Polymer supports containing polyoxyalkylenes

Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...

Reexamination Certificate

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Details

C525S385000, C526S320000, C526S329600

Reexamination Certificate

active

06395842

ABSTRACT:

The present invention relates to polymers which are useful as supports in solid phase organic synthesis (SPOS).
Cross-linked insoluble polystyrene resin supports, normally in the form of spherical beads, are one of the most important types of substrate used for SPOS. They are relatively cheap and robust, can be made with a high functional group loading, with a wide range of functionalities available, and they swell in a variety of non hydroxylic solvents, thus giving access to a variety of reagents. Their main drawbacks are the lack of swelling in water or alcohols, and the close proximity of the functional groups to the hydrophobic core, which can cause steric hindrance to reactions, slowing or even preventing them, and may also give rise to poor NMR spectra due to slow relaxation times.
‘Tentagel’™ (trademark of Rapp Polymere GMBH) polymer supports are used widely in SPOS. These polymer supports have a polystyrene core with polyethylene glycol (MWt ca 4000) chains grafted onto this core. The terminal hydroxy groups are then functionalised to allow the synthesis to take place. The polymer supports are useful in that they are hydrophilic and so can swell in polar solvents such as water and alcohols as well as the usual solvents (toluene, tetrahydrofuran, dichloromethane) used for SPOS. The functional groups are well separated from the crosslinked polystyrene core and are thus unhindered for reaction and very mobile for good NMR analysis. The main deficiencies are that the functional group loading is low and they possess an acid labile benzyl ether linkage, thus restricting the range of reaction conditions under which they can be employed.
We have designed and made a series of novel polymer resin supports that can have a higher functional loading than that of ‘Tentagel’™ and yet, in certain embodiments, still swell in water or alcohols and at the same time do not have unduly slow relaxation times enabling NMR to be used.
Accordingly the present invention provides a polymer support which comprises hydroxypolyC
2-4
alkyleneoxy chains attached to a cross-linked polymer wherein the hydroxypolyC
2-4
alkyleneoxy chain contains from 2 to 8 C
2-4
alkyleneoxy groups and wherein the resulting polymer support has from about 0.1 to about 5 meq free hydroxy groups per gram of polymer.
The hydroxypolyC
2-4
alkyleneoxy chains in the supports according to the present invention are often selected from hydroxypolyethyleneoxy (HO(CH
2
CH
2
O)
2-8
—), hydroxypolypropyleneoxy (HO(CH
2
CH(CH
3
)O)
2-8
—) and hydroxypolybutyleneoxy (HO(CH
2
CH(C
2
H
5
)O)
2-8
—) chains. In a preferred embodiment of the invention the hydroxypolyC
2-4
alkyleneoxy chain is hydroxypolyethyleneoxy.
The number of C
2-4
alkyleneoxy groups in the hydroxypolyC
2-4
alkyleneoxy chain can range from 2 to 8, but is preferably from 3 to 5. Most preferably, there are 4 C
2-4
alkyleneoxy groups in the hydroxypolyC
2-4
alkyleneoxy chain.
In the most preferred embodiment of the invention the hydroxypolyC
2-4
alkyleneoxy chain is hydroxytetraethyleneoxy (HO(CH
2
CH
2
O)
4
—).
The cross-linked polymer in the supports according to the present invention may be, for example, a cross-linked polymer obtainable by polymerising a monomer mixture comprising at least one monomer selected from hydroxystyrene, hydroxymethylstyrene, chloromethylstyrene, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate and N-methylol (meth)acrylamide; wherein the phenyl ring in the styrenes is optionally substituted by 1 or 2 substituents often selected from methyl, ethyl, propyl, fluoro, chloro and bromo and wherein hydroxy groups, especially phenolic hydroxy groups, which may be present in the monomers are optionally protected and may subsequently be deprotected.
Preferably the cross-linked polymer is a copolymer comprising phenylethylene and hydroxyphenylethylene units or phenylethylene and chloromethylphenylethylene units, and more preferably a copolymer comprising phenylethylene and 4-hydroxyphenylethylene units or phenylethylene and 4-chloromethylphenylethylene units. The polymer support formed from a cross-linked polymer comprising phenylethylene and 4-hydroxyphenylethylene units has the additional advantage of not containing an acid labile benzyl ether linkage. Even more preferably the cross-linked polymer is a copolymer comprising phenylethylene and 4-hydroxyphenylethylene units. The cross-linked polymer can often be derived by polymerising a monomer mixture comprising styrene and optionally protected hydroxystyrene and subsequently deprotecting the hydroxy group if protected, or a monomer mixture comprising styrene and chloromethylstyrene. Most preferably the cross-linked copolymer is obtainable by polymerising styrene and optionally protected 4-hydroxystyrene under conditions to produce cross-linking, and subsequently deprotecting the hydroxy group if protected.
Protecting groups for hydroxy groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the hydroxy group in question, and may be introduced by conventional methods. Where protecting groups are present during a polymerisation process, the protecting groups are selected so as to survive the conditions of the polymerisation.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which “lower” signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
Examples of hydroxy protecting groups include tetrahydropyranyl, lower alkyl groups (for example t-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example t-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxy-carbonyl, p-nitrobenzyloxycarbonyl); tri lower alkysilyl (for example trimethylsilyl, t-butyldimethylsilyl) and phenyl lower alkyl (for example benzyl) groups.
The hydroxy protecting group may subsequently be removed to give the cross-linked polymer containing free hydroxy groups.
Methods appropriate for removal of hydroxy protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups aso-nitrobenzyloxycarbonyl, photolytically. The reader is referred to Advanced Organic Chemistry, 4
th
Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis, 2
nd
Edition, by Green et al., published by John Wiley and Sons for general guidance on protecting groups.
Acetyl is a preferred protecting group for the hydroxy group in protected-hydroxy styrene.
When the cross-linked polymer is produced by polymerisiation of a mixture of monomers comprising styrene and optionally protected hydroxystyrene or chloromethylstyrene, the weight percentage of optionally protected-hydroxystyrene or chloromethylstyrene of the total weight of optionally protected-hydroxystyrene or chloromethylstyrene plus styrene is preferably in the range of from 1-99%, more preferably in the range of from 5-80% and most preferably from 15% to 70%.
The extent of cross linking in the polymers is determined by the concentration of cross linking monomer in the polymerisation reaction. Generally the weight % of cross-linking monomer is in the range o

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