ITRM20000221A1 - NEW TETRAMIDIC MACROCYCLES, PROCEDURE FOR THEIR PREPARATION AND USE AS CHIRAL STATIONARY STAGE RECEPTORS. - Google Patents
NEW TETRAMIDIC MACROCYCLES, PROCEDURE FOR THEIR PREPARATION AND USE AS CHIRAL STATIONARY STAGE RECEPTORS. Download PDFInfo
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- ITRM20000221A1 ITRM20000221A1 IT2000RM000221A ITRM20000221A ITRM20000221A1 IT RM20000221 A1 ITRM20000221 A1 IT RM20000221A1 IT 2000RM000221 A IT2000RM000221 A IT 2000RM000221A IT RM20000221 A ITRM20000221 A IT RM20000221A IT RM20000221 A1 ITRM20000221 A1 IT RM20000221A1
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- Prior art keywords
- tetramide
- formula
- macrocycle
- preparation
- chiral stationary
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- 238000000034 method Methods 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title claims description 18
- 150000002678 macrocyclic compounds Chemical class 0.000 title description 4
- -1 Tetramide macrocycle Chemical class 0.000 claims description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 33
- 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 15
- 230000005526 G1 to G0 transition Effects 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 239000000377 silicon dioxide Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000005336 allyloxy group Chemical group 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 230000001588 bifunctional effect Effects 0.000 claims description 6
- 239000012069 chiral reagent Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 150000002894 organic compounds Chemical class 0.000 claims description 4
- 150000002902 organometallic compounds Chemical class 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
- 150000004645 aluminates Chemical class 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- 230000002051 biphasic effect Effects 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 235000014633 carbohydrates Nutrition 0.000 claims description 2
- ZZASRJYLQUPYFI-UHFFFAOYSA-N chloroform;n,n-dimethylformamide Chemical compound ClC(Cl)Cl.CN(C)C=O ZZASRJYLQUPYFI-UHFFFAOYSA-N 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000012634 fragment Substances 0.000 claims description 2
- 239000003999 initiator Substances 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 239000002952 polymeric resin Substances 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 229920002223 polystyrene Polymers 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000004760 silicates Chemical class 0.000 claims description 2
- 229920003002 synthetic resin Polymers 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 230000003100 immobilizing effect Effects 0.000 claims 1
- 238000007342 radical addition reaction Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- OZMHCDOSPHJOKL-UHFFFAOYSA-N 5-prop-2-enoxybenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(OCC=C)=CC(C(O)=O)=C1 OZMHCDOSPHJOKL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QNVNLUSHGRBCLO-UHFFFAOYSA-N 5-hydroxybenzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=CC(O)=CC(C(O)=O)=C1 QNVNLUSHGRBCLO-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000011208 chromatographic data Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PONXTPCRRASWKW-ZIAGYGMSSA-N (1r,2r)-1,2-diphenylethane-1,2-diamine Chemical compound C1([C@@H](N)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-ZIAGYGMSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 description 1
- UUEWCQRISZBELL-UHFFFAOYSA-N 3-trimethoxysilylpropane-1-thiol Chemical compound CO[Si](OC)(OC)CCCS UUEWCQRISZBELL-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- RSLUFPUYQPGPNC-UHFFFAOYSA-N dimethyl 5-prop-2-enoxybenzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC(OCC=C)=CC(C(=O)OC)=C1 RSLUFPUYQPGPNC-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000003004 phosphinoxides Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Descrizione dell'invenzione industriale dal titolo: "NUOVI MACROCICLI TETRAMMIDICI, PROCEDIMENTO PER LA LORO PREPARAZIONE E LORO USO COME RECETTORI IN FASI STAZIONARIE CHIRALI " Description of the industrial invention entitled: "NEW TETRAMIDE MACROCYCLES, PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS RECEPTORS IN CHIRAL STATIONARY PHASES"
DESCRIZIONE DESCRIPTION
La presente invenzione ha per oggetto principale nuove molecole che possono essere usate come recettori chirali per la separazione e la purificazione di enantiomeri, e in generale stereoìsomeri , di composti organici ed organometallici, sia a livello analitico che preparativo . The present invention has as its main object new molecules which can be used as chiral receptors for the separation and purification of enantiomers, and in general stereoisomers, of organic and organometallic compounds, both at the analytical and preparatory level.
In particolare è oggetto principale della presente invenzione un macrociclo tetrammidico con molecola di formula (I) In particular, the main object of the present invention is a tetramide macrocycle with a molecule of formula (I)
m cui m which
X è un alchile, un arile oppure un frammento polimetilenico -(CH2)n- dove n è un numero intero > 2; X is an alkyl, an aryl or a polymethylene fragment - (CH2) n- where n is an integer> 2;
Y è un gruppo allilossi, alcossi o arilmetossi; R è un idrogeno o un alchile, Y is an allyloxy, alkoxy or arylmethoxy group; R is a hydrogen or an alkyl,
ed il suo enantiomero. and its enantiomer.
Particolarmente interessante per la sua versatilità applicativa è il macrociclo tetrammidico in cui X è fenile, Y è allilossi ed R è idrogeno. Particularly interesting for its application versatility is the tetramide macrocycle in which X is phenyl, Y is allyloxy and R is hydrogen.
L'invenzione si riferisce anche ad un procedimento per la preparazione del macrociclo tetrammidico come da rivendicazione 1 o 2, caratterizzato dal fatto di far reagire - in solvente aprotico, in presenza di un'ammina terziaria - un reagente chirale bifunzionale con due gruppi amminici di formula (II) The invention also refers to a process for the preparation of the tetramide macrocycle as per claim 1 or 2, characterized in that a bifunctional chiral reagent with two amino groups of formula (II)
m cui m which
X è un alchile, un arile oppure un frammento polimetilenico -(CH2)n- dove n è un numero intero > 2; e X is an alkyl, an aryl or a polymethylene fragment - (CH2) n- where n is an integer> 2; And
R è un idrogeno oppure un alchile, R is a hydrogen or an alkyl,
con la forma attivata di un diacido carbossilico aromatico di formula (III) with the activated form of an aromatic carboxylic diacid of formula (III)
in cui in which
Y è un gruppo allilossi, alcossi oppure arilmetossi. Y is an allyloxy, alkoxy or arylmethoxy group.
Il reagente chirale bifunzionale con due gruppi amminici di formula (II) e la forma attivata del diacido carbossilico aromatico di formula (III) possono reagire in quantità equimolari. The bifunctional chiral reagent with two amino groups of formula (II) and the activated form of the aromatic carboxylic diacid of formula (III) can react in equimolar quantities.
Il solvente aprotico può essere scelto dal gruppo comprendente tetraidrofurano; diossano; cloroformio; N, N-dimetilformammide e loro combinazioni. The aprotic solvent can be selected from the group comprising tetrahydrofuran; dioxane; chloroform; N, N-dimethylformamide and their combinations.
L'ammina terziaria può essere scelta dal gruppo comprendente trietilammina, diisopropiletilammina, N-metilmorfolina, piridina e loro combinazioni. The tertiary amine can be selected from the group comprising triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and combinations thereof.
La forma attivata del diacido bicarbossilico aromatico di formula (III) può essere scelta dal gruppo comprendente dicloruro acido, pnitrofenilestere, pentafluorofenilestere e loro combinazioni. The activated form of the aromatic dicarboxylic diacid of formula (III) can be selected from the group comprising acid dichloride, pnitrophenyl ester, pentafluorophenyl ester and combinations thereof.
La reazione fra il reagente chirale bifunzionale con due gruppi amminici di formula (II) e la forma attivata del diacido bicarbossilico aromatico di formula (III) può essere fatta avvenire a temperature comprese nell'intervallo tra -10°C e 100°C, preferibilmente -10°C e 25°C. The reaction between the bifunctional chiral reagent with two amino groups of formula (II) and the activated form of the aromatic dicarboxylic diacid of formula (III) can be carried out at temperatures ranging from -10 ° C to 100 ° C, preferably -10 ° C and 25 ° C.
E' anche oggetto dell'invenzione l'uso dei macrocicli tetrammidici sopra menzionati come recettori chirali per la separazione e la purificazione di enantiomeri, e in generale di stereoisomeri, di composti organici ed organometallici sia a livello analitico che preparativo. In queste applicazioni il macrociclo tetrammidico può essere in forma legata ad un supporto insolubile oppure in un sistema bifasico liquido/liquido . The use of the above mentioned tetramide macrocycles as chiral receptors for the separation and purification of enantiomers, and in general of stereoisomers, of organic and organometallic compounds both at the analytical and preparative level, is also an object of the invention. In these applications, the tetramide macrocycle can be in the form linked to an insoluble support or in a liquid / liquid biphasic system.
Come è noto, i metodi classici di separazione di enantiomeri prevedono la formazione di derivati diastereomerici per interazioni con un agente chìrale e successiva separazione dei diasterìsomeri per cristallizzazione, distillazione, estrazione o cromatografia. Recenti sviluppi tecnologici hanno permesso di affrontare il problema in maniera più soddisfacente, sfruttando la elevata efficienza delle moderne tecniche cromatografiche e l'impiego di fasi stazionarie chirali, nelle quali un enantiomero di una molecola chirale (selettore) è immobilizzato su un supporto insolubile. Con questo approccio è possibile separare, in tempi brevi ed in maniera riproducibile, sia a livello analitico {microgrammi) che preparativo (grammi) gli enantiomeri di svariati composti. La possibilità di effettuare tali separazioni è di notevole importanza economica e pratica, ed ha ricadute immediate in svariati campi di attività (accademica ed industriale) che riguardano la produzione di sostanze bioattive e di interesse farmaceutico. As is known, the classical methods of separation of enantiomers provide for the formation of diastereomeric derivatives by interactions with a chiral agent and subsequent separation of the diasterisomers by crystallization, distillation, extraction or chromatography. Recent technological developments have made it possible to tackle the problem in a more satisfactory way, exploiting the high efficiency of modern chromatographic techniques and the use of chiral stationary phases, in which an enantiomer of a chiral molecule (selector) is immobilized on an insoluble support. With this approach it is possible to separate, in a short time and in a reproducible way, both analytically (micrograms) and preparative (grams) the enantiomers of various compounds. The possibility of carrying out these separations is of considerable economic and practical importance, and has immediate repercussions in various fields of activity (academic and industrial) concerning the production of bioactive substances and of pharmaceutical interest.
La capacità di una molecola (selettore) di discriminare i due enantiomeri di una seconda molecola è strettamente legata ad alcuni elementi strutturali che sono comuni ai più efficaci selettori noti in letteratura: struttura macrociclica, rigidità conformazionale, presenza di gruppi funzionali altamente direzionali. Sono noti diversi sistemi molecolari che possiedono questi requisiti e che mostrano elevata enantioselettività per una specifica classe di composti. Macrocicli chirali altamente enantioselettivi verso gli enantiomeri di derivati di amminoacidi del tipo R-CONH-CH (R)-CONHCH3 sono stati preparati a partire da una unità aromatica trifunzionale e tre residui di fenilalanina o tirosina uniti da legami ammidici (Stili, W.C.; J. Am. Chem. Soc. 113, 1991, 5111). L'enantioselettività di tale macrociclo, espressa come differenza nelle energie di associazione con i due enantiomeri (ΔΔG tra 1 e 3 Kcal/mole) si avvicina per entità a quelle tipiche dei recettori biologici. Un analogo recettore preparato a partire da due unità triarilbenzeniche e tre residui tirosinici connessi da legami ammidici mostra elevata enantioselettività (ΔΔG ~ 1 Kcal/mole) per gli enantiomeri di amminoacidi N-protetti (Diederich, F.; J. Chem. Soc. Perkin Trans.2, 1997, 1891). The ability of a molecule (selector) to discriminate the two enantiomers of a second molecule is closely linked to some structural elements that are common to the most effective selectors known in literature: macrocyclic structure, conformational rigidity, presence of highly directional functional groups. Several molecular systems are known which possess these requisites and which show high enantioselectivity for a specific class of compounds. Highly enantioselective chiral macrocycles towards the enantiomers of amino acid derivatives of the R-CONH-CH (R) -CONHCH3 type were prepared starting from a trifunctional aromatic unit and three phenylalanine or tyrosine residues joined by amide bonds (Stili, W.C .; J . Am. Chem. Soc. 113, 1991, 5111). The enantioselectivity of this macrocycle, expressed as the difference in the energies of association with the two enantiomers (ΔΔG between 1 and 3 Kcal / mole) is close in entity to those typical of biological receptors. An analogue receptor prepared starting from two triarylbenzene units and three tyrosine residues connected by amide bonds shows high enantioselectivity (ΔΔG ~ 1 Kcal / mole) for the N-protected amino acid enantiomers (Diederich, F .; J. Chem. Soc. Perkin Trans. 2, 1997, 1891).
Sebbene siano noti selettori chirali capaci di discriminare in maniera efficace gli enantiomeri di specifiche classi di sostanze organiche, non esistono nello stato della tecnica, come si è venuto evolvendo, composti di utilità pratica che abbiano allo stesso tempo enantioselettività di tipo recettoriale (ΔΔG > 1 Kcal/mole) e siano in grado di separare gli enantiomeri di composti appartenenti a diverse classi. Although chiral selectors capable of effectively discriminating the enantiomers of specific classes of organic substances are known, in the state of the art, as has evolved, there are no compounds of practical utility which at the same time have receptor-type enantioselectivity (ΔΔG> 1 Kcal / mole) and are able to separate the enantiomers of compounds belonging to different classes.
Il macrociclo tetrammidico secondo la presente invenzione esibisce invece una struttura molecolare che possiede enantioselettività elevate con ampio campo di applicazione ed è di utilità pratica nella separazione di enantiomeri e di stereoisomeri ed, in generale, nella purificazione di composti organici ed organometallici. The tetramide macrocycle according to the present invention, on the other hand, exhibits a molecular structure that possesses high enantioselectivities with a wide field of application and is of practical utility in the separation of enantiomers and stereoisomers and, in general, in the purification of organic and organometallic compounds.
E' pertanto anche oggetto della presente invenzione un procedimento per la preparazione di una fase stazionaria chirale, utile alla separazione di sostanze organiche ed inorganiche con tecnologìe cromatografiche, mediante immobilizzazione del macrociclo tetrammidico secondo l 'invenzione sulla superficie di un supporto solido. Therefore, the present invention also relates to a process for the preparation of a chiral stationary phase, useful for the separation of organic and inorganic substances with chromatographic technologies, by means of immobilization of the tetramide macrocycle according to the invention on the surface of a solid support.
Il supporto solido può essere scelto dal gruppo comprendente silice, silice microporosa, resine polimeriche funzionalizzate quali poliacrilammide, polimetacrilato, polistirene, materiali polimerici come carboidrati, alluminati, silicati e loro combinazioni. The solid support can be selected from the group comprising silica, microporous silica, functionalized polymeric resins such as polyacrylamide, polymethacrylate, polystyrene, polymeric materials such as carbohydrates, aluminates, silicates and their combinations.
In una forma di realizzazione preferita del procedimento per la preparazione di una fase stazionaria chirale secondo la presente invenzione, il macrociclo tetrammidico, in cui X è fenile, Y è allilossi ed R è idrogeno, viene immobilizzato sulla superficie di silice 3-mercaptopropilsilanizzata mediante addizione radicalica dei gruppi tiolici ai doppi legami dei frammenti allilici. L'iniziatore radicalico può essere scelto dal gruppo comprendente α, α -azobisisobutirronitrile (AIBN), dibenzoilperossido e loro combinazioni . In a preferred embodiment of the process for the preparation of a chiral stationary phase according to the present invention, the tetramide macrocycle, in which X is phenyl, Y is allyloxy and R is hydrogen, is immobilized on the 3-mercaptopropylsilanized silica surface by addition radical of the thiol groups to the double bonds of allyl fragments. The radical initiator can be selected from the group comprising α, α -azobisisobutyronitrile (AIBN), dibenzoyl peroxide and combinations thereof.
Questa fase stazionaria chirale, con il macrociclo tetrammidico secondo l'invenzione, in cui X è fenile, Y è allilossi ed R è idrogeno, immobilizzato su silice, risulta particolarmente efficace e potenzialmente utile in processi di sviluppo e produzione di molecole chirali per le seguenti ragioni: This chiral stationary phase, with the tetramide macrocycle according to the invention, in which X is phenyl, Y is allyloxy and R is hydrogen, immobilized on silica, is particularly effective and potentially useful in the development and production processes of chiral molecules for the following reasons:
- facilità di preparazione del selettore e della silice derivatizzata,· - ease of preparation of the selector and derivatized silica,
- stabilità chimica, stereochimica e termica, che rendono questa molecola adatta all'impiego con solventi organici, acquosi e fluidi supercritici, contenenti modificatori acidi e basici (CH3COOH, CF3COOH, Et3N) ed in condizioni estreme di temperatura (da -80°C a 100°C); - chemical, stereochemical and thermal stability, which make this molecule suitable for use with organic, aqueous solvents and supercritical fluids, containing acid and basic modifiers (CH3COOH, CF3COOH, Et3N) and in extreme temperature conditions (from -80 ° C to 100 ° C);
- elevate efficienze cromatografiche, dovute alla passivazione efficace della superficie silicea, che rendono il materiale cromatografico adatto all'analisi enantiomerica di tracce; - high chromatographic efficiencies, due to the effective passivation of the silica surface, which make the chromatographic material suitable for the enantiomeric analysis of traces;
- ampio campo di applicazione; - wide field of application;
- enantioselettività non convenzionali (a > 100) verso specifiche classi di composti, con differenze nei tempi di eluizione per i due enantiomeri dell'ordine di ore. - unconventional enantioselectivity (a> 100) towards specific classes of compounds, with differences in elution times for the two enantiomers in the order of hours.
La silice contenente il selettore immobilizzato può essere impiegata come impaccamento per la preparazione di colonne cromatografiche adatte alla cromatografia liquida ad alte prestazioni (HPLC). Data la facilità di sintesi del selettore chirale, è possibile preparare quantità rilevanti (50-100g) di silice derivatizzata per applicazioni cromatografiche preparative, sia in modalità batch che S.M.B. (Simulated Moving Bed). The silica containing the immobilized selector can be used as a packing for the preparation of chromatography columns suitable for high performance liquid chromatography (HPLC). Given the ease of synthesis of the chiral selector, it is possible to prepare relevant quantities (50-100g) of derivatized silica for preparative chromatographic applications, both in batch and S.M.B. (Simulated Moving Bed).
In una serie di applicazioni pratiche, la silice modificata è stata impaccata mediante la tecnica slurry in colonne di acciaio {dimensioni 1,8 x 250 e 4,0 x 250 mm) ed impiegata nella risoluzione diretta degli enantiomeri di una vasta gamma di molecole a chiralità centrale, assiale e planare e contraddistinte dalla presenza di svariati gruppi funzionali (alcoli, acidi, ammidi, immidi, solfossidi, fosfinossidi, organometallici). In a number of practical applications, the modified silica was packed by the slurry technique into steel columns (dimensions 1.8 x 250 and 4.0 x 250 mm) and used in the direct resolution of the enantiomers of a wide range of molecules at central, axial and planar chirality and characterized by the presence of various functional groups (alcohols, acids, amides, imides, sulfoxides, phosphinoxides, organometallics).
E' infine oggetto della presente invenzione anche la fase stazionaria chirale che è ottenibile con il procedimento sopra descritto. Finally, the chiral stationary phase which can be obtained with the process described above is also an object of the present invention.
Si è data finora della presente invenzione una descrizione di carattere generale. Con l'aiuto dei seguenti esempi verrà ora fornita una descrizione più dettagliata di sue specifiche forme di realizzazione finalizzate a far meglio comprendere scopi, caratteristiche, vantaggi e modalità di applicazione dell'invenzione. Up to now, a general description of the present invention has been given. With the help of the following examples, a more detailed description of its specific embodiments will now be provided, aimed at better understanding the purposes, characteristics, advantages and methods of application of the invention.
ESEMPIO 1 EXAMPLE 1
PREPARAZIONE DEL MACROCICLO TETRAMMIDICO DELL'INVENZIONE IN CUI X È FENILE. Y È ALLILOSSI ED R È IDROGENO PREPARATION OF THE TETRAMIDE MACROCYCLE OF THE INVENTION WHERE X IS PHENYL. Y IS ALLYLOX AND R IS HYDROGEN
Preparazione del dicloruro del diacido carbossilico aromatico di formula III con Y = allilossi Preparation of the dichloride of the aromatic carboxylic diacid of formula III with Y = allyloxy
5 mL di cloruro di acetile vengono aggiunti a 100 mL dì metanolo, sotto agitazione magnetica alla temperatura di 0°C. Terminata l'aggiunta si agita per 10 minuti a 25°C e si aggiungono 5,0 g (27,45 mmoli) di acido 5-idrossiisoftalico. La miscela viene tenuta alla temperatura di riflusso per 4 ore e, dopo raffreddamento a temperatura ambiente, il solvente viene rimosso a pressione ridotta. Si ottengono 5,8 g (27,34 mmoli) del diestere metilico (5-idrossi dimetilisoftalato) riconoscibile dai seguenti spettri IR e NMR: 5 mL of acetyl chloride are added to 100 mL of methanol, under magnetic stirring at a temperature of 0 ° C. At the end of the addition, the mixture is stirred for 10 minutes at 25 ° C and 5.0 g (27.45 mmoles) of 5-hydroxyisophthalic acid are added. The mixture is kept at the reflux temperature for 4 hours and, after cooling to room temperature, the solvent is removed under reduced pressure. 5.8 g (27.34 mmoles) of the methyl diester (5-hydroxy dimethylisophthalate) are obtained, recognizable by the following IR and NMR spectra:
IR(KBr): 3361, 1728, 1704, 1597, 1269, 1253, 760 cm-1 IR (KBr): 3361, 1728, 1704, 1597, 1269, 1253, 760 cm-1
1H-NMR(CDC13):d 8,25(t, IH, J=l,6 Hz), 7,75 (d, 2H, J=1,6 Hz), 3,95 (s, 6H). 1H-NMR (CDC13): d 8.25 (t, 1H, J = 1.6 Hz), 7.75 (d, 2H, J = 1.6 Hz), 3.95 (s, 6H).
Una sospensione di carbonato di potassio (5,5 g, 40,30 mmoli) e 5-idrossi dimetilisoftalato (5,7 g, 26,87 mmoli) in 80 mL di N, N-dimetilformammide (DMF) viene tenuta sotto agitazione magnetica a temperatura ambiente in atmosfera di Argon. Dopo 30 minuti si aggiungono 3,4 mL (40,30 mmoli) di allil bromuro e si mantiene sotto agitazione per 12 ore. Si addizionano alla miscela di reazione 60 mL di etile acetato e la soluzione viene estratta con 3 porzioni (3*60 mL) di acqua. Il solvente organico viene separato, disidratato con solfato di sodio anidro e rimosso a pressione ridotta. Si ottiene dimetil-5-allilossi-isoftalato riconoscibile dai seguenti spettri IR e NMR: A suspension of potassium carbonate (5.5 g, 40.30 mmol) and 5-hydroxy dimethylisophthalate (5.7 g, 26.87 mmol) in 80 mL of N, N-dimethylformamide (DMF) is held under magnetic stirring at room temperature in an Argon atmosphere. After 30 minutes, 3.4 mL (40.30 mmoles) of allyl bromide are added and the mixture is kept under stirring for 12 hours. 60 mL of ethyl acetate are added to the reaction mixture and the solution is extracted with 3 portions (3 * 60 mL) of water. The organic solvent is separated, dehydrated with anhydrous sodium sulfate and removed under reduced pressure. Dimethyl-5-allyloxy-isophthalate is obtained, recognizable by the following IR and NMR spectra:
IR(KBr) : 3025, 3018, 3000, 2951, 1737, 1720, 1597, 1269, 760 cm-1 IR (KBr): 3025, 3018, 3000, 2951, 1737, 1720, 1597, 1269, 760 cm-1
Hl-NMR(CDC13)d 8,20 (t, IH, J=l,4 Hz), 7,65 (d, 2H, J=1,4 Hz), 6,05 (m, IH), 5,48 (m, IH), 5,32 (m, IH), 4,63 (τη, 2H). H1-NMR (CDC13) d 8.20 (t, 1H, J = 1.4 Hz), 7.65 (d, 2H, J = 1.4 Hz), 6.05 (m, 1H), 5, 48 (m, 1H), 5.32 (m, 1H), 4.63 (τη, 2H).
Una sospensione di 0,3 g (1,31 mmoli) di acido 5-allilossiisoftalico, 2 mL di cloruro di tionile e 2 mL di benzene sono tenuti alla temperatura di riflusso per 4 ore. Dopo raffreddamento i componenti volatili sono rimossi per evaporazione a pressione ridotta ed il residuo, cloruro dell'acido 5-allilossiisoftalico viene usato direttamente per la preparazione del macrociclo tetrammidico di interesse. A suspension of 0.3 g (1.31 mmol) of 5-allyloxyisophthalic acid, 2 mL of thionyl chloride and 2 mL of benzene are kept at reflux temperature for 4 hours. After cooling, the volatile components are removed by evaporation under reduced pressure and the residue, chloride of the 5-allyloxyisophthalic acid is used directly for the preparation of the tetramide macrocycle of interest.
Preparazione del macrociclo tetrammidico del titolo Ad una soluzione di (R, R)-l,2-dìfenìletilendiammìna (0,28 g, 1,31 mmoli) e diisopropiletilammina (0,36 mL, 2,6 mmoli) in 300 mL di tetraidrofurano (THF), vengono aggiunti, a 0°C e sotto agitazione magnetica, 0,35 g (1,31 mmoli) del cloruro dell'acido 5-allilossiisoftalico disciolti in 15 mL di THF. Dopo un'ora si porta la miscela a temperatura ambiente e si tiene sotto agitazione per 12 ore. Dopo evaporazione del solvente a pressione ridotta, il residuo viene purificato per cromatografia preparativa ad alta efficienza (LiChroprep Si 60, 15-25 μιη, colonna a compressione assiale 200*20 mm I.D., P=12 Bar, eluente diclorometano/metanolo 97,5/2,5). Si ottengono 0,28 g del macrociclo Tetrammidico di interesse in cui X è C6H5, Y è allilossi ed R è H (resa 56%). Il macrociclo tetrammidico di interesse è riconosciuto dai seguenti spettri IR, NMR e MS: Preparation of the tetramide macrocycle of title Ad a solution of (R, R) -1, 2-diphenylethylenediamin (0.28 g, 1.31 mmol) and diisopropylethylamine (0.36 mL, 2.6 mmol) in 300 mL of tetrahydrofuran (THF), 0.35 g (1.31 mmoles) of 5-allyloxyisophthalic acid chloride dissolved in 15 mL of THF are added at 0 ° C and under magnetic stirring. After one hour the mixture is brought to room temperature and kept under stirring for 12 hours. After evaporation of the solvent under reduced pressure, the residue is purified by high efficiency preparative chromatography (LiChroprep Si 60, 15-25 μιη, axial compression column 200 * 20 mm I.D., P = 12 Bar, eluent dichloromethane / methanol 97.5 / 2.5). 0.28 g of the Tetramide macrocycle of interest are obtained in which X is C6H5, Y is allyloxy and R is H (yield 56%). The tetramide macrocycle of interest is recognized by the following IR, NMR and MS spectra:
ESEMPIO 2 EXAMPLE 2
Immobilizzazione del macrociclo tetrammidico dell'invenzione in cui, X è fenile. 3L è allilossi ed R è idrogeno. su particelle di silice per applicazioni cromatografiche Immobilization of the tetramide macrocycle of the invention wherein, X is phenyl. 3L is allyloxy and R is hydrogen. on silica particles for chromatographic applications
Una miscela di 5 μιη (2,7 g) di silice Hypersil e 100 mL di toluene viene tenuta alla temperatura di riflusso finché tutta l'acqua adsorbita sulla silice non viene rimossa per distillazione azeotropica. Dopo raffreddamento a temperatura ambiente, si aggiungono 12,2 mi (64,6 mmoli) di 3-mercaptopropiltrimetossisilano e 5,4 mL di 4-metilmorfolina . La miscela viene tenuta alla temperatura di riflusso per 8 ore. Dopo raffreddamento la silice modificata viene isolata per filtrazione e lavata in sequenza con toluene, metanolo, etile acetato ed esano (200 mL ognuno) e seccata a pressione ridotta a 40°C. A mixture of 5 μιη (2.7 g) of Hypersil silica and 100 mL of toluene is kept at the reflux temperature until all the water adsorbed on the silica is removed by azeotropic distillation. After cooling to room temperature, 12.2 ml (64.6 mmol) of 3-mercaptopropyltrimethoxysilane and 5.4 ml of 4-methylmorpholine are added. The mixture is kept at the reflux temperature for 8 hours. After cooling, the modified silica is isolated by filtration and washed in sequence with toluene, methanol, ethyl acetate and hexane (200 mL each) and dried under reduced pressure at 40 ° C.
Analisi elementare: %C, 4,43; %H, 0,92. Elemental analysis:% C, 4.43; % H, 0.92.
Una miscela di silice 3-mercaptopropilsilanizzata (800 mg), del macrociclo tetrammidico dell'Esempio 1 (114 mg, 0,14 mmoli), α,α-bis-azobisìsobutirronitrile (7 mg, 0,04 mmoli) e diclorometano (5 mL) viene scaldata a 50°C in un recipiente chiuso di acciaio e mantenuta a questa temperatura, sotto agitazione, per 72 ore. A mixture of 3-mercaptopropylsilanized silica (800 mg), of the tetramide macrocycle of Example 1 (114 mg, 0.14 mmol), α, α-bis-azobisisobutyronitrile (7 mg, 0.04 mmol) and dichloromethane (5 mL ) is heated to 50 ° C in a closed steel container and kept at this temperature, under stirring, for 72 hours.
Dopo raffreddamento a temperatura ambiente, la silice modificata viene isolata per filtrazione e lavata in sequenza con diclorometano, metanolo, etile acetato ed esano (200 mL ognuno) e seccata a pressione ridotta a 40°C. After cooling to room temperature, the modified silica is isolated by filtration and washed in sequence with dichloromethane, methanol, ethyl acetate and hexane (200 mL each) and dried under reduced pressure at 40 ° C.
Analisi elementare: %C, 11,08; %H, 1,43; %N, 0,83 Elemental analysis:% C, 11.08; % H, 1.43; % N, 0.83
IR (KBr): 1653, 1595, 1531 cm-1. IR (KBr): 1653, 1595, 1531 cm-1.
Nel primo stadio del seguente Schema 1 di reazione viene mostrata la preparazione del macrociclo tetrammidico dell'Esempio 1, mentre nel secondo stadio di reazione viene mostrata la formazione della fase stazionaria chirale dell'esempio 2 con questo macrociclo immobilizzato su particelle di silice. In the first stage of the following reaction Scheme 1 the preparation of the tetramide macrocycle of Example 1 is shown, while in the second reaction stage the formation of the chiral stationary phase of Example 2 is shown with this macrocycle immobilized on silica particles.
ESEMPIO 3 EXAMPLE 3
Formule di alcuni composti chirali i cui enantiomeri sono separabili con la fase stazionaria chirale dell ' Esempio 2* Formulas of some chiral compounds whose enantiomers are separable with the chiral stationary phase of Example 2 *
* Il significato del radicale R è quello indicato in questo Esempio e non deve essere confuso con quello del radicale R delle formule I e II * The meaning of the radical R is that indicated in this Example and must not be confused with that of the radical R of formulas I and II
ESEMPIO 4 EXAMPLE 4
Alcuni risultati cromatografici ottenuti a livello analitico con la fase stazionaria chirale dell'Esempio 2 (colonna 4.0 x 250 mm) Some chromatographic results obtained at the analytical level with the chiral stationary phase of Example 2 (column 4.0 x 250 mm)
I dati cromatografici riportati nelle seguenti Tabelle 1, 2, 3, 4 sono stati ottenuti rispettivamente con gli eluenti a, b,c, d, e, g i cui significati sono i seguenti The chromatographic data reported in the following Tables 1, 2, 3, 4 were obtained respectively with the eluents a, b, c, d, e, g whose meanings are the following
Eluente: a, CH2Cl2/MeOH 99,5/0,5; b, esano/2propanolo 90/10 0 , 1% CF3C00H; Eluent: a, CH2Cl2 / MeOH 99.5 / 0.5; b, hexane / 2propanol 90/10 0.1% CF3C00H;
C, esano/2 -propanol 95/5; d, esano/2-propanolo 85/15. C, hexane / 2 -propanol 95/5; d, hexane / 2-propanol 85/15.
g , esano/2-propanolo 90/10; g CH2Cl2/MeOH 90/10. g, hexane / 2-propanol 90/10; g CH2Cl2 / MeOH 90/10.
Il significato di R è quello indicato per ciascuna Tabella e non deve essere confuso con il significato del radicale R nelle formule I e II indicate nella descrizione. The meaning of R is that indicated for each Table and must not be confused with the meaning of the radical R in formulas I and II indicated in the description.
TABELLA 1 TABLE 1
TABELLA 2 TABLE 2
2. Dati cromatografici 2. Chromatographic data
TABELLA 3 TABLE 3
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