊns and polyacrylates are prepared separately before coupling reactions.

Due to the excellent biocompatibility of these polymers a special field of utility relates to medical devices, specifically implantable or insertable-medical devices containing these polymers. In some applications the polymer can be used as a coating of a medical device (e.g., stents, pacemaker leads) while in other applications the polymer is used itself (e g., artificial vascular grafts). The compositions of the present invention can also be used as medical drug eluting articles and drug eluting coatings in medical devices from which a therapeutic agent is released.

DETAILED DESCRIPTION OF THE INVENTION

Generally, useful block copolymers combine two different properties of the two homopolymers, such as rubbery-plastic or hydrophobic-hydrophilic behaviors. For example, polyisobutylene - block - methacrylates combine the rubbery properties of polyisobutylene and the plastic properties of methacrylates. Polyisobutylene - block - methacrylates diblock copolymers are useful as compatibilizers, adhesives, dispersants, sealants, etc.

"ABA" type triblock or "(AB) _n " type starblock copolymers, where B is polyisobutylene and A is polymethacrylate, are thermoplastic elastomers. They are useful in the same applications as other thermoplastic elastomers, for instance as adhesives, coatings, elastic-threads or other elastic objects. The term "alkyl", as used herein, unless otherwise indicated, means straight or branched saturated monovalent hydrocarbon radicals of formula C _n H _2n +!. Typically n is 1-1000, more typically, n is 1 -100. Alkyl can optionally be substituted with -OSiR ⁸ R ⁹ R ¹⁰ , wherein R ⁸ , R ⁹ , and R ¹⁰ are each independently hydrogen or an optionally substituted alkyl as defined herein, -OH, -SH, halogen, amino, cyano, nitro, a C 1 -C 12 alky], C 1 -C 12 haloalkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkoxy or Cl -C 12 alkyl sulfanyl. In some embodiments, alkyl can optionally be substituted with one or more halogen, hydroxyl, Cl -C 12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl group, Cl -C 12 alkoxy, or Cl -C 12 haloalkyl. The term alkyl can also refer to cycloalkyl. The term "cycloalkyl", as used herein, means saturated cyclic hydrocarbons, i.e. compounds where all ring atoms are carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl: In some embodiments, cycloalkyl can optionally be substituted with one or more halogen, hydroxyl, Cl -C 12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl group, C1-C12 alkoxy, or C1-C12 haloalkyl.

"Bicycloalkyl" groups are non-aromatic saturated carbocyclic groups consistingcof two rings. Examples of bicycloalkyl groups include, but are not limited to, bicyclo-[2.2.2]-octyI and norbornyl. The term "cycloalkenyl" and "bicycloalkenyl" refer to non-aromatic carbocyclic cycloalkyl and bicycloalkyl moieties as defined above, except comprising of one or more carbon-carbon double bonds connecting carbon ring members (an "endocyclic" double bond) and/or one or more carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an "exocyclic" double bond). Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl. A non-limiting example of a bicycloalkenyl group is norborenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups similar to those described above for each of these respective categories, but which are substituted

with one or more oxo moieties. Examples of such groups with oxo moieties include, but are not limitedto oxocyclopentyl, oxocyclobutyl, oxσcyclopentenyl, and norcamphoryl. The term "cycloalkynyl" and "bicycloalkynyl" refer to non-aromatic carbocyclic cycl'oalkyl and bicycloalkyl moieties as defined above, except comprising of one or more carbon-carbon triple bonds connecting carbon ring members (an "endocyclic" bond) and7or one or more carbon-carbon triple bonds connecting a carbon ring member and an adjacent non-ring carbon (an "exocyclic" bond).

As used herein, the term "alkenyl" means a saturated straight chain or branched hydrocarbon having from 2 to 20 carbon atoms and having at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.

As used herein, the term "alkynyl" means a saturated straight chain or branched hydrocarbon having from 2 to 20 carbon atoms and having at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

The term "haloalkyl", as used herein, includes an alkyl substituted with one or more F, Cl ₅ Br ₅ or I, wherein alkyl is defined above.

The terms "alkoxy", as used herein, means an "alkyl-O-" group, wherein alkyl is defined above. Examples of alkoxy group include methoxy or ethoxy groups. The term '"cycloalkoxy", as used herein, unless otherwise indicated, includes "cycloalkyl-O-" group, wherein cycloalkyl is defined above.

The term "aryl", as used herein, refers to a carbocyclic aromatic group.

Examples of ary] groups include, but are not limited to phenyl and naphthyl. Examples of aryl groups include optionally substituted groups such as phenyl, biphenyl, naphthyl, phenanthryl, anthracenyl, pyrenyl, fluoranthyl or fluorenyl.

Examples of suitable substituents on an aryl include halogen, hydroxyl, Cl -C 12 alkyl, C2-C12 alkene or C2-C12 alkyne, C3-C12 cycloalkyl, Cl -C 12 haloalkyl, Cl-

C 12 alkoxy, aryloxy, arylamino or aryl group The term "aryloxy", as used herein, means an "aryl-O-" group, wherein aryl is defined above. Examples of an aryloxy group include phenoxy or naphthoxy groups.

The term arylamine, as used herein, means an "aryl-NH-", an "aryl-N(alkyl)- ", or an "(aryl) ₂ -N-" groups, wherein aryl and alkyl are defined above.

The term "heteroaryl", as used herein, refers to aromatic groups containing one or more heteroatoms (O, S, or N). A heteroaryl group can be monocyclic or polycyclic, e.g. a monocyclic heteroaryl ring fused to one or more carbocychc aromatic groups or other monocyclic heteroaryl groups. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl ^" , furyl, thienyl, isoxazdlyl, thiazolyl, oxazolyl, isothiazoly], pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl," indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl. , _^ . . The foregoing heteroaryl groups may be C-attached or N-attached (where such is possible). For instance, a group derived from pyrrole may be pyrrol- 1-yl (N- attached) or pyrrol -3 -yl (C-attached).

Suitable substituents for heteroaryl are as defined above with respect to aryl group.

Suitable substituents for an alkyl, cycloalkyl include a halogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cycloalkynyl, an aryl, a heteroaryl, a haloalkyl, cyano, nitro, haloalkoxy.

Further examples of suitable substituents for a substitutable carbon atom in an aryl, a heteroaryl, alkyl or cycloalkyl, (cycio)alkenyl, (cyclo) alkynyl include but are not limited to -OH, halogen (-F, -Cl ₃ -Br, and -I), -R, -OR, -CH ₂ R, -CH ₂ OR, .-CH ₂ CH ₂ OR. Each R is independently an alkyl group. In some embodiments, suitable substituents for a substitutable carbon atom in an aryl, a heteroaryl or an aryl portion of an arylalkenyl include halogen,

hydroxyl, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl group, C1-C12 alkoxy, aryloxy group, arylamino group and C1-C12 haloalkyl.

In addition, the above-mentioned groups may also be substituted with =0, =S, =N-alkyl.

In the context of the present invention, an amino group may be a primary ^' (-NH ₂ ), secondary (-NHR _P ), or tertiary (-NR _p R _q ), wherein R _p and R _q may be any of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, heteroaryl, and a bicyclic carbocyclic group.

A "living" polyolefin, generally, is any polyolefϊn with a terminal cationic group and is termed "living" because it is typically made by one of many living polymerization methods known to those of ordinary skill in the art. In various embodiments, a polyolefin, e.g., polyisoolefϊn, polymultiolefin or poly(substituted or unsubstituted vinylidene aromatic compounds), and, more typically polyisobutylene, can be reacted with an optionally substituted conjugated diene, e.g., butadiene, to "cap" the polymer, wherein the cap is halide terminated group. Suitable polyolefins can include C ₄ to Ci ₈ polyisomonoolefins, C ₄ to CH polymultiolefins, and poly(substituted or unsubstituted vinylidene aromatic compounds), for example C ₄ to Cio polyisomonoolefins, or more, typically C4 to C ₈ polyisomonoolefins. Polyisobutylene is an example of a preferred isoolefin polymer.

The term "hexanes" refers to a commercially available n-hexane, with a small admixture of methylpentanes.

In one embodiment, the present invention is a method of preparing a compound of formula (III), comprising reacting a compound of formula (I) with a compound of formula (II), according to Scheme (I):

Scheme (I) The substituents in formulas (I), (II) and (III) are defined as follows-

Ri for each occasion is independently H or an optionally substituted Cl -C4 alkyl; preferably, R ¹ is methyl;

R ₂ for each occasion is independently H, X ² , -CH ₂ X ² , -CHX ² ₂ , -CX ² ₃ , -ON, or -NO ₂ ; preferably, R is hydrogen; n and m are independently integers not less than 2;

X ¹ and X ² are, for each occurrence, independently, a halogen, preferably Cl, Br or I; more preferably, bromide;

R ³ is hydrogen, an optionally substituted C1-C4 alkyl, or a C5-C20 aralkyl, having a Cl-C 14 alkyl portion. Examples of such C5-C20 aralklyls inlude an initiator residues such as cumyl, dicumyl arid tricumyl, when cumyl, dicumyl or tricumyl chloride, methylether or ester is used as initiator. Other examples include 1 -phenyl -ethyl, 1-para-methoxyphenyl-ethyl , which arise when 1-phenyl-ethyl chloride or 1-para-methoxyphenyl-ethyl chloride is used as initiator. Many other cationic mono- and multifunctional initiators are known in the art, R ⁴ is hydrogen, an optionally substituted C1-C4 alkyl or -C≡N; preferably,

R ⁴ is hydrogen or methyl;

R ⁵ is an optionally substituted C1-C20 alkyl. Preferred optional substituents include C1 -C20 hydroxyalkyl (e.g., hydroxyethyl), C2-C20 alkloxyalkyl, C6-C20 alkylsiloxyalkyl (e g., trialkylsiloxyethyl). Preferably, either R ⁵ - is a C1-C4 alkyJ, ^{' '} optionally substituted with a C1-C4 perfluoroalkyl, hydroxyl, C 1-C6 alkoxy, amino, or thiol. λ-lternatively, R' ¹ is poly(ethylene glycol) of a formula -(CH ₂ O) _P -R ⁷ . Typically, p is 1 -2000. R ⁷ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted bicyclic carbocyclic group. Preferably, R ⁷ is hydrogen, methyl, ethyl, vinyl, allyl, phenyl, or benzyl; more preferably, R ⁷ is hydrogen or methyl.

Preferably, R ⁵ is methyl, «-butyl, tert-butγl, 2-ethylhexyl, 2- trimethylsilyloxyethyl, 2-ter/-butyldirnethylsilyloxyethyl _;i or 2-hydroxyethyl. Even more preferably, R ⁵ is methyl. In cases of a monomer having a functional group, proper protection of the functional group is needed for the anionic polymerization. Non-limiting examples for nonfunctional and functional protected methacrylate monomers include methyl methacrylate, ethyl methacrylate, terl-buXyl methacrylate,

2-ethylhexyl methacrylate, dodecyl methacrylate, stearyl methacrylate, 2- [(tπmethylsilyl)oxy]ethyl melhacrylate, 2-[(fer/-butyldimethylsilyl)oxy]ethyl methacrylate, 2-[(methoxymethyl)oxy]ethyl methacrylate;

R ⁶ is hydrogen, an optionally substituted C1-C20 alkyl, or an initiator residue Preferably, R ⁶ is re-butyl, sec-butyl, /er/-butyl or an initiator residue such as 1 , 1 -d iphenylhexan- 1 -yl, 1,1 -diphenyl-3-methylpentan- 1-yl, 3 ,3 -dimethyl- 1,1- diphenyl-butan-1 -yl, cumyl, and oligo(α-methylstyryl); preferably, R ⁶ is 1,1- diphenylhexan- 1 -yl .

M is an alkali metal cation, such as lithium, sodium, potassium, cesium. As used herein, a sυbstituent on" a carbon atom that forms an unsaturated carbon-carbon bond and whose attachment to such carbon atom is denoted by the symbol vo/vrvr _can be in either cis or trans substituent.

Preferably, R ¹ is a C1-C4 alkyl; R ² is hydrogen; X ¹ and X ² are each independently a chloride or bromide; R ⁴ is hydrogen, a C1-C4 alkyl or -C≡N; R ⁵ is a C1-C4 alkyl, optionally substituted with a C1-C4 perfluoroalkyl, hydroxy], C 1-C6 alkoxy, amino, or thiol; or R ⁵ is poly(ethylene glycol) of formula -(CH ₂ O) _P -R ⁷ , wherein R ⁷ is hydrogen, methyl, ethyl, vinyl, phenyl, or benzyl. Values and preferred values of the remainder of the variables are as defined above with respect to formulas (I), ^" (II) ^' and (III). Preferably, in formulas (I), (II) and (III), R ¹ is a C 1 -C4 alkyl; R ² is hydrogen; n and m are independently integers not less than 2; X ¹ is chloride or bromide; R ³ is hydrogen, an optionally substituted C1-C4 alkyl, or a C5-C20 aralkyl, having a Cl- C14 alkyl portion; JR ⁴ is hydrogen, a C1-C4 alkyl, or -C≡N; R ^s is a C1-C4 alkyl, optionally substituted with a C1 -C4 perfluoroalkyl, hydroxy!, C 1-C6 alkoxy, amino, or thiol; or R ⁵ is poly(ethylene glycol) of formula -(CH ₂ O) _P -R ⁷ , wherein R ⁷ is R ⁷ is hydrogen, methyl,'ethyl, vinyl, phenyl, or benzyl; R ⁶ is hydrogen, an optionally substituted C1-C20 alkyl or an initiator residue.

In another preferred embodiment, in formulas (I), (II) and (III), R ¹ is methyl; R ² is hydrogen; n and m are independently integers not less than 2; X ¹ is bromide; R ³ is hydrogen, an optionally substituted C1-C4 alkyl, or a C5-C20 aralkyl, having a Cl -C 14 alkyl portion; R ⁴ is methyl; R ⁵ is methyl, π-butyl, /er/-butyl, 2-ethylhexyl,

2-trimethylsilyloxyethyl, 2-/er/-butyldimethylsilyloxyethyl, or 2-hydroxyethyl; R ⁶ is hydrogen, an optionally substituted C1-C20 alkyl or an initiator residue.

In another preferred embodiment, in formulas (I), (II) and (III), R ¹ is a Cl- C4 alkyl; R ² is hydrogen; n and m are independently integers not less than 2; X ¹ is chloride or bromide; R ³ is a C1-C4 alkyl; R ⁴ is hydrogen, a C1 -C4 alkyl, or -O≡N; R ⁵ is a C1-C4 alkyl, optionally substituted with a C1 -C4 perfluoroalkyl, hydroxyl, C1 -C6 alkoxy, amino, or thiol; or R ^s is poly( ethylene glycol) of formula -(CH ₂ O) _P -R ⁷ , wherein R ⁷ is R ⁷ is hydrogen, methyl, ethyl, vinyl, phenyl, or benzyl; R ⁶ is an initiator residue.

In some embodiments, the present invention is a method for preparing diblock copolymers, triblock copolymers or radial-shaped block copolymers. These block co-polymers can be prepared by using monofunctional, difunctional or multifunctional polymers, respectively without substantially modifying Scheme (I). For example, by using a compound of formula (IA):

where k is an integer greater than or equal to 1, mono-, di-, tri- and tetrablock copolymers can be prepared. In formula (IA), L is an initiator residue such as cumyl, dicumyl and tricumyl when cumyl, dicumyl or tricumyl chloride, methylether or ester is used as initiator. Other values for L are given above with respect to R ³ . Preferably, L is when cumyl, dicumyl or tricumyl.

When a compound of formula (IA) is reacted with a compound of formula (II), a compound of formula (HIA) is produced:

Values and preferred values of the variables in formula (IIIA) are as defined above with respect to formulas (I), (IA), (II) and (III).

In one embodiment of the present invention, multiblock copolymers of a general formula (AB) _q , where A and B 'are each independently a block polymer and q is an integer greater than 1, can be prepared. An example of such a multiblock copolymer is a compound of formula (IIIB):

In formula (IIIB), ni and mi are each independently an integer not less than 2, q is an integer not less than I ₅ L' is an initiator residue, such as oligo(styryl), oligo(α-methylstyryl), and diadduct product of l,3-bis(l-phenylethenyl)benzene with RM, wherein R is a Cl-ClO alkyl and M is an alkali metal having formula (XXX).

The values and preferred values o the remainder of the variables in formula (IIIB) are as defined above with respect to formulas (IA), (II) and (II1A). -

Preferably, in formula (IIIB), L is cumyl, dicumyl, or tricumyl and L' is a compound of formula (XXX), wherein R is a Cl-ClO alkyl. More preferably, L is cumyl, dicumyl, or tricumyl, R is n- or sec-hnty\ and M is Li.

It should be noted that in formula (IIIB), R ¹ , R ² , R ⁴ and R ⁵ are, for each occurrence, independently selected from the values and preferred values as defined above with respect to formulas (IA), (II) and (IIIA). For instance, a copolymer of methyl methacrylate and trimethylsiloxyethyl methacrylate can be coupled to the end-functionalized polyisobutylene. Alternative combination of monomers for a copolymer can be any of choice from methyl methacrylate, trimethylsiloxyethyl methacrylate, ter/-butyldimethylsiloxyethyl methacrylate, ethyl methacrylate, n- butyl methacrylate, lert-huty\ methacrylate, 2-ethylhexyl methacrylate, benzyl methacrylate, 2-perfluoroalkyl methacrylate, oligo(ethylene glycol) methacrylate.

Compounds of formula (IIIB) can be prepared by reacting a compound of formula (IB) with a compound of formula (HA) according to Scheme (IA):

Scheme (IA).

The values and preferred values of the variables in formulas (IB) and (I1A) are as defined above with respect to formulas (IA), (II) and (IIIB).

In one embodiment, the present invention is a method of preparing a compound of formula (VI), comprising reacting a compound of formula (IV) with a compound of formula (V), according to Scheme (II):

Scheme (II).

In Scheme (II), X ¹ , R ³ and R ⁶ are as defined with respect to Scheme (I). Preferably, R ⁶ is n-butyl, sec-butyl, /erf-butyl, 1 ,1-diphenylhexan-l-yl, l ,l-diphenyl-3- methylpentan-1 -yl, 3 _! 3-dimethyl-l _! l-diphenyl-butan-l-yl, cumyl, and oligo(α- methylstyryl). Preferably, X ¹ is Cl or Br. More preferably, X ¹ is bromide

In one preferred embodiment, the present invention is a method of preparing a compound of formula (IX) comprising reacting a compound of formula (VII) with a compound of formula (VIII), according to Scheme (III):

Scheme (III). ^{' '}

Compound of formula (VIII) can be prepared according to any of the methods known in the art using an initializing residue R ⁶ . In one preferred embodiment, a compound of formula (VIII) can be prepared according to Scheme (IV):

Scheme (IV).

Typical conditions for the process for (meth)acrylate polymerization such as Scheme (IV) and coupling reactions such as Schemes (I) ₅ (II) and (III) (with bromoallyl end-functionalized polyisoolefin) are as follows Both reactions are carried out in the presence of a diluent or mixture of diluents. Suitable diluents are hydrocarbon solvent which include paraffinic, cycloparaffinic, and aromatic hydrocarbon solvent. Suitable polar solvents are ether which include tetrahydrofuran, ether, dioxane, and 1 ,2-dimethoxyethane.

Reaction time for the coupling reaction between living (meth)acrylate and bromoallyl end-functional polyisoolefin will generally range from 3 to 96 hours depending on the concentrations and reaction conditions. The molar ratios of living (meth)acrylate over bromoallyl end-functional polyisoolefin usually range from 1/3 to 3/1, preferably 1 to 1.3

(Meth)acrylate polymerization and coupling reaction temperature will general Iy. range from 0 ⁰ C to -100 ⁰ C, preferably from -40 ⁰ C to -80 ⁰ C.

The number average molecular weight of poly(meth)acrylate block will generally range from 100 to 1,000,000, preferably from 500 to 500,000. The composition of polyisoolefin to polymethacrylates in the block copolymer usually ranges from 1/99 to 99/1, preferably from 30/70 to 95/5.

The preparation of block copolymer by using bromoallyl end-functionalized polyisoolefin involves the polymerization of (meth)acrylate and coupling reaction • ^■ between bromoallyl end-functionalized polyisoolefin and living (meth)acrylate. Bromoallyl end-functional polyisoolefin is added to polymerization zone to form polyisobutylene-poly(meth)acrylate block copolymer. Degassed alcohol is charged to the polymerization ^" zone to quench the reaction.

In another embodiment of the invention, bromoallyl functional polyisobutylene can be prepared by a halogen exchange reaction of haloallyl functional polyisobutylene, such as chloroallyl polyisobutylene, with an alkali metal halide MX ¹ , according to Scheme (V):

Scheme (V).

The values and preferred values of variables in formulas (I) and (X) are as defined above with respect to formulas (I) where M is Li, Na, K, or Cs and X ¹ is Br, Cl- or I. -X ³ is a halide, different from ^' X ¹ . Preferably M is Li or Na, X ¹ is Br or I, and X ³ is Cl.

It should also be understood that the ^' reaction of Scheme (V) can -be carried out using a compound of formula (XA), as a starting material:

resulting in a compound of formula (IA):

In one embodiment, X' is Br and X ^J is Cl.

In one embodiment, the reaction of Scheme (V) is represented by Scheme (VI):

Scheme (VI)

In another embodiment, the reaction of Scheme (V) is represented by Scheme (VII):

Scheme (VII).

In a preferred embodiment, the reaction of Scheme (V) is represented by Scheme (VIII)

Scheme (VIII) In one embodiment, the present invention is a compound of formula (XIIl).

The values and preferre values of the variables in formula (XIII) are as defined above with respect to formulas (1) and (IA).

In another embodiment, the present invention is a compound of formula (XIV):

The values and preferred values of the variables in the compound of formula (XlV) are as defined above with respect to formula (I).

In one embodiment, the present invention is a compound of formula (XXII):

The values and preferred value for the variable R ³ is as defined above with respect to formula (I).

In one preferred embodiment, the present invention is a compound of formula (XII).

The methods of preparing compounds of formulas (I) and (IA) ₅ e.g. the compound of formulas (XII)-(XIV), according to Schemes (V), (VI) and (VII) allow a very high yield (up to 100%). The compounds of formula (XA) can be beneficially used in the methods of preparing block co-polymers described ^• above (Schemes (I), (II) and (TII)). Specifically, while the chloroallyl functionality has low reactivity in the reaction presented in Schemes (I)-(III), the bromoallyl functionality readily and efficiently reacts with living anionic polymers.

The typical conditions for the reactions of Scheme (V) are described below. The suitable alkali metal halides arc lithium bromide, sodium bromide, potassium bromide, cesium bromide, lithium iodide, sodium iodide, potassium iodide, and cesium iodide. Lithium bromide is the preferred reagent The reagent is usually used in concentrations of 10 to 1000 times higher than that of polymer, preferably 30 to 300 times higher than that of polymer.

The halogen exchange reaction is usually carried out in the presence of a diluent or mixture of diluents. The suitable diluents are ketones, halogenated

hydrocarbons, ethers, and aromatic hydrocarbons which contain from 1 to 20 carbon atoms per molecule, or mixtures thereof. Preferred diluent is a mixture of acetone and toluene (90/10 to 35/65 by vol.).

Temperature for the halogen exchanging reaction will generally range from 25 ⁰ C to 200 ⁰ C, preferably from 25 ⁰ C to 100 ⁰ C.

Reaction time for the halogen exchanging reaction will generally range from a 1 to 48 hours, preferably from 5 to 12 hours.

The following examples arc not intended to be limiting in any way.

EXAMPLES

Example 1 Synthesis of chloroallyl end-functionalized polyisobutylene

■ Preparation of chloroallyl end-functionalized polyisobutylene was carried out at —80 ⁰ C under a dry nitrogen atmosphere ([H ₂ O] < 0.5 ppm) in an MBraun 150-M glove box. To a prechilled 2 L flask equipped with mechanical stirrer were added 600 mL of hexane at 25 ⁰ C, 357 mL of methyl chloride at -80 ⁰ C, 0.62 mL of 2- chloro-2,4,4-trimethylpentane (3.6 x 10 ^"3 mol), 0.54 mL of 2,6-dWe/7-butylpyridine (3.6 x 10 ^"3 mol), and 21 mL of isobutylene (0.27 mol) at — 80 ⁰ C sequentially. Then 3.6 mL of titanium tetrachloride (3.3 x 10 ^"2 mol) dissolved in a mixture of hcxanes (12 mL) and methyl chloride (8 mL) was added into the reactor to start isobutylene polymerization. After 75 minutes, 2.8 mL of 1 ,3-butadiene (4.1 x 10 ^"2 mol) was added into the reactor. The capping reaction was completed in 5 h, and then 10 mL of prechilled methanol was added into the reactor to terminate the reaction. After the evaporation of solvents, the polymer was dissolved in hexane. The inorganic salts were removed by filtration. The polymer solution was washed with water/2- propanol/sodium chloride (77.5/15/7.5, v/v/w) twice and then with distilled water twice. The polymer was recovered and purified two times by reprecφitation from hexanes/methanol, followed by drying in vacuum.

According to ¹ H NMR and GPC measurements, functionalization at polyisobutylene chain end was essentially complete. The number average molecular weight of allylchoro end-functionalized polyisobutylene from GPC (4,600) agreed well with that from NMR (4,500) and polydispersity is narrow (MJM _n = 1.10), confirming no side reaction.

Example 1 Halogen-exchange reaction of chloroallyl end-functionalized polyisobutylene into bromoallyl end-funclionalized polyisobutylene

Halogen-exchange reaction of chloroallyl end-functionalized polyisobutylene was carried out under a dry nitrogen atmosphere. In a 1 L three-necked round- bottomed flask, 5.00 g of chloroallyl end-functionalizcd polyisobutylene (M _n = 4,600, PDl = 1.10, 1.09 mmol), 19.0 g of lithium bromide anhydrous (217.3 mmol) were dissolved in a mixture solvent of toluene (325 mL) and acetone (175 mL). The reaction solution was refluxed with stirring for 16 h. After cooling down to room temperature the reaction solution was washed with distilled water twice to remove excess lithium bromide. The organic layer was precipitated in methanol to give polymer. The polymer was dissolved in hexane and recovered by the precipitation in methanol, followed by drying under vacuum.

According to ¹ H NMR and GPC measurements, halogen exchange was essentially complete. The number average molecular weight and polydispersity (M _n = 4,700, PDI = 1.12) of bromoallyl end-functionalized polyisobutylene did not change in comparison with those of chloroallyl end-functionalized polyisobutylene (M _n — 4,600, PDI = 1.10), confirming the absence of side reaction.

Example 3 Coupling reaction between bromoallyl end-functionalized ^~ polyisobutylene and polyf methyl methacrylate) Example 3.1

Purifications of chemicals, polymerization and coupling reaction were carried out under high vacuum condition (< 10 ^"6 mbar). Bromoallyl end- functional ized polyisobutylene (M _n ~ 4,700, PDI = 1.12) was purified by azeotropic distillation with toluene three times and then dissolved in tetrahydrofuran for use. The coupling reaction was carried out at — 78 ⁰ C. 0.035 g (1.9 x 10 ^"4 mol) of 1,1- diphenylethylene and n-butyllithium in hexanes (1.6 M, 0.4 mL, 6.4 x 10 ^"4 mol) were added into a reactor under an argon atmosphere. After removing hexanes under high vacuum, 80 mL of tetrahydrofuran was introduced into the reactor by trap-to- trap distillation at —78 ⁰ C. The solution was degassed for 20 min under high vacuum, and then the reactor was detached from vacuum line by heat-sealing. The initiating

solution stood at room temperature for 2 hours to decompose excess /7-butyllithium and then was cooled down to —78 ⁰ C. 3.6 g of methyl methacrylate (3.6 x lO ^"2 rnol) in 10 mL of tetrahydrofuran was added by in-situ distillation in the reactor under vigorous stirring for polymerization. After 30 min, a small portion of polymer solution was taken to determine molecular weight of homo poly(methyl methacrylate). To the remainder of the solution 0.30 g of bromoallyl end- functionalized polyisobutylene (M _n = 4,700, PDI = 1.12, 6.4 x 10 ^'5 mol) in 10 mL of tetrahydrofuran was added. The coupling reaction proceeded at -78 ⁰ C for 24 h, and then was quenched with a large excess of benzyl bromide (6.0 x 10 ^"3 moi). The solution was precipitated in methanol to give white solid polymer.

The sampled poly(methyl methacrylate) had an average molecular weight of about 22,800 and a polydispersity of 1.05. The initial molar ratio of living poly(methyl methacrylate) and bromoallyl end-functionalized polyisobutylene was calculated as 2.5/1. The coupling efficiency was measured by using GPC and ¹ H NMR and calculated to be minimum 96 %.

Example 3.2

0.014 g (7.8 x 10 ^"5 mol) of 1,1-diphenylethylene and /7-butyllithium in hexanes (1.6 M, 0.20 mL, 3.2 x 10 ^'4 mol) were added into a reactor under an argon atmosphere. After removing hexanes under high vacuum, 40 mL of tetrahydrofuran was introduced into the reactor by trap-to-trap distillation at —78 ⁰ C. The solution was degassed for 20 min under high vacuum, and then the reactor was detached from vacuum line by heat-sealing. The initiating solution stood at room temperature for 2 hours to decompose excess 77-butyllithium and then was cooled down to —78 ⁰ C. 1.4 g of methyl methacrylate (1.4 x 10 ^"2 mol) in 5 mL of tetrahydrofuran was added by in-situ distillation in the reactor under vigorous stirring for polymerization. After 30 miή, a small portion of polymer solution was taken for sampling. To the remainder of the solution was added 0.30 g of bromoallyl end-functionalized polyisobutylene (M _n = 4,700, PDI = 1.12, 6.4 x 10 ^"5 mol) in 5 mL of tetrahydrofuran. The coupling reaction proceeded at —78 ⁰ C for 16 h, and then was quenched with a large excess of benzyl bromide (6.0 x ] 0 ^"3 mol). The solution was precipitated in methanol to give white solid polymer.

The sampled poly(methyl methacrylate) had an average molecular weight of about 22,600 and a polydispersity of 1.09. The initial molar ratio of living poly(methyl methacrylate) and bromoallyl end-functionalized polyisobutylene was calculated as 1.1/1. The coupling efficiency was measured by using GPC and ¹ H 5 NMR and calculated to be minimum 75 %.

Example 3 3

0.026 g (1.4 x 10 ^"4 mol) of 1,1-diphenyIethylene and n-butyllifhium in hexanes (1.6 M, 0.28 mL, 4.5 x 10 ^"4 mol) were added into a reactor under an argon

10 atmosphere After removing hexanes under high ^" vacuum, 35 mL of tetrahydrofuran was introduced into the reactor by trap-to-trap distillation at -78 ⁰ C. The solution was degassed for 20 min under high vacuum, and then the reactor was detached from vacuum line by heat-sealing. The initiating solution stood at room temperature for 2 hours to decompose excess n-butyllithium and then was cooled down to —78

] 5 ⁰ C. 2.5 g of methyl methacrylate (2 5 x 10 ^"2 mol) in 5 mL of tetrahydrofuran was added by w-silu distillation in the reactor under vigorous stirring for polymerization. After 30 min, a small- portion of living polymer solution was taken for sampling. To the remainder of the solution 0.50 g of bromoallyl end-functionalized ^" polyisobutylene (M _n = 4,700, PDl = 1.12, 1.06 x 10 ^"4 mol) in 5 mL of 0 tetrahydrofuran was added. The coupling reaction proceeded at —78 ⁰ C for r6 h, and then was quenched with a large excess of benzyl bromide (6.0 x 10 ^"3 mol). The solution was precipitated in methanol to give white solid polymer.

The sampled poly(methyl methacrylate) had average molecular weight of about 19,400 and a polydispersity of 1.12. The initial molar ratio of living

25 poly(methyl methacrylate) and bromoallyl end-functionalized polyisobutylene was calculated as 1.1/1. The coupling efficiency was measured by using GPC and ¹ H NMR and calculated to be minimum 90 %.

Example 3 4 30 0.027 g (1.5 x 10 ^"4 mol) of 1,1-diphenylethylene and /7-butyllithium in hexanes (1.6 M, .0.28 mL, 4.5 x 10 ^"4 mol) were added into a reactor under an argon atmosphere. After removing hexanes under high vacuum, 35 mL of tetrahydrofuran

was introduced into the reactor by trap-to-trap distillation at —78 ⁰ C. The solution was degassed for 20 min under high vacuum, and then the reactor was detached from vacuum line by heat-sealing. The initiating solution stood at room temperature for 2 hours to decompose excess «-butyllithium and then was cooled down to -78 ⁰ C. 2.5 g of methyl methacrylate (2.5 x 10 ^"2 mol) in 5 mL of tetrahydrofuran was added by in-silu distillation in the reactor under vigorous stirring for polymerization. After 30 min, a small portion of living polymer solution was taken for sampling. To the remainder of the solution was added 0.45 g of bromoallyl end-functionalized polyisobutylenc (M _n = 4,700, PDI = 1.12, 9.6 x 1O ^'5 mol) in 5 mL of tetrahydrofuran. The coupling reaction proceeded at —78 ⁰ C for 16 h, and then was quenched with a large excess of benzyl bromide (6.0 x 10 ^"3 mol). The solution was precipitated in methanol to give white solid polymer.

The sampled poly(methyl methacrylate) had an average molecular weight of about 19,600 and a polydispersity of 1.10. The initial molar ratio of living poJy(methy] methacrylate) and bromoallyl end-functionalized polyisobutylene was calculated as 1.25/1.The coupling efficiency was measured by using GPC and ¹ H NMR and calculated to be minimum 95 %.

Example 3.5 - . 0.017 g (9.5 x 10 ^"5 mol) of 1,1-diphenylethylene and /7-butyllithium in

" hexanes (1:6 M, 0.20 mL, 3.2 x 10 ^"4 mol) were added into a reactor under an argon atmosphere. After removing hexanes under high vacuum, 20 mL of tetrahydrofuran was introduced into the reactor by trap-to-trap distillation at —78 ⁰ C. The solution was degassed for 20 min under high vacuum, and then the reactor was detached from vacuum line by heat-sealing. The initiating solution stood at room temperature for 2 hours to decompose excess n-butyllithium and then was cooled down to -78 ⁰ C. 2.2 g of methyl methacrylate (2.2 x 10 ^"2 mol) in 5 mL of tetrahydrofuran was added by in-situ distillation in the reactor under vigorous stirring for polymerization. After 30 min, a small portion of sample was taken for measurement of molecular weight of homo poly(methyl methacrylate). To the remainder of the solution was added 0.34 g of bromoallyl end-functionalized polyisobutylene (M _n = 4,700, PDI = 1.12, 7.2 x 10 ^"3 mol) in 5 mL of tetrahydrofuran. The coupling reaction proceeded at

—78 ⁰ C for 42 h, and then was quenched with a large excess of benzyl bromide (6.0 x 10 ^"3 mol). The solution was precipitated in methanol to give white solid polymer.

The sampled poly(methyl methacrylate) had an average molecular weight of about 26,800 and a polydispersity of 1.09. The initial molar ratio of living poly(methyl methacrylate) and bromoallyl end -functional ized polyisobutylene was calculated as 1.1/1. The blocking efficiency was measured by using GPC and ¹ H NMR and calculated to be minimum 96 %.

Example 3 6 Chloroallyl end-functionalized polyisobulylene (M _n = 4,600, PDI = 1.10) was dried by azeotropic distillation with benzene three times and then dissolved in tetrahydrofuran. 0.036 g (2.0 x 10 ^"4 mol) of 1,1 -diphenyl ethylene and /7-butyllithium in hexanes (1.6 M, 0.40 mL, 6.4 x 10 ^"4 mol) were added into a reactor under an argon atmosphere. After removing hexanes under high vacuum, 90 mL of tetrahydrofuran was introduced into the reactor by trap-to-trap distillation at —78 ⁰ C. The initiating solution stood at room temperature for 2 hours to decompose excess n- butyllithium and then was cooled down to -78 ⁰ C. 4.0 g of methyl methacrylate (5.0 x I O ^"2 mol) was introduced into the reactor by trap-to-trap distillation under vigorous stirring to start polymerization for 30 min. The reaction solution was degassed for 10 min under high vacuum before the reactor was detached from vacuum line by heat- sealing. A small portion of living polymer solution was taken for sampling. To the remainder of the solution was added 0.50 g of chloroallyl end-functionalized polyisobutylene (M _n = 4,600, PDI = 1.10, 1.09 x 10 ^"4 mol) in 10 mL of tetrahydrofuran. The coupling reaction proceeded at —78 ⁰ C for 16 h, and then was quenched with a large excess of benzyl bromide (6.0 x 10 ^"3 mol). The solution was precipitated in methanol to give white solid polymer.

The sampled poly(methyl methacrylate) had an average molecular weight of about 26,400 and a polydispersity of 1.06. The initial molar ratio of living poly(methyl methacrylate) and bromoallyl end-functionalized polyisobutylene was calculated as 2.3/1. GPC and ¹ H NMR results indicated negligible coupling efficiency (< 10%) in this system.

EQUIVALENTS

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.