JP2007327041A - Method for producing chitosan derivative - Google Patents
Method for producing chitosan derivative Download PDFInfo
- Publication number
- JP2007327041A JP2007327041A JP2007120843A JP2007120843A JP2007327041A JP 2007327041 A JP2007327041 A JP 2007327041A JP 2007120843 A JP2007120843 A JP 2007120843A JP 2007120843 A JP2007120843 A JP 2007120843A JP 2007327041 A JP2007327041 A JP 2007327041A
- Authority
- JP
- Japan
- Prior art keywords
- chitosan
- group
- substituent
- general formula
- hydrocarbon group
- 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.)
- Granted
Links
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 175
- 238000004519 manufacturing process Methods 0.000 title claims description 28
- 125000001424 substituent group Chemical group 0.000 claims abstract description 59
- 230000003287 optical effect Effects 0.000 claims abstract description 34
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 24
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 20
- 239000007864 aqueous solution Substances 0.000 claims abstract description 19
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- 125000005462 imide group Chemical group 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 abstract description 17
- 239000000243 solution Substances 0.000 abstract description 11
- 230000000850 deacetylating effect Effects 0.000 abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- 150000001875 compounds Chemical class 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000007983 Tris buffer Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 150000003222 pyridines Chemical class 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- DZSGDHNHQAJZCO-UHFFFAOYSA-N 1-isocyanato-3,5-dimethylbenzene Chemical compound CC1=CC(C)=CC(N=C=O)=C1 DZSGDHNHQAJZCO-UHFFFAOYSA-N 0.000 description 8
- 230000005526 G1 to G0 transition Effects 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- -1 acid amide compound Chemical class 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- XEFUJGURFLOFAN-UHFFFAOYSA-N 1,3-dichloro-5-isocyanatobenzene Chemical compound ClC1=CC(Cl)=CC(N=C=O)=C1 XEFUJGURFLOFAN-UHFFFAOYSA-N 0.000 description 7
- 230000006196 deacetylation Effects 0.000 description 7
- 238000003381 deacetylation reaction Methods 0.000 description 7
- VTAQLGRULYHNQX-UHFFFAOYSA-N (3,4-dichlorophenyl)carbamic acid Chemical compound OC(=O)NC1=CC=C(Cl)C(Cl)=C1 VTAQLGRULYHNQX-UHFFFAOYSA-N 0.000 description 6
- KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 150000004676 glycans Chemical class 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 150000003949 imides Chemical group 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229920001282 polysaccharide Polymers 0.000 description 6
- 239000005017 polysaccharide Substances 0.000 description 6
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 5
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 5
- MFUVCHZWGSJKEQ-UHFFFAOYSA-N 3,4-dichlorphenylisocyanate Chemical compound ClC1=CC=C(N=C=O)C=C1Cl MFUVCHZWGSJKEQ-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 4
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- SHXGGYLLZCCNAX-UHFFFAOYSA-N (3-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=CC(Cl)=C1 SHXGGYLLZCCNAX-UHFFFAOYSA-N 0.000 description 2
- PHVSUUGFGMGZPE-UHFFFAOYSA-N (4-bromophenyl)carbamic acid Chemical compound OC(=O)NC1=CC=C(Br)C=C1 PHVSUUGFGMGZPE-UHFFFAOYSA-N 0.000 description 2
- CCENBZDJMALWCH-UHFFFAOYSA-N (4-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(Cl)C=C1 CCENBZDJMALWCH-UHFFFAOYSA-N 0.000 description 2
- CZQIJQFTRGDODI-UHFFFAOYSA-N 1-bromo-4-isocyanatobenzene Chemical compound BrC1=CC=C(N=C=O)C=C1 CZQIJQFTRGDODI-UHFFFAOYSA-N 0.000 description 2
- HHIRBXHEYVDUAM-UHFFFAOYSA-N 1-chloro-3-isocyanatobenzene Chemical compound ClC1=CC=CC(N=C=O)=C1 HHIRBXHEYVDUAM-UHFFFAOYSA-N 0.000 description 2
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 2
- CPPGZWWUPFWALU-UHFFFAOYSA-N 1-isocyanato-3-methylbenzene Chemical compound CC1=CC=CC(N=C=O)=C1 CPPGZWWUPFWALU-UHFFFAOYSA-N 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 2
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 description 2
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 2
- MGYGFNQQGAQEON-UHFFFAOYSA-N 4-tolyl isocyanate Chemical compound CC1=CC=C(N=C=O)C=C1 MGYGFNQQGAQEON-UHFFFAOYSA-N 0.000 description 2
- 0 C[C@@](C(*)C1NC(*)=O)C(C*)O[C@@]1OC Chemical compound C[C@@](C(*)C1NC(*)=O)C(C*)O[C@@]1OC 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 238000004381 surface treatment Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- VTONZKDPQTYHLV-UHFFFAOYSA-N (3-methylphenyl) carbamate Chemical compound CC1=CC=CC(OC(N)=O)=C1 VTONZKDPQTYHLV-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- CAOOVUTXOZVQON-UHFFFAOYSA-N (4-methylphenyl) carbamate Chemical compound CC1=CC=C(OC(N)=O)C=C1 CAOOVUTXOZVQON-UHFFFAOYSA-N 0.000 description 1
- GUFMBISUSZUUCB-UHFFFAOYSA-N 1,3,5-tritert-butylbenzene Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC(C(C)(C)C)=C1 GUFMBISUSZUUCB-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
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- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Treatment Of Liquids With Adsorbents In General (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
本発明はキトサン誘導体の製造方法に関する。 The present invention relates to a method for producing a chitosan derivative.
多糖誘導体が優れた光学分割能を示すことは良く知られている（特許文献1、2等）。しかし、これら光学分割能に優れた多糖誘導体を用いても分割することが難しい化合物もある。
多糖誘導体が優れた光学分割能を示すのは、多糖誘導体の高次構造が分割対象たる光学異性体の構造に良好に適合し、両者の間で種々の相互作用が効果的に働くためであると考えられている。
そして、このような光学分割能を示す多糖誘導体の一つとして、キトサン誘導体も研究されてきた（特許文献3、非特許文献1、2等）。
しかし、これまで光学異性体分離用充填剤として用いられてきたキトサン誘導体は、必ずしもその光学分割能は充分とはいえなかった（特許文献3）。
The reason why the polysaccharide derivative has an excellent optical resolution is that the higher order structure of the polysaccharide derivative is well adapted to the structure of the optical isomer to be resolved, and various interactions work between them effectively. It is believed that.
In addition, chitosan derivatives have been studied as one of the polysaccharide derivatives exhibiting such optical resolution (Patent Document 3, Non-Patent Documents 1 and 2, etc.).
However, chitosan derivatives that have been used as fillers for separating optical isomers so far have not always had sufficient optical resolution (Patent Document 3).
本発明は、置換基が効率よく導入され、光学分割能が向上したキトサン誘導体の製造方法に関する。 The present invention relates to a method for producing a chitosan derivative in which substituents are efficiently introduced and optical resolution is improved.
本発明者らはキトサン誘導体の光学分割能を向上させるべく鋭意検討を行った。その結果、原料キトサンの脱アセチル化を十分に行った後に置換基導入反応を行うことで、置換基の導入効率がよく、光学分割能が向上したキトサン誘導体の光学分割能が得られることを見出し、本発明に達した。 The present inventors diligently studied to improve the optical resolution of chitosan derivatives. As a result, it was found that by carrying out a substituent introduction reaction after sufficiently deacetylating the raw material chitosan, the introduction efficiency of the substituent can be improved and the optical resolution of the chitosan derivative with improved optical resolution can be obtained. The present invention has been reached.
すなわち、本発明は以下のとおりである。
（１）下記一般式（Ｉ）で表されるキトサン誘導体の製造方法であって、塩基性水溶液中で原料のキトサンを加熱処理して脱アセチル化し、脱アセチル化されたキトサンに置換基を導入してキトサン誘導体を得ることを特徴とする方法。
族炭化水素基を含む置換基を示し、Ｒaは、置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基もしくは芳香族炭化水素基を含む置換基、水素原子、ピリジルアルキル基、ベンジルアルキル基、キトサンの窒素原子およびＲｂとともにイミド環を形成する基、または、キトサンの窒素原子およびＲｂとともにピリジルイミンもしくはベンジルイミンを形成する基を示し、Ｒｂは、水素原子、キトサンの窒素原子およびＲａとともにイミド環を形成する基、または、キトサンの窒素原子およびＲａとともにピリジルイミンもしくはベンジルイミンを形成する基を示し、nは5以上の整数を示す。
（２）一般式（Ｉ）中、ＲおよびＲaが下記の一般式（II）または（III）のいずれかで表される置換基であり、Ｒｂが水素原子であることを特徴とする、（１）のキトサン誘導体の製造方法。
（３）一般式（Ｉ）中、RおよびＲaが下記一般式（IV）で表される置換基であり、Ｒｂが水素原子であることを特徴とする、（１）または（２）のキトサン誘導体の製造方法。
（４）一般式（Ｉ）中、ＲおよびＲaが下記の一般式（V）で表される置換基であり、Ｒｂが水素原子であることを特徴とする、（１）のキトサン誘導体の製造方法。
（５）一般式（Ｉ）中、Ｒが下記の一般式(II）で表される置換基であり、Ｒａがピリジルアルキル基またはベンジルアルキル基であり、Ｒｂが水素原子であることを特徴とする、（１）のキトサン誘導体の製造方法。
（６）一般式（Ｉ）中、Ｒが下記の一般式(II）で表される置換基であり、Ｒａが、キトサンの窒素原子およびＲｂとともにピリジルイミンを形成する基であることを特徴とする、（１）のキトサン誘導体の製造方法。
（７）一般式（Ｉ）中、Ｒが下記の一般式(II）で表される置換基であり、Ｒａが、キトサンの窒素原子およびＲｂとともにベンジルイミンを形成する基であることを特徴とする、（１）のキトサン誘導体の製造方法。
（８）塩基性水溶液が水酸化ナトリウム、水酸化カリウムのいずれかであることを特徴とする、（１）〜（７）のいずれかのキトサン誘導体の製造方法。
（９）（１）〜（８）のいずれかの製造方法によりキトサン誘導体を製造し、得られたキトサン誘導体を用いて光学異性体用分離剤を製造する、光学異性体用分離剤の製造方法。（１０）（１）〜（８）のいずれかの製造方法により製造されたキトサン誘導体。
（１１）（１０）のキトサン誘導体からなる光学異性体用分離剤。
That is, the present invention is as follows.
(1) A method for producing a chitosan derivative represented by the following general formula (I), wherein the raw chitosan is deacetylated by heat treatment in a basic aqueous solution, and a substituent is introduced into the deacetylated chitosan. To obtain a chitosan derivative.
(2) In the general formula (I), R and Ra are substituents represented by the following general formula (II) or (III), and Rb is a hydrogen atom, A method for producing a chitosan derivative according to 1).
(3) The chitosan of (1) or (2), wherein in general formula (I), R and Ra are substituents represented by the following general formula (IV), and Rb is a hydrogen atom A method for producing a derivative.
(4) Production of a chitosan derivative according to (1), wherein R and Ra in general formula (I) are substituents represented by the following general formula (V), and Rb is a hydrogen atom Method.
(5) In the general formula (I), R is a substituent represented by the following general formula (II), Ra is a pyridylalkyl group or a benzylalkyl group, and Rb is a hydrogen atom, A method for producing a chitosan derivative according to (1).
(6) In the general formula (I), R is a substituent represented by the following general formula (II), and Ra is a group that forms pyridylimine together with the nitrogen atom of chitosan and Rb, A method for producing a chitosan derivative according to (1).
(7) In the general formula (I), R is a substituent represented by the following general formula (II), and Ra is a group that forms benzylimine with the nitrogen atom and Rb of chitosan, A method for producing a chitosan derivative according to (1).
(8) The method for producing a chitosan derivative according to any one of (1) to (7), wherein the basic aqueous solution is either sodium hydroxide or potassium hydroxide.
(9) A method for producing a separating agent for optical isomers, wherein a chitosan derivative is produced by the production method of any one of (1) to (8), and a separating agent for optical isomers is produced using the obtained chitosan derivative. . (10) A chitosan derivative produced by the production method of any one of (1) to (8).
(11) A separating agent for optical isomers comprising the chitosan derivative of (10).
本発明によれば、置換基が効率がよく導入され、光学分割能が向上したキトサン誘導体が得られる。得られたキトサン誘導体は、光学異性体用分離剤として有用である。
According to the present invention, a chitosan derivative in which substituents are efficiently introduced and optical resolution is improved can be obtained. The obtained chitosan derivative is useful as a separating agent for optical isomers.
本発明においては、塩基性水溶液中で原料のキトサンを加熱処理して脱アセチル化し、
脱アセチル化されたキトサンに置換基を導入することにより、下記一般式（Ｉ）で表されるキトサン誘導体を製造する。
In the present invention, the raw chitosan is deacetylated by heat treatment in a basic aqueous solution,
A chitosan derivative represented by the following general formula (I) is produced by introducing a substituent into deacetylated chitosan.
一般式（Ｉ）において、Ｒaは、置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基もしくは芳香族炭化水素基を含む置換基、水素原子、ピリジルアルキル基、ベンジルアルキル基、キトサンの窒素原子およびＲｂとともにイミド環を形成する基、または、キトサンの窒素原子およびＲｂとともにピリジルイミンもしくはベンジルイミンを形成する基を示す。
一般式（Ｉ）において、Ｒｂは、水素原子、キトサンの窒素原子およびＲａとともにイミド環を形成する基、または、キトサンの窒素原子およびＲａとともにピリジルイミンもしくはベンジルイミンを形成する基を示す。なお、Ｒaが置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基もしくは芳香族炭化水素基を含む置換基、ピリジルアルキル基、ベンジルアルキル基、または水素原子であるとき、Ｒｂは水素原子である。
一般式（Ｉ）において、nは5以上の整数を示す。
炭素数1〜３０の脂肪族基は、直鎖脂肪族基でも分岐脂肪族基でもよいし、不飽和結合を有していてもよい。
炭素数1〜３０の脂肪族炭化水素基又は芳香族炭化水素基が置換基を有するとき、置換基の例としては、炭素数１〜１２のアルキル基、炭素数１〜１２のアルコキシ基、炭素数１〜１２のアルキルチオ基、シアノ基、ハロゲン原子、炭素数１〜８のアシル基、炭素数１〜８のアルコキシカルボニル基、ニトロ基、アミノ基、炭素数１〜８のアルキルアミノ基などが挙げられる。なお、置換基は複数でもよい。
In the general formula (I), Ra is a substituent containing a C 1-30 aliphatic hydrocarbon group or aromatic hydrocarbon group which may have a substituent, a hydrogen atom, a pyridylalkyl group, a benzylalkyl group. A group that forms an imide ring with the nitrogen atom and Rb of the group, chitosan, or a group that forms pyridymine or benzylimine with the nitrogen atom and Rb of chitosan.
In the general formula (I), Rb represents a group that forms an imide ring together with a hydrogen atom, a nitrogen atom of chitosan, and Ra, or a group that forms a pyridymine or benzylimine together with the nitrogen atom and Ra of chitosan. In addition, when Ra is a substituent containing a C1-C30 aliphatic hydrocarbon group or aromatic hydrocarbon group which may have a substituent, a pyridylalkyl group, a benzylalkyl group, or a hydrogen atom, Rb is a hydrogen atom.
In general formula (I), n represents an integer of 5 or more.
The aliphatic group having 1 to 30 carbon atoms may be a linear aliphatic group or a branched aliphatic group, and may have an unsaturated bond.
When the aliphatic hydrocarbon group or aromatic hydrocarbon group having 1 to 30 carbon atoms has a substituent, examples of the substituent include alkyl groups having 1 to 12 carbon atoms, alkoxy groups having 1 to 12 carbon atoms, carbon An alkylthio group having 1 to 12 carbon atoms, a cyano group, a halogen atom, an acyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 1 to 8 carbon atoms, a nitro group, an amino group, an alkylamino group having 1 to 8 carbon atoms, and the like. Can be mentioned. A plurality of substituents may be used.
好ましくは、ＲおよびＲaは下記の一般式（II）または（III）のいずれかで表される。このときＲｂは水素原子である。
式（II）の置換基は、例えば、脱アセチル化されたキトサンを、R’を含むイソシアン酸と反応させることにより導入することができる。
式（III）の置換基は、例えば、脱アセチル化されたキトサンを、R’を含む、カルボン
酸、エステル、酸ハロゲン化物、酸アミド化合物、またはアルデヒドと反応させることにより導入することができる。
Preferably, R and Ra are represented by any of the following general formulas (II) or (III). At this time, Rb is a hydrogen atom.
The substituent of formula (II) can be introduced, for example, by reacting deacetylated chitosan with isocyanic acid containing R ′.
The substituent of formula (III) can be introduced, for example, by reacting deacetylated chitosan with a carboxylic acid, ester, acid halide, acid amide compound or aldehyde containing R ′.
より好ましくは、ＲおよびＲaは下記のものである。このときＲｂは水素原子である。
式（IＶ）の置換基は、例えば、脱アセチル化されたキトサンを、3,5-ジメチル、3,5-ジクロロ、3,4-ジクロロ、4-クロロ、4-ブロモ、3-クロロ、3-メチル、および4-メチルから選択される置換基を有するフェニル基を含む、イソシアン酸と反応させることにより導入することができる。
また、他の好ましい誘導体としては、一般式（Ｉ）中、ＲおよびＲaが下記の一般式（V）で表される置換基であり、Ｒｂが水素原子であるものが挙げられる。
Substituents of formula (IV) are, for example, deacetylated chitosan, 3,5-dimethyl, 3,5-dichloro, 3,4-dichloro, 4-chloro, 4-bromo, 3-chloro, 3 It can be introduced by reacting with isocyanic acid containing a phenyl group having a substituent selected from -methyl and 4-methyl.
Other preferable derivatives include those in which, in general formula (I), R and Ra are substituents represented by the following general formula (V), and Rb is a hydrogen atom.
なお、Ｒaは、キトサンの窒素原子およびＲｂとともにイミド環を形成する基であってもよい。Ｒaがキトサンの窒素原子およびＲｂとともにイミド環を形成する場合、キトサン誘導体の２位には、例えば、下記のような構造を有する基が結合する。
また、一般式（Ｉ）において、Ｒが上記式（II）の置換基であり、Ｒａがピリジルアルキル基またはベンジルアルキル基であり、Ｒｂが水素原子であってもよい。ピリジルアルキル基としてはピリジルメチル基が好ましく、ベンジルアルキル基としてはベンジルメチル基が好ましい。
このような誘導体（下記に例を示す）は、例えば、脱アセチル化されたキトサンを、還元条件下で、２−ピリジンカルボキシアルデヒドまたはベンズアルデヒドと反応させ、次に、R’を含むイソシアン酸と反応させることにより得ることができる。
Such derivatives (examples shown below) are for example reacted with deacetylated chitosan under reducing conditions with 2-pyridinecarboxaldehyde or benzaldehyde and then with isocyanate containing R ′. Can be obtained.
また、一般式（Ｉ）において、Ｒが上記式（II）の置換基であり、Ｒａが、キトサンの窒素原子およびＲｂとともにピリジルイミンまたはベンジルイミンを形成する基であってもよい。
このような誘導体（下記に例を示す）は、例えば、脱アセチル化されたキトサンを、２−ピリジンカルボキシアルデヒドと反応させ、次に、R’を含むイソシアン酸と反応させることにより得ることができる。
Such derivatives (examples shown below) can be obtained, for example, by reacting deacetylated chitosan with 2-pyridinecarboxaldehyde and then with isocyanic acid containing R ′. .
本発明の方法により製造される多糖誘導体において、ＲおよびＲaはすべて上記で例示したような置換基であってもよいが、一部が水素原子のままであってもよい。また、RとＲaがともに上記置換基であってもよいが、Rが上記置換基であり、Ｒaは水素原子のままでもよい。例えば、脱アセチル化されたキトサンと、置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基又は芳香族炭化水素基を含むアルコールとを反応させたときは、Ｒは置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基又は芳香族炭化水素基を含む置換基であるが、ＲaおよびＲｂは水素原子である、キトサン誘導体が得られる。
また、一般式（I）において、ＲおよびＲａの種類は、１種類でも複数種類でもよい。
ＲおよびＲaに含まれる、置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基又は芳香族炭化水素基は、同じ種類であってもよいし、異なる種類であってもよい。
In the polysaccharide derivative produced by the method of the present invention, R and Ra may all be substituents as exemplified above, but a part of them may remain as hydrogen atoms. In addition, both R and Ra may be the above substituents, but R is the above substituent and Ra may be a hydrogen atom. For example, when deacetylated chitosan is reacted with an alcohol containing an optionally substituted aliphatic hydrocarbon group or aromatic hydrocarbon group having 1 to 30 carbon atoms, R is substituted. A chitosan derivative is obtained, which is a substituent containing an aliphatic hydrocarbon group having 1 to 30 carbon atoms or an aromatic hydrocarbon group which may have a group, but Ra and Rb are hydrogen atoms.
In the general formula (I), the types of R and Ra may be one type or plural types.
The same or different types of the aliphatic hydrocarbon group or aromatic hydrocarbon group having 1 to 30 carbon atoms which may have a substituent, contained in R and Ra, may be used. Good.
原料のキトサンの重合度は、5以上、好ましくは10以上であり、特に上限はないが500以下であることが取り扱いの容易さから好ましい。
原料のキトサンは市販のものでもよい。
The degree of polymerization of the raw material chitosan is 5 or more, preferably 10 or more. Although there is no particular upper limit, it is preferably 500 or less from the viewpoint of ease of handling.
The raw material chitosan may be commercially available.
本発明のキトサン誘導体の製造法においては、まず、原料のキトサンを塩基性水溶液中で加熱処理して脱アセチル化する。塩基性水溶液は、ｐＨ９〜１４が好ましい。塩基性水溶液としては、M(OH)n（但しMはアルカリ金属またはアルカリ土類金属、nは１または２）に代表される水酸化物の水溶液が挙げられ、好ましくは水酸化ナトリウムや水酸化カリウム水溶液などが挙げられる。また、キトサンを脱アセチル化するときの塩基性水溶液の濃度は、３０ｗｔ％〜５０ｗｔ％が好ましい。加熱処理の時間と温度はキトサンを十分脱アセチル化できる時間と温度であれば特に制限されないが、５０℃〜１２０℃の温度で１〜４時間加熱処理することが好ましい。
なお、原料のキトサンが不純物を含む場合などは、脱アセチル化処理の前に、酢酸などの酸でキトサンを処理し、酸不溶部を除いて酸可溶部のみを脱アセチル化処理に用いてもよい。また、脱アセチル化処理を行った後に、酸で処理して酸不溶部を除いて酸可溶部のみを次の置換基導入反応に用いてもよい。なお、後者の場合、キトサンの再アセチル化を防ぐために得られた酸可溶部を塩基性にすることが好ましい。
In the method for producing a chitosan derivative of the present invention, first, the raw material chitosan is deacetylated by heat treatment in a basic aqueous solution. The basic aqueous solution preferably has a pH of 9-14. Examples of the basic aqueous solution include hydroxide aqueous solutions represented by M (OH) n (where M is an alkali metal or alkaline earth metal, and n is 1 or 2), preferably sodium hydroxide or hydroxide. Examples thereof include an aqueous potassium solution. Further, the concentration of the basic aqueous solution when deacetylating chitosan is preferably 30 wt% to 50 wt%. The time and temperature of the heat treatment are not particularly limited as long as the time and temperature can sufficiently deacetylate chitosan, but the heat treatment is preferably performed at a temperature of 50 ° C. to 120 ° C. for 1 to 4 hours.
In addition, when the raw material chitosan contains impurities, chitosan is treated with an acid such as acetic acid before the deacetylation treatment, and only the acid soluble portion is used for the deacetylation treatment except the acid insoluble portion. Also good. Moreover, after performing a deacetylation process, you may process with an acid and remove an acid insoluble part, and you may use only an acid soluble part for the following substituent introduction | transduction reaction. In the latter case, it is preferable to make the acid-soluble part obtained to prevent reacetylation of chitosan basic.
上記脱アセチル化処理の後に、キトサンを、置換基を有していてもよい炭素数1〜３０の脂肪族炭化水素基又は芳香族炭化水素基を含むイソシアン酸、カルボン酸、エステル、酸ハロゲン化物、酸アミド化合物、ハロゲン化物、アルデヒド、アルコールなどと反応させることにより、一般式（Ｉ）で示されるキトサン誘導体が得られる。反応溶媒としては、例えば、ピリジン、N,N-ジメチルアセトアミド/リチウムクロライドなどが挙げられる。反応は加熱・撹拌しながら行うことが好ましい。 After the deacetylation treatment, chitosan is converted to an isocyanic acid, carboxylic acid, ester or acid halide containing an optionally substituted aliphatic hydrocarbon group or aromatic hydrocarbon group having 1 to 30 carbon atoms. , An acid amide compound, a halide, an aldehyde, an alcohol and the like can be reacted to obtain a chitosan derivative represented by the general formula (I). Examples of the reaction solvent include pyridine, N, N-dimethylacetamide / lithium chloride, and the like. The reaction is preferably carried out with heating and stirring.
上記製造方法によって得られたキトサン誘導体を用いて光学異性体用分離剤を作製することができる。例えば、キトサン誘導体を担体に担持させるか、またはキトサン誘導体自体を破砕、又は公知の方法により球状粒子化（例えば、特開平７−２８５８８９号公報）することにより光学異性体用分離剤を作製することができる。なお、ここでいう担持とは、担体上にキトサン誘導体が固定化されていることである。担持方法は公知の担持方法を適用することができ、キトサン誘導体と担体との間の物理的な吸着、担体との間の化学結合、キトサン誘導体同士の化学結合、第三成分の化学結合、キトサン誘導体への光照射、ラジカル反応等の方法を適用することができる（例えば、特開平６−９３００２公報参照）。 A separation agent for optical isomers can be produced using the chitosan derivative obtained by the above production method. For example, a separation agent for optical isomers is prepared by supporting a chitosan derivative on a carrier, or crushing the chitosan derivative itself or making it spherical by a known method (for example, JP-A-7-285889) Can do. Here, the term “support” means that a chitosan derivative is immobilized on a carrier. As the loading method, a known loading method can be applied, physical adsorption between the chitosan derivative and the carrier, chemical bond between the carrier, chemical bond between the chitosan derivatives, chemical bond of the third component, chitosan Methods such as light irradiation to the derivative and radical reaction can be applied (see, for example, JP-A-6-93002).
担体としては、多孔質有機担体及び多孔質無機担体が挙げられ、好ましくは多孔質無機担体である。多孔質担体の平均孔径は１nm〜１００μmが好ましく、５nm〜５μmがより好
ましい。多孔質有機担体として適当なものは、ポリスチレン、ポリアクリルアミド、ポリアクリレート等からなる高分子物質であり、多孔質無機担体として適当なものは、シリカ、アルミナ、マグネシア、ガラス、カオリン、酸化チタン、ケイ酸塩、ヒドロキシアパタイトなどである。
特に好ましい担体はシリカゲルであり、シリカゲルの粒径は１μm〜１mm、好ましくは１μm〜３００μm、更に好ましくは１μm〜１００μmである。
また、担体は、キトサン誘導体との親和性を良くしたり、担体自身の表面の特性を改質するための処理を施したものを用いても良い。表面処理の方法としては有機シラン化合物によるシラン化処理やプラズマ重合による表面処理方法がある。
担体上へのキトサン誘導体の担持量は、光学異性体用分離剤１００質量部に対して、１〜１００質量部が好ましく、更に５〜６０質量部が好ましく、特に１０〜４０質量部が望ましい。
またキトサン誘導体自体を破砕又は球状粒子化するとき、乳鉢等を用いることで得られた破砕状又は球状のキトサン誘導体は、分級して粒度を揃えておくことが望ましい。
Examples of the carrier include a porous organic carrier and a porous inorganic carrier, and a porous inorganic carrier is preferable. The average pore diameter of the porous carrier is preferably 1 nm to 100 μm, more preferably 5 nm to 5 μm. Suitable materials for the porous organic carrier are polymeric substances composed of polystyrene, polyacrylamide, polyacrylate, etc., and suitable materials for the porous inorganic carrier are silica, alumina, magnesia, glass, kaolin, titanium oxide, silica. Acid salts, hydroxyapatite, and the like.
A particularly preferable carrier is silica gel, and the particle size of the silica gel is 1 μm to 1 mm, preferably 1 μm to 300 μm, and more preferably 1 μm to 100 μm.
In addition, a carrier that has been treated to improve the affinity with the chitosan derivative or to modify the surface properties of the carrier itself may be used. As the surface treatment method, there are a silanization treatment with an organosilane compound and a surface treatment method by plasma polymerization.
The amount of the chitosan derivative supported on the carrier is preferably 1 to 100 parts by weight, more preferably 5 to 60 parts by weight, and particularly preferably 10 to 40 parts by weight with respect to 100 parts by weight of the optical isomer separating agent.
Further, when the chitosan derivative itself is crushed or formed into spherical particles, it is desirable that the crushed or spherical chitosan derivative obtained by using a mortar or the like is classified to have a uniform particle size.
キトサン誘導体から作製される光学異性体用分離剤は、例えば、クロマトグラフィーの固定相として用いることができ、ガスクロマトグラフィー、液体クロマトグラフィー、薄層クロマトグラフィー、超臨界流体クロマトグラフィー、電気泳動等に適用することができ、特に（連続式）液体クロマトグラフィー法、薄層クロマトグラフィー、電気泳動に好適である。また、クロマトグラフィー用分離剤のみならず、ホストゲスト分離剤、膜分離、液晶材料への応用もできる。 Separating agents for optical isomers produced from chitosan derivatives can be used, for example, as a stationary phase for chromatography, and can be used for gas chromatography, liquid chromatography, thin layer chromatography, supercritical fluid chromatography, electrophoresis, etc. It can be applied and is particularly suitable for (continuous) liquid chromatography, thin layer chromatography, and electrophoresis. Moreover, it can be applied not only to chromatographic separation agents, but also to host guest separation agents, membrane separations, and liquid crystal materials.
wako chitosan100を用いて以下の実験を行った。
１．キトサンの精製
＊脱アセチル化処理
キトサンの脱アセチル化処理は、50wt%NaOH水溶液中120〜130℃で二時間煮沸し、一度洗浄、溶媒を取り替えて煮沸することを３回行った。
The following experiment was performed using wako chitosan100.
1. Purification of chitosan * Deacetylation treatment The deacetylation treatment of chitosan was boiled for 3 hours at 120 to 130 ° C in 50 wt% NaOH aqueous solution, washed once, and boiled after changing the solvent.
＊酸可溶部の回収
キトサン0.5gを１％酢酸水溶液500mlに溶解させ、不溶部を濾過し、可溶部のみをNaOH塩基性条件下（pH10以上）で回収した。
濃NaOH水溶液に注射器でキトサンの酢酸溶液を押し出す方法では、キトサン溶液500mlに対し、1L以上の塩基溶液を必要とし、押し出した形のままキトサン溶液がゲル化した。
逆に、酸性溶液を撹拌しながら塩基性水溶液を滴下し、pH10以上とすることで、繊維状のキトサンが析出したので、これを濾過し、水で洗浄した。
固定相として用いたキトサンの精製は、全て後者の方法で行った。
* Recovery of acid-soluble part 0.5 g of chitosan was dissolved in 500 ml of 1% acetic acid aqueous solution, the insoluble part was filtered, and only the soluble part was recovered under NaOH basic conditions (pH 10 or more).
In the method of extruding an acetic acid solution of chitosan to concentrated NaOH aqueous solution with a syringe, 1 L or more of base solution was required for 500 ml of chitosan solution, and the chitosan solution gelled in the extruded form.
Conversely, a basic aqueous solution was added dropwise while stirring the acidic solution to adjust the pH to 10 or more, so that fibrous chitosan was precipitated, which was filtered and washed with water.
All the purification of chitosan used as the stationary phase was performed by the latter method.
２. キトサン誘導体の合成
＜キトサンのトリスカルバメート、またはN-アシル化3,6-ビスベンゾエート誘導体の合成＞
乾燥したキトサンに、脱水ピリジンとイソシアナートまたは酸クロライドを反応部位の1.3等量以上加え、IRで反応の進行を確認しながら約一日反応させ、メタノール中に沈殿させて回収した。
以下、それぞれの誘導体の合成例を示す。
2. Synthesis of chitosan derivatives <Synthesis of triscarbamate or N-acylated 3,6-bisbenzoate derivatives of chitosan>
To the dried chitosan, dehydrated pyridine and isocyanate or acid chloride were added in an amount equal to or greater than 1.3 equivalents of the reaction site, reacted for about one day while confirming the progress of the reaction by IR, and precipitated in methanol for recovery.
Hereinafter, synthesis examples of each derivative will be shown.
［合成例１］
＊chitosan tris(3,5-dimethylphenylcarbamate)
以下のスキームにしたがって合成した。
* Chitosan tris (3,5-dimethylphenylcarbamate)
Synthesized according to the following scheme.
＜塩基処理キトサン誘導体＞
脱アセチル化処理（塩基処理）したキトサン0.51gにpyridine 20mLと3,5-dimethylphenylisocyanate 1.9gを加えて80℃で加熱撹拌し、溶解し始めてから、pyridine10mLを追加した。さらに3,5-dimethylphenylisocyanateを2.5g追加し、IRで反応の進行を確認後、メタノール不溶部として回収したところ、2gのガム状の固体を得た。THFに溶解させ再びメタノールで再沈殿させたところ1.8g(92%)の収量を得た(キトサン誘導体１)。
<Base-treated chitosan derivative>
To 0.51 g of deacetylated (base-treated) chitosan, 20 mL of pyridine and 1.9 g of 3,5-dimethylphenylisocyanate were added, heated and stirred at 80 ° C., and dissolved, and then 10 mL of pyridine was added. Further, 2.5 g of 3,5-dimethylphenylisocyanate was added, and after confirming the progress of the reaction by IR, it was recovered as a methanol-insoluble part to obtain 2 g of a gummy solid. When dissolved in THF and reprecipitated again with methanol, a yield of 1.8 g (92%) was obtained (chitosan derivative 1).
＜塩基・酸処理キトサン誘導体＞
脱アセチル化処理（塩基処理）し、酢酸水溶液可溶部を回収したキトサン0.48gにpyridine 10mLと3,5-dimethylphenylisocyanate 1.7gを加えて80℃で加熱撹拌し、反応液の様子をIRで確認しながら、3,5-dimethylphenylisocyanateを2.3g加え、メタノール不溶部として回収したところ、2gのガム状の固体を得た。不純物を除くため、THFに溶解させ再びメタノールで再沈殿させたところ0.51g(28%)の収量を得た(キトサン誘導体２)。
<Base / acid-treated chitosan derivative>
Deacetylation treatment (base treatment) and 0.48 g of chitosan collected with acetic acid aqueous solution, add 10 mL of pyridine and 1.7 g of 3,5-dimethylphenylisocyanate, heat and stir at 80 ° C, and confirm the reaction state by IR While 2.3 g of 3,5-dimethylphenylisocyanate was added and recovered as a methanol-insoluble part, 2 g of a gummy solid was obtained. In order to remove impurities, it was dissolved in THF and reprecipitated with methanol to obtain a yield of 0.51 g (28%) (chitosan derivative 2).
＜未処理キトサン誘導体＞
脱アセチル化処理（塩基処理）を行っていないキトサン(wako chitosan100) 0.50gにpyridine 20mLと3,5-dimethylphenylisocyanate 1.9gを加えて80℃で加熱撹拌し、溶解し始めてからpyridine10mLを追加し、反応液の様子をIRで確認しながら、pyridinie10mLと3,5-dimethylphenylisocyanateを0.69g加え、メタノール不溶部として回収したが、反応系に不溶部が残っていた。不純物を除くため、THF可溶部をメタノールで再沈殿させたところ0.51g(28%)の収量を得た(キトサン誘導体３)。
<Untreated chitosan derivative>
Add 20mL of pyridine and 1.9g of 3,5-dimethylphenylisocyanate to 0.50g of chitosan (wako chitosan100) that has not been deacetylated (base treatment), heat and stir at 80 ° C, add 10mL of pyridine after starting dissolution. While confirming the state of the solution by IR, 0.69 g of pyridinie and 3,5-dimethylphenylisocyanate were added and recovered as a methanol-insoluble part, but an insoluble part remained in the reaction system. In order to remove impurities, the THF soluble part was reprecipitated with methanol to obtain a yield of 0.51 g (28%) (chitosan derivative 3).
［合成例２］
＊chitosan tris(3,5-dichlorophenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (3,5-dichlorophenylcarbamate)
Synthesized according to the following scheme.
［合成３］
＊chitosan tris(3,4-dichlorophenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (3,4-dichlorophenylcarbamate)
Synthesized according to the following scheme.
［合成例４］
＊chitosan tris(4-chlorophenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (4-chlorophenylcarbamate)
Synthesized according to the following scheme.
［合成例５］
＊chitosan tris(4-bromophenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (4-bromophenylcarbamate)
Synthesized according to the following scheme.
［合成例６］
＊chitosan tris(3-chlorophenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (3-chlorophenylcarbamate)
Synthesized according to the following scheme.
［合成例７］
＊chitosan tris(phenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (phenylcarbamate)
Synthesized according to the following scheme.
［合成例８］
＊chitosan tris(4-methylphenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (4-methylphenylcarbamate)
Synthesized according to the following scheme.
［合成例９］
＊chitosan tris(3-methylphenylcarbamate)
次のスキームにしたがって合成した。
* Chitosan tris (3-methylphenylcarbamate)
Synthesized according to the following scheme.
［合成例１０］
＊N-(4-methylbenzoyl)chitosan 3,6-bis(4-methylbenzoate)
次のスキームにしたがって合成した。
* N- (4-methylbenzoyl) chitosan 3,6-bis (4-methylbenzoate)
Synthesized according to the following scheme.
［合成例１１］
＊N-(3-methylbenzoyl)chitosan 3,6-bis(3-methylbenzoate)
次のスキームにしたがって合成した。
* N- (3-methylbenzoyl) chitosan 3,6-bis (3-methylbenzoate)
Synthesized according to the following scheme.
３．キラル固定相の調製
各誘導体を公知の方法でシリカゲルにコーティングして光学異性体用分離剤を作製した。
3. Preparation of chiral stationary phase Each derivative was coated on silica gel by a known method to prepare a separating agent for optical isomers.
４．高速液体クロマトグラフィーによる光学分割能の評価
上記合成例１で調製した、未処理、塩基処理、または塩基・酸処理のキトサンに３,５−ジメチルフェニル基が導入されたキトサン誘導体を固定化して作製された光学異性体用分離剤を、それぞれ、内径2.0mmまたは4.6mm、長さ25cmのステンレスカラムに充填し、HPLC用キラル固定相とした。それぞれのHPLC用キラル固定相を用いて下記ラセミ化合物１〜１０の光学分割を行った。
4). Evaluation of optical resolution by high performance liquid chromatography Prepared by immobilizing a chitosan derivative with 3,5-dimethylphenyl group introduced into untreated, base-treated, or base / acid-treated chitosan prepared in Synthesis Example 1 above. The obtained optical isomer separation agent was packed in a stainless steel column having an inner diameter of 2.0 mm or 4.6 mm and a length of 25 cm, respectively, to obtain a chiral stationary phase for HPLC. The following racemic compounds 1 to 10 were optically resolved using the respective chiral stationary phases for HPLC.
なお、ＨＰＬＣは、（PU-980またはPU-986, 日本分光）を用い、溶離液にはヘキサン／２−プロパノール＝90/10、流速は0.5 ml/minとし、ＵＶ検出器（UV-970またはMD-2010-plus、日本分光、254 nm）と旋光検出器（OR-990、日本分光）を用いてピークの検出、同
定を行った。なお、理論段数Ｎはベンゼンのピークから、また溶離液がカラムを素通りする時間ｔ０は１，３，５−トリ−ｔｅｒｔ−ブチルベンゼンの溶出時間から求めた。
The HPLC was (PU-980 or PU-986, JASCO), the eluent was hexane / 2-propanol = 90/10, the flow rate was 0.5 ml / min, and the UV detector (UV-970 or Peak detection and identification were performed using MD-2010-plus (JASCO, 254 nm) and an optical rotation detector (OR-990, JASCO). The theoretical plate number N was determined from the peak of benzene, and the time t0 for the eluent to pass through the column was determined from the elution time of 1,3,5-tri-tert-butylbenzene.
光学分割結果を表１に示す。
表中の値は容量比ｋ１’と分離係数αで、かっこの中の符号は先に溶出したエナンチオマーの旋光性である。なお、容量比ｋ１’、分離係数αは下式で定義される。以下の実施例及び比較例においても同じ式を用いて容量比及び分離係数を算出した。
Table 1 shows the optical resolution results.
The values in the table are the volume ratio k1 ′ and the separation factor α, and the sign in parentheses is the optical rotation of the enantiomer eluted earlier. The capacity ratio k1 ′ and the separation factor α are defined by the following equations. In the following examples and comparative examples, the capacity ratio and the separation factor were calculated using the same formula.
表１の結果から、塩基による脱アセチル化処理を行ったキトサンを用いて得られたキトサン誘導体は、未処理キトサンを用いて得られたキトサン誘導体に比べて、光学異性体の分離度が向上することが確認できた。 From the results in Table 1, chitosan derivatives obtained using chitosan that has been deacetylated with a base have improved resolution of optical isomers compared to chitosan derivatives obtained using untreated chitosan. I was able to confirm.
※) カラム: 25 x 0.46 (i.d.) cm, 流速: 0.5ml/min, 移動相: ヘキサン/2-プロパノール=90/10, 温度: 室温
同様に、上記実施例で得られたキトサン誘導体について、光学分割能の評価を行った。得られたキトサン誘導体は以下のとおりである。
chitosan tris(3,5-dichlorophenylcarbamate) (目的化合物１)
chitosan tris(3,4-dichlorophenylcarbamate) (目的化合物２)
chitosan tris(4-chlorophenylcarbamate) (目的化合物３)
chitosan tris(4-bromophenylcarbamate) (目的化合物４)
chitosan tris(3-chlorophenylcarbamate) (目的化合物５)
結果を表２に示す。表２の結果から、塩基による脱アセチル化処理を行ったキトサンを用いて得られたその他のキトサン誘導体も光学異性体の分離度が向上することが確認できた。
Similarly, the optical resolution of the chitosan derivatives obtained in the above examples was evaluated. The obtained chitosan derivatives are as follows.
chitosan tris (3,5-dichlorophenylcarbamate) (Target compound 1)
chitosan tris (3,4-dichlorophenylcarbamate) (target compound 2)
chitosan tris (4-chlorophenylcarbamate) (Target compound 3)
chitosan tris (4-bromophenylcarbamate) (Target compound 4)
chitosan tris (3-chlorophenylcarbamate) (Target compound 5)
The results are shown in Table 2. From the results in Table 2, it was confirmed that other chitosan derivatives obtained using chitosan that had been deacetylated with a base also improved the resolution of optical isomers.
[合成例１２]
* chitosan 2-(2-pyridylimine)-3,6-bis(3,5-dimethylphenylcarbamate)
次のスキームに従って合成した。
pyridinecarboxaldehyde 6.7g(10 等量)を水50mL で希釈したものを滴下したところ、ゲル状の粒子が析出した（中間化合物１）。
得られた中間化合物１の0.45 g を乾燥させ、脱水ピリジン15ml と3,5-dimethylphenyl
isocyanateを0.90g 加え、80℃で加熱し反応させた。IR で反応の進行を確認後、メタノール不溶部として回収したところ、収量0.81g を得た(目的化合物１１)。
[Synthesis Example 12]
* chitosan 2- (2-pyridylimine) -3,6-bis (3,5-dimethylphenylcarbamate)
Synthesized according to the following scheme.
When 6.7 g (10 equivalents) of pyridinecarboxaldehyde diluted with 50 mL of water was added dropwise, gel-like particles were precipitated (intermediate compound 1).
0.45 g of the obtained intermediate compound 1 was dried, dehydrated pyridine 15 ml and 3,5-dimethylphenyl
0.90g of isocyanate was added and heated to react at 80 ° C. After confirming the progress of the reaction by IR, it was recovered as a methanol-insoluble part to obtain a yield of 0.81 g (target compound 11).
[合成例１３]
* chitosan 2-(2-pyridylimine)-3,6-bis(3,5-dichlorophenylcarbamate)
次のスキームに従って合成した。
* chitosan 2- (2-pyridylimine) -3,6-bis (3,5-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例１４]
* chitosan 2-(2-pyridylimine)-3,6-bis(3,4-dichlorophenylcarbamate)
次のスキームに従って合成した。
* chitosan 2- (2-pyridylimine) -3,6-bis (3,4-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例１５]
* chitosan 2-(benzylimine)-3,6-bis(3,5-dimethylphenylcarbamate)
次のスキームに従って合成した。
脱アセチル化処理したキトサン1.0g を2%酢酸水溶液100mL に溶解させ、メ
タノール100mL で希釈した。benzaldehyde 12g(20 等量)をメタノール30mLで希釈したものを滴下し、35℃で24 時間熟成させたところ、ゲル化した中間体（中間化合物２）を得た。
中間化合物２を乾燥させ、脱水ピリジン中で3,5-dichlorophenyl isocyanate と80℃で加熱し反応させた。IR で反応の進行を確認してメタノール不溶部として回収した(目的化合物１４)。
[Synthesis Example 15]
* chitosan 2- (benzylimine) -3,6-bis (3,5-dimethylphenylcarbamate)
Synthesized according to the following scheme.
1.0 g of deacetylated chitosan was dissolved in 100 mL of 2% aqueous acetic acid and diluted with 100 mL of methanol. A solution obtained by diluting 12 g (20 equivalents) of benzaldehyde with 30 mL of methanol was dropped and aged at 35 ° C. for 24 hours to obtain a gelled intermediate (intermediate compound 2).
Intermediate compound 2 was dried and reacted with 3,5-dichlorophenyl isocyanate at 80 ° C. in dehydrated pyridine. The progress of the reaction was confirmed by IR and recovered as a methanol-insoluble part (target compound 14).
[合成例１６]
* chitosan 2-(benzylimine)-3,6-bis(3,5-dichlorophenylcarbamate)
次のスキームに従って合成した。
* chitosan 2- (benzylimine) -3,6-bis (3,5-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例１７]
* chitosan 2-(benzylimine)-3,6-bis(3,4-dichlorophenylcarbamate)
次のスキームに従って合成した。
した後、メタノール不溶部として回収し、収量0.30g を得た(目的化合物１６)。
[Synthesis Example 17]
* chitosan 2- (benzylimine) -3,6-bis (3,4-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例１８]
* N-(2-pyridyl)methyl chitosan 3,6-bis(3,5-dimethylphenylcarbamate)
次のスキームに従って合成した。
ろ別し、シアノトリヒドロホウ素化ナトリウム3.0g を加えた。そこへ、水で希釈した2-pyridinecarboxaldehyde 3.5g(2.5 等量)を加え、室温で5 時間撹拌した。水、エタノール、ヘキサンで洗浄し、乾燥させると白色の粉末が2.4g得られた(中間化合物３)。
中間化合物３の0.73 g を乾燥させ、脱水ピリジン25ml と3,5-dimethylphenyl isocyanateを3.0g 加え、80℃で加熱し反応させた。IR で反応の進行を確認後、メタノール／水（95/5）不溶部として回収したところ、収量1.78g を得た(目的化合物１７)。
[Synthesis Example 18]
* N- (2-pyridyl) methyl chitosan 3,6-bis (3,5-dimethylphenylcarbamate)
Synthesized according to the following scheme.
0.73 g of the intermediate compound 3 was dried, 25 ml of dehydrated pyridine and 3.0 g of 3,5-dimethylphenyl isocyanate were added, and the mixture was heated at 80 ° C. for reaction. After confirming the progress of the reaction by IR, the product was recovered as an insoluble part of methanol / water (95/5), yielding 1.78 g (target compound 17).
[合成例１９]
* N-(2-pyridyl)methyl chitosan 3,6-bis(3,5-dichlorophenylcarbamate)
次のスキームに従って合成した。
* N- (2-pyridyl) methyl chitosan 3,6-bis (3,5-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例２０]
* N-(2-pyridyl)methyl chitosan 3,6-bis(3,4-dichlorophenylcarbamate)
次のスキームに従って合成した。
* N- (2-pyridyl) methyl chitosan 3,6-bis (3,4-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例２１]
* N-benzyl chitosan 3,6-bis(3,5-dimethylphenylcarbamate)
次のスキームに従って合成した。
加えた。そこへ、エタノールで希釈した2-pyridinecarboxaldehyde 3.5g (2.5等量)を加えたところ、白色の粉末が析出した。乾燥させると白色の粉末が得られ、収量は2.6g であった(中間化合物４)。
乾燥させた中間化合物４の 0.70 g に脱水ピリジン20ml と3,5-dimethylphenyl isocyanate を2.0g 加え、80℃で加熱し反応させた。IR で反応の進行を確認後、メタノール不溶部として回収し、収量2.8g を得た(目的化合物２０)。
[Synthesis Example 21]
* N-benzyl chitosan 3,6-bis (3,5-dimethylphenylcarbamate)
Synthesized according to the following scheme.
To 0.70 g of the dried intermediate compound 4, 20 ml of dehydrated pyridine and 2.0 g of 3,5-dimethylphenyl isocyanate were added and reacted by heating at 80 ° C. After confirming the progress of the reaction by IR, it was recovered as a methanol-insoluble part to obtain a yield of 2.8 g (target compound 20).
[合成例２２]
* N-benzyl chitosan 3,6-bis(3,5-dichlorophenylcarbamate)
次のスキームに従って合成した。
* N-benzyl chitosan 3,6-bis (3,5-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例２３]
* N-benzyl chitosan 3,6-bis(3,4-dichlorophenylcarbamate)
次のスキームに従って合成した。
* N-benzyl chitosan 3,6-bis (3,4-dichlorophenylcarbamate)
Synthesized according to the following scheme.
[合成例２４]
* 2 -位にアミノ基を残したキトサン誘導体
次のスキームに従って合成した。
析出した尿素の固体ごとメタノールに溶解させ、水に再沈殿させて固体を分
離した。次に1.4%のアンモニア水で中和した後、水、メタノール、エーテルで
洗浄した。 (参照化合物１)
[Synthesis Example 24]
* Chitosan derivative leaving an amino group in the 2-position was synthesized according to the following scheme.
The precipitated urea solid was dissolved in methanol and reprecipitated in water to separate the solid. Next, the mixture was neutralized with 1.4% aqueous ammonia and washed with water, methanol, and ether. (Reference compound 1)
[固定相の調製]
目的化合物１１〜２０及び参照化合物１を、表面処理したシリカゲルに公知の方法でコーティングした。それを長さ25cm、内径0.46cmまたは0.20cm のステンレススチール製のカラムにそれぞれスラリー法により充填し、HPLC用キラル固定相とした。それぞれのHPLC用キラル固定相を用いて、前記ラセミ化合物１〜１０の光学分割を行った。
[Preparation of stationary phase]
The target compounds 11 to 20 and the reference compound 1 were coated on the surface-treated silica gel by a known method. It was packed in a stainless steel column having a length of 25 cm and an inner diameter of 0.46 cm or 0.20 cm by a slurry method to obtain a chiral stationary phase for HPLC. The racemic compounds 1 to 10 were optically resolved using the respective chiral stationary phases for HPLC.
[光学分割能の評価]
測定装置は前述の通りである。溶離液は、Hexane-2-propanol（9:1）を用い、内径0.46cm のカラムでは流速0.5ml/min とし、室温で測定を行った。理論段数、t0、αは前述と同様に算出した。
以下に結果を示す。
[Evaluation of optical resolution]
The measuring device is as described above. Hexane-2-propanol (9: 1) was used as the eluent, and measurement was performed at room temperature with a flow rate of 0.5 ml / min for a 0.46 cm inner diameter column. The number of theoretical plates, t0, and α were calculated in the same manner as described above.
The results are shown below.
a) カラム: 25 x 0.20 (i.d.) cm, 流速: 0.1ml/min, 移動相: ヘキサン/2-プロパノール=90/10, 温度: 室温
a) Column: 25 x 0.20 (id) cm, Flow rate: 0.1 ml / min, Mobile phase: Hexane / 2-propanol = 90/10, Temperature: Room temperature
Claims (11)
。 3. The production of a chitosan derivative according to claim 1 or 2, wherein in general formula (I), R and Ra are substituents represented by the following general formula (IV), and Rb is a hydrogen atom. Method.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016152996A1 (en) * | 2015-03-24 | 2016-09-29 | 株式会社ダイセル | Stationary phase for supercritical fluid chromatography |
| WO2020241678A1 (en) * | 2019-05-30 | 2020-12-03 | 株式会社ダイセル | Chitosan compounds and optical isomer separating agent |
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| JPS60226831A (en) * | 1984-04-02 | 1985-11-12 | Daicel Chem Ind Ltd | Separating agent |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016152996A1 (en) * | 2015-03-24 | 2016-09-29 | 株式会社ダイセル | Stationary phase for supercritical fluid chromatography |
| CN107430100A (en) * | 2015-03-24 | 2017-12-01 | 株式会社大赛璐 | The stationary phase of supercritical fluid chromatography |
| JPWO2016152996A1 (en) * | 2015-03-24 | 2018-01-18 | 株式会社ダイセル | Stationary phases for supercritical fluid chromatography. |
| US11065558B2 (en) | 2015-03-24 | 2021-07-20 | Daicel Corporation | Stationary phase for supercritical fluid chromatography |
| WO2020241678A1 (en) * | 2019-05-30 | 2020-12-03 | 株式会社ダイセル | Chitosan compounds and optical isomer separating agent |
| CN113891899A (en) * | 2019-05-30 | 2022-01-04 | 株式会社大赛璐 | Chitosan compound and separating agent for optical isomers |
| JP7428706B2 (en) | 2019-05-30 | 2024-02-06 | 株式会社ダイセル | Separating agent for chitosan compounds and optical isomers |
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