United States Patent (19) 11 Patent Number: 5,198,429 König Et Al

USOO5198429A United States Patent (19) 11 Patent Number: 5,198,429 König et al. (45) Date of Patent: Mar. 30, 1993

54 SUBSTITUTED CYCLODEXTRINS AND cally Modified Cyclodextrins", pp. 1417, 1427-1433, PROCESS FOR CHROMATOGRAPHC 1472, see page 1431. SEPARATION OF CHRAL ORGANIC Starch/Starke, vol. 39, No. 10, Oct. 1987, VCH Ver COMPOUNDS lagsgesellschaft mbH (Weinheim, DE), J. Szejtli: "Ap plication of Cyclodextrins in the Chromatography', pp. 75) Inventors: Wilfried König, Pinneberg; Gerhard 357-362, see page 358. Wenz, Mainz; Sabine Lutz, Hamburg; Chemical Abstracts, vol. 109, No. 15, Oct. 10, 1988 Eva von der Bey, Mainz, all of Fed. (Columbus, Ohio, US), W. A. Koenig et al.: "Modified Rep. of Germany cyclodextrin a New Highly Enantioselective Stationary 73) Assignee: Macherey-Nagel & Co., Phase for Gas Chromatography', p. 331, Abstract No. Duren-Rolsdorf, Fed. Rep. of 125206x of Angew. Chem. 1988, 100(7), 989-90. Germany Primary Examiner-Ronald W. Griffin 21) Appl. No.: 585,117 57 ABSTRACT (22) PCT Filed: Mar. 25, 1989 Substituted cyclodextrins of the general formula (86 PCT No.: PCT/EP89/00332 S 371 Date: Dec. 3, 1990 S 102(e) Date: Dec. 3, 1990 87 PCT Pub. No.: WO89/09235 PCT Pub. Date: Oct. 5, 1989 30 Foreign Application Priority Data Mar. 30, 1988 DE Fed. Rep. of Germany ...... 38,0737 51 Int. Cl...... C08B 37/16; CO7B 63/00 in which 52 U.S. C...... 514/58; 536/103; R2 and R6 mean straight-chain or branched alkyl or 435/280,562/401; 210/632; 210/634; 210/635; alkenyl groups with 1 to 8 carbon atoms or cycloal 210/636 kyl groups with 5 to 8 carbon atoms which can be 58) Field of Search ...... 536/103; 514/58; the same or different, and 435/280; 562/401; 210/632, 634, 635, 636 R3 represents a straight-chain or branched alkyl or (56) References Cited alkenyl group, which can be the same or different to the residues R2 and R6, with 1 to 8 carbon atoms U.S. PATENT DOCUMENTS or a cycloalkyl group with 5 to 8 carbon atoms, or 4,582,900 4/1986 Brandt et al...... 536/103 an acyl group with an optionally substituted, satu 4,590,167 5/1986 Gunther et al...... 436/162 rated or olefinically unsaturated aliphatic or cyclo 5,078,886 l/1992 Hsu ...... 562/401 aliphatic or with an aromatic hydrocarbon residue with 1 to 8 carbon atoms, and FOREIGN PATENT DOCUMENTS n=6 or 7, 0.146841 7/1985 European Pat. Off. . a process for their production, and a process for the separation of chiral organic compounds by chro OTHER PUBLICATIONS matographic separation processes in which the Chemical Abstracts, vol. 109, Oct. 10, 1988 Abstract substituted cyclodextrins are used as stationary 109: 125206X. phase. Tetrahedron, vol.39, No. 9, 1983 Pergamon Press Ltd. (Oxford, GB), A. P. Croft et al.: "Synthesis of Chemi 15 Clains, 6 Drawing Sheets U.S. Patent Mar. 30, 1993 Sheet 1 of 6 5,198,429

- - -

1,2-BUTANEDIOL

,2-PENTANEDIOL

1,2-HEXANEDIOL 1,2-TR.CYCLOHEXANEDIOL g 1,2-HEPTANEDIOL 1,2-TRCYCLOHEPTANEDIOL ,2-OCTANEDIOL S. PHENYGLYCOL

1,2-NONANEDIOL - U.S. Patent Mar. 30, 1993 Sheet 2 of 6 5,198,429

22 XC-3 CH-O CH3 CH2-O-COCF3 RS

IO - 5MIN O FG.2

COOCH3 H-C-O-COCF3 F3 Co C-O-CH COOCH3

-l 5MIN s- O U.S. Patent Mar. 30, 1993 Sheet 3 of 6 5,198,429

IO -- 5 MIN O FG4

( )-CH-CH2Cd co CF3

(C-GH-CH2BrO Rs co CFs

U.S. Patent Mar. 30, 1993 Sheet 5 of 6 . 5,198,429

HC-CH-CH2COOCH3 NH CH3 bo Ha-GH-COOCH3 efs HN

as to H-CH2CH W. fe

O -- - 5 MN O FIG.8

fisco-O-CH2CH-CH C-CH2CH-CH O -CH3 NH -: s O CH3 CO ' '. U.S. Patent Mar. 30, 1993 Sheet 6 of 6 5,198,429

5, 198,429 1 2 R2 and R6 mean straight-chain or branched alkyl or SUBSTITUTED CYCLODEXTRENS AND PROCESS alkenyl groups with 1 to 8 carbon atoms or cyclo FOR CHROMATOGRAPHIC SEPARATION OF alkyl groups with 5 to 8 carbon atoms which can be CHRAL, ORGANIC COMPOUNDS the same or different, and 5 R3 represents a straight-chain or branched alkyl or The present invention relates to substituted cyclodex alkenyl group, which can be the same or different trins, to a process for their production, and to a process to the residues R2 and R6, with 1 to 8 carbon atoms for the separation of chiral organic compounds by chro or a cycloalkyl group with 5 to 8 carbon atoms, or matographic separation processes, particularly gas an acyl group with an optionally substituted, satu chromatography, using the substituted cyclodextrins as 10 rated or olefinically unsaturated aliphatic or cyclo stationary phase. aliphatic or with an aromatic hydrocarbon residue Substituted cyclodextrins are known, for example, with 1 to 8 carbon atoms, and from DE-OS 37 10569, which is no prior publication, n=6 or 7, which describes the production of ultrathin films from whereby compounds with these cyclodextrin compounds or an inclusion com 15 R2 = R3 =R6= methyl, n=6 or 7 pound on the basis of the cyclodextrin compounds. R2 = R3 =R6=ethyl, n=7 These ultrathin films can be used, for example, as pro R2 =R6=allyl, R3 = methyl, n = 7 tective film for compounds which are sensitive to light R2s=R6=prop-1-enyl, R3=methyl, n=7 and oxygen, or as carrier in chromatography. R2=R6= methyl, R3 =n-butyl, n = 7 Triethyl-g-cyclodextrin is described in Journal of R2 =R6=methyl, R3=benzoyl, n=7 and Pharmaceutical Sciences (1987, 660). An alkyl-acyl R2 = R3 = alkyl or acyl, R6=C>4-alkyl compound (R2=R6= methyl, R3 =benzoyl, n=7, of the are excluded. following general formula) is described in J. Chem. Soc. A further solution. of the problem underlying the Perkin Trans. (1987), 1323. present invention is the provision of a process for the Single cyclodextrin derivatives were also mentioned 25 chromatographic separation of chiral compounds, par as possible stationary phases, however, realization of ticularly of enantiomers. this possibility was limited due to the properties of the In this connection, compounds with known substances, this is described, for example, in R2 = R3 =R6=methyl, n=6 or 7 ACS Symposium Series, 1987, vol. 342, pages 200 to R2=R6=allyl, R3 = methyl, n = 7 217, and in Starch/Stärke, 1987, pages 357 to 358. 30 R2=R6=prop-1-enyl, R3 = methyl, n = 7 Up to now, the separation of enantiomeric, low R2=R6= methyl, R3 =n-butyl, n=7 molecular chiral compounds by gas-chromatography are excluded. has been conducted by using chiral low-molecular or The substituted cyclodextrins according to the pres polymeric separation phases with amide or diamide: ent invention permit a separation of enantiomers which Structure. 35 is mainly caused by inclusion effects at the macrocyclic Such a separation is almost exclusively limited to chiral cyclodextrins, and which-due to the separation enantioners with amide, carbamate, oxime, or hydroxyl mechanism which, compared to the separation phases groups. In this connection, intermolecular hydrogen according to the prior art, is completely different-can bridge bonds are built so that diastereomeric associates be employed even for those enantiomers not being able between chiral separation phase and chiral substrates to form hydrogen bridges and therefore could not be are formed. separated on the chiral separating phases used until In order to improve the separation results, the enan OW. tiomers to be separated were mostly converted into For the use as separation phases in gas-chromatogra derivatives with amide or carbamoyl functions. phy the compounds according to the present invention Due to the fact that the formed derivatives are diffi 45 on the one hand have the advantage of having a very cultly volatile, high operating temperatures of the chro high temperature stability of more than 200 C., on the matographic columns are required and thus leads to other hand, the separation mechanism which-com uneven courses of the base-lines of the chromatrograms pared to the separation phases known until now-is and to reduced separation efficiency due to cross diffu different in most cases permits the conversion into very SO. readily volatile derivatives, such as trifluoroacetylated It was the object of the present invention to provide compounds, which in case of correspondingly low tem improved stationary phases for the separation of chiral peratures are eluted from the column. compounds, particularly of enantiomers, and a process Those compounds in which the residues R2, R and for the separation of chiral compounds. R6 are alkyl or alkenyl groups with 3 to 6 carbon atoms 55 and/or R3 means the acetyl group are particularly pre Surprisingly,it was found that this object is achieved ferred from the series of compounds according to the by substituted cyclodextrins of the general formula: present invention of the O-peralkylated a- and 3 cyclodextrin derivatives and those in which the hy droxyl groups of the cyclodextrin are alkylated in the 2 OR6 and 6-position of the glucose units and the hydroxyl group is acylated in 3-position. O Particularly preferred are the substituted cyclodex OR3 trins consisting of 6 or 7 glucose rings and having as substituents R2, R3 and R6 the n-pentyl-group or as 65 substituent R3 the acetyl group and as R2 and Rn-pen OR2 tyl groups. The products according to the present invention are in which: produced in that at first a- or g-cyclodextrin is dis 5, 198,429 3 4. solved in an anhydrous solvent and reacted with an FIG. 6: Separation of enantiomers of amines and alkyl halide under addition of powdered alkali hydrox amino alcohols after trifluoroacetylation. R-enantiom ide. This reaction stage can be conducted in such a way ers are eluted first. 45 m-glass capillary with hep that optionally either the hydroxyl groups in 2 or 6 takis(2,6-di-O-pentyl-3-O-acetyl)-g-cyclodextrin; 140 position or the three hydroxyl groups being in 2-, 3-, C., 2/min. o and 6-position are alkylated. FIG. 7: Separation of enantiomers of chiral pharma The 2,6-di-O-alkylated intermediate product is op ceuticals (amphetamine, mexiletin, pholedrine, tranyl tionally isolated and reacted in an anhydrous solvent cypromine). 45 m-glass capillary with heptakis(2,6-di with an acylating agent, preferably an acid anhydride or O-pentyl-3-O-acetyl)-g-cyclodextrin; 175' C. an acid chloride, under the addition of a tertiary amine. 10 FIG. 8: Separation of enantiomers of a-aminobutyric The crude products respectively obtained can be acid, S-aminobutyric acid, and g-aminoisobutyric acid purified by column chromatography and isolated in after esterification with methanolic HCl and tri pure form. The characterization was carried out by H fluoroacetylation, 45 m-glass capillary with hep and C-nuclear resonance spectroscopy, respectively, takis(2,6-di-O-pentyl-3-O-acetyl)-f3-cyclodextrin; 140 and by chemical degradation with subsequent analysis 15 C. of the degradation products by combined gas chroma FIG. 9: Separation of enantiomers of spiro-acetals. 40 tography and mass spectrometry according to P. Misc m-glass capillary with hexakis(2,3,6-tri-O-pentyl)-a- hnickLibbecke, W. A. König and M. Radeloff, cyclodextrin; 100' C. Starch/Starke 39 (1987) 425. FIG. 10; Separation of enantiomers of y-lactones. 38 Coating of the separating capillary columns with the 20 m-glass capillary with hexakis(3-O-acetyl-2,6-di-O-pen substituted cyclodextrins according to the present in tyl)-a-cyclodextrin; 150 C. vention is carried out according to W. A. König and K. The invention will be illustrated by the following Ernst, J. Chromatogr. 280 (1983) 135. - examples: The capillaries filled with the separating phases ac cording to the present invention are particularly suit- 25 EXAMPLE 1. able for the separation of, for example, enantiomers of Production of hexakis(2,6-di-O-pentyl)-a-cyclodex diols, polyols, monosaccharides, methylglycosides, 1,5- trin. 10.5 g (10 mmol) a-cyclodextrin (Consortium fir anhydroalditols, hydroxy esters, alcohols, aldols, lac Elektrochemische Industrie, Minchen) Syndicate for tones, spiro acetals, amino alcohols, amines, amino-acid electrochemical industry, Munich) are dissolved in 250 esters, and other chiral compounds which, if necessary, 30 ml dimethyl sulfoxide (Riedel-de Haen) (dried over are trifluoroacetylated with trifluoroacetic acid anhy molecular sieve 4 A) under protective gas (nitrogen). dride in dichloromethane according to known pro 14.4 g (360 mmol) powdered sodium hydroxide (Merck) cesses and thus can be converted into volatile deriva and 54.4 g n-pentylbromide (Fluka) are added thereto tives suitable for gas-chromatography. 35 and stirred at room temperature. Sedimentation of a Glass or "fused-silica'-capillary columns having a white precipitate (sodium bromide) indicates the start of length of 25 m, 40 m, or 50 m were filled with the sepa the reaction. During the course of 4 further days, 18.5g ration phases according to the present invention. FIGS. (120 mmol) n-pentylbromide and 4.8 g (120 mmol) so 1 to 10 demonstrate exemplary separations of enantio dium hydroxide are each added daily. After a total of 5 mers on the separating phases hexakis(2,3,6-tri-O-pen days of reaction time, the reaction mixture is poured on tyl)-a-cyclodextrin (FIGS. 1 to 5 and 9), hexakis(2,6-di 1.5 1 water and extracted twice with 500 ml t-butyl O-pentyl-3-O-acetyl)-a-cyclodextrin (FIG. 10) and methyl ether. The combined ether phases are washed heptakis(2,6-di-O-pentyl-3-O-acetyl)-g-cyclodextrin with water and conc. solution of sodium chloride and (FIGS. 6 to 8), respectively. The Figures clearly show are concentrated under vacuum. The residue, a yellow the even baseline of the chromatograms and the excel 45 oil, is dried under vacuum (0.05 torr) at 70° C. for 16 lent separation efficiency of the separating columns hours. filled with the substituted cyclodextrins according to The crude product (15g) is fractionated by column the present invention. chromatography over 500 g silica gel Si6O (40-60 um; The following exemplary separations are shown by Merck). As mobile solvent petroleum ether (boiling the individual Figures: 50 range 60-90' C.)/t-butyl-methyl ether are used, blend FIG. 1: Separation of enantiomers of a mixture of ing ratio 70:30 (v/v). The following fractions are ob racemic diols after trifluoroacetylation, 40 m-glass cap tained:- - illary with hexakis(2,3,6-tri-O-pentyl)-a-cyclodextrin; I 800 ml impurities 48 C., 5 min. isothermal, then 2/min. II 775 ml pure product FIG. 2: Separation of enantiomers of isopropylidene 55 III 700 ml impure product glycerol after trifluoroacetylation. 40 m-glass capillary The volumes of the fractions to some extent depend with hexakis(2,3,6-tri-O-pentyl)-a-cyclodextrin; 70° C. on the water content of the silica gel. After distilling off FIG. 3: Separation of enantiomers of glyceric acid the solvent from fraction II and drying under vacuum and tartaric acid after esterification with methanolic (0.05 torr) at 70' C., 7.42 g of the pure product in form HCl and trifluoroacetylation; 40 m-glass capillary with of a colorless glass are obtained. hexakis(2,3,6-tri-O-pentyl)-a-cyclodextrin; 90' C. 1H-NMR-data (Bruker, 300 MHz, internal standard FIG. 4: Separation of enantiomers of D- and L tetramethylsilane, 8-values in toluene-ds): 5.04 (C1-H), glucose after trifluoroacetylation. 40 m-hexakis(2,3,6- 3.37 (C2-H), 4.37 (C3-H), 3.69 (C-H), 4.00 tri-O-pentyl)-a-cyclodextrin-glass-capillary; 115 C. (C5-H), 3.84 (C6-Ha), 4.0 (C6-H), 3.57 FIG. 5: Separation of enantiomers of 2-chloro-1- 65 (O-CH2(6), 3.65 (O-CH2(6)), 3.57 (O-CH2(2), 4.15 phenylethanol and 2-bromo-1-phenylethanol after tri (O-CH2(2), 1.5-1.7 (O-CH2-CH2), 1.2-1.4 fluoroacetylation. 40 m-glass capillary with hex (O-CH2-CH2-CH2), 1.2-1.4 (O-CH2-CH2-CH akis(2,3,6-tri-O-pentyl)-a-cyclodextrin; 110' C. 2-CH2), 0.8-1.0 (CH3), 5.33 (OH). 5, 198,429 5 6 The crude product so obtained (0.93 g) is fractionated EXAMPLE 2 by chromatography over 35 g silica gel Si60 (Merck, Hexakis(2,3,6-tri-O-pentyl)-a-cyclodextrin. 10.5 g (10 40-63 m). As eluting agent dichloromethane/t-butyl mmol) d-cyclodextrin are reacted with n-pentyl bromi methyl ether 50:50 (v/v) are used. The following frac de/sodium hydroxide according to Example 1. The tions are obtained: crude product so obtained is dissolved in 300 ml tetra I 65 ml impurities hydrofuran (Fluka, dried over sodium/benzophenone) II 40 ml impure product under protective gas (nitrogen). This solution is added III 180 ml pure product to 4.3 g (180 mmol) sodium hydride (Fluka, 80% sus After distilling off the solvent and drying, 0.35 g of pension in mineral oil). Adherent mineral oil is removed 10 the pure product is obtained as yellowish glass. by washing the sodium hydride with tetrahydrofuran. 1H-NMR-data (Bruker, 300 MHz, internal standard Subsequently, 27.2 g (180 mmol) n-pentyl bromide tetramethylsilane, 6-values in CDCl3): 5.03 (C1-H), (Fluka) are added thereto and refluxed under stirring 3.26-3.30 (C-H), 5.18 (C3-H), 3.81 (C4-H), for 5 days. Then the reaction mixture is poured on 500 3.90-3.99 (C5-H and C6-H), 3.36-3.54 (C6-H, ml water, and the tetrahydrofuran is distilled off. The 15 O-CH2(6), O-CH2(2), O-CH2(2), 1.4-1.59 residue is extracted twice with 200 ml t-butyl-methyl (O-CH2-CH2, O-CH2-CH2-CH2), 1.21-1.33 ether each. The unified ether phases are washed with (O-CH2-CH2-CH2-CH2), 0.86-0.92 (CH3); 2.05 water and conc. solution of sodium chloride and boiled (CH3-CO). down under vacuum. The yellow, oily residue is dried It is understood that the specification and examples under vacuum (0.05 torr) at 70° C. for 16 hours. The crude product is fractionated by column chro are illustrative but not limitative of the present inven matography over 500 g silica gel Si6O (Merck, 40-63 tion and that other embodiments within the spirit and um). As solvent petroleum ether (boiling range 60-95 scope of the invention will suggest themselves to those C.)/t-butyl-methyl ether are used, blending ratio 85:15 skilled in the art. (v/v). The following fractions are obtained: 25 We claim: I 825 ml impurities 1. A substituted cyclodextrin of the formula II 150 ml pure product (8.0 g) III 225 ml impure product (5.0 g) The volumes of the fractions to some extent depend on the water content of the silica gel. By chromatogra 30 phy of fraction III, 2.5g pure product could once again be obtained. After chromatography, the product is slightly yellowish. After filtration over 50 g aluminum oxide (basic, Merck) with petroleum ether/t-butyl methyl ether 85:15 (v/v) the compound is a transparent, 35 viscous oil. H-NMR-data (Bruker, 300 MHz, internal standard in which tetramethylsilane, 8-values in CDCl3): 5.21 (C1-H), R2, R3 and R6 each independently is an alkyl or alke 3.21 (C2-H), 3.59 (C3-H), 3.79 (C4-H), 3.70 40 nyl group having 1 to 8 carbon atoms, or a cycloal (C5-H), 3.45 (C6-H), 3.98 (C6-H), 3.35 kyl group having 5 to 8 carbon atoms, or (O-CH2(6), 3.47 (O-CH2(6), 3.66 (O-CH2(2), 3.95 R3 may be an acyl group having 1 to 8 carbon atoms (O-CH2(2), 3.53 (O-CH2(3), 3.62 (O-CH2(3)), or an acyl group substituted with an aromatic hy 1.5-1.7 (O-CH2-CH2), 1.2-1.4 (O-CH2-CH drocarbon radical or a saturated or olefinically . 2-CH2), 1.2-1.4 (O-CH2-CH2-CH2-CH2), 45 unsaturated aliphatic or cycloaliphatic radical hav 0.8-1.0 (CH3). ing 1 to 8 carbon atoms, and n is 6 or 7, EXAMPLE 3 with the exclusion of those compounds wherein R2 = R3 =R6= methyl, ne6 Ot 7, Heptakis(2,6-di-O-pentyl-3-acetyl)-3-cyclodextrin. R2 = R3 =R6=ethyl, n=7, R2 =R6=allyl, 1.06 g (0.5 mmol) heptakis(2,6-di-O-pentyl)-f3-cyclodex 50 trin (produced according to the direction of Example 2) R3=methyl, n=7, R2 =R6=prop-1-enyl, are dissolved with 21 mg (0.175 mmol) 4-dime R3=methyl, n=7, R2=R6= methyl, R3=n-butyl, thylamino pyridine (Merck) in 5 ml CH2Cl2 (Aldrich; n=7, R2=R6=methyl, R3=benzoyl, n=7 and dried by distillation over diphosphorus pentaoxide) R2 = R3 = alkyl or acyl, R6=C>4-alkyl. over nitrogen as protective gas. At first, 0.6 ml (8 mmol) 55 2. A substituted cyclodextrin according to claim 1, triethylamine (Fluka, dried by distillation over calcium wherein the alkyl and/or acyl groups have 3 to 6 carbon hydride) and subsequently 0.7 ml (7 mmol) acetic anhy atons. dride (Fluka) are added thereto. After 24 hours of re 3. A substituted cyclodextrin according to claim 1, fluxing, another 0.6 ml (8 mmol) triethylamine and 0.7 wherein R2, R3 and Rare alkyl or alkenyl groups with ml (7 mmol) acetic anhydride are added. After 72 hours 60 3 to 6 carbon atoms or R3 may be an acetyl group. of reaction, the solvent is removed under water-jet 4. A substituted cyclodextrin according to claim 1, vacuum, and the residue is taken up in 40 ml t-butyl wherein R2 and Reach is a n-pentyl-group and R is an methyl ether (Merck). The organic phase is washed acetyl group. with water, diluted NaHCO3-solution, once again wa 5. A process for the production of a substituted cy ter, diluted NaH2PO4-solution and water. The organic 65 clodextrin according to claim 1, which comprises dis phase is subsequently concentrated under vacuum, and solving an a- or £-cyclodextrin in an anhydrous sol after drying under vacuum an orange-brown oil is ob vent, adding a pulverized alkali hydroxide, and reacting tained. the cyclodextrin with an alkyl halide. 5, 198,429 7 8 6. A process according to claim 5, including the fur 11. A separation process according to claim 10, wherein the contact is made with the chiral organic ther step of reacting the product with an acylating agent compounds in gas phase. in an anhydrous solvent containing an amine. 12. A separation process according to claim 10, 7. A process according to claim 5 wherein the anhy wherein the chiral organic compounds are enantiomers. drous solvent is aprotic. 13. A separation process according to claim 12, wherein the enantiomers are selected from the group 8. A process according to claim 6 wherein the anhy consisting of alcohols, polyols, 1,5-anhydro-alditols, drous solvent is aprotic. hydroxy esters, aldols, lactones, spiro-acetals, amines, 9. A process according to claim 16, 17, or 8 wherein 10 anino-alcohols, amino-acid esters and a trifluoroacety lation product of any of the foregoing. the reactions are carried out under inert gas. 14. A separation process according to claim 13, 10. In the chromatographic separation of individual wherein the enantiomers are polyols selected from the chiral organic compounds from a mixture by contacting group consisting of diols, polyols containing more than 5 two hydroxy groups and monosaccharides. the mixture with a stationary phase, the improvement 15. A separation process according to claim 14, which comprises employing- as the stationary phase a wherein the enantionners are methylglycosides. substituted cyclodextrin according to claim 1.

65 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 5, 198, 429 DATED : March 30, 1993 INVENTOR(S): Konig et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below: 1 Title page, item (56): OTHER PUBLICATIONS: Line 4 delete " Croft " and substitute -- Groft -- Col. 7, line 10 Delete " claim 16, 17, " and substitute 6, 7,

Signed and Sealed this Twenty-eighth Day of June, 1994 (a teen

BRUCE LEHMAN Attesting Officer Commissioner of Patents and Trademarks