JPH0356423B2 - - Google Patents
Info
- Publication number
- JPH0356423B2 JPH0356423B2 JP57173688A JP17368882A JPH0356423B2 JP H0356423 B2 JPH0356423 B2 JP H0356423B2 JP 57173688 A JP57173688 A JP 57173688A JP 17368882 A JP17368882 A JP 17368882A JP H0356423 B2 JPH0356423 B2 JP H0356423B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- packing material
- acid derivative
- general formula
- chromatographic packing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 carbamoyloxy Chemical group 0.000 claims description 27
- 238000012856 packing Methods 0.000 claims description 22
- 239000000463 material Substances 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012948 isocyanate Substances 0.000 claims description 10
- 238000004458 analytical method Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000002513 isocyanates Chemical class 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000004811 liquid chromatography Methods 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 150000001282 organosilanes Chemical class 0.000 claims description 6
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- 125000001624 naphthyl group Chemical group 0.000 claims 2
- 238000000034 method Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- 239000000945 filler Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960004295 valine Drugs 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- JZPRXQSCMBDGKP-UHFFFAOYSA-N 1-isocyanato-3,5-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC(N=C=O)=CC([N+]([O-])=O)=C1 JZPRXQSCMBDGKP-UHFFFAOYSA-N 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- RFWQKLFRYNTMOB-UHFFFAOYSA-N n-(1-naphthalen-1-ylethyl)acetamide Chemical compound C1=CC=C2C(C(NC(C)=O)C)=CC=CC2=C1 RFWQKLFRYNTMOB-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 2
- BDQNKCYCTYYMAA-UHFFFAOYSA-N 1-isocyanatonaphthalene Chemical compound C1=CC=C2C(N=C=O)=CC=CC2=C1 BDQNKCYCTYYMAA-UHFFFAOYSA-N 0.000 description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- UKYTVDGCEZQLSZ-SNVBAGLBSA-N (2r)-2-phenyl-2-(propan-2-ylcarbamoylamino)acetic acid Chemical compound CC(C)NC(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 UKYTVDGCEZQLSZ-SNVBAGLBSA-N 0.000 description 1
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- ZDRPGZZYVSGSMA-SNVBAGLBSA-N C(C)(C)NC(=O)OC([C@H](O)C1=CC=CC=C1)=O Chemical compound C(C)(C)NC(=O)OC([C@H](O)C1=CC=CC=C1)=O ZDRPGZZYVSGSMA-SNVBAGLBSA-N 0.000 description 1
- IDLFUUJULKURJT-KRWDZBQOSA-N C1(=CC=CC2=CC=CC=C12)NC(=O)OC([C@@H](O)C1=CC=CC=C1)=O Chemical compound C1(=CC=CC2=CC=CC=C12)NC(=O)OC([C@@H](O)C1=CC=CC=C1)=O IDLFUUJULKURJT-KRWDZBQOSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- IHYJTAOFMMMOPX-LURJTMIESA-N N-acetyl-L-valine Chemical compound CC(C)[C@@H](C(O)=O)NC(C)=O IHYJTAOFMMMOPX-LURJTMIESA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- JFIDZKXHSFEXRV-CYBMUJFWSA-N [N+](=O)([O-])C=1C=C(C=C(C=1)[N+](=O)[O-])NC(=O)N[C@H](C1=CC=CC=C1)C(=O)O Chemical compound [N+](=O)([O-])C=1C=C(C=C(C=1)[N+](=O)[O-])NC(=O)N[C@H](C1=CC=CC=C1)C(=O)O JFIDZKXHSFEXRV-CYBMUJFWSA-N 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- KCHNPFJMSOGXIT-UHFFFAOYSA-N methyl N-acetylvalinate Chemical compound COC(=O)C(C(C)C)NC(C)=O KCHNPFJMSOGXIT-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- ICZHJFWIOPYQCA-UHFFFAOYSA-N pirkle's alcohol Chemical compound C1=CC=C2C(C(O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 ICZHJFWIOPYQCA-UHFFFAOYSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/29—Chiral phases
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3204—Inorganic carriers, supports or substrates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3244—Non-macromolecular compounds
- B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
- B01J20/3257—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one of the heteroatoms nitrogen, oxygen or sulfur together with at least one silicon atom, these atoms not being part of the carrier as such
- B01J20/3259—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one of the heteroatoms nitrogen, oxygen or sulfur together with at least one silicon atom, these atoms not being part of the carrier as such comprising at least two different types of heteroatoms selected from nitrogen, oxygen or sulfur with at least one silicon atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2220/00—Aspects relating to sorbent materials
- B01J2220/50—Aspects relating to the use of sorbent or filter aid materials
- B01J2220/54—Sorbents specially adapted for analytical or investigative chromatography
Landscapes
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は新規な光学活性オルガノシランをグラ
フトしたクロマトグラフ充填剤およびそれを用い
て不斉炭素に結合した
The present invention relates to a chromatographic packing material grafted with a novel optically active organosilane, and a method of bonding to an asymmetric carbon using the same.
【式】基、−
CONH−基、−OCO−基、−OCONH−基、−
NHCONH−基または[Formula] Group, -CONH- group, -OCO- group, -OCONH- group, -
NHCONH- group or
【式】基を有
する化合物の鏡像体混合物を液体クロマトグラフ
イーにより分離し、分析する方法に関するもので
ある。
液体クロマトグラフイーにより不斉炭素を有す
る化合物の鏡像体混合物を直接分離、分析するた
めの光学活性な化合物をグラフトした充填剤とし
てはこれまでに例えば、Davankov等による光学
活性なプロリンをグラフトした充填剤を用いる配
位子交換による方法、Gil−Av等によるπ電子不
足の光学活性化合物をグラフトした充填剤を用い
る電荷移動錯体による方法、原等による光学活性
なＮ−アシル化アミノ酸をグラフトした充填剤を
用いるＮ−アシル化アミノ酸エステルやＮ−アシ
ル化ジペプチドエステルの分離あるいはPirkle等
による光学活性な１−（９−アンスリル）トリフ
ルオロエタノールをグラフトした充填剤を用いる
３，５−ジニトロベンゾイル化したアミノ酸、ア
ミン、オキシ酸、スルホキシド等の分離および
３，５−ジニトロベンゾイル化した光学活性なフ
エニルグリシンをグラフトした充填剤を用いる芳
香族アルコールの分離などが報告されている。し
かし、これらの方法は分離し得る化合物が狭範囲
のものに限定されたり、また、分離の程度が小さ
かつたりさらにはグラフトした充填剤の製造が困
難で、再現性のある性能を持つ充填剤が得にくか
つたりして、いずれも実用的な充填剤とは言い難
い。
本発明者らはかかる状況のもとで分析し得る化
合物の適用範囲が広く、製造が比較的容易でしか
も化学的に安定で実用的なグラフトした充填剤の
開発を目標に鋭意検討を続けて来た結果、ヒドロ
キシル基をその表面に持つ無機担体に、光学不活
性なイソシアネートを用いてカルバモイル化した
光学活性なアミノ酸誘導体またはオキシ酸誘導体
とアミノアルキルシランとが結合して成るＮ−カ
ルバモイルアミノ酸誘導体またはＯ−カルバモイ
ルオキシ酸誘導体がグラフトされているクロマト
グラフ充填剤が不斉炭素に結合した
This invention relates to a method for separating and analyzing a mixture of enantiomers of a compound having a group represented by the formula: by liquid chromatography. As a packing material grafted with an optically active compound for direct separation and analysis of an enantiomeric mixture of a compound having an asymmetric carbon by liquid chromatography, for example, a packing material grafted with an optically active proline by Davankov et al. A method using a charge transfer complex using a filler grafted with an optically active compound lacking π electrons such as Gil-Av, a filling method using an optically active N-acylated amino acid grafted by Hara et al. Separation of N-acylated amino acid esters and N-acylated dipeptide esters using an agent or 3,5-dinitrobenzoylation using a packing material grafted with optically active 1-(9-anthryl)trifluoroethanol according to Pirkle et al. Separation of amino acids, amines, oxyacids, sulfoxides, etc., and separation of aromatic alcohols using fillers grafted with 3,5-dinitrobenzoylated optically active phenylglycine have been reported. However, these methods are limited to a narrow range of compounds that can be separated, the degree of separation is small, and it is difficult to produce grafted fillers, making it difficult to produce fillers with reproducible performance. It is difficult to obtain a filler, and it is difficult to say that any of them are practical fillers. Under such circumstances, the present inventors have continued to conduct intensive studies with the aim of developing a grafted filler that is applicable to a wide range of compounds that can be analyzed, is relatively easy to manufacture, and is chemically stable and practical. As a result, an N-carbamoyl amino acid derivative is formed by bonding an optically active amino acid derivative or oxyacid derivative carbamoylated with an optically inactive isocyanate and an aminoalkylsilane to an inorganic carrier having a hydroxyl group on its surface. or a chromatographic packing material to which an O-carbamoyloxy acid derivative is grafted is attached to an asymmetric carbon.
【式】基、−CONH−基、−OCO−基、−
OCONH−基、−NHCONH−基または
[Formula] group, -CONH- group, -OCO- group, -OCONH- group, -NHCONH- group or
【式】基を有する化合物の鏡像体混
合物の分離に優れた効果を示すのみならず、通常
の化学反応で容易に製造し得るうえ化学的にも安
定であるなど極めて有用な充填剤であることを見
出し、本発明に至つたものである。
即ち、本発明は、ヒドロキシル基をその表面に
持つ無機担体に、光学不活性なイソシアネートを
用いてカルバモイル化した光学活性なアミノ酸誘
導体またはオキシ酸誘導体とアミノアルキルシラ
ンとが結合して成るＮ−カルバモイルアミノ酸誘
導体またはＯ−カルバモイルオキシ酸誘導体がグ
ラフトされているクロマトグラフ充填剤およびそ
れを液体クロマトグラフイーの固定相に用いて、
不斉炭素に結合した[Formula] It is an extremely useful filler that not only exhibits an excellent effect in separating a mixture of enantiomers of a compound having the group, but also can be easily produced by ordinary chemical reactions and is chemically stable. This discovery led to the present invention. That is, the present invention provides an N-carbamoyl compound in which an optically active amino acid derivative or oxyacid derivative and an aminoalkylsilane are bonded to an inorganic carrier having a hydroxyl group on its surface, which is carbamoylated using an optically inactive isocyanate. A chromatographic packing material to which an amino acid derivative or an O-carbamoyloxy acid derivative is grafted, and its use in a stationary phase of liquid chromatography,
bonded to asymmetric carbon
【式】基、−CONH
−基、−OCO−基、−OCONH−基、−NHCONH
−基または[Formula] group, -CONH - group, -OCO- group, -OCONH- group, -NHCONH
- group or
【式】基を有する化合物
の鏡像体混合物を分離し、分析する方法を提供す
るものである。
本発明においてグラフトされているＮ−カルバ
モイルアミノ酸誘導体またはＯ−カルバモイルオ
キシ酸誘導体としては、例えば一般式〔〕
〔式中、R1、R2およびR3は同一または相異なり、
アルキシ基、アルコキシル基、ヒドロキシル基ま
たはハロゲン原子を表わし、少なくともその１つ
はアルコキシル基またはハロゲン原子である。Ｘ
は−NHCO−基または−NH3・OCO−基を表わ
し、R4はアルキル基、アラルキル基またはアリ
ール基を表わす。Ｙは−NH−基または酸素原子
を表わし、R5はアルキル基、アラルキル基また
はアリール基を表わす。ｎは２から４までの整数
を表わし、＊は不斉炭素を表わす。〕
で示されるオルガノシランを挙げることができ
る。
さらに詳しくは、上記一般式〔〕で示される
Ｎ−カルバモイルアミノ酸誘導体またはＯ−カル
バモイルオキシ酸誘導体において、光学不活性な
イソシアネート成分としては低級アルキルイソシ
アネートまたはアリールイソシアネートが好まし
く、例えば、イソプロピルイソシアネート、α−
ナフチルイソシアネートまたは３，５−ジニトロ
フエニルイソシアネートなどを挙げることができ
る。
不斉炭素を含む光学活性なアミノ酸またはオキ
シ酸成分としては、α−アルキルアミノ酸、α−
アリールアミノ酸またはα−アリールオキシ酸が
好ましく、例えば、Ｌ−バリン、Ｄ−フエニルグ
リシン、（Ｓ）−マンデル酸または(B)−マンデル酸
などを挙げることができる。
Ｘの部分は−NHCO−基、−NH3・OCO−基
のいずれでも差支えなく、目的と用途により選択
することができる。
また、アミノアルキルシラン成分としてはω−
アミノアルキルアルコキシシランまたはω−アミ
ノアルキルハロゲノシランが好ましく、例えばω
−アミノプロピルトリエトキシシラン、ω−アミ
ノプロピルトリクロロシランなどを挙げることが
できる。
本発明において、ヒドロキシル基をその表面に
持つ無機担体としては例えばシリカゲルなどのシ
リカ含有担体が好ましく、担体の形状は球状、破
砕状などのいずれの形状でも差支えないが、高効
率のクロマトグラフ用カラムを得るために、でき
るだけ粒径の揃つた微細な粒子が好ましい。
本発明の新規なクロマトグラフ充填剤を調製す
るに際しては種々のグラフト方法が採用でき、例
えば以下のような方法が挙げられる。
その表面にヒドロキシル基を有する無機担体
に、アミノアルキルシランを反応させ、無機担
体の表面にアミノアルキルシリル残基を導入
し、これに光学不活性なイソシアネートを用い
てカルバモイル化した光学活性なアミノ酸また
はオキシ酸を反応させ、脱水縮合させるか、ま
たはイオン結合させる方法。
具体的には、その表面にヒドロキシル基を有
する無機担体に一般式〔〕
〔式中、R1、R2、R3およびＮは前述と同じ意
味を有する。〕
で示されるアミノアルキルシランを既知の方法
により反応させ、無機担体の表面にアミノアル
キルシリル残基を導入し、次いでこれに一般式
〔〕
〔式中、R4、R5、Ｙおよび＊は前述と同じ意
味を有する。〕
で示される不斉炭素を持つＮ−カルバモイルア
ミノ酸またはＯ−カルバモイルオキシ酸、例え
ばＮ−アルキルカルバモイル−Ｌ−バリン、Ｎ
−アリールカルバモイル−Ｄ−フエニルグリシ
ン、Ｏ−アリールカルバモイル−（Ｓ）−マンデ
ル酸等を反応せしめ、脱水縮合またはイオン結
合させることにより目的の充填剤が得られる。
なお、一般式〔〕に示す不斉炭素を持つＮ
−カルバモイルアミノ酸またはＯ−カルバモイ
ルオキシ酸は一般によく用いられる方法で合成
でき、市販されているイソシアネートまたは当
該アミンをホスゲンと反応させて得られるイソ
シアネート等、例えばイソプロピルイソシアネ
ート、α−ナフチルイソシアネートまたは３，
５−ジニトロフエニルイソシアネートを、アミ
ノ酸、例えばＬ−バリン、Ｄ−フエニルグリシ
ン等のナトリウム塩と水溶液中で反応させる
か、またはオキシ酸、例えば（Ｓ）−マンデル
酸のトリエチルアミン塩と脱水テトラヒドロフ
ラン中で反応させることにより得られる。
光学不活性なイソシアネートを用いてカルバ
モイル化した光学活性なアミノ酸またはオキシ
酸に、アミノアルキルシランを反応させて得ら
れるオルガノシランを、その表面にヒドロキシ
ル基を有する無機担体にグラフトする方法。
具体的には前記一般式〔〕で示されるＮ−
カルバモイルアミノ酸またはＯ−カルバモイル
オキシ酸に、一般式〔〕で示されるアミノア
ルキルシランを反応させて得られる一般式
〔〕で示されるオルガノシランをシリカゲル
等の無機担体にグラフトすることにより目的の
充填剤が得られる。
本発明によつて得られた光学活性なＮ−カルバ
モイル化α−アミノ酸残基またはＯ−カルバモイ
ル化α−オキシ酸残基を持つ充填剤は常法に従つ
てクロマトグラフ用のカラムに充填され、液体ク
ロマトグラフイーの固定相として使用される。な
お、前述のグラフト法の場合は、シリカゲル等
の無機担体に一般式〔〕で示されるアミノアル
キルシランを反応させ、無機担体の表面にアミノ
アルキルシリル残基を導入した充填剤を予め、常
法に従つてクロマトグラフ用のカラムに充填し、
このカラム内で、前述一般式〔〕で示されるＮ
−カルバモイルアミノ酸またはＯ−カルバモイル
オキシ酸をグラフトさせることにより、同様の液
体クロマトグラフイー用固定相を作製することも
できる。本固定相を用いる液体クロマトグラフイ
ーにおいて適当な溶離条件、特に通常よく用いら
れる順相分配の条件を選ぶことにより、不斉炭素
に結合したProvided are methods for separating and analyzing enantiomeric mixtures of compounds having the group ##STR1##. The N-carbamoyl amino acid derivative or O-carbamoyloxy acid derivative grafted in the present invention includes, for example, the general formula [] [In the formula, R 1 , R 2 and R 3 are the same or different,
It represents an alkoxy group, an alkoxyl group, a hydroxyl group, or a halogen atom, and at least one of them is an alkoxyl group or a halogen atom. X
represents an -NHCO- group or an -NH3.OCO- group, and R4 represents an alkyl group, an aralkyl group or an aryl group. Y represents an -NH- group or an oxygen atom, and R5 represents an alkyl group, an aralkyl group or an aryl group. n represents an integer from 2 to 4, and * represents an asymmetric carbon. ] Organosilanes shown in the following can be mentioned. More specifically, in the N-carbamoyl amino acid derivative or O-carbamoyloxy acid derivative represented by the above general formula [], the optically inactive isocyanate component is preferably a lower alkyl isocyanate or an aryl isocyanate, such as isopropylisocyanate, α-
Naphthyl isocyanate or 3,5-dinitrophenyl isocyanate can be mentioned. Optically active amino acids or oxyacid components containing an asymmetric carbon include α-alkyl amino acids, α-
Aryl amino acids or α-aryloxy acids are preferred, such as L-valine, D-phenylglycine, (S)-mandelic acid or (B)-mandelic acid. The moiety X may be either an -NHCO- group or an -NH3.OCO- group, which can be selected depending on the purpose and use. In addition, as an aminoalkylsilane component, ω-
Aminoalkylalkoxysilanes or ω-aminoalkylhalogenosilanes are preferred, e.g.
Examples include -aminopropyltriethoxysilane and ω-aminopropyltrichlorosilane. In the present invention, the inorganic carrier having hydroxyl groups on its surface is preferably a silica-containing carrier such as silica gel, and the shape of the carrier may be any shape such as spherical or crushed. In order to obtain this, it is preferable to use fine particles with as uniform a particle size as possible. Various grafting methods can be employed to prepare the novel chromatographic packing material of the present invention, including the following methods. Optically active amino acids or A method in which oxyacids are reacted and subjected to dehydration condensation or ionic bonding. Specifically, an inorganic carrier having a hydroxyl group on its surface has the general formula [] [In the formula, R 1 , R 2 , R 3 and N have the same meanings as above. ] The aminoalkylsilane represented by the formula [] is reacted by a known method to introduce an aminoalkylsilyl residue onto the surface of the inorganic carrier, and then the general formula [] [In the formula, R 4 , R 5 , Y and * have the same meanings as above. ] N-carbamoyl amino acid or O-carbamoyloxy acid having an asymmetric carbon represented by, for example, N-alkylcarbamoyl-L-valine, N
-Arylcarbamoyl-D-phenylglycine, O-arylcarbamoyl-(S)-mandelic acid, etc. are reacted, and the desired filler is obtained by dehydration condensation or ionic bonding. In addition, N having an asymmetric carbon shown in the general formula []
-Carbamoyl amino acids or O-carbamoyloxy acids can be synthesized by commonly used methods, and commercially available isocyanates or isocyanates obtained by reacting the amine with phosgene, such as isopropyl isocyanate, α-naphthyl isocyanate, or 3,
5-dinitrophenyl isocyanate is reacted with an amino acid, e.g., the sodium salt of L-valine, D-phenylglycine, etc., in aqueous solution, or with an oxyacid, e.g., the triethylamine salt of (S)-mandelic acid, in dehydrated tetrahydrofuran. It can be obtained by reacting with A method in which an organosilane obtained by reacting an aminoalkylsilane with an optically active amino acid or oxyacid that has been carbamoylated using an optically inactive isocyanate is grafted onto an inorganic carrier having a hydroxyl group on its surface. Specifically, N- represented by the general formula []
The desired filler can be obtained by grafting an organosilane represented by the general formula [] obtained by reacting a carbamoyl amino acid or an O-carbamoyloxy acid with an aminoalkylsilane represented by the general formula [] onto an inorganic carrier such as silica gel. is obtained. The optically active packing material having N-carbamoylated α-amino acid residues or O-carbamoylated α-oxyacid residues obtained according to the present invention is packed into a chromatographic column according to a conventional method, Used as a stationary phase in liquid chromatography. In the case of the above-mentioned grafting method, an inorganic carrier such as silica gel is reacted with an aminoalkylsilane represented by the general formula Fill a chromatographic column according to
Within this column, N represented by the general formula []
A similar stationary phase for liquid chromatography can also be prepared by grafting -carbamoyl amino acids or O-carbamoyloxy acids. In liquid chromatography using this stationary phase, by selecting appropriate elution conditions, especially the commonly used normal phase partition conditions, it is possible to
【式】基、−CONH−基、−
OCO−基、−OCONH−基、−NHCONH−基ま
たは[Formula] group, -CONH- group, -OCO- group, -OCONH- group, -NHCONH- group or
【式】基を有する化合物の鏡像
体混合物の分離、分析が分離能良く、かつ短時間
で行なうことができる。
実施例 １
シリカゲル（平均粒径10μｍ、平均孔径60Å、
表面積500m2／ｇ）10ｇを減圧、130℃で４時間乾
燥したのち、３−アミノプロピルトリエトキシシ
ラン20ｇを200mlの脱水トルエンに溶かした液に
加え、60℃にて６時間撹拌する。反応物をろ過
し、残留物をアセトン100mlで洗い、乾燥して３
−アミノプロピルシリル化シリカゲル（以下
APSと略す）を得た。このものの元素分析値は
Ｎ：1.20％、Ｃ：3.40％であり、これはこのもの
の１ｇに対し、３−アミノプロピル基が約0.90ｍ
molグラフトされたことに相当する。
別に、Ｌ−バリン4.69ｇを1N水酸化ナトリウ
ム水溶液40mlに溶かし、テトラヒドロフラン５ml
を加えたのち、撹拌しながら、イソプロピルイソ
シアネート3.4ｇを加え、室温で一夜撹拌を続け
る。反応液に1N水酸化ナトリウム水溶液10mlを
加えてから、酢酸エチル50mlで２回洗い、6N塩
酸で酸性とし、析出する白色結晶を、ろ取し、水
30mlで５回洗つたのち、50℃で減圧乾燥して2.5
ｇを得た。
融点（分解）：154〜155℃
施光度：〔α〕20 D＝7.4゜（ｃ＝0.81％、メタノール）
元素分析値
炭素(%) 水素(%) 窒素(%)
計算値 53.45 8.97 13.85
実測値 52.73 8.73 13.41
（C9H18N2O3として）
次にこの化合物1.19ｇをとり、ジメチルホルム
アミド14mlに溶かし、前記APS2.3ｇおよび１−
ヒドロキシベンゾトリアゾール1.02ｇを加えて減
圧下で十分に脱気したのち、撹拌しながら氷冷す
る。これに、ジシクロヘキシルカルボジイミド
1.5ｇをジメチルホルムアミド６mlに溶かした液
を加え、０℃で１時間撹拌し、さらに室温で一夜
撹拌を続ける。上記のようにして得られたグラフ
トしたシリカゲルを遠心分離し、クロロホルム、
メタノール、アセトンおよびエチルエーテルで洗
浄後、乾燥してＮ−イソプロピルカルバモイル−
Ｌ−バリンをグラフトした目的の充填剤（以下、
IPC−VAL−Siと略す）を得た。このものの元素
分析値はＮ：2.78％、Ｃ：8.98％であり、これは
このもの１ｇに対し、Ｎ−イソプロピルカルバモ
イル−Ｌ−バリンが約0.62ｍmolグラフトされた
ことを示す。
このようにして得られた充填剤を内径４mm、長
さ25cmのステンレス製カラムにスラリー充填し、
次の条件でＮ−アセチル−DL−バリンメチルエ
ステルを分析し、図−１のクロマトグラムを得
た。
温 度：室温
移動相：ヘキサン／イソプロパノール（24：１）
流 量：1.0ml／min
検出器：紫外線吸収計（波長225nｍ）
図−１中、ピーク番号(1)は溶媒のクロロホルム
であり、(2)はＮ−アセチル−Ｄ−バリンイソプロ
ピルエステル、(3)はＮ−アセチル−Ｌ−バリンイ
ソプロピルエステルの各ピークである。(3)のピー
クが溶出するまでに要する時間は約８分、分離係
数は1.46、(2)と(3)のピークの面積比は50：50であ
る。
実施例 ２
トルエン200mlにトリクロロメチルクロロホー
メート58ｇを注ぎ込み、静かに振り混ぜ、粒状活
性炭１ｇを加えて一夜放置して緩やかにホスゲン
を発生させたのち、活性炭をろ過して取り除いた
液に３，５−ジニトロアニリン10ｇを酢酸エチル
50mlに溶かした液を加え、撹拌しながら４時間加
熱還流する。冷後、過剰のホスゲンおよび溶媒を
減圧留去して、３，５−ジニトロフエニルイソシ
アネート10.5ｇを得た。
融 点：72℃〜74℃
元素分析値
炭素(%) 水素(%) 窒素(%)
計算値 40.21 1.45 20.09
実測値 38.83 1.66 18.89
（C7H3N3O5として）
別にＳ（＋）−マンデル酸2.59ｇを脱水テトラヒ
ドロフラン30mlに溶かし、トリエチルアミン3.0
ｇを加えたのち、前述の３，５−ジニトロフエニ
ルイソシアネート4.18ｇを加えて沸騰水浴上で５
時間加熱還流する。冷後、溶媒を減圧下で濃縮
し、酢酸エチル−ヘキサン（１：１）混液100ml
に溶かしたのち、５％炭酸水素ナトリウム水溶液
100mlで３回抽出を行ない、合わせた抽出液を酢
酸エチル−ヘキサン（１：１）混液50mlで洗い、
6N塩酸で酸性とし、生成する白色固体状物質を
酢酸エチル100mlで２回抽出する。抽出液を水100
mlで２回洗い、無水硫酸ナトリウムで脱水後、減
圧下で濃縮したのち、テトラヒドロフラン−ヘキ
サン（１：２）混液から再結晶し、Ｏ−（３，５
−ジニトロフエニルカルバモイル）−（Ｓ）−マン
デル酸2.6ｇを白色結晶として得た。
融点（分解）：195〜196℃
施光度：〔α〕20 D＝98.0゜（ｃ＝0.58％、メタノール
）
元素分析値
炭素(%) 水素(%) 窒素(%)
計算値 49.87 3.07 11.63
分析値 49.96 3.10 11.55
（C15H11N3O8として）
次にこの化合物1.8ｇをとり、テトラヒドロフ
ラン50mlを加えて溶かし、これを、別に実施例１
で得られたAPSを内径４mm、長さ25cmのステン
レス製カラムにスラリー充填したカラム内で約２
ml／minの流速で２時間循環させてＯ−（３，５
−ジニトロフエニルカルバモイル）−Ｓ−マンデ
ル酸をグラフトしたのち、テトラヒドロフラン、
メタノールおよびクロロホルムを順次流して、カ
ラムのコンデイシヨニングを行なう（以下、この
カラムをDNC−MND−Siと略す）。本カラムを
用いて次の条件でＮ−アセチル−（±）−１−（α
−ナフチル）エチルアミンを分析し、図−２のク
ロマトグラムを得た。
温 度：室温
移動相：ヘキサン／ジクロロメタン／エタノール
（15：４：１）
流 量：1.0ml／min
検出器：紫外線吸収計（波長254nｍ）
図−２中、ピーク番号(1)はＮ−アセチル−（−）
−１−（α−ナフチル）エチルアミン、(2)はＮ−
アセチル−（＋）−１−（α−ナフチル）エチルア
ミンの各ピークである。(2)のピークが溶出するま
でに要する時間は約15分、分離係数は1.30、(1)と
(2)のピーク面積比は50：50であつた。
実施例 ３
実施例１で得られたIPC−VAL−Siの充填剤を
内径４mm、長さ25cmのステンレスカラムにスラリ
ー充填したカラムおよび実施例２で得たPNC−
MND−Siのカラム、さらに、実施例１または２
に準じた方法で合成されたＮ−イソプロピルカル
バモイル−Ｄ−フエニルグリシン、Ｏ−イソプロ
ピルカルバモイル−（Ｒ）−マンデル酸、Ｎ−（３，
５−ジニトロフエニルカルバモイル）−Ｄ−フエ
ニルグリシンおよびＯ−（α−ナフチルカルバモ
イル）−（Ｓ）−マンデル酸を、前二者は実施例１
に準じて、後二者は実施例２に準じてそれぞれ実
施例１で得られたAPSにグラフトし（これらの
充填剤を順にIPC−PHG−Si、IPC−MND−Si、
DNC−PHG−SiおよびNPC−MND−Siと略
す）、調製された各カラムを用いて、次の条件で
種々の化合物の鏡像体混合物を分離し、分離係数
を求めた。
温 度：室温
流 量：１ml／min
検出器：紫外線吸収計（波長254nｍまたは225n
ｍ）
結果を第１表〜第４表に示す。Separation and analysis of a mixture of enantiomers of a compound having the group [Formula] can be performed with good resolution and in a short time. Example 1 Silica gel (average particle size 10 μm, average pore size 60 Å,
After drying 10 g (surface area: 500 m 2 /g) under reduced pressure at 130°C for 4 hours, it was added to a solution of 20 g of 3-aminopropyltriethoxysilane dissolved in 200 ml of dehydrated toluene, and the mixture was stirred at 60°C for 6 hours. The reaction product was filtered, the residue was washed with 100 ml of acetone, and dried.
-Aminopropyl silylated silica gel (hereinafter
(abbreviated as APS). The elemental analysis values of this product are N: 1.20% and C: 3.40%, which means that 3-aminopropyl group is about 0.90m per 1g of this product.
This corresponds to mol grafting. Separately, dissolve 4.69 g of L-valine in 40 ml of 1N aqueous sodium hydroxide solution, and dissolve 5 ml of tetrahydrofuran.
After that, 3.4 g of isopropylisocyanate is added while stirring, and stirring is continued at room temperature overnight. Add 10 ml of 1N aqueous sodium hydroxide solution to the reaction solution, wash twice with 50 ml of ethyl acetate, acidify with 6N hydrochloric acid, collect the precipitated white crystals by filtration, and add water.
After washing 5 times with 30ml, dry at 50℃ under reduced pressure to obtain 2.5
I got g. Melting point (decomposition): 154-155℃ Light exposure: [α] 20 D = 7.4゜ (c = 0.81%, methanol) Elemental analysis values Carbon (%) Hydrogen (%) Nitrogen (%) Calculated value 53.45 8.97 13.85 Actual value 52.73 8.73 13.41 (as C 9 H 18 N 2 O 3 ) Next, take 1.19 g of this compound, dissolve it in 14 ml of dimethylformamide, and add 2.3 g of the above APS and 1-
After adding 1.02 g of hydroxybenzotriazole and thoroughly degassing under reduced pressure, the mixture was cooled on ice while stirring. To this, dicyclohexylcarbodiimide
Add a solution of 1.5 g dissolved in 6 ml of dimethylformamide, stir at 0°C for 1 hour, and continue stirring at room temperature overnight. The grafted silica gel obtained as above was centrifuged, chloroform and
After washing with methanol, acetone and ethyl ether, drying yields N-isopropylcarbamoyl-
The desired filler grafted with L-valine (hereinafter referred to as
IPC-VAL-Si) was obtained. The elemental analysis values of this product were N: 2.78% and C: 8.98%, which indicates that about 0.62 mmol of N-isopropylcarbamoyl-L-valine was grafted to 1 g of this product. The thus obtained packing material was slurried packed into a stainless steel column with an inner diameter of 4 mm and a length of 25 cm.
N-acetyl-DL-valine methyl ester was analyzed under the following conditions, and the chromatogram shown in Figure 1 was obtained. Temperature: Room temperature Mobile phase: Hexane/isopropanol (24:1) Flow rate: 1.0 ml/min Detector: Ultraviolet absorption meter (wavelength 225 nm) In Figure 1, peak number (1) is the solvent chloroform; 2) is the peak of N-acetyl-D-valine isopropyl ester, and (3) is the peak of N-acetyl-L-valine isopropyl ester. The time required for peak (3) to elute is approximately 8 minutes, the separation coefficient is 1.46, and the area ratio of peaks (2) and (3) is 50:50. Example 2 Pour 58 g of trichloromethyl chloroformate into 200 ml of toluene, shake gently, add 1 g of granular activated carbon, and leave it overnight to slowly generate phosgene. After removing the activated carbon by filtration, add 3. 10g of 5-dinitroaniline in ethyl acetate
Add the solution dissolved in 50 ml and heat under reflux for 4 hours while stirring. After cooling, excess phosgene and the solvent were distilled off under reduced pressure to obtain 10.5 g of 3,5-dinitrophenyl isocyanate. Melting point: 72℃～74℃ Elemental analysis values Carbon (%) Hydrogen (%) Nitrogen (%) Calculated value 40.21 1.45 20.09 Actual value 38.83 1.66 18.89 (as C 7 H 3 N 3 O 5 ) Separately S (+) − Dissolve 2.59 g of mandelic acid in 30 ml of dehydrated tetrahydrofuran and dissolve 3.0 g of triethylamine.
After adding 4.18 g of the above-mentioned 3,5-dinitrophenyl isocyanate,
Heat to reflux for an hour. After cooling, concentrate the solvent under reduced pressure and add 100 ml of ethyl acetate-hexane (1:1) mixture.
After dissolving in 5% sodium bicarbonate aqueous solution
Extract 3 times with 100 ml, wash the combined extracts with 50 ml of ethyl acetate-hexane (1:1) mixture,
Acidify with 6N hydrochloric acid and extract the resulting white solid substance twice with 100 ml of ethyl acetate. Extract with water 100%
ml twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized from a tetrahydrofuran-hexane (1:2) mixture, and O-(3,5
2.6 g of -dinitrophenylcarbamoyl)-(S)-mandelic acid were obtained as white crystals. Melting point (decomposition): 195-196℃ Light exposure: [α] 20 D = 98.0゜ (c = 0.58%, methanol) Elemental analysis values Carbon (%) Hydrogen (%) Nitrogen (%) Calculated value 49.87 3.07 11.63 Analysis value 49.96 3.10 11.55 (as C 15 H 11 N 3 O 8 ) Next, 1.8 g of this compound was added and dissolved in 50 ml of tetrahydrofuran.
Approximately 20% of the APS obtained was packed in a slurry-filled stainless steel column with an inner diameter of 4 mm and a length of 25 cm.
O-(3,5
-dinitrophenylcarbamoyl)-S-mandelic acid, tetrahydrofuran,
The column is conditioned by sequentially flowing methanol and chloroform (hereinafter, this column will be abbreviated as DNC-MND-Si). Using this column, N-acetyl-(±)-1-(α
-Naphthyl)ethylamine was analyzed and the chromatogram shown in Figure 2 was obtained. Temperature: Room temperature Mobile phase: Hexane/dichloromethane/ethanol (15:4:1) Flow rate: 1.0ml/min Detector: Ultraviolet absorption meter (wavelength 254nm) In Figure 2, peak number (1) is N-acetyl −(−)
-1-(α-naphthyl)ethylamine, (2) is N-
These are the peaks of acetyl-(+)-1-(α-naphthyl)ethylamine. The time required for peak (2) to elute is approximately 15 minutes, the separation factor is 1.30, and (1).
The peak area ratio of (2) was 50:50. Example 3 A stainless steel column with an inner diameter of 4 mm and a length of 25 cm was filled with the IPC-VAL-Si packing material obtained in Example 1 as a slurry, and a column containing the PNC-VAL-Si obtained in Example 2 was prepared.
MND-Si column, further Example 1 or 2
N-isopropylcarbamoyl-D-phenylglycine, O-isopropylcarbamoyl-(R)-mandelic acid, N-(3,
5-dinitrophenylcarbamoyl)-D-phenylglycine and O-(α-naphthylcarbamoyl)-(S)-mandelic acid, the former two being the same as in Example 1.
The latter two were grafted onto the APS obtained in Example 1 according to Example 2 (these fillers were sequentially grafted to IPC-PHG-Si, IPC-MND-Si,
Using the prepared columns (abbreviated as DNC-PHG-Si and NPC-MND-Si), enantiomeric mixtures of various compounds were separated under the following conditions, and the separation coefficients were determined. Temperature: Room temperature Flow rate: 1ml/min Detector: Ultraviolet absorption meter (wavelength 254nm or 225nm)
m) The results are shown in Tables 1 to 4.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
図−１および図−２は、それぞれ実施例１およ
び実施例２において得られたクロマトグラムであ
り、縦軸は強度を、横軸は保持時間を表わす。
Figures 1 and 2 are chromatograms obtained in Example 1 and Example 2, respectively, where the vertical axis represents intensity and the horizontal axis represents retention time.
Claims (1)
に、光学不活性なイソシアネートを用いてカルバ
モイル化した光学活性なアミノ酸誘導体またはオ
キシ酸誘導体とアミノアルキルシランとが結合し
て成るＮ−カルバモイルアミノ酸誘導体またはＯ
−カルバモイルオキシ酸誘導体がグラフトされて
いるクロマトグラフ充填剤。 ２ ヒドロキシル基をその表面に持つ無機担体に
グラフトされているＮ−カルバモイルアミノ酸誘
導体またはＯ−カルバモイルオキシ酸誘導体が一
般式〔〕 〔式中、R1、R2およびR3は同一または相異なり、
アルキル基、アルコキシル基、ヒドロキシル基ま
たはハロゲン原子を表わし、少なくともその１つ
はアルコキシル基またはハロゲン原子である。Ｘ
は−NHCO−基または−NH3・OCO−基を表わ
し、R4はアルキル基、アラルキル基またはアリ
ール基を表わす。Ｙは−NH−基または酸素原子
を表わし、R5はアルキル基、アラルキル基また
はアリール基を表わす。ｎは２から４までの整数
を表わし、＊は不斉炭素を表わす。〕 で示されるオルガノシランである特許請求の範囲
第１項に記載のクロマトグラフ充填剤。 ３ ヒドロキシル基をその表面に持つ無機担体が
シリカゲルである特許請求の範囲第１項または第
２項に記載のクロマトグラフ充填剤。 ４ 上記一般式〔〕において、アミノアルキル
シラン残基がω−アミノプロピルトリエトキシシ
ラン残基またはω−アミノプロピルトリクロロシ
ラン残基である特許請求の範囲第２項または第３
項に記載のクロマトグラフ充填剤。 ５ 上記一般式〔〕において、R5がイソプロ
ピル基、ナフチル基または３，５−ジニトロフエ
ニル基である特許請求の範囲第２項、第３項また
は第４項に記載のクロマトグラフ充填剤。 ６ 上記一般式〔〕において、R4がイソプロ
ピル基もしくはフエニル基であるときＹが−NH
−基であるか、またはR4がフエニル基であると
きＹが酸素原子である特許請求の範囲第２項、第
３項、第４項または第５項に記載のクロマトグラ
フ充填剤。 ７ ヒドロキシル基をその表面に持つ無機担体
に、光学不活性なイソシアネートを用いてカルバ
モイル化した光学活性なアミノ酸誘導体またはオ
キシ酸誘導体とアミノアルキルシランとが結合し
て成るＮ−カルバモイルアミノ酸誘導体またはＯ
−カルバモイルオキシ酸誘導体がグラフトされて
いるクロマトグラフ充填剤を用いて、不斉炭素に
結合した【式】基、−CONH−基、− OCO−基、−OCONH−基、−NHCONH−基ま
たは【式】基を有する化合物の鏡像 体混合物を分離し、分析することを特徴とする液
体クロマトグラフイー分析法。 ８ ヒドロキシル基をその表面に持つ無機担体に
グラフトされているＮ−カルバモイルアミノ酸誘
導体またはＯ−カルバモイルオキシ酸誘導体が、
一般式〔〕 〔式中、R1、R2およびR3は同一または相異なり、
アルキル基、アルコキシル基、ヒドロキシル基ま
たはハロゲン原子を表わし、少なくともその１つ
はアルコキシル基またはハロゲン原子である。Ｘ
は−NHCO−基または−NH3・OCO−基を表わ
し、R4はアルキル基、アラルキル基またはアリ
ール基を表わす。Ｙは−NH−基または酸素原子
を表わし、R5はアルキル基、アラルキル基また
はアリール基を表わす。ｎは２から４までの整数
を表わし、＊は不斉炭素を表わす。〕 で示されるオルガノシランであるクロマトグラフ
充填剤を用いる特許請求の範囲第７項に記載の分
析法。 ９ ヒドロキシル基をその表面に持つ無機担体が
シリカゲルであるクロマトグラフ充填剤を用いる
特許請求の範囲第７項または第８項に記載の分析
法。 １０ 上記一般式〔〕において、アミノアルキ
ルシラン残基がω−アミノプロピルトリエトキシ
シラン残基またはω−アミノプロピルトリクロロ
シラン残基であるクロマトグラフ充填剤を用いる
特許請求の範囲第８項または第９項に記載の分析
法。 １１ 上記一般式〔〕において、R5がイソプ
ロピル基、ナフチル基または３，５−ジニトロフ
エニル基であるクロマトグラフ充填剤を用いる特
許請求の範囲第８項、第９項または第１０項に記
載の分析法。 １２ 上記一般式〔〕において、R4がイソプ
ロピル基もしくはフエニル基であるときＹが−
NH−であるか、またはR4がフエニル基であると
きＹが酸素原子であるクロマトグラフ充填剤を用
いる特許請求の範囲第８項、第９項、第１０項ま
たは第１１項に記載の分析法。[Scope of Claims] 1 N- formed by bonding an optically active amino acid derivative or oxyacid derivative carbamoylated using an optically inactive isocyanate and an aminoalkylsilane to an inorganic carrier having a hydroxyl group on its surface. Carbamoyl amino acid derivative or O
- Chromatographic packings to which carbamoyloxy acid derivatives are grafted. 2 An N-carbamoyl amino acid derivative or an O-carbamoyloxy acid derivative grafted onto an inorganic carrier having a hydroxyl group on its surface has the general formula [] [In the formula, R 1 , R 2 and R 3 are the same or different,
It represents an alkyl group, an alkoxyl group, a hydroxyl group, or a halogen atom, at least one of which is an alkoxyl group or a halogen atom. X
represents an -NHCO- group or an -NH3.OCO- group, and R4 represents an alkyl group, an aralkyl group or an aryl group. Y represents an -NH- group or an oxygen atom, and R5 represents an alkyl group, an aralkyl group or an aryl group. n represents an integer from 2 to 4, and * represents an asymmetric carbon. ] The chromatographic packing material according to claim 1, which is an organosilane represented by the following. 3. The chromatographic packing material according to claim 1 or 2, wherein the inorganic carrier having hydroxyl groups on its surface is silica gel. 4 Claim 2 or 3, wherein in the above general formula [], the aminoalkylsilane residue is an ω-aminopropyltriethoxysilane residue or an ω-aminopropyltrichlorosilane residue.
Chromatographic packing material described in Section. 5. The chromatographic packing material according to claim 2, 3, or 4, wherein in the general formula [], R5 is an isopropyl group, a naphthyl group, or a 3,5-dinitrophenyl group. 6 In the above general formula [], when R 4 is an isopropyl group or a phenyl group, Y is -NH
- group, or when R4 is a phenyl group, Y is an oxygen atom, the chromatographic packing material according to claim 2, 3, 4 or 5. 7 N-carbamoyl amino acid derivative or O, which is formed by bonding an optically active amino acid derivative or oxyacid derivative carbamoylated using an optically inactive isocyanate and an aminoalkylsilane to an inorganic carrier having a hydroxyl group on its surface.
Using a chromatographic packing material to which a -carbamoyloxy acid derivative is grafted, [formula] group, -CONH- group, -OCO- group, -OCONH- group, -NHCONH- group or [ A liquid chromatography analysis method characterized by separating and analyzing a mixture of enantiomers of a compound having the formula [Formula]. 8 N-carbamoyl amino acid derivative or O-carbamoyloxy acid derivative grafted onto an inorganic carrier having hydroxyl groups on its surface,
General formula [] [In the formula, R 1 , R 2 and R 3 are the same or different,
It represents an alkyl group, an alkoxyl group, a hydroxyl group, or a halogen atom, at least one of which is an alkoxyl group or a halogen atom. X
represents an -NHCO- group or an -NH3.OCO- group, and R4 represents an alkyl group, an aralkyl group or an aryl group. Y represents an -NH- group or an oxygen atom, and R5 represents an alkyl group, an aralkyl group or an aryl group. n represents an integer from 2 to 4, and * represents an asymmetric carbon. ] The analytical method according to claim 7, which uses a chromatographic packing material which is an organosilane represented by the following. 9. The analytical method according to claim 7 or 8, which uses a chromatographic packing material in which the inorganic carrier having hydroxyl groups on its surface is silica gel. 10 Claims 8 or 9 using a chromatographic packing material in which the aminoalkylsilane residue is an ω-aminopropyltriethoxysilane residue or an ω-aminopropyltrichlorosilane residue in the above general formula [] Analytical methods described in Section. 11 Analysis according to claim 8, 9, or 10 using a chromatographic packing material in which R 5 is an isopropyl group, a naphthyl group, or a 3,5-dinitrophenyl group in the above general formula [] Law. 12 In the above general formula [], when R 4 is an isopropyl group or a phenyl group, Y is -
The analysis according to claim 8, 9, 10 or 11 using a chromatographic packing material in which Y is NH-, or when R4 is a phenyl group, Y is an oxygen atom. Law.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57173688A JPS5963565A (en) | 1982-10-01 | 1982-10-01 | Chromatograph filler and analyzing method of mixture of enantiomer using chromatograph filler |
| CA000437948A CA1204720A (en) | 1982-09-30 | 1983-09-29 | Packing materials for chromatographic use and a method for analysis of an enantiomer mixture using the same |
| EP83305933A EP0105745B1 (en) | 1982-09-30 | 1983-09-30 | Packing materials for chromatographic use and their employment in analysing enantiomeric mixtures |
| US06/538,011 US4512898A (en) | 1982-09-30 | 1983-09-30 | Packing materials for chromatographic use and a method for analysis of an enantiomer mixture using the same |
| DE8383305933T DE3374917D1 (en) | 1982-09-30 | 1983-09-30 | Packing materials for chromatographic use and their employment in analysing enantiomeric mixtures |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57173688A JPS5963565A (en) | 1982-10-01 | 1982-10-01 | Chromatograph filler and analyzing method of mixture of enantiomer using chromatograph filler |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5963565A JPS5963565A (en) | 1984-04-11 |
| JPH0356423B2 true JPH0356423B2 (en) | 1991-08-28 |
Family
ID=15965258
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57173688A Granted JPS5963565A (en) | 1982-09-30 | 1982-10-01 | Chromatograph filler and analyzing method of mixture of enantiomer using chromatograph filler |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5963565A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2538618B2 (en) * | 1987-10-13 | 1996-09-25 | 昭二 原 | Separation agent |
-
1982
- 1982-10-01 JP JP57173688A patent/JPS5963565A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5963565A (en) | 1984-04-11 |
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