CA2482945C - Monomers containing polyoxyalkylenes and polymer supports therefrom - Google Patents
Monomers containing polyoxyalkylenes and polymer supports therefrom Download PDFInfo
- Publication number
- CA2482945C CA2482945C CA2482945A CA2482945A CA2482945C CA 2482945 C CA2482945 C CA 2482945C CA 2482945 A CA2482945 A CA 2482945A CA 2482945 A CA2482945 A CA 2482945A CA 2482945 C CA2482945 C CA 2482945C
- Authority
- CA
- Canada
- Prior art keywords
- protected
- monomer
- alkyleneoxy
- optionally substituted
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F12/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
- C08F12/02—Monomers containing only one unsaturated aliphatic radical
- C08F12/04—Monomers containing only one unsaturated aliphatic radical containing one ring
- C08F12/14—Monomers containing only one unsaturated aliphatic radical containing one ring substituted by hetero atoms or groups containing heteroatoms
- C08F12/22—Oxygen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
- C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
- C08F290/06—Polymers provided for in subclass C08G
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
- C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
- C08F290/06—Polymers provided for in subclass C08G
- C08F290/062—Polyethers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic
- C08G65/3326—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic aromatic
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/05—Polymer mixtures characterised by other features containing polymer components which can react with one another
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
A polymer support is provided which comprises protected hydroxypolyC2-4 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chains are protected with an acid labile group. The acid labile protecting group is preferably a poly-aryl methane protecting group. A monomer and process for the preparation of said support are also provided.
Description
MONOMERS CONTAINING POLYOXYALKYLENES AND
POLYMER SUPPORTS THEREFROM
The present invention relates to a process for the synthesis of polymers which are useful as supports in solid phase organic synthesis (SPOS) and to intermediates for use therein.
PCT/GB99/02193 (published as WO 00/02953) discloses a series of novel polymer resin supports which find use as supports in solid phase organic synthesis (SPOS).
These polymer resins are of commercial importance and there exists a need for improved methods for their synthesis. We have found that certain novel monomers and resins find use in improved routes to these polymers.
In an embodiment, the invention provides a monomer which comprises a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with a poly(aryl)methane protecting group.
In another embodiment, the invention provides a monomer of formula (1) R
R5O~-C2-4 alkylene-O
n wherein Rl is an optionally substituted ethylene group;
la R2-4 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is a poly(aryl)methane protecting group; and n is 2 to 10.
In another embodiment, the invention provides a process for the preparation of a polymer support comprising polymerisation of a monomer comprising a protected hydroxypolYC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolYC2-4 alkyleneoxy chain comprises from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolYC2-4 alkyleneoxy chain is protected with a poly(aryl)methane protecting group, under conditions to produce cross-linking.
In another embodiment, the invention provides a polymer support which comprises protected hydroxypolYC2-4 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC2_4 alkyleneoxy chain comprises from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolyC2.4 alkyleneoxy chains are protected with a poly(aryl)methane protecting group.
In another embodiment, the invention provides use of the polymer support as described herein in solid phase organic synthesis.
Hence, according to a first aspect of the present invention there is provided a monomer which comprises a protected hydroxypolYC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolYC2-4 alkyleneoxy chain contains from 2 to 10 C2.4 alkyleneoxy groups and wherein the hydroxypolYC2-4 alkyleneoxy chain is protected with an acid labile protecting group.
lb The hydroxypolyC2-4alkyleneoxy chains attached to the monomer according to the present invention are -often selected from hydroxypolyethyleneoxy (HO(CH2CH2O)2_111-), hydroxypolypropyteneoxy (HO(CH2CH(CH3)O)2_,o-) and hydroxypolybutyleneoxy (HO(CH2CH(C2H5)O)2.fo-) chains. In a preferred embodiment of the invention the hydroxypolyC2-4alkyleneoxy chain is hydroxypolyethyleneoxy.
The number of C2.4alkyleneoxy groups in the hydroxypolyC24alkyleneoxy chain can range from 2 to 10, but is preferably from 2 to 8 and more preferably from 3 to. 5. Most preferably, there are four C2-4alkyleneoxy groups in the hydroxypolyC2.4alkyleneoxy chain.
In a highly preferred embodiment of the invention the hydroxypolyC2.4alkyleneoxy chain is hydroxytetraethyleneoxy (HO(CH2CH2O)4 ).
The polymerisable unit of the monomer according to the present invention is often selected from optionally substituted styrenes, acrylates and acrylamides. In a preferred embodiment of the invention the polymerisable unit is an optionally substituted styrene, optionally substituted methylstyrene, optionally substituted ethyl (meth)acrylate, optionally substituted propyl (meth)acrylate or optionally substituted N-methyl (meth)acrylamide.
In a highly preferred embodiment of the invention the polymerisable unit is an optionally substituted styrene or optionally substituted methylstyrene.
When the polymerisable unit is an optionally substituted styrene or optionally substituted methylstyrene, the phenyl ring of the styrene is preferably optionally 2 0 substituted by 1 or 2 substituents often selected from methyl, ethyl, propyl, fluoro, chloro and bromo.
When the polymerisable unit is an optionally substituted styrene or optionally substituted methylstyrene, preferably the protected hydroxypolyC2.4 alkyleneoxy chain is attached to an optionally substituted styrene or optionally substituted methylstyrene via an oxygen atom directly attached to the phenyl ring of the optionally substituted styrene or optionally substituted methylstyrene.
Acid labile protecting groups are groups which are labile under acid conditions.
Acid labile protecting groups include poly-aryl methane protecting groups.
Poly-aryl methane protecting groups include optionally substituted di-aryl methanes and optionally substituted tri-aryl methanes. Optional substituents may reside on one or more of the aryl groups, and each aryl group may carry one or more substituents. Di-aryl methanes may also be optionally substituted on the carbon to which the two aryls are attached, preferably the optional substituent is an alkyl group.
Aryl refers to aryl groups which may contain 1 ring or 2 or more fused rings, the fused rings optionally may include cycloalkyl, aryl or heterocyclic rings.
Examples of aryl groups include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl xanthyl, pyridyl, pyrimidyl, thiophenyl, furanyl, indolyl, quinolyl and isoquinolyl groups.
Preferred aryl groups are optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted xanthyl groups.
Alkyl groups which may substitute the carbon of a di-aryl methane include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms, preferably from 1 to 5 carbon atoms, most preferably I or 2 carbon atoms.
Examples include methyl, ethyl, propyl, and iso-propyl groups.
When the poly-aryl methane is substituted, the substituent(s) should be such so as not to adversely affect the stability of the protecting group or the ability to remove the protecting group under acid conditions. Optional substituents include halogen, cyano, nitro, hydrocarbyl, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, poly(oxyalkylene)oxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are generally alkyl or aryl groups as defined above.
One or more substituents may be present.
Examples of poly-aryl methane protecting groups include diphenylmethyl, naphthyldiphenylmethyl, phenylxanthyl [pixy!], triphenylmethyl [trityl], di-methoxyphenylphenylmethyl [dimethoxy trityl], methoxyphenyl-di-phenylmethyl [monomethoxy trityl], and 2-chlorophenyldi-phenylmethyl [2-chlorotrityl]
groups In a preferred embodiment of the invention, the monomer is a compound of formula (1) R5-0+24 alkylene_0 n R2.4 wherein R' is an optionally substituted ethylene group;
R21 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is an acid labile protecting group; and nis2to10.
Preferably, the acid labile protecting group is a poly-aryl methane protecting group.
More preferably R5 is a poly-aryl methane protecting group of formula:
wherein:
R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl group; and R7 and R8 are each independently optionally substituted aryl groups, or R7 &
R8 are optionally substituted aryl groups which may be linked to form an optionally substituted ring.
Alkyl groups which may be represented by R6 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms, preferably from 1 to 5 carbon atoms, most preferably 1 or 2 carbon atoms.
Examples include methyl, ethyl, propyl, and iso-propyl.
Aryl groups which may be represented by R6, R7 and R8 may contain 1 ring or 2 or more fused rings, the fused rings optionally may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl, pyridyl, pyrimidyl, thiophenyl, furanyl, indolyl, quinolyl and isoquinolyl groups.
Preferred aryl groups are optionally substituted phenyl.
When R7 & R8 are optionally substituted aryl groups which are linked in such a way that when taken together with the carbon atom to which they are attached that a ring is formed, it is preferred that the ring is a 5, 6 or 7 membered ring. Examples where R7 & R8 are optionally substituted aryl groups which are linked to form an optionally substituted ring include xanthyl groups.
When any of R6, R7 or R8 is a substituted alkyl or substituted aryl group, the substituent(s) should be such so as not to adversely affect the stability of the protecting group or the ability to remove the protecting group under acid conditions.
Optional substituents include halogen, cyano, nitro, hydrocarbyl, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, poly(oxyalkylene)oxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are generally alkyl, aryl, alkaryl and aralkyl groups, the alkyl and aryl groups are as defined above. One or more substituents may be present.
Most preferably, R5 is a poly-aryl methane protecting group of formula:
POLYMER SUPPORTS THEREFROM
The present invention relates to a process for the synthesis of polymers which are useful as supports in solid phase organic synthesis (SPOS) and to intermediates for use therein.
PCT/GB99/02193 (published as WO 00/02953) discloses a series of novel polymer resin supports which find use as supports in solid phase organic synthesis (SPOS).
These polymer resins are of commercial importance and there exists a need for improved methods for their synthesis. We have found that certain novel monomers and resins find use in improved routes to these polymers.
In an embodiment, the invention provides a monomer which comprises a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with a poly(aryl)methane protecting group.
In another embodiment, the invention provides a monomer of formula (1) R
R5O~-C2-4 alkylene-O
n wherein Rl is an optionally substituted ethylene group;
la R2-4 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is a poly(aryl)methane protecting group; and n is 2 to 10.
In another embodiment, the invention provides a process for the preparation of a polymer support comprising polymerisation of a monomer comprising a protected hydroxypolYC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolYC2-4 alkyleneoxy chain comprises from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolYC2-4 alkyleneoxy chain is protected with a poly(aryl)methane protecting group, under conditions to produce cross-linking.
In another embodiment, the invention provides a polymer support which comprises protected hydroxypolYC2-4 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC2_4 alkyleneoxy chain comprises from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolyC2.4 alkyleneoxy chains are protected with a poly(aryl)methane protecting group.
In another embodiment, the invention provides use of the polymer support as described herein in solid phase organic synthesis.
Hence, according to a first aspect of the present invention there is provided a monomer which comprises a protected hydroxypolYC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolYC2-4 alkyleneoxy chain contains from 2 to 10 C2.4 alkyleneoxy groups and wherein the hydroxypolYC2-4 alkyleneoxy chain is protected with an acid labile protecting group.
lb The hydroxypolyC2-4alkyleneoxy chains attached to the monomer according to the present invention are -often selected from hydroxypolyethyleneoxy (HO(CH2CH2O)2_111-), hydroxypolypropyteneoxy (HO(CH2CH(CH3)O)2_,o-) and hydroxypolybutyleneoxy (HO(CH2CH(C2H5)O)2.fo-) chains. In a preferred embodiment of the invention the hydroxypolyC2-4alkyleneoxy chain is hydroxypolyethyleneoxy.
The number of C2.4alkyleneoxy groups in the hydroxypolyC24alkyleneoxy chain can range from 2 to 10, but is preferably from 2 to 8 and more preferably from 3 to. 5. Most preferably, there are four C2-4alkyleneoxy groups in the hydroxypolyC2.4alkyleneoxy chain.
In a highly preferred embodiment of the invention the hydroxypolyC2.4alkyleneoxy chain is hydroxytetraethyleneoxy (HO(CH2CH2O)4 ).
The polymerisable unit of the monomer according to the present invention is often selected from optionally substituted styrenes, acrylates and acrylamides. In a preferred embodiment of the invention the polymerisable unit is an optionally substituted styrene, optionally substituted methylstyrene, optionally substituted ethyl (meth)acrylate, optionally substituted propyl (meth)acrylate or optionally substituted N-methyl (meth)acrylamide.
In a highly preferred embodiment of the invention the polymerisable unit is an optionally substituted styrene or optionally substituted methylstyrene.
When the polymerisable unit is an optionally substituted styrene or optionally substituted methylstyrene, the phenyl ring of the styrene is preferably optionally 2 0 substituted by 1 or 2 substituents often selected from methyl, ethyl, propyl, fluoro, chloro and bromo.
When the polymerisable unit is an optionally substituted styrene or optionally substituted methylstyrene, preferably the protected hydroxypolyC2.4 alkyleneoxy chain is attached to an optionally substituted styrene or optionally substituted methylstyrene via an oxygen atom directly attached to the phenyl ring of the optionally substituted styrene or optionally substituted methylstyrene.
Acid labile protecting groups are groups which are labile under acid conditions.
Acid labile protecting groups include poly-aryl methane protecting groups.
Poly-aryl methane protecting groups include optionally substituted di-aryl methanes and optionally substituted tri-aryl methanes. Optional substituents may reside on one or more of the aryl groups, and each aryl group may carry one or more substituents. Di-aryl methanes may also be optionally substituted on the carbon to which the two aryls are attached, preferably the optional substituent is an alkyl group.
Aryl refers to aryl groups which may contain 1 ring or 2 or more fused rings, the fused rings optionally may include cycloalkyl, aryl or heterocyclic rings.
Examples of aryl groups include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl xanthyl, pyridyl, pyrimidyl, thiophenyl, furanyl, indolyl, quinolyl and isoquinolyl groups.
Preferred aryl groups are optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted xanthyl groups.
Alkyl groups which may substitute the carbon of a di-aryl methane include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms, preferably from 1 to 5 carbon atoms, most preferably I or 2 carbon atoms.
Examples include methyl, ethyl, propyl, and iso-propyl groups.
When the poly-aryl methane is substituted, the substituent(s) should be such so as not to adversely affect the stability of the protecting group or the ability to remove the protecting group under acid conditions. Optional substituents include halogen, cyano, nitro, hydrocarbyl, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, poly(oxyalkylene)oxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are generally alkyl or aryl groups as defined above.
One or more substituents may be present.
Examples of poly-aryl methane protecting groups include diphenylmethyl, naphthyldiphenylmethyl, phenylxanthyl [pixy!], triphenylmethyl [trityl], di-methoxyphenylphenylmethyl [dimethoxy trityl], methoxyphenyl-di-phenylmethyl [monomethoxy trityl], and 2-chlorophenyldi-phenylmethyl [2-chlorotrityl]
groups In a preferred embodiment of the invention, the monomer is a compound of formula (1) R5-0+24 alkylene_0 n R2.4 wherein R' is an optionally substituted ethylene group;
R21 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is an acid labile protecting group; and nis2to10.
Preferably, the acid labile protecting group is a poly-aryl methane protecting group.
More preferably R5 is a poly-aryl methane protecting group of formula:
wherein:
R6 is hydrogen, optionally substituted alkyl or optionally substituted aryl group; and R7 and R8 are each independently optionally substituted aryl groups, or R7 &
R8 are optionally substituted aryl groups which may be linked to form an optionally substituted ring.
Alkyl groups which may be represented by R6 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms, preferably from 1 to 5 carbon atoms, most preferably 1 or 2 carbon atoms.
Examples include methyl, ethyl, propyl, and iso-propyl.
Aryl groups which may be represented by R6, R7 and R8 may contain 1 ring or 2 or more fused rings, the fused rings optionally may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl, pyridyl, pyrimidyl, thiophenyl, furanyl, indolyl, quinolyl and isoquinolyl groups.
Preferred aryl groups are optionally substituted phenyl.
When R7 & R8 are optionally substituted aryl groups which are linked in such a way that when taken together with the carbon atom to which they are attached that a ring is formed, it is preferred that the ring is a 5, 6 or 7 membered ring. Examples where R7 & R8 are optionally substituted aryl groups which are linked to form an optionally substituted ring include xanthyl groups.
When any of R6, R7 or R8 is a substituted alkyl or substituted aryl group, the substituent(s) should be such so as not to adversely affect the stability of the protecting group or the ability to remove the protecting group under acid conditions.
Optional substituents include halogen, cyano, nitro, hydrocarbyl, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, poly(oxyalkylene)oxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are generally alkyl, aryl, alkaryl and aralkyl groups, the alkyl and aryl groups are as defined above. One or more substituents may be present.
Most preferably, R5 is a poly-aryl methane protecting group of formula:
wherein:
R6 is an optionally substituted aryl group; and R' and R' are each independently optionally substituted aryl groups, or R' &
R8 are optionally substituted aryl groups which may be linked to form an optionally substituted ring.
In a highly preferred embodiment of the present invention, the acid labile protecting group is an optionally substituted trityl group.
According to a second aspect of the present invention there is provided a monomer which comprises a protected hydroxypolyC2.4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chain is protected with an optionally substituted trityl group.
Optionally substituted trityl groups include triphenylmethyl [trityl], di-methoxyphenylphenylmethyl [dimethoxy trityll, methoxyphenyl-di-phenylmethyl (monomethoxy trityl], and 2-chiorophenyldi-phenylmethyl [2-chiorotrityl]
groups.
In a most preferred embodiment of the present invention, the monomer is a compound of formula (1a) R
R5-O-}C2.4 al kylene__ O
ll n wherein R' is an optionally substituted ethylene group;
R24 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is an optionally substituted trityl group; and nis2to10.
Preferably, R' is a CH=CH2, CH=CHCH3i or C(CH3)=CH2 group. Most preferably, R' is a CH=CH2.
Preferably, the R5O-[-C2 alkylene-O-], group is pars to R'.
Preferably, [-C24alkylene-O-]õ is [-CH2CH2O-]n, [-CH2CH(CH3)O-J,,, [-CH2CH2CH2CH2O-]1 or [-CH2CH(C2H5)O-]n, and most preferably [-CH2CH2O-]n.
Preferably n is 2 to 8, more preferably n is 3 to 5. Most preferably n is 4.
Preferably R--' are all hydrogen.
Hydrocarbyl includes alkyl, aryl, alkaryl and aralkyl groups. Preferably when any of R`4 are hydrocarbyl or hydrocarbyloxy groups the hydrocarbyl is an alkyl group, most preferably a C,-, alkyl group.
The monomers according to the first and second aspects of the present invention are useful in polymerisation reactions to form resins from which the polymer supports disclosed in PCT/GB99/02193 (published as WO 00/02953) can be obtained.
Accordingly, a third aspect of the present invention provides a process for the preparation of a polymer support comprising polymerisation of a monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2_4 alkyleneoxy groups 5 and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an acid labile protecting group, under conditions to produce cross-linking.
The monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an acid labile protecting group can be as described above in the first and second aspects of the present invention.
Preferably the acid labile protecting group is a poly-aryl methane protecting group, more preferably an optionally substituted trityl group. The preferred poly-aryl methane protecting groups and the optionally substituted trityl groups are as defined above in the is first and second aspects of the present invention.
Optionally, in the process of the present invention the monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an acid labile protecting group, preferably an optionally substituted tritly group, may comprise a mixture of isomers.
Preferably, when a mixture of isomers is used in the process of the present invention, the monomer is a compound of formula (1) or (1a). Most preferably, the monomer is a mixture of isomers wherein R5O-[-C2-4alkylene-O-], group and R1 occupy isomeric positions on the phenyl ring.
Preferably, in the process of the present invention, the monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit is co-polymerised in the presence of a cross linking monomer.
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 of from 0.1 to 70%, commonly from 0.5 to 20%, such as from 1 to 10%, and most preferably no more than 5% by weight. Polymers comprising no more than 20% by weight of cross-linking monomer are generally swellable, whilst polymers comprising greater than 20% of crosslinking monomer are generally not swellable.
Suitable cross-linking monomers include divinyl benzene (DVB) or multifunctional (meth)acrylates such as di/tri acrylates or di/tri methacrylates such as ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylopropane trimethacrylate, trivinylbenzene or N,N'-bis-acryloyl ethylene diamine. Preferably the cross-linking monomer is DVB.
Preferably 0.5 to 5% by weight of DVB is used. Most preferably 1 to 3% by weight DVB is used.
In one aspect of the present invention a level of at least 5% crosslinking monomer is used in conjunction with compounds miscible with the organic phase which can act as pore-forming agents or porogens. Typical porogens can include, but are not limited to, organic compounds which are good solvents for the polymer, such as organic aromatic hydrocarbons, chlorinated aliphatic or aromatic hydrocarbons and cyclic aliphatic ethers, organic compounds which are poor solvents for the resulting polymer, such as aliphatic alcohols, ketones, aliphatic hydrocarbons, aliphatic carboxylic acids and linear polymers.
Preferably porogens are selected from toluene, xylene, chlorobenzene, tetrahydrofuran, dioxane, 2-ethyl-1-hexanol, 2-octanol, 1-decanol, 1-dodecanol, acetone, butanone, n-heptane, n-decane, 1-decanoic acid and linear polystyrene of molecular weight 500 to 5000000 g/mol. The resulting polymers have substantially non-swelling behaviour and generally possess a meso- to macro-porous nature, by which mode reagents can access the polymer-bound functionality.
Optionally, in the process of the present invention, the monomer comprising a protected hydroxypolyC2_4alkyleneoxy chain attached to a polymerisable unit is co-polymerised in the presence of one or more monomers selected from styrenes, for example styrene, hydroxystyrene, methoxystyrene, methylstyrene, hydroxymethylstyrene and chloromethylstyrene, esters of acrylic acid and esters of (meth)acrylic acid, for example methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl acrylate, hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate, and acrylamides, for example N-methyl acrylamide 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.
In a preferred process of the present invention, the monomer comprising a protected hydroxypolyC2-4alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an optionally substituted trityl group is co-polymerised in the presence of one or more cross linking monomers, and one or more monomers selected from styrenes, esters of acrylic acid and esters of (meth)acrylic acid, or acrylamides.
In a highly preferred process of the present invention, the monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2_4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2.4 alkyleneoxy chain is protected with an optionally substituted trityl group is co-polymerised in the presence of DVB and styrene.
When the polymer support is produced by polymerisiation of a mixture of monomers comprising the monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4alkyleneoxy chain contains from 2 to 10 C2-4alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chain is protected with an acid labile protecting group, preferably an optionally substituted trityl group, and one or more monomers selected from styrenes, esters of acrylic acid and esters of (meth)acrylic acid, or acrylamides, the weight percentage of the monomer comprising a protected hydroxypolyC2-4alkyleneoxy chain attached to a polymerisable unit of the total weight of the monomers present 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 process of the present invention is preferably carried out by aqueous suspension polymerisation. The monomers are suspended as droplets (1-1000 m) in water. Stabilisers are usually added to prevent agglomeration of the droplets, for example polyvinyl alcohol, polyacrylic acid, polyvinyl pyrrolidone, polyalkylene oxide, derivatives of cellulose, such as hyd roxypropyl methylcel I u lose or ethylcellulose, barium sulphate, magnesium sulphate or sodium sulphate. The suspension is also normally stirred to maintain the suspension.
Optionally, organic non-water miscible solvents may be used in the polymerisation process. Organic non-water miscible solvents may assist droplet formation in aqueous suspension polymerisation, or may act as porogens.
Optionally inorganic salts may be added to the aqueous phase in aqueous suspension polymerisation. Inorganic salts may assist droplet formation by suppressing monomer solubility in the aqueous medium.
A free radical initiator is preferably used to initiate polymerisation. The type of initiator will generally be selected based on the monomers used. Examples of preferred free radical initiators include benzoyl peroxide, dioctanoyl peroxide, lauroyl peroxide, 2,2'-azobisisobutyronitrile and 2,2'-azobis(2,4-dimethylvaleronitrile).
Polymerisation is typically assisted by heating the mixture in the range of 15 C to 160 C, preferably 50 C to 90 C. It will be recognised that the temperature to which the mixture can be heated depends upon the type of monomer and initiator employed.
The resultant polymer may then be washed with suitable solvents such as tetrahydrofuran, methanol and water, dried and bead size classified, for example, by sieving.
Accordingly a further aspect of the present invention provides a polymer support which comprises protected hydroxypolyC2-4 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2_ 4 alkyleneoxy groups and wherein the hydroxypolyC2-4alkyleneoxy chains are protected with an acid labile protecting group, preferably an optionally substituted trityl group.
The protected hydroxypolyC2 4alkyleneoxy chains attached to a cross-linked polymer according to the present invention are often selected from protected hydroxypolyethyleneoxy (protected HO(CH2CH2O)2_10-), protected hydroxypolypropyleneoxy (protected HO(CH2CH(CH3)O)2_10-) and protected hydroxypolybutyleneoxy (protected HO(CH2CH(C2H5)O)2_10-) chains. In a preferred embodiment of the invention the protected hydroxypolyC2-4alkyleneoxy chain is protected hydroxypolyethyleneoxy.
The number of C2_4alkyleneoxy groups in the protected hydroxypolyC2-4alkyleneoxy chain can range from 2 to 10, but is preferably from 2 to 8 and more preferably from 3 to 5.
Most preferably, there are four C2,alkyleneoxy groups in the protected hydroxypolyC2.4alkyleneoxy chain.
In a highly preferred embodiment of the invention the protected hydroxypolyC2.4alkyleneoxy chain is protected hydroxytetraethyleneoxy (protected HO(CH2CH2O)4-).
Preferably the protected hydroxypolyC2_4 alkyleneoxy chains are attached to a cross-linked polymer via phenoxy ether linkages.
The invention, in its broadest aspect, relates to the particular polymer supports however prepared.
Preferably, the polymer support of the present invention is obtainable by the process of the third aspect of the present invention.
The acid labile protecting groups may subsequently be removed to give the cross-linked polymer containing free hydroxy groups.
Methods appropriate for removal of the optionally substituted trityl group include, for example, acid- hydrolysis. Commonly a mixture of trifluoroacetic acid in methylene chloride can be employed. The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.
Where appropriate, other methods may be also used for the removal of the acid labile protecting groups, for example the use of iodine under neutral conditions may be used to remove trityl groups, and photolysis may be used to remove pixyl groups.
Preferably, when the protecting groups are removed the resulting polymer support has from about 0.1 to about 5 meq free hydroxy groups per gram of polymer.
Cross-linked polymers containing a free hydroxy group are usually produced as beads which range in size from 10 m to 2000 m. Preferably the bead size is from 50 m to 1000 m and most preferably from 75 m to 500gm. The cross-linked polymer beads are generally produced by an aqueous suspension polymerisation process, for example see Journal of Applied Polymer Science, 1982, 27, 133-138.
The polymer support obtained when the protecting groups are removed from the support according to the present invention has a hydroxy functionality of from 0.1 to about 5, for example up to 4.8 meq (milliequivalents) of hydroxy per gram of polymer, and often from 0.5 to 3.5, commonly 1.0 to 3.3 meq per gram for example from 1.5 to 3 meq per gram of polymer. In many embodiments, the polymer support obtained when the protecting groups are removed have from 0.5 to 2 meq of hydroxy per gram of polymer.
The polymer supports described above are of use in solid phase organic synthesis, accordingly there is provided the use of a polymer support which comprises protected hydroxypolyC24 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC24 alkyleneoxy chain contains from 2 to 10 C24alkyleneoxy groups and wherein the hydroxypolyC2.4 alkyleneoxy chains are protected with an acid labile group in solid phase organic synthesis.
Preferably, the polymer support is obtained by the process of third aspect of the present invention.
Preferably, the polymer support is deprotected prior to use.
The invention will now be described, without limitation, by the following examples in which, unless otherwise stated:-a) FT-IR spectra were obtained using swollen gels in dichloromethane held between sodium chloride plates, and an ATI Genesis (Matteson)spectrometer.
b) 13C magic angle (MAS) NMR spectra were obtained using solvent swollen gels in the rotor of a Bruker MAS probe on a 400MHz NMR spectrometer.
c) yields are given for illustration and are not necessarily the maximum attainable.
d) the following abreviations have been used: THE = tetrahydrofuran, DMF =
N,N-dimethylformamide, FMOC = fluorenylmethoxycarbonyl, PEG =
polyethyleneglycol and THP = tetrahydropyranyl.
Examples EXAMPLE I - Preparation of trityl-tetraethyleneglycoxystyrene Tetraethyleneglycol (174g, 0.9mol) was placed in a 3 necked round bottom flask fitted with a thermometer and reflux condenser. Pyridine (11 cm3, 0.135mo1) was added to the mixture stirred. Triphenylmethylchloride (25g, 0.09mol) was dissolved in toluene (30cm3) and this solution was added slowly to the mixture. The mixture was heated to 50 C and the temperature maintained for 1 h.
The mixture was allowed to cool and toluene (200cm3) was added to the flask.
The solution was extracted with water (500cm3). The aqueous phase was back extracted with toluene (2 x 100cm3). The organic layers were combined and washed with water (2 x 100cm3), dried over MgSO4 and filtered. The toluene was removed by evaporation under 5 reduced pressure to yield a pale yellow oil (yield 38.5g, 98% based on trityl).
Mono(trityl)tetraethyleneglycol (30g, 0.069mo1), 4-toluenesulfonyl chloride (14.4g, 0.076mol) and dry tetrahydrofuran (50cm3) were placed in a 3 necked round bottom flask 10 fitted with a thermometer and reflux condenser. The flask was placed in a dry-ice bath and the mixture allowed to cool to - -20 C. A solution of KOH (25.2g, 0.45mol) in water (100cm3) was added drop-wise over a period of 1h whilst maintaining the temperature at <0 C. Following the addition the reaction mixture was stirred for 1h whilst allowing the solution to warm to ambient.
The solution was extracted with diethylether (3 x 150cm3). The ether layer was dried over MgSO4,filtered and evaporated under reduced pressure. The solid was washed with MeOH and dried under vacuum (yield 34.3g, 85%).
NaOMe (0.55g, 10.2mmol) was dissolved in the minimum amount of N,N-dimethylformamide (DMF) and added to 4-acetoxystyrene (1.3cm3, 8.5mmol) contained in a round bottom flask. This solution was stirred at ambient for 45min then a solution of the tosyl derivative of mono(trityl)tetraethyleneglycol (5g, 8.5mmol) in DMF was added. The reaction was allowed to continue overnight at ambient.
The DMF was removed by evaporation under reduced pressure. The oil remaining was dissolved in isopropylacetate and extracted with water. The organic layers were combined, dried over MgSO4 and filtered. The solvent was removed by evaporation under reduced pressure to leave a pale yellow oil that crystallised on standing (yield 3.5g, 77%).
EXAMPLE 2 - 10 litre scale Preparation of trityl-tetraethyleneglycoxystyrene STAGE I
R6 is an optionally substituted aryl group; and R' and R' are each independently optionally substituted aryl groups, or R' &
R8 are optionally substituted aryl groups which may be linked to form an optionally substituted ring.
In a highly preferred embodiment of the present invention, the acid labile protecting group is an optionally substituted trityl group.
According to a second aspect of the present invention there is provided a monomer which comprises a protected hydroxypolyC2.4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chain is protected with an optionally substituted trityl group.
Optionally substituted trityl groups include triphenylmethyl [trityl], di-methoxyphenylphenylmethyl [dimethoxy trityll, methoxyphenyl-di-phenylmethyl (monomethoxy trityl], and 2-chiorophenyldi-phenylmethyl [2-chiorotrityl]
groups.
In a most preferred embodiment of the present invention, the monomer is a compound of formula (1a) R
R5-O-}C2.4 al kylene__ O
ll n wherein R' is an optionally substituted ethylene group;
R24 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is an optionally substituted trityl group; and nis2to10.
Preferably, R' is a CH=CH2, CH=CHCH3i or C(CH3)=CH2 group. Most preferably, R' is a CH=CH2.
Preferably, the R5O-[-C2 alkylene-O-], group is pars to R'.
Preferably, [-C24alkylene-O-]õ is [-CH2CH2O-]n, [-CH2CH(CH3)O-J,,, [-CH2CH2CH2CH2O-]1 or [-CH2CH(C2H5)O-]n, and most preferably [-CH2CH2O-]n.
Preferably n is 2 to 8, more preferably n is 3 to 5. Most preferably n is 4.
Preferably R--' are all hydrogen.
Hydrocarbyl includes alkyl, aryl, alkaryl and aralkyl groups. Preferably when any of R`4 are hydrocarbyl or hydrocarbyloxy groups the hydrocarbyl is an alkyl group, most preferably a C,-, alkyl group.
The monomers according to the first and second aspects of the present invention are useful in polymerisation reactions to form resins from which the polymer supports disclosed in PCT/GB99/02193 (published as WO 00/02953) can be obtained.
Accordingly, a third aspect of the present invention provides a process for the preparation of a polymer support comprising polymerisation of a monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2_4 alkyleneoxy groups 5 and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an acid labile protecting group, under conditions to produce cross-linking.
The monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an acid labile protecting group can be as described above in the first and second aspects of the present invention.
Preferably the acid labile protecting group is a poly-aryl methane protecting group, more preferably an optionally substituted trityl group. The preferred poly-aryl methane protecting groups and the optionally substituted trityl groups are as defined above in the is first and second aspects of the present invention.
Optionally, in the process of the present invention the monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2_4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an acid labile protecting group, preferably an optionally substituted tritly group, may comprise a mixture of isomers.
Preferably, when a mixture of isomers is used in the process of the present invention, the monomer is a compound of formula (1) or (1a). Most preferably, the monomer is a mixture of isomers wherein R5O-[-C2-4alkylene-O-], group and R1 occupy isomeric positions on the phenyl ring.
Preferably, in the process of the present invention, the monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit is co-polymerised in the presence of a cross linking monomer.
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 of from 0.1 to 70%, commonly from 0.5 to 20%, such as from 1 to 10%, and most preferably no more than 5% by weight. Polymers comprising no more than 20% by weight of cross-linking monomer are generally swellable, whilst polymers comprising greater than 20% of crosslinking monomer are generally not swellable.
Suitable cross-linking monomers include divinyl benzene (DVB) or multifunctional (meth)acrylates such as di/tri acrylates or di/tri methacrylates such as ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylopropane trimethacrylate, trivinylbenzene or N,N'-bis-acryloyl ethylene diamine. Preferably the cross-linking monomer is DVB.
Preferably 0.5 to 5% by weight of DVB is used. Most preferably 1 to 3% by weight DVB is used.
In one aspect of the present invention a level of at least 5% crosslinking monomer is used in conjunction with compounds miscible with the organic phase which can act as pore-forming agents or porogens. Typical porogens can include, but are not limited to, organic compounds which are good solvents for the polymer, such as organic aromatic hydrocarbons, chlorinated aliphatic or aromatic hydrocarbons and cyclic aliphatic ethers, organic compounds which are poor solvents for the resulting polymer, such as aliphatic alcohols, ketones, aliphatic hydrocarbons, aliphatic carboxylic acids and linear polymers.
Preferably porogens are selected from toluene, xylene, chlorobenzene, tetrahydrofuran, dioxane, 2-ethyl-1-hexanol, 2-octanol, 1-decanol, 1-dodecanol, acetone, butanone, n-heptane, n-decane, 1-decanoic acid and linear polystyrene of molecular weight 500 to 5000000 g/mol. The resulting polymers have substantially non-swelling behaviour and generally possess a meso- to macro-porous nature, by which mode reagents can access the polymer-bound functionality.
Optionally, in the process of the present invention, the monomer comprising a protected hydroxypolyC2_4alkyleneoxy chain attached to a polymerisable unit is co-polymerised in the presence of one or more monomers selected from styrenes, for example styrene, hydroxystyrene, methoxystyrene, methylstyrene, hydroxymethylstyrene and chloromethylstyrene, esters of acrylic acid and esters of (meth)acrylic acid, for example methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl acrylate, hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate, and acrylamides, for example N-methyl acrylamide 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.
In a preferred process of the present invention, the monomer comprising a protected hydroxypolyC2-4alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2_4 alkyleneoxy chain is protected with an optionally substituted trityl group is co-polymerised in the presence of one or more cross linking monomers, and one or more monomers selected from styrenes, esters of acrylic acid and esters of (meth)acrylic acid, or acrylamides.
In a highly preferred process of the present invention, the monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2_4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2.4 alkyleneoxy chain is protected with an optionally substituted trityl group is co-polymerised in the presence of DVB and styrene.
When the polymer support is produced by polymerisiation of a mixture of monomers comprising the monomer comprising a protected hydroxypolyC2_4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4alkyleneoxy chain contains from 2 to 10 C2-4alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chain is protected with an acid labile protecting group, preferably an optionally substituted trityl group, and one or more monomers selected from styrenes, esters of acrylic acid and esters of (meth)acrylic acid, or acrylamides, the weight percentage of the monomer comprising a protected hydroxypolyC2-4alkyleneoxy chain attached to a polymerisable unit of the total weight of the monomers present 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 process of the present invention is preferably carried out by aqueous suspension polymerisation. The monomers are suspended as droplets (1-1000 m) in water. Stabilisers are usually added to prevent agglomeration of the droplets, for example polyvinyl alcohol, polyacrylic acid, polyvinyl pyrrolidone, polyalkylene oxide, derivatives of cellulose, such as hyd roxypropyl methylcel I u lose or ethylcellulose, barium sulphate, magnesium sulphate or sodium sulphate. The suspension is also normally stirred to maintain the suspension.
Optionally, organic non-water miscible solvents may be used in the polymerisation process. Organic non-water miscible solvents may assist droplet formation in aqueous suspension polymerisation, or may act as porogens.
Optionally inorganic salts may be added to the aqueous phase in aqueous suspension polymerisation. Inorganic salts may assist droplet formation by suppressing monomer solubility in the aqueous medium.
A free radical initiator is preferably used to initiate polymerisation. The type of initiator will generally be selected based on the monomers used. Examples of preferred free radical initiators include benzoyl peroxide, dioctanoyl peroxide, lauroyl peroxide, 2,2'-azobisisobutyronitrile and 2,2'-azobis(2,4-dimethylvaleronitrile).
Polymerisation is typically assisted by heating the mixture in the range of 15 C to 160 C, preferably 50 C to 90 C. It will be recognised that the temperature to which the mixture can be heated depends upon the type of monomer and initiator employed.
The resultant polymer may then be washed with suitable solvents such as tetrahydrofuran, methanol and water, dried and bead size classified, for example, by sieving.
Accordingly a further aspect of the present invention provides a polymer support which comprises protected hydroxypolyC2-4 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC2.4 alkyleneoxy chain contains from 2 to 10 C2_ 4 alkyleneoxy groups and wherein the hydroxypolyC2-4alkyleneoxy chains are protected with an acid labile protecting group, preferably an optionally substituted trityl group.
The protected hydroxypolyC2 4alkyleneoxy chains attached to a cross-linked polymer according to the present invention are often selected from protected hydroxypolyethyleneoxy (protected HO(CH2CH2O)2_10-), protected hydroxypolypropyleneoxy (protected HO(CH2CH(CH3)O)2_10-) and protected hydroxypolybutyleneoxy (protected HO(CH2CH(C2H5)O)2_10-) chains. In a preferred embodiment of the invention the protected hydroxypolyC2-4alkyleneoxy chain is protected hydroxypolyethyleneoxy.
The number of C2_4alkyleneoxy groups in the protected hydroxypolyC2-4alkyleneoxy chain can range from 2 to 10, but is preferably from 2 to 8 and more preferably from 3 to 5.
Most preferably, there are four C2,alkyleneoxy groups in the protected hydroxypolyC2.4alkyleneoxy chain.
In a highly preferred embodiment of the invention the protected hydroxypolyC2.4alkyleneoxy chain is protected hydroxytetraethyleneoxy (protected HO(CH2CH2O)4-).
Preferably the protected hydroxypolyC2_4 alkyleneoxy chains are attached to a cross-linked polymer via phenoxy ether linkages.
The invention, in its broadest aspect, relates to the particular polymer supports however prepared.
Preferably, the polymer support of the present invention is obtainable by the process of the third aspect of the present invention.
The acid labile protecting groups may subsequently be removed to give the cross-linked polymer containing free hydroxy groups.
Methods appropriate for removal of the optionally substituted trityl group include, for example, acid- hydrolysis. Commonly a mixture of trifluoroacetic acid in methylene chloride can be employed. The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.
Where appropriate, other methods may be also used for the removal of the acid labile protecting groups, for example the use of iodine under neutral conditions may be used to remove trityl groups, and photolysis may be used to remove pixyl groups.
Preferably, when the protecting groups are removed the resulting polymer support has from about 0.1 to about 5 meq free hydroxy groups per gram of polymer.
Cross-linked polymers containing a free hydroxy group are usually produced as beads which range in size from 10 m to 2000 m. Preferably the bead size is from 50 m to 1000 m and most preferably from 75 m to 500gm. The cross-linked polymer beads are generally produced by an aqueous suspension polymerisation process, for example see Journal of Applied Polymer Science, 1982, 27, 133-138.
The polymer support obtained when the protecting groups are removed from the support according to the present invention has a hydroxy functionality of from 0.1 to about 5, for example up to 4.8 meq (milliequivalents) of hydroxy per gram of polymer, and often from 0.5 to 3.5, commonly 1.0 to 3.3 meq per gram for example from 1.5 to 3 meq per gram of polymer. In many embodiments, the polymer support obtained when the protecting groups are removed have from 0.5 to 2 meq of hydroxy per gram of polymer.
The polymer supports described above are of use in solid phase organic synthesis, accordingly there is provided the use of a polymer support which comprises protected hydroxypolyC24 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC24 alkyleneoxy chain contains from 2 to 10 C24alkyleneoxy groups and wherein the hydroxypolyC2.4 alkyleneoxy chains are protected with an acid labile group in solid phase organic synthesis.
Preferably, the polymer support is obtained by the process of third aspect of the present invention.
Preferably, the polymer support is deprotected prior to use.
The invention will now be described, without limitation, by the following examples in which, unless otherwise stated:-a) FT-IR spectra were obtained using swollen gels in dichloromethane held between sodium chloride plates, and an ATI Genesis (Matteson)spectrometer.
b) 13C magic angle (MAS) NMR spectra were obtained using solvent swollen gels in the rotor of a Bruker MAS probe on a 400MHz NMR spectrometer.
c) yields are given for illustration and are not necessarily the maximum attainable.
d) the following abreviations have been used: THE = tetrahydrofuran, DMF =
N,N-dimethylformamide, FMOC = fluorenylmethoxycarbonyl, PEG =
polyethyleneglycol and THP = tetrahydropyranyl.
Examples EXAMPLE I - Preparation of trityl-tetraethyleneglycoxystyrene Tetraethyleneglycol (174g, 0.9mol) was placed in a 3 necked round bottom flask fitted with a thermometer and reflux condenser. Pyridine (11 cm3, 0.135mo1) was added to the mixture stirred. Triphenylmethylchloride (25g, 0.09mol) was dissolved in toluene (30cm3) and this solution was added slowly to the mixture. The mixture was heated to 50 C and the temperature maintained for 1 h.
The mixture was allowed to cool and toluene (200cm3) was added to the flask.
The solution was extracted with water (500cm3). The aqueous phase was back extracted with toluene (2 x 100cm3). The organic layers were combined and washed with water (2 x 100cm3), dried over MgSO4 and filtered. The toluene was removed by evaporation under 5 reduced pressure to yield a pale yellow oil (yield 38.5g, 98% based on trityl).
Mono(trityl)tetraethyleneglycol (30g, 0.069mo1), 4-toluenesulfonyl chloride (14.4g, 0.076mol) and dry tetrahydrofuran (50cm3) were placed in a 3 necked round bottom flask 10 fitted with a thermometer and reflux condenser. The flask was placed in a dry-ice bath and the mixture allowed to cool to - -20 C. A solution of KOH (25.2g, 0.45mol) in water (100cm3) was added drop-wise over a period of 1h whilst maintaining the temperature at <0 C. Following the addition the reaction mixture was stirred for 1h whilst allowing the solution to warm to ambient.
The solution was extracted with diethylether (3 x 150cm3). The ether layer was dried over MgSO4,filtered and evaporated under reduced pressure. The solid was washed with MeOH and dried under vacuum (yield 34.3g, 85%).
NaOMe (0.55g, 10.2mmol) was dissolved in the minimum amount of N,N-dimethylformamide (DMF) and added to 4-acetoxystyrene (1.3cm3, 8.5mmol) contained in a round bottom flask. This solution was stirred at ambient for 45min then a solution of the tosyl derivative of mono(trityl)tetraethyleneglycol (5g, 8.5mmol) in DMF was added. The reaction was allowed to continue overnight at ambient.
The DMF was removed by evaporation under reduced pressure. The oil remaining was dissolved in isopropylacetate and extracted with water. The organic layers were combined, dried over MgSO4 and filtered. The solvent was removed by evaporation under reduced pressure to leave a pale yellow oil that crystallised on standing (yield 3.5g, 77%).
EXAMPLE 2 - 10 litre scale Preparation of trityl-tetraethyleneglycoxystyrene STAGE I
Tetraethylene glycol (4188g, 21.5 mol) was added under a nitrogen atmosphere to a 101 vessel equipped with a mechanical stirrer and stirred at 60 rpm. Pyridine (544g, 6.9 mol) was added to the vessel and the mixture heated to 50 C. Triphenylmethyl chloride (1000g, 3.6 mol) was dissolved in toluene (3000m1) under N2 atmosphere and added slowly to the glycol keeping the temperature below 60 C. The temperature was held at 50 C for 2 hours and then cooled to room temperature. 21 of toluene were added and the mixture extracted with 61 of deionised water, the water phase extracted with 51 of toluene.
The combined organic extracts were washed with 2 x 41 of DI water, dried over 500g sodium sulphate and solvent removed under reduced pressure to yield 1230g (74%
based on trityl) of a pale yellow oil, 94.3% purity (by NMR) Mono(trityl)tetraethyleneglycol (1766.4g, 3.8 mol) was added to a 101 vessel together with is 31 THE and cooled under agitation to -12 C. p-Toluenesulphonyl chloride (945g, 5 mol) was added to the glycol/THF mixture. A solution of KOH (880g, 15.7 mol) in deionised water (31) was added to the solution over 1 hour keeping the temp below -5 C.
After completion of the addition the vessel was warmed to 25 C and held for 12 hours. The phases were separated and the lower aqueous layer washed with 2x2.5L THF, the organic layers combined and solvent removed under reduced pressure. The orange/brown oil in 7.51 isopropyl acetate was extracted with 101 water and then 5 x 21 water, dried over magnesium sulphate (500g) and solvent removed to give 1837g (78.0%) of the product as a viscous orange oil, purity 95.3% (by NMR).
Deoinised water (1.51) and THE (2.11) were added to a 1OL vessel and agitation started at 100rpm. The vessel was cooled down to -12 C and potassium hydroxide (535g, 9.5 mol) was added slowly. Acetoxystyrene (575m1, 3.7 mol) in THE (11), was added to the vessel over about 30 minutes with cooling. The vessel was heated to 30 C and held for 1 hr, then cooled to 20 C. The Stage 2 product (1800g, 2.9 mol) in 1050 ml THE was added to reaction vessel over 15mins, then the mixture heated at 60 C for 40 hrs. The reaction was cooled, the phases separated and the organic layers washed with 2x21 of 8M
aqueous potassium hydroxide. The solvent was removed under reduced pressure and the residue dissolved in toluene (51), washed with 3x21 deionised water, then 2x21 1M
aqueous sodium hydroxide, and finally 2x31 DI water. The organic layer was dried with sodium sulphate (500g) and solvent removed under reduced pressure to yield 1471 g (75%) of the product as an orange oil, purity 79.7% by NMR.
The combined organic extracts were washed with 2 x 41 of DI water, dried over 500g sodium sulphate and solvent removed under reduced pressure to yield 1230g (74%
based on trityl) of a pale yellow oil, 94.3% purity (by NMR) Mono(trityl)tetraethyleneglycol (1766.4g, 3.8 mol) was added to a 101 vessel together with is 31 THE and cooled under agitation to -12 C. p-Toluenesulphonyl chloride (945g, 5 mol) was added to the glycol/THF mixture. A solution of KOH (880g, 15.7 mol) in deionised water (31) was added to the solution over 1 hour keeping the temp below -5 C.
After completion of the addition the vessel was warmed to 25 C and held for 12 hours. The phases were separated and the lower aqueous layer washed with 2x2.5L THF, the organic layers combined and solvent removed under reduced pressure. The orange/brown oil in 7.51 isopropyl acetate was extracted with 101 water and then 5 x 21 water, dried over magnesium sulphate (500g) and solvent removed to give 1837g (78.0%) of the product as a viscous orange oil, purity 95.3% (by NMR).
Deoinised water (1.51) and THE (2.11) were added to a 1OL vessel and agitation started at 100rpm. The vessel was cooled down to -12 C and potassium hydroxide (535g, 9.5 mol) was added slowly. Acetoxystyrene (575m1, 3.7 mol) in THE (11), was added to the vessel over about 30 minutes with cooling. The vessel was heated to 30 C and held for 1 hr, then cooled to 20 C. The Stage 2 product (1800g, 2.9 mol) in 1050 ml THE was added to reaction vessel over 15mins, then the mixture heated at 60 C for 40 hrs. The reaction was cooled, the phases separated and the organic layers washed with 2x21 of 8M
aqueous potassium hydroxide. The solvent was removed under reduced pressure and the residue dissolved in toluene (51), washed with 3x21 deionised water, then 2x21 1M
aqueous sodium hydroxide, and finally 2x31 DI water. The organic layer was dried with sodium sulphate (500g) and solvent removed under reduced pressure to yield 1471 g (75%) of the product as an orange oil, purity 79.7% by NMR.
EXAMPLE 3 - Synthesis of Polymer and subsequent deprotection Partially hydrolysed poly(vinyl alcohol) (Airvol 540, 34.9 g of 2.5 wt-%
aqueous solution) and sodium chloride (31.2 g) were charged into a 21 cylindrical baffled reactor containing deionised water (1181 ml) and equipped with a mechanical stirrer. A mixture of Stage 3 product (79.7%, 87.2 g), styrene (59.1 g), divinylbenzene (80%, 1.4g) and lauroyl peroxide (5.2 g) were charged to the reactor and agitated at 400 rpm. After 20 minutes the stirrer speed was reduced to 300 rpm and the reaction heated with a water bath to 8000 over 50 minutes. After 16h, the reaction mixture was cooled, transferred to a 50 pm filter cloth bag and washed with deionised water (5x11). The polymer beads were then washed with THE
(4x11) and dichloromethane (2x11) and stirred at room temperature under nitrogen in a 51 flange flask/overhead stirrer with a mixture of dichloromethane (1800 ml), trifluoroacetic acid (128 g) and triethylsilane (51.5 g) for 4 hours. The product was then washed with dichloromethane (4x11) and hexane (5x11) before drying to constant weight in a vacuum oven, yielding 78g of white polymer beads with a hydroxyl loading of 0.97 mmol/g.
aqueous solution) and sodium chloride (31.2 g) were charged into a 21 cylindrical baffled reactor containing deionised water (1181 ml) and equipped with a mechanical stirrer. A mixture of Stage 3 product (79.7%, 87.2 g), styrene (59.1 g), divinylbenzene (80%, 1.4g) and lauroyl peroxide (5.2 g) were charged to the reactor and agitated at 400 rpm. After 20 minutes the stirrer speed was reduced to 300 rpm and the reaction heated with a water bath to 8000 over 50 minutes. After 16h, the reaction mixture was cooled, transferred to a 50 pm filter cloth bag and washed with deionised water (5x11). The polymer beads were then washed with THE
(4x11) and dichloromethane (2x11) and stirred at room temperature under nitrogen in a 51 flange flask/overhead stirrer with a mixture of dichloromethane (1800 ml), trifluoroacetic acid (128 g) and triethylsilane (51.5 g) for 4 hours. The product was then washed with dichloromethane (4x11) and hexane (5x11) before drying to constant weight in a vacuum oven, yielding 78g of white polymer beads with a hydroxyl loading of 0.97 mmol/g.
Claims (18)
1. A monomer which comprises a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain contains from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chain is protected with a poly(aryl)methane protecting group.
2. A monomer of formula (1) wherein R1 is an optionally substituted ethylene group;
R2-4 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is a poly(aryl)methane protecting group; and n is 2 to 10.
R2-4 are independently hydrogen, hydrocarbyl, halogen, or hydrocarbyloxy;
R5 is a poly(aryl)methane protecting group; and n is 2 to 10.
3. The monomer according to claim 2 wherein R1 is a CH=CH2, CH=CHCH3, or C(CH3)=CH2 group.
4. The monomer according to claim 2 or 3 wherein [-C2-4alkylene-O-]n is [-CH2CH2O-]n, [-CH2CH(CH3)O-]n, [-CH2CH2CH2CH2O-]n or [-CH2CH(C2H5)O-]n.
5. The monomer according to any one of claims 2 to 4 wherein R2-4 are hydrogen.
6. The monomer according to any one of claims 1 to 5 wherein the poly(aryl) methane protecting group is of formula:
wherein:
R6 is hydrogen, an optionally substituted alkyl or optionally substituted aryl group; and R7 and R8 are each independently optionally substituted aryl groups, or R7 & R8 are optionally substituted aryl groups which are linked to form an optionally substituted ring.
wherein:
R6 is hydrogen, an optionally substituted alkyl or optionally substituted aryl group; and R7 and R8 are each independently optionally substituted aryl groups, or R7 & R8 are optionally substituted aryl groups which are linked to form an optionally substituted ring.
7. The monomer according to claim 5 wherein the poly(aryl)methane protecting group is an optionally substituted trityl group.
8. A process for the preparation of a polymer support comprising polymerisation of a monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit wherein the protected hydroxypolyC2-4 alkyleneoxy chain comprises from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chain is protected with a poly(aryl)methane protecting group, under conditions to produce cross-linking.
9. The process according to claim 8 wherein the monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit is copolymerised in the presence of at least one monomer selected from a styrene, an ester of acrylic acid, an ester of methacrylic acid and an acrylamide.
10. The process according to claim 9 wherein the styrene is styrene, hydroxystyrene, methoxystyrene, methylstyrene, hydroxymethylstyrene or chloromethylstyrene.
11. The process according to claim 9 or 10 wherein the ester of acrylic acid or ester of methacrylic acid is methyl acrylate, ethyl acrylate, methyl methacrylate, hydroxyethyl (meth)acrylate or hydroxypropyl (meth)acrylate.
12. The process according to any one of claims 9 to 11 wherein the acrylamide is N-methyl acrylamide or N-methylol (meth)acrylamide.
13. The process according to claim 8 wherein the monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit is copolymerised in the presence of one or more cross linking monomers, and at least one monomer selected from a styrene, an ester of acrylic acid, an ester of methacrylic acid and an acrylamide.
14. The process according to any one of claims 8 to 13 wherein the monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit is copolymerised in the presence of divinyl benzene and styrene.
15. The process according to any one of claims 8 to 14 wherein the monomer comprising a protected hydroxypolyC2-4 alkyleneoxy chain attached to a polymerisable unit is a monomer according to any one of claims 1 to 7.
16. A polymer support which comprises protected hydroxypolyC2-4 alkyleneoxy chains attached to a cross-linked polymer wherein the protected hydroxypolyC2-4 alkyleneoxy chain comprises from 2 to 10 C2-4 alkyleneoxy groups and wherein the hydroxypolyC2-4 alkyleneoxy chains are protected with a poly(aryl)methane protecting group.
17. A polymer support according to claim 16 wherein the poly(aryl)methane protecting group is an optionally substituted trityl group.
18. The polymer support obtained by the process of any one of claims 8 to 15.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0209539.6 | 2002-04-26 | ||
| GBGB0209539.6A GB0209539D0 (en) | 2002-04-26 | 2002-04-26 | Monomer Polymer and process |
| PCT/GB2003/001774 WO2003091311A1 (en) | 2002-04-26 | 2003-04-25 | Monomers containing polyoxyalkylenes and polymer supports therefrom |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2482945A1 CA2482945A1 (en) | 2003-11-06 |
| CA2482945C true CA2482945C (en) | 2011-05-24 |
Family
ID=9935542
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2483483A Expired - Lifetime CA2483483C (en) | 2002-04-26 | 2003-04-25 | Process for preparing oligonucleotides |
| CA2482945A Expired - Lifetime CA2482945C (en) | 2002-04-26 | 2003-04-25 | Monomers containing polyoxyalkylenes and polymer supports therefrom |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2483483A Expired - Lifetime CA2483483C (en) | 2002-04-26 | 2003-04-25 | Process for preparing oligonucleotides |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US7476709B2 (en) |
| EP (2) | EP1501851B1 (en) |
| JP (2) | JP4497931B2 (en) |
| KR (2) | KR20050000406A (en) |
| CN (2) | CN1649889A (en) |
| AU (2) | AU2003229938A1 (en) |
| CA (2) | CA2483483C (en) |
| GB (1) | GB0209539D0 (en) |
| WO (2) | WO2003091267A1 (en) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9425138D0 (en) | 1994-12-12 | 1995-02-08 | Dynal As | Isolation of nucleic acid |
| WO2002046205A2 (en) * | 2000-12-05 | 2002-06-13 | Avecia Limited | Process for the preparation of phosphorothionate oligonucleotides |
| AU2003202026A1 (en) | 2002-01-16 | 2003-09-02 | Dynal Biotech Asa | Method for isolating nucleic acids and protein from a single sample |
| GB0209539D0 (en) * | 2002-04-26 | 2002-06-05 | Avecia Ltd | Monomer Polymer and process |
| GB0229287D0 (en) * | 2002-12-16 | 2003-01-22 | Dna Res Innovations Ltd | Polyfunctional reagents |
| GB0229443D0 (en) * | 2002-12-18 | 2003-01-22 | Avecia Ltd | Process |
| JP5956108B2 (en) * | 2007-10-15 | 2016-07-20 | ハネウェル・インターナショナル・インコーポレーテッド | Synthesis of oligonucleotides or phosphorothioate oligonucleotides using N-methylimidazole capping agent containing no 1,3,5-trimethylhexahydro-1,3,5-triazine |
| US8039612B2 (en) * | 2007-10-15 | 2011-10-18 | Honeywell International, Inc. | Synthesis of oligonucleotides or phosphorothioate oligonucleotide with a capping agent of N-methylimidazole free of 1,3,5-trimethylhexahydro-1,3,5-triazine |
| JP5276367B2 (en) | 2008-06-25 | 2013-08-28 | 日東電工株式会社 | Porous resin beads and method for producing nucleic acid using the same |
| WO2012019168A2 (en) | 2010-08-06 | 2012-02-09 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| PL3590949T3 (en) | 2010-10-01 | 2022-08-29 | Modernatx, Inc. | Ribonucleic acids containing n1-methyl-pseudouracils and uses thereof |
| AU2012236099A1 (en) | 2011-03-31 | 2013-10-03 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
| US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
| RS62993B1 (en) | 2011-10-03 | 2022-03-31 | Modernatx Inc | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
| EP4144378A1 (en) | 2011-12-16 | 2023-03-08 | ModernaTX, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
| US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
| US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
| US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
| JP2015513914A (en) | 2012-04-02 | 2015-05-18 | モデルナ セラピューティクス インコーポレイテッドＭｏｄｅｒｎａ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． | Modified polynucleotides for the production of secreted proteins |
| SI2922554T1 (en) | 2012-11-26 | 2022-06-30 | Modernatx, Inc. | Terminally modified rna |
| US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
| TWI695067B (en) | 2013-08-05 | 2020-06-01 | 美商扭轉生物科技有限公司 | De novo synthesized gene libraries |
| US20160194625A1 (en) | 2013-09-03 | 2016-07-07 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
| EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| CA2955250A1 (en) | 2014-07-16 | 2016-01-21 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
| US10669304B2 (en) | 2015-02-04 | 2020-06-02 | Twist Bioscience Corporation | Methods and devices for de novo oligonucleic acid assembly |
| US9981239B2 (en) | 2015-04-21 | 2018-05-29 | Twist Bioscience Corporation | Devices and methods for oligonucleic acid library synthesis |
| KR20180050411A (en) | 2015-09-18 | 2018-05-14 | 트위스트 바이오사이언스 코포레이션 | Oligonucleotide mutant library and its synthesis |
| CN108698012A (en) | 2015-09-22 | 2018-10-23 | 特韦斯特生物科学公司 | Flexible substrates for nucleic acid synthesis |
| EP3384077A4 (en) | 2015-12-01 | 2019-05-08 | Twist Bioscience Corporation | Functionalized surfaces and preparation thereof |
| AU2017315294B2 (en) | 2016-08-22 | 2023-12-21 | Twist Bioscience Corporation | De novo synthesized nucleic acid libraries |
| US10417457B2 (en) | 2016-09-21 | 2019-09-17 | Twist Bioscience Corporation | Nucleic acid based data storage |
| CN110366613A (en) | 2016-12-16 | 2019-10-22 | 特韦斯特生物科学公司 | The Mutant libraries of immunological synapse and its synthesis |
| US11550939B2 (en) | 2017-02-22 | 2023-01-10 | Twist Bioscience Corporation | Nucleic acid based data storage using enzymatic bioencryption |
| CN110913865A (en) | 2017-03-15 | 2020-03-24 | 特韦斯特生物科学公司 | Library of variants of immune synapses and synthesis thereof |
| WO2018231864A1 (en) | 2017-06-12 | 2018-12-20 | Twist Bioscience Corporation | Methods for seamless nucleic acid assembly |
| KR102628876B1 (en) | 2017-06-12 | 2024-01-23 | 트위스트 바이오사이언스 코포레이션 | Methods for seamless nucleic acid assembly |
| CN111566125A (en) | 2017-09-11 | 2020-08-21 | 特韦斯特生物科学公司 | GPCR binding proteins and synthesis thereof |
| CA3079613A1 (en) | 2017-10-20 | 2019-04-25 | Twist Bioscience Corporation | Heated nanowells for polynucleotide synthesis |
| CA3088911A1 (en) | 2018-01-04 | 2019-07-11 | Twist Bioscience Corporation | Dna-based digital information storage |
| AU2019270243A1 (en) | 2018-05-18 | 2021-01-07 | Twist Bioscience Corporation | Polynucleotides, reagents, and methods for nucleic acid hybridization |
| KR20210143766A (en) | 2019-02-26 | 2021-11-29 | 트위스트 바이오사이언스 코포레이션 | Variant Nucleic Acid Libraries for the GLP1 Receptor |
| KR20210144698A (en) | 2019-02-26 | 2021-11-30 | 트위스트 바이오사이언스 코포레이션 | Variant Nucleic Acid Libraries for Antibody Optimization |
| US11332738B2 (en) | 2019-06-21 | 2022-05-17 | Twist Bioscience Corporation | Barcode-based nucleic acid sequence assembly |
| CN117241803A (en) * | 2021-04-28 | 2023-12-15 | 阿斯特罗赛特制药公司 | Purine nucleosides, intermediates and methods of making the same |
| CN113248352A (en) * | 2021-05-18 | 2021-08-13 | 湖南华腾制药有限公司 | Method for solid-phase synthesis of heptaethylene glycol monomethyl ether |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE755158A (en) * | 1969-08-22 | 1971-02-22 | Rhodiaceta | ANTISTATIC THERMOPLASTIC COMPOSITIONS |
| DE3500180A1 (en) * | 1985-01-04 | 1986-07-10 | Ernst Prof. Dr. 7400 Tübingen Bayer | Graft copolymers from crosslinked polymers and polyoxyethylene, process for their preparation and their use |
| DE3777441D1 (en) * | 1986-05-07 | 1992-04-23 | Dai Ichi Kogyo Seiyaku Co Ltd | A POLYMERIZABLE PART CONTAINING SURFACE ACTIVE CONNECTIONS. |
| JPH06260383A (en) * | 1993-03-03 | 1994-09-16 | Nikon Corp | Exposure method |
| US5614010A (en) | 1994-03-14 | 1997-03-25 | Clearwater, Inc. | Hydrocarbon gels useful in formation fracturing |
| US5466758A (en) * | 1994-04-13 | 1995-11-14 | Yoon-Sik; Lee | Process for preparing polystyrenes having β hydroxy group and polyglycol-grafted polystyrenes thereof |
| US5696248A (en) * | 1994-06-15 | 1997-12-09 | Hoechst Aktiengesellschaft | 3'-modified oligonucleotide derivatives |
| JP2000500740A (en) * | 1995-10-19 | 2000-01-25 | プロリゴ・エルエルシー | Solution-phase synthesis of oligonucleotides |
| DE19781535T1 (en) * | 1996-01-23 | 1999-01-28 | Argonaut Technologies Inc | Highly functionalized polystyrene carriers grafted with polyethylene glycol |
| US5869696A (en) * | 1996-04-22 | 1999-02-09 | Beckman Instruments, Inc. | Universal solid supports and methods for their use |
| US6096881A (en) * | 1997-05-30 | 2000-08-01 | Hybridon, Inc. | Sulfur transfer reagents for oligonucleotide synthesis |
| GB9717158D0 (en) * | 1997-08-13 | 1997-10-22 | King S College London | Solution synthesis of oligonucleotides and their phosphorothioate analogues |
| US6274725B1 (en) * | 1998-06-02 | 2001-08-14 | Isis Pharmaceuticals, Inc. | Activators for oligonucleotide synthesis |
| GB9814876D0 (en) * | 1998-07-10 | 1998-09-09 | Zeneca Ltd | Polymer |
| WO2000059855A1 (en) * | 1999-04-01 | 2000-10-12 | Esperion Therapeutics, Inc. | Ether compounds, compositions, and uses thereof |
| JP2001064297A (en) * | 1999-06-25 | 2001-03-13 | Sankyo Co Ltd | New bicyclo nucleoside derivative |
| US6147200A (en) * | 1999-08-19 | 2000-11-14 | Isis Pharmaceuticals, Inc. | 2'-O-acetamido modified monomers and oligomers |
| EP1455839B1 (en) | 1999-10-08 | 2013-01-23 | Nektar Therapeutics | Heterobifunctional poly(ethylene glycol) derivatives and methods for their preparation |
| DE60109047T2 (en) * | 2000-09-07 | 2006-04-06 | Avecia Biotechnology, Inc., Milford | SYNTHONE FOR THE MANUFACTURE OF OLIGONUCLEOTIDES |
| WO2003045969A1 (en) | 2001-11-21 | 2003-06-05 | Avecia Biotechnology Inc. | Coupling reagent for h-phosphonate chemistry |
| GB0209539D0 (en) * | 2002-04-26 | 2002-06-05 | Avecia Ltd | Monomer Polymer and process |
-
2002
- 2002-04-26 GB GBGB0209539.6A patent/GB0209539D0/en not_active Ceased
-
2003
- 2003-04-25 EP EP03722784A patent/EP1501851B1/en not_active Expired - Lifetime
- 2003-04-25 JP JP2003587864A patent/JP4497931B2/en not_active Expired - Lifetime
- 2003-04-25 CA CA2483483A patent/CA2483483C/en not_active Expired - Lifetime
- 2003-04-25 CA CA2482945A patent/CA2482945C/en not_active Expired - Lifetime
- 2003-04-25 KR KR10-2004-7017120A patent/KR20050000406A/en not_active Application Discontinuation
- 2003-04-25 WO PCT/GB2003/001795 patent/WO2003091267A1/en active Application Filing
- 2003-04-25 US US10/512,138 patent/US7476709B2/en active Active
- 2003-04-25 CN CNA038092026A patent/CN1649889A/en active Pending
- 2003-04-25 AU AU2003229938A patent/AU2003229938A1/en not_active Abandoned
- 2003-04-25 CN CNB038091933A patent/CN1310999C/en not_active Expired - Fee Related
- 2003-04-25 WO PCT/GB2003/001774 patent/WO2003091311A1/en active Application Filing
- 2003-04-25 AU AU2003229946A patent/AU2003229946A1/en not_active Abandoned
- 2003-04-25 EP EP03722776.6A patent/EP1504049B1/en not_active Expired - Lifetime
- 2003-04-25 JP JP2003587825A patent/JP4657609B2/en not_active Expired - Lifetime
- 2003-04-25 KR KR10-2004-7017119A patent/KR20050006186A/en not_active Application Discontinuation
- 2003-04-25 US US10/512,145 patent/US7365132B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2483483A1 (en) | 2003-11-06 |
| CN1649889A (en) | 2005-08-03 |
| WO2003091311A1 (en) | 2003-11-06 |
| KR20050006186A (en) | 2005-01-15 |
| CA2482945A1 (en) | 2003-11-06 |
| CN1310999C (en) | 2007-04-18 |
| JP2005534629A (en) | 2005-11-17 |
| EP1504049A1 (en) | 2005-02-09 |
| EP1501851B1 (en) | 2013-02-13 |
| WO2003091267A1 (en) | 2003-11-06 |
| US7365132B2 (en) | 2008-04-29 |
| CN1649935A (en) | 2005-08-03 |
| US20050256283A1 (en) | 2005-11-17 |
| JP4497931B2 (en) | 2010-07-07 |
| JP4657609B2 (en) | 2011-03-23 |
| KR20050000406A (en) | 2005-01-03 |
| WO2003091311A8 (en) | 2004-02-26 |
| US20060036028A1 (en) | 2006-02-16 |
| AU2003229938A1 (en) | 2003-11-10 |
| CA2483483C (en) | 2013-04-09 |
| EP1501851A1 (en) | 2005-02-02 |
| US7476709B2 (en) | 2009-01-13 |
| JP2005523962A (en) | 2005-08-11 |
| EP1504049B1 (en) | 2013-05-22 |
| GB0209539D0 (en) | 2002-06-05 |
| AU2003229946A1 (en) | 2003-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2482945C (en) | Monomers containing polyoxyalkylenes and polymer supports therefrom | |
| US5254632A (en) | Method of manufacturing polyalkyl methacrylate macromonomers, and use of same in the manufacture of comb polymers | |
| CA2336914C (en) | Polymer supports containing polyoxyalkylenes | |
| JP5443682B2 (en) | Porous resin particles having hydroxy group or primary amino group and method for producing the same | |
| JPH0649736B2 (en) | Method for manufacturing high refractive index resin material | |
| EP0373687B1 (en) | Method for the photochemical conversion of tachysterol compounds into previtamin d compounds and of trans-vitamin d compounds into cis-vitamin d compounds | |
| Iwakura et al. | Synthesis and polymerization of N‐[1‐(1‐substituted‐2‐oxopropyl)] acrylamides and‐methacrylamides. copolymerization of these monomers with styrene and substituent effects | |
| EP1299429A1 (en) | Scavenger resin and processes for the use thereof | |
| JP2011038093A (en) | Polyvinyl ether resin | |
| CN115093565B (en) | Polyphenyl sulfone ether triazole and preparation method and application thereof | |
| JP7441526B2 (en) | Crosslinked polymer compound and method for producing the same, and method for producing the polymer compound | |
| CN110922548B (en) | Immobilized L-proline CO2 responsive block polymer and preparation method thereof | |
| Dobashi et al. | Control of the solubility transition in novel temperature-responsive linear polymers comprising α-amino acid diamide derivatives | |
| JPS61207414A (en) | Crown ether polymer | |
| US5175217A (en) | Method for the photochemical conversion of tachysterol compounds into previtamin D compounds and of trans-vitamin D compounds into cis-vitamin D compounds using a polymeric photoinitiator | |
| JP2023124226A (en) | Rotaxane and method for producing the same, and crosslinked polymer, polymer fine particle and polymer resin member | |
| Soykan et al. | New poly (methacrylate) s containing benzylpiperazine and methylpiperidine moieties | |
| KR0137424B1 (en) | Resin of a bead type having polystyrene matrix and polyoxyethylene surface, and process therefor | |
| JP2523803B2 (en) | Optically active polymerization catalyst and method for synthesizing optically active polymer | |
| JP2000264937A (en) | Polyvinyl chloride-polystyrene block copolymer, polyvinyl chloride-polyvinyl acetate block copolymer and their production | |
| Yang et al. | Preparation and properties of polyesters and copolyesters based on 4‐methyl‐2, 4‐bis (p‐hydroxyphenyl)‐1‐pentene |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20230425 |