DK178227B1 - A novel synthetic process of a block copolymer and a novel use - Google Patents
A novel synthetic process of a block copolymer and a novel use Download PDFInfo
- Publication number
- DK178227B1 DK178227B1 DK201400240A DKPA201400240A DK178227B1 DK 178227 B1 DK178227 B1 DK 178227B1 DK 201400240 A DK201400240 A DK 201400240A DK PA201400240 A DKPA201400240 A DK PA201400240A DK 178227 B1 DK178227 B1 DK 178227B1
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- 229920001400 block copolymer Polymers 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- -1 polydimethylsiloxane Polymers 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 42
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 40
- 229920000642 polymer Polymers 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- 229920000428 triblock copolymer Polymers 0.000 claims description 16
- GUXJXWKCUUWCLX-UHFFFAOYSA-N 2-methyl-2-oxazoline Chemical compound CC1=NCCO1 GUXJXWKCUUWCLX-UHFFFAOYSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 125000002091 cationic group Chemical group 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- 229920000359 diblock copolymer Polymers 0.000 claims description 10
- 239000011877 solvent mixture Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229920001600 hydrophobic polymer Polymers 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229920013730 reactive polymer Polymers 0.000 claims description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 3
- 238000001212 derivatisation Methods 0.000 claims description 3
- 150000003141 primary amines Chemical group 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 150000002118 epoxides Chemical class 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 3
- 230000003252 repetitive effect Effects 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 125000005936 piperidyl group Chemical group 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- 102000010637 Aquaporins Human genes 0.000 abstract description 12
- 108010063290 Aquaporins Proteins 0.000 abstract description 9
- 230000002194 synthesizing effect Effects 0.000 abstract description 6
- 238000010348 incorporation Methods 0.000 abstract description 5
- 229920000469 amphiphilic block copolymer Polymers 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 239000011159 matrix material Substances 0.000 abstract description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 33
- 239000000243 solution Substances 0.000 description 21
- 229920001577 copolymer Polymers 0.000 description 19
- 238000006116 polymerization reaction Methods 0.000 description 15
- 239000000178 monomer Substances 0.000 description 13
- 239000003999 initiator Substances 0.000 description 12
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 7
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229920000765 poly(2-oxazolines) Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108091005703 transmembrane proteins Proteins 0.000 description 6
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- 108091006146 Channels Proteins 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 150000004985 diamines Chemical class 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000007334 copolymerization reaction Methods 0.000 description 4
- 238000009795 derivation Methods 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 229920000575 polymersome Polymers 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 108050005714 Aquaporin Z Proteins 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 239000012434 nucleophilic reagent Substances 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920001559 poly(2-methyloxazoline)-block-poly(dimethylsiloxane) Polymers 0.000 description 3
- 229920001921 poly-methyl-phenyl-siloxane Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108010026389 Gramicidin Proteins 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000012656 cationic ring opening polymerization Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 150000002918 oxazolines Chemical class 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 229920000773 poly(2-methyl-2-oxazoline) polymer Polymers 0.000 description 2
- 230000000379 polymerizing effect Effects 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 125000005490 tosylate group Chemical group 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- XULIXFLCVXWHRF-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidine Chemical compound CN1C(C)(C)CCCC1(C)C XULIXFLCVXWHRF-UHFFFAOYSA-N 0.000 description 1
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- WPIRXWKNGFPYPO-UHFFFAOYSA-N 2,4-dimethylbenzenesulfonic acid;methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1.CC1=CC=C(S(O)(=O)=O)C(C)=C1 WPIRXWKNGFPYPO-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- NYEZZYQZRQDLEH-UHFFFAOYSA-N 2-ethyl-4,5-dihydro-1,3-oxazole Chemical compound CCC1=NCCO1 NYEZZYQZRQDLEH-UHFFFAOYSA-N 0.000 description 1
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 1
- WWMWQHDWRQAZFW-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CC1=CC=C(S(O)(=O)=O)C=C1 WWMWQHDWRQAZFW-UHFFFAOYSA-N 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000004612 Calcium-Transporting ATPases Human genes 0.000 description 1
- 108010017954 Calcium-Transporting ATPases Proteins 0.000 description 1
- 102000034573 Channels Human genes 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 1
- 239000005062 Polybutadiene Substances 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- 102000017033 Porins Human genes 0.000 description 1
- 108010013381 Porins Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102100028873 Sodium- and chloride-dependent taurine transporter Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000010982 kinetic investigation Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012778 molding material Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- FEBNTWHYQKGEIQ-BIMULSAOSA-N nardin Natural products C[C@H]1CC[C@H](C=C(/C)C(=O)O)C2=C(C)CC[C@@H]12 FEBNTWHYQKGEIQ-BIMULSAOSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229920005573 silicon-containing polymer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 108010017629 taurine transporter Proteins 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- 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
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/0233—Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/14—Dynamic membranes
- B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
- B01D69/142—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers"
- B01D69/144—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers" containing embedded or bound biomolecules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/70—Polymers having silicon in the main chain, with or without sulfur, nitrogen, oxygen or carbon only
- B01D71/702—Polysilsesquioxanes or combination of silica with bridging organosilane groups
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
- B01D71/80—Block polymers
-
- 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
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/42—Block-or graft-polymers containing polysiloxane sequences
- C08G77/452—Block-or graft-polymers containing polysiloxane sequences containing nitrogen-containing sequences
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/56—Polyamides, e.g. polyester-amides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
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Abstract
The present invention relates to a process for synthesizing amphiphilic block copolymers. The invention further relates to novel vesicles comprising said block copolymers having the structures according to Formulae (I) and (II) and novel uses of said block copolymers as a matrix forming material for incorporation of transmembrane molecules, such as aquaporins.
Description
A NOVEL SYNTHETIC PROCESS OF A BLOCK COPOLYMER AND A NOVEL USE FIELD OF THE INVENTION
The present invention relates to a novel process for synthesizing block copolymers, where said process may be performed in a reaction using a sterically hindered base, optionally using a solvent mixture, and where an increased degree of PDMS derivatization is obtained. The invention further relates to certain di- and triblock copolymers produced in higher degrees of purity as well as novel di- and triblock copolymer mixtures haying a controlled degree of molecular weight dispersity.
BACKGROUND OF THE INVENTION
Nardin et al. (Langmuir 2000, 1035-1041) describes the synthesis of a poiy(2-methyloxazoline)-block-poly(dimethylsiioxane)-biock-poly(2-methyloxazoline) (PMOXA-PDMS-PMOXA) triblock copolymer carrying polymerizable groups at both chain ends.
Isaacman et ai. (2012) describes a modular synthesis of poly(oxazoline)-poly(siloxane)-poly(oxazoline) block copolymers that have been clicked together using the copper catalyzed azide-alkyne cycloaddition reaction.
Chujo et al. (1992) describes the preparation of polyoxazoline-polysiloxane-polyoxazoline block copolymers having the formula
The block copolymers are prepared by reacting amino-terminated telechelic poly (dime thylsiloxane)s (3) at the end of poly(2-methyl-2-oxazoline)s in CHCI3 at 60°C in the form of reactive oxazolinium (4) species using three different (4)/(3) reactant ratios: 20.6, 19,6, and 25.2 resulting in correspondingly increasing yields of 13.5, 23.8, and 29.0 %, respectively, WO 2013072378 Al (Byk-Chemie GMBH) discloses uses as additives in thermal hardening coating material compositions and molding materials of polysiloxane-polyoxazoline block copolymers having units of the general formulae
wherein n is in the range of 1 to 400 preferably in the range of 5 to 100, and Rl and R2 represent alkyl moieties of various kinds having from 4 to 6 carbon atoms or they represent cyclic alkenyl, aryl, alkylaryl or arylalkyl moieties having up to 12 carbon atoms; m is in the range of 1 to 400 preferably in the range of 5 to 100, and R3 represents alkyl, alkenyl or aryl moieties of various kinds having from 3 to 12 carbon atoms. However, for the syntheses described in the preparation of said copolymers only single component solvents, such as toluol or acetonitrile, are used. For the reactants a large surplus of the polyoxazoline component is needed, cf. the synthesis of Chujo et al. (1992), and where the polyoxazoline-polysiloxane-copolymers are prepared in a one-pot reaction using methyl toluenesulfonate as initiator, PMOXA in excess amounts and as solvent toluene or acetonitrile.
Moreover, the block copolymers of the prior art exhibit a large variation in chain lengths of the blocks and may form different kinds of reaction by-products. In block copolymers polydispersity may be manifested through a molecular weight distribution. It has been shown by Meier et al. (2000) that amphiphilic block copolymers, such as PMOXA-PDMS-PMOXA, when forming biomimetic membranes, e.g. when self assembled into polymersomes, can incorporate transmembrane proteins in the amphiphilic lipid bilayer like wall (a polymeric bilayer). However, when incorporating transmembrane proteins and peptides in polymersome walls or membranes, the polydispersity of the block copolymer chains may result in a membrane thickness mismatch that could pose a problem for transmembrane protein incorporation. Pata & Dan (2003) found that the mechanism for the inhibition of protein incorporation in polymeric bilayers differs from that of their inclusion in lipid vesicles; because in polymersomes, the equilibrium concentration of transmembrane proteins decreases as a function of the thickness mismatch between the protein and the bilayer core. Thus, it is an additional object of the invention to provide a method of preparing block copolymers, such as PMOXA-PDMS-PMOXA triblock copolymers having a controlled, well defined and narrow molecular dispersity range making them useful for incorporation of various transmembrane molecules being proteins, such as aquaporin water channels, ion channel proteins, or being transmembrane peptide channels such as gramicidins, and the like according to the preferred incorporation requirements of said molecules.
A further object of the invention is the novel use of a triblock copolymer according to Formula I
a diblock copolymer according to Formula ΪΙ
or a mixture of said block copolymers: wherein R., R2, Li, L2, m, and n are defined as below; said novel use being as matrix forming material in vesicles being useful for having incorporated transmembrane proteins. In an exemplary embodiment of the invention said use comprises a mixture wherein the triblock copolymer comprises more than about 65 to 70 % (w/w), such as more than about 80 % (w/w). In another exemplary embodiment of the invention said use comprises a mixture wherein the triblock copolymer comprises about 25 to 40 % (w/w) or about one third, and the diblock copolymer comprises about 55 to 70 % (w/w) or about two thirds.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples. A significant feature of the compounds of Formula I and II is that the PMOXA blocks exhibit a retro configuration of the repeat unit compared to PMOXA-PDMS-PMOXA block copolymers used in the relevant prior art cf. Isaacman et al. (2012), and another feature is that the Ri end groups are directly attached to the nitrogen atom of the repeat sequence, whereas end groups in prior art PMOXA-PDMS-PMOXA block copolymers, typically a hydroxyl group, is bound to the -(CH2)2- group of the repeat unit.
SUMMARY OF THE INVENTION
The present invention relates to a process for synthesizing a preferably amphiphilic block copolymer having at least one hydrophilic A block polymer and a hydrophobic B block polymer, the process comprising the step of reacting a terminally cationic reactive A block polymer (A+) with a terminally di- or mono functionalized B block in a reaction to obtain an A-B or an A-B-A block copolymer wherein said A block is selected from hydrophilic polymeric compounds, such as polyethyleneoxide (PEO/OEG) or polyalkyloxazoline (POXA) polymers, such as PMOX A polymers (poly(2-methyl-oxazoline)) and PEOXA (poly(2-ethyl-oxazoline)), and said B block is selected from hydrophobic polymeric compounds such as polybutadiene or silicone compounds, such as polyorganosiloxanes including polydimethylsiloxane (PDMS), polydiethylsiloxane (PDES) and polymethylphenylsiloxane (POPS) polymers. In particular the present invention relates to a process for synthesizing a block copolymer comprising reacting at least one hydrophilic and terminally cationic reactive polymer, A\ with a terminally di- or mono functionalized hydrophobic polymer, B, comprising polydimethylsiloxane (PDMS), to obtain an A-B block copolymer, an A-B-A block copolymer, or a mixture of said block copolymers; wherein said reaction is carried out in the presence of a sterically hindered base. In addition, said process preferably takes place in a reaction vessel using a solvent mixture where said mixture comprises a polar organic solvent and an apolar organic solvent where both are able to dissolve the hydrophilic as well as the hydrophobic reactants and reaction products. In addition, said process of preparing an amphiphilic block copolymer is terminated by quenching the reaction with water.
In particular, the invention relates to a process for synthesizing a block copolymer, wherein said terminally cationic reactive A block polymer (A A is formed by reacting 2-alkyloxazoline monomers with a nucleophilic reagent, such as having a lower alkyl substituent on the leaving group, e.g, methyl, to produce the desired length of polyalkyloxazoline (POXAH‘) polymer, such as PMQXA+ polymer (poly(2-methyl-oxazoline)), and reacting said POXA+ with said terminally di- or monoamine functionalized B block in the same reaction vessel without the need to exchange solvent (one-pot reaction), thus obtaining the desired A-B or A-B-A block copolymer. In addition, the method of polymerization of the invention can be used to incorporate functional end-groups. Such end-groups are normally added post-polymerization. However, functional end-groups including -NH2, -OH, -SH, -CHO, -C2H4OH, -COCH3, -COOH, methacrylate and epoxides may be introduced in the compounds of the invention via or as the Rj-group in Ts-O-Ri and thus be transferred to the POX Λ ends during the nucleophilic substitution reaction, cf. Scheme 1 below. If necessary, the functional end-groups can be protected. The block copolymers prepared using the method of the invention are useful as matrix materials in vesicles having incorporated transmembrane proteins, such as aquaporins including bacterial and yeast aquaporins and aquaporins from higher plants; ion channels including sodium, potassium, chloride, and calcium channels, ligand and voltage gated channels, stretch activated channels and constitutively open channels, such as porins; transporters including NaK atpase, F0F1 atp-synthase, calcium atpases and lithium transporters, taurine transporters and GLUT4.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the invention relates to a process wherein a mono or diamine end-functionalized silicone polymer, such as of Formula i): X1-L1-PDMS-L2-X2 or Formula ii): X.-L1-PDMS-L2, wherein X·, and X?, each represents a primary amine group (-NIL) or one of Xi and X2 represents a -NIL group and the other is absent; Lj and L2 each represents a hydrocarbon chain, such as alkylene, i.a. a ~(CH2)y- group where y is an integer selected from 1, 2, 3, and 4 and where y preferably is the same in Li and L2; or when one of the Ri groups is absent then the L{ or L2 group which is would be connected to said absent Rj group is also absent, and the number of repeating units of the PDMS is in the range of about 10 to about 100, such as about 35 to about 65, such as about 40.
In one aspect of the process of the invention, i.a. the synthesis of an A-B copolymer and/or an A-B-A copolymer, the synthetic route to POXA-HN-(CH2)y-PDMS-(CH2)yH and POXA-HN-(CH2)y-PDMS-(CH2)y-NH-POXA comprises the steps of: a) providing the reactant ΡΟΧΛ'. e.g. through polymerization of the monomer alkyl-2-oxazoline using an initiator such as tosylate, both in a suitable polar organic solvent; b) reacting the POXA+ with H2N-(CH2)y-PDMS-(CH2)y-NH2 in the presence of a proton scavenger, preferably a stericaliy hindered base, in a suitable apolar organic solvent; c) quenching the polymerization reaction in water.
In a further aspect of the process of the invention formula i) represents FLN-CCFLL-PDMS-(CH2)3-NH2 which is reacted with a terminally cationic reactive PMOXAT where the number of repeating units of the PMGXA is in the range of about 3 to about 50, such as about 5 to about 20, and the molar ratio of said PMOXA+ to the amine groups in the compound i) is about 1, such as about 1.1 or such as 0.5, to obtain the desired PMOXA-HN-(CH2)3-PDMS-(CH2)3-NH-PMOXA.
In a further aspect of the process of the invention formula ii) represents H2N-(CH2)3-PDMS-(('H2 )dl which is reacted with a terminally cationic reactive P.V10XA' where the number of repeating units of the PMOXA is in the range of about 3 to about 50, such as about 5 to about 20, and the molar ratio of said PMOXA+ to the amine groups in the compound i) is about 1, such as about LI or such as 0,5, to obtain the desired PMOXA-HN-tCHiL-PDMS-iCTLh-NH-PMOXA.
In the process of the invention the compounds of formulae i) and ii), such as H2N-(CH2)3-PDMS-(CH2)3-NH2 or H2N-(CH2)3-PDMS-(CH2)4H, is preferably dissolved in an organic solvent, such as dichloromethane, chloroform, or the like, and added to the POXA+ reagent,, in the reaction vessel, and the A-B or A-B-A reaction may be performed at a temperature of between 20 and 70°C lasting for a period of between 2 hours and up to 30 hours. An example of said coupling reaction is shown in scheme 1 below where a terminal -NI L group in the presence of a proton scavenger, such as a Hiinig's base, e.g. DIPEA, participates in a ring opening of a terminal oxazoline moiety and resulting addition reaction with the release of protons from said -NH2 group.
Furthermore, prior to reacting terminally cationic reactive POXAH‘ with H2N-(CH2)3-PDMS-(CH2)3-NH2 or H2N-(CH2)3-PDMS, the process of the invention may comprise the step of polymerizing 2-alkyl oxazoline monomers, preferably 2-methyl-2-oxazoline, to obtain said cationic reactive PQXAL
In the process of the invention the polymerization of the A block monomer (e.g. 2-methyl-2-oxazoiine) is preferably performed with a nucleophilic reagent initiator capable of initiating an Sn2 reaction (also known as bimolecular nucleophilic substitution), such as alkyl p-toluene sulfonate Ri-O-Ts (e.g, methyl tosylate), alkyl trifluoromethane sulfonate (e.g. methyl inflate) or alkyl methanesulfonate (e.g, methyl mesylate), preferably methyl p-toluenesulfonate (methyl tosylate) in a nucleophilic substitution reaction leading to alkyl end capped PMOXA, i.e. methyl end capped PMOXA, ef. Formula II below'. When using 2-dimethylammoniumethyl methacrylate tosylate as the initiator the final block copolymer would possess methacrylate end-groups suitable for crosslinking by UV light. The initiator is used at a molar ratio dependent of the desired chain length, and said polymerization of 2-methyl-2-oxazoline monomers is preferably conducted in a solvent such as acetonitrile or DMSO both solvents being compatible wdth solvents such as dichloromethane or chloroform.
In a further embodiment of the invention the mono functionalized B block is a compound of Formula i), i): Xj-Li-PDMS-L2-X2, wherein Xj, Lj, L2 and X2 are as defined below.
In a preferred embodiment of the process of the invention the compound of Formula i) is H2N-(CH2)3-PDMS-(CH2)3-NH2, such as a compound, wherein the average number of repeating units of the PDMS is in the range of about 10 to about 100, such as about 25 to about 55, such as about 35. In other preferred embodiments of the invention the compound of Formula ii) is H2N-(CH2)3-PDMS-(CH2)4H, such as a compound wherein the average number of repeating units of the PDMS is in the range of about 10 to about 100, such as about 20 to about 30. Examples of amino functionalized PDMS polymers useful in the process of the invention preferably have a number average molecular weight, Mn, of from about 2000 Da to about 4500 Da, e.g. such as about 2500 to about 3000 Da.
In a further embodiment of the invention the polymer, B, is a terminally mono functionalized block polymer and the block copolymer obtained is predominantly an A-B block copolymer. In a further embodiment the polymer, B, is a terminally difunctionalized polymer and the block copolymer obtained is a mixture of A-B-A and A-B block copolymers. In a further embodiment the polymer, B, is a terminally difunctionalized polymer and the block copolymer obtained is predominantly an A-B-A block copolymer.
In a further embodiment of the invention, the process is being conducted in a solvent mixture which dissolves all of the A+, B, A-B, and A-B-A polymers which are present in the reaction mixture. In a further embodiment said solvent mixture a comprises * a polar aprotic solvent selected from acetonitrile or DMSO; ® and an apolar solvent selected from dichloromethane, trichloromethane, or trichloroethylene.
In a special embodiment, solvent mixture comprises acetonitrile and methylene chloride, preferably in the ratio ranges of from 1:3 to 3:1.
In a further embodiment, the hydrophobic polymer, B, is dissolved in the apolar solvent prior to addition to the reaction pot.
In a further embodiment of the process of the invention POXA+ is PMOXA+, and the molar ratio of PMOXA+ to functionalized groups is at least 1:1, such as equal to or larger than 1.1:1, such as larger than 1.2:1. In a further embodiment, POXA+ is PMOXA+, and the molar ratio of PMOXA+ to functionalized groups is at least 0.5:1, such as equal to or larger than 0.55:1, such as larger than 0.6:1.
In a further embodiment of the invention the process comprises the step prior to reacting the terminally cationic reactive POXA+ with said terminally di- or monoamine functionalized B block, of: polymerization of 2-alkyl oxazoline monomers, such as 2-methyl oxazoline, to obtain said cationic reactive POXA+. In a further embodiment the polymerization of 2-alkyl oxazoline monomers, such as 2-methyl oxazoline, is performed with a nucleophilic reagent or initiator, such as methyl p-toluenesulfonate, being capable of initiating an SN2 reaction. In a special embodiment the polymerization is conducted in a polar aprotic solvent, such as acetonitrile.
The invention further relates to a vesicle comprising a triblock copolymer according to Formula I,
a diblock copolymer according to Formula II,
and a transmembrane molecule selected from the group consisting of aquaporin water channel molecules.
In a special embodiment of the above use both Ri groups are the same and selected from straight or branched Ci to C3 lower alkyl groups, such as methyl and ethyl; Li and L2 are the same and selected from -(CFFk- and -(CFbri-; m is an integer between 60 and 100; and n is an integer between 7 and 19, such as 9 to 11.
In a further embodiment of the above use the triblock copolymer has the structure of Formula III:
The invention further relates to a block copolymer composition comprising a compound according to Formula I and a compound according to Formula II, said composition being prepared according to the process as disclosed herein, and wherein each of said compounds has a degree of PDMS derivatization of more than about 30 to 40 %, such as more than or equal to 50%.
An exemplary synthetic route of preparing an A-B-A type compound of Formula I is shown below in Scheme 1 where Ts-O-Rt represents a tosylate, Ts representing the leaving group, and Ri is a group, such as alkyl (eg. methyl) and H2N-L1-PDMS-L2-NH2 represents the diamine functionalized PDMS, cf. also formula i) above.
Scheme 1: Synthesis reaction scheme. Hiinig's base is shown here while other sterieahy hindered bases also may be useful as proton scavengers.
Definitions and Terms
The term amine functionalized PDMS as used herein refers to mono- or diamine functionalized polydimethyl siloxane polymers, e.g. such as aminomethyl, aminoethyl, aminopropyl, or aminobutyl terminated polydimethylsiloxane (CAS: 106214-84-0 ), Example of a diamine functionalized PDMS is the cheap commercial oligomer DMS A21 (bis(3-aminopropyl)-polydimethylsiloxane, calculated Mn app, 6400 Da) trom Gelest or polydimethylsiloxane, aminopropyl terminated (Mw 3000,00 g/mol from abcr specialty chemicals, Karlsruhe, Germany). Or PDMS diamine can be synthesized if needed to tailor the PDMS portion in Mw. Example of synthesis of oligomers with targeted number average molecular weights (Mn) of 1000, 2000, 5000, and 11000 g/mol is disclosed in Bowens, A.D. Synthesis and Characterization of Polyisiioxane irnide) Block Copolymers and End-Functional Polyimides for Interphase Applications (Ph. D. dissertation 1999-11-29) cf. url> hlip:// wh· Tir.iih.vi vGiiAiwsoDawuk-MoA.k!· i 20?vv·: 5 1523/ retrieved from the internet on 28-04-2014. Alternatively as disclosed in Baranauskas, V.V. url> hUpF/sdn-kir kk \ kodu/kH: ws/uvniiahD/elu -04272=)05 · i 9·'·-48/ retrieved from the internet on 28-04-2014.
The term PMOXA as used herein refers to the polyoxazoline poly(2-methyloxazoline) or poly(2-methyl-2-oxazoline) being prepared by polymerizing 2-methyloxazoline CAS No. 1120-64-5: 2-methyl-2-oxazoiine. Other similar oxazolines may be useful in the method of the invention, e.g. oxazoline and 2-ethyl-2-oxazoline.
The term PDMS as used herein refers to polydimethylsiloxane. However, in general other polyorganosiloxanes including polydiethylsiloxane (PDES) and polymethylphenylsiloxane (PDFS) polymers may be useful in synthesizing block copolymers according to the methods described herein.
Sterically hindered base A sterically hindered base is an organic base that has the ability to abstract an acidic hydrogen atom from a compound without otherwise chemically reacting with the compound, that is without displacing a functional group within the compound (i.e. nucleophilic substitution). Tertiary amines are good examples of non-nucleophilic bases because they have the ability to abstract an acidic proton from a compound but because of their steric hindrance, they cannot otherwise react with the compound. Other non-limiting illustrative examples of non-nucleophilic bases include lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperdine (LIMP), lithium hexamethyldisilazide (LHMDS), and the like.
Specifical examples of sterically hindered bases for use in the present invention include: Ν,Ν-Diisopropylethylamine (DIPEA, or Hunig's Base), l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-Diazabicyclo[2.2.2]octan (TED), tert-butylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo(2.2.2)octane (DABCO), N,N-dicyclohexylmethylamine, 2,6-di-tert-butyI-4-methylpyridine, quinuclidine, 1,2,2,6,6-pentamethylpiperidine (PMP), 7-methyl-l,5,7-triazabicyclo(4.4.0)dee-5-ene (MTBD), triphenylphosphine, tri-tert-butylphosphine an d trie y c I oh ex y I ph o sph ine.
The abbreviation Mn means number average molecular weight. It means the total weight of polymer divided by the number of polymer molecules. Thus, M„ is the molecular weight weighted according to number fractions.
The abbreviation Mw means weight average molecular weight. The molecular weight weighted according to weight fractions.
The term PDI means the polydispersity index. The polydispersity index is calculated as the ratio of Mw to M„.
The term ''transmembrane molecule" as used herein means in particular membrane proteins haying at least one transmembrane domain such as aquaporin water channels including bacterial aquaporins, yeast aquaporins, plant aquaporins, mammalian aquaporins, and other euc ary otic aquaporins. In addition, "transmembrane molecule" means membrane bound peptides, such as gramicidin peptides, having transmembrane spanning properties as well as other transmembrane molecules having sufficient amphiphilic features to enable transmembrane binding or localization.
The process according to the invention exhibits several advantages compared with the prior art, such as the use of a single solvent mixture that abolishes the need to exchange solvent during the reactions and enables the reaction to be performed in one reaction vessel, i.e. as a one-pot reaction. The use of functional tosylates or triflates for the cationic ring-opening polymerization of 2-methyl- 1,3-oxazoline is described in Einzmann & Binder (2001), and the polymerization of 2-methyl oxazoline is well described in literature (e.g. Matyjazewski & Hrkach 1992).
In addition the following synthesis examples show that:
The process is highly reproducible.
The process is scalable due to one-pot reaction in one or two steps without a need to exchange solvents.
The POXA polymerization is fast as compared to literature.
It is possible to control the polydispersity of the end product through control of the POXA+ polymerisation step.
It is possible to obtain a consistently low polydispersity matching the lowest found in literature yielding a very defined product.
The synthesis of the invention provides a simple way of generating a relatively well-defined di-or triblock copolymer which would exhibit a lower polydispersity compared to similar block copolymers synthesized according to the prior art.
EXAMPLES
The present invention is further illustrated by the following examples should not be construed as further limiting the general scope of the invention.
Experimental section
General procedere
The reaction according to the invention for the synthesis of PMOXAn-PDMSm-PMOXAn (poly(2-methyl oxazolin) block polydimethylsiloxan block poly(2-methyl oxazolin)) in general is as shown in Scheme 1 above.
Example 1. Preparation of PMOXA-PDMS-PMOXA/PMOXA-PDMS block copolymers in a two step reaction, cf. Formulae III and IV below:
Prior to reaction the solvent (acetonitrile) and the monomer (2-methyl-2-oxazoline) are both dried, such as using molecular sieve 4. 130 g acetonitrile is charged into a 500 ml glass reactor with stirrer. 50 g 2-methyl-2-oxazoline monomer is added by means of a dried (such as Ar flushed) syringe. The monomer reaction solution is heated to 40 °C, 50 g on initiator solution (methyl-p-toluenesulfonate in acetonitrile with a concentration of 1.0 mol/L) is added with a dried syringe. The reaction solution is heated to 100 °C. After 3 hours at 100 °C the reaction solution is cooled to room temperature, 113 g Dichloromethane is added to the resulting PMOXA+ reaction solution.
10 g Aminopropyl terminated polydimethylsiloxane, symmetric (PDMS difunctional amine, CAS No. 106214-84-0, molecular weight around 3000 kDa, obtained from Gelest DMS A15), 33 g acetonitrile and 3 g Ν,Ν-Diisopropylethylamine (DIPEA) are added to a 250 ml reaction flask. 50 g of the previously prepared PMOXA+ reaction solution are added. The reaction is kept at 60 °C for 64 hours. The copolymerization reaction is quenched in water. The resulting copolymer is purified by ultrafiltration. Derivation of amines from PDMS: 92%, as determined by NMR. We infer from this finding using binominal distribution modelling that a high percentage of the final copolymer is a triblock copolymer, such as about > 70% or about > 80%, and a low percentage of the final copolymer is a diblock copolymer with a negligible amount of unreacted PDMS.
Example 2. Preparation of PMOXA-PDMS and PMOXA-PDMS-PMOXA block copolymers according to Formulae III and IV below in a two step reaction: a) 130 g acetonitrile is charged into a 500 ml glass reactor with stirrer. 50 g 2-methyl-2-oxazoline is added by means of a dried syringe. The monomer reaction solution is heated to 40 °C. 50 g initiator solution (methyl-p-toluenesulfonate in acetonitrile with a concentration of 1.0 moi/L) is added with a dried syringe. The reaction solution is heated to 100 °C. After 3 hours at 100 °C the reaction solution comprising the resulting PMOXA+ polymer is cooled to room temperature, 10 g Aminopropyl terminated polydimethylsiloxane, symmetric (PDMS difunctional amine, CAS No. 106214-84-0, obtained from Gelest DMS A15), 17 g dichloromethane and 3 g Ν,Ν-Diisopropylethylamine are added to a 250 ml reaction flask. 47 g of acetonitrile and 15 g of the previously prepared PMOXA+ reaction solution are added. The reaction is kept at 60 °C for 64 hours. The copolymerization reaction is quenched in water. The resulting copolymer is purified by ultrafiltration. Derivation of amines from PDMS: 56%, as determined by NMR. We infer from this finding using binominal distribution modelling that about two thirds of the final copolymer is a diblock copolymer and about one third is a tribloek copolymer.
Alternatively, b) 130 g acetonitrile is charged into a 500 ml glass reactor with stirrer, 50 g 2-methyl-2-oxazoline is added by means of a dried syringe. The monomer reaction solution is heated to 40 °C. 50 g initiator solution (methyl-p-toluenesulfonate in acetonitrile with a concentration of 1.0 moI/L) is added with a dried syringe. The reaction solution is heated to 100 °C. After 3 hours at 100 °C the reaction solution comprising the resulting PMOXA+ polymer is cooled to room temperature.
10 g Aminopropyl terminated polydimethylsiloxane, symmetric (PDMS difunctional amine, CAS NR 106214-84-0, obtained trom Gelest DMS A15), 17 g dichloromethane and 3 g N,N-Diisopropylethylamine are added to a 250 ml reaction flask. 13 g of acetonitri le and 15 g of the previously prepared PMOXA reaction solution are added. The reaction is kept at 60 °C for 64 hours. The copolymerization reaction is quenched in water. The resulting copolymer is purified by ultrafiltration. Derivation of amines from PDMS: 53%, as determined by NMR. We infer from this finding using binominal distribution modelling that about two thirds of the final copolymer is a diblock copolymer and about one third is a triblock copolymer.
Example 3: Preparation of diblock copolymer PMOXA-PDMS of Formula IV below.
130 g acetonitrile is charged into a 500 ml glass reactor with stirrer. 50 g 2-methyl-2-oxazoline is added by means of a dried syringe. The monomer reaction solution is heated to 40 °C. 50 g initiator solution (methyl-p-toluenesulfonate in acetonitrile with a concentration of 1,0 mol/L) is added with a dried syringe. The reaction solution is heated to 100 °C. After 3 hours at 100 °C the reaction solution comprising the resulting PMOXA+ polymer is cooled to room temperature, 10 g Monoaminopropyl terminated polydimethylsiloxane, asymmetric, cf. Formula ii) where n is approximately 24 (mean value) (PDMS monofunctional amine, molecular weight around 2000 kDa, obtained from Gelest MCR A12), 17 g dichloromethane, and 2 g N,N-diisopropylethylamine are added to a 250 ml reaction flask. 8 g of acetonitrile and 21 g of the previously prepared PMOXA+ reaction solution are added. The reaction is kept at 60 °C for 64 hours. The copolymerization reaction is quenched in water. The resulting copolymer is purified by ultrafiltration. Derivation of amines from PDMS: 50%, as determined by NMR. We infer from this finding using binominal distribution modelling that about two thirds of the final copolymer is a diblock copolymer and about one third is a triblock copolymer.
Formula ii), n » 24
Table i) mol amounts and mol ratios used in the above examples
Table i) clearly shows that the PM OX A reactant is used in approximately equimolar amount relative to the amino functionality.
Formula III; n * 9 and m » 35-40
Formula IV; n » 9 and m = 25
Example 4. Protocol for lmg/ml proteo-polymersomes, protein to polymer ratio (PQPR) 50
Materials:
Polyoxazoline Based Di- and Triblock Copolymers prepared and purified as described in the examples above, having an average molecular weight of between approximately 1500 (diblock copolymers) and approximately 6000 (triblock copolymers).
Protein: Aquaporin Z (AqpZ), Mw 27233.
Preparation: 1) Fill a 50 mi glass evaporation vial with 5mi of a 2 mg/ml stock solution of copolymers (either in pure diblock or pure triblock form or as mixtures of di- and tribloek copolymers) in CHCI3.
2) Evaporate the CHCE using a rotation evaporator for at least 2h to complete dryness.
3) Add 3.0 mL of buffer solution (1.3% O.G.; 2Q0mM Sucrose; lOmM Tris pH 8; 50mM Nad) to rehydrate the film obtained in the evaporation vial in step 2.
4) Shake the vial at 200 rpm on a platform shaker (Heidolph orbital platform shaker Unimax 2010 or equivalent) for 3 hours to obtain dissolution of the copolymer.
5) Add 1,55mg μ L of AqpZ in a protein buffer containing Tris, glucose and OG, and rotate vial over night at 200rpm and 4°C.
6) Add 6.88 ml buffer (lOmM Tris pH 8; 50mM NaCl) slowly while mixing up and down with pipette.
7) Add 180mg hydrated Biobeads and rotate for Ih at 200rpm.
8) Add 210mg hydrated Biobeads and rotate for lh at 200rpm.
9) Add 240mg hydrated Biobeads and rotate O.N. at 200rpm 4°C.
10) Add 240mg hydrated Biobeads and rotate O.N. at 200rpm 4°C.
11) The Biobeads with adsorbed OG are then removed by pipetting off the suspension.
12) Extrude the suspension for about 21 times through a 200nm track etched polycarbonate filter using an extruder, such as from at least l time and up to about 22 times to obtain a uniform proteopolymersome suspension (vesicles) suspension.
References
Veena Pata and Nily Dan, Biophysical Journal Volume 85 October 2003 2111-2118]
Einzmann & Binder, Journal of Polymer Science Part A: Polymer Chemistry, Volume 39, Issue 16, pages 2821-2831, 15 August 2001.
T, Saegusa, H. Ikeda, H, Fujii; Macromolecules 1972, 5, 359-362; Isomerization Polymerization of 2-Oxazoline IV. Kinetic study of 2-MethyI-2-oxazoIine Polymerization, B. Brissault, C. Guis, H. Cheradame; European Polymer Journal 2002, 38, 219-228; Kinetic study of poly(ethylene oxide-b-2-methyl-2-oxazoline) diblocks synthesis from poly(ethylene oxide) maeroinitia tor s, R, Hoogenboom, M.W.M. Fijten, U.S.Schubert; journal of Polymer Science Part A: Polymer Chemistry 2004, 42, 1830-1840: Parallel kinetic Investigation of 2-Oxazoline Polymerizations with Different Initiators as Basis for Designed Copolymer Synthesis, R. Hoogenboom, M.W.M. Fijten, R.M. Paulus, H.M.L. Thijs, S. Hoeppener, G, Kickelbiek, U.S. Schubert; Polymer 2006, 47, 75-84; Accelerated pressure synthesis and characterization of 2-oxazoline block copolymers.
S. Ji, T.T. Hoye, C.W. Macosko: Macromolecules 2005, 38, 4679-4686, Primary Amine (-NH2) Quantification in Polymers: Functionality by 19F NMR Spectroscopy.
Corinne Nardin, Thomas Hirt, Jorg Leukel and Wolfgang Meier, Polymerized ABA tribloek Copolymer Vesicles, Langmuir 2000, 1035 - 1041Michael J. Isaacman, Kathryn A. Barron and Michael J. Isaacman, Kathryn A, Barron and Luke S. Theogarajan, Clickable Amphiphilic Triblock Copolymers, Polymer Chemistry 2012, 50, 2319 -- 2329.
Corinne Nardin, Sandra Thoeni, Jorg Widmer, Mathias Winterhalter and Wolfgang Meier, Nanoreactors based on (polymerized) ABA-triblock copolymer vesicles, ('hem. Commun., 2000, 1433 -- 1434.
Matyjaszewski, Krzysztof & Jeffrey S. Hrkach. Cationic ring opening polymerization of oxazolines initiated by trimethylsilyl derivatives. Technical Report, Carnegie Mellon University, Department of Chemistry, May 25, 1992.
W. Meier, C. Nardin, M. Winterhalter, Reconstitution of channel proteins in (polymerised) ABA tribloek copolymer membranes. Angew. Chem. Ini. Ed. 39(24) (2000) 4599 Mirko Einzmann & W olfgang H. Binder (2001) Novel functional initiators for oxazoline polymerization. Journal of Polymer Science Part A: Polymer Chemistry,Volume 39, Issue 16, pages 2821-2831, 15 August 2001 Y. Chujo, E. Ihara & T. Saegusa, Synthesis of Polyoxazoline-polysiloxane block copolymers. Kobunshi ronbunshu, 1992, vol 49, no. 11, pages 943-946.
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| KR20190079670A (en) | 2016-11-11 | 2019-07-05 | 아쿠아포린 에이에스 | Self-assembling polymer vesicle structure with functional molecules |
| CN110430937B (en) * | 2017-02-06 | 2022-03-11 | 水通道蛋白有限公司 | Diblock copolymer vesicles and separation membranes comprising aquaporin water channels and methods of making and using the same |
| CN107474119B (en) * | 2017-06-28 | 2020-07-10 | 宁波日新恒力科技有限公司 | Antibacterial aquaporin vesicles and preparation method and application thereof |
| CN115160560B (en) * | 2022-08-09 | 2024-06-04 | 西北工业大学 | Block copolymer and preparation method and application thereof |
| WO2024055284A1 (en) * | 2022-09-16 | 2024-03-21 | 深圳华大生命科学研究院 | Ion cross-linked biomimetic membrane, preparation method therefor, and use thereof |
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| WO2001032146A2 (en) * | 1999-11-05 | 2001-05-10 | Biocure, Inc. | Amphiphilic polymeric vesicles |
| US20080305149A1 (en) * | 2007-06-11 | 2008-12-11 | Thomas Hirt | Mucoadhesive vesicles for drug delivery |
| WO2009130144A2 (en) * | 2008-04-23 | 2009-10-29 | Basf Se | Delivery of hydrophobic benefit agents from bodywashes and the like onto a keratinous substrate |
| WO2013090691A1 (en) * | 2011-12-14 | 2013-06-20 | Dow Corning Corporation | Curable compositions of resin-linear organosiloxane block copolymers |
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| EP1040153A1 (en) * | 1997-12-19 | 2000-10-04 | The Procter & Gamble Company | Multi-cationic silicone polymers |
| TWI475051B (en) * | 2009-11-18 | 2015-03-01 | Kao Corp | Organic polysiloxane |
| WO2013072378A1 (en) * | 2011-11-14 | 2013-05-23 | Byk-Chemie Gmbh | Use of modified polysiloxanes in coating material compositions and molding materials |
| US20140051785A1 (en) * | 2012-08-17 | 2014-02-20 | Manish Kumar | High density membrane protein membranes |
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| US20080305149A1 (en) * | 2007-06-11 | 2008-12-11 | Thomas Hirt | Mucoadhesive vesicles for drug delivery |
| WO2009130144A2 (en) * | 2008-04-23 | 2009-10-29 | Basf Se | Delivery of hydrophobic benefit agents from bodywashes and the like onto a keratinous substrate |
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