SEPARATION AGENT COMPRISING POLYSACCHARIDE CARBAMATE

Abstract: A chemical substance is separated by treating a mixture containing the same with a carbamate derivative of a poly­ saccharide selected from the group consisting of cellulose, amylose, chitosan, xylan, dextran and inulin, except for an aromatic carbamate of cellulose.

Description: Separation Agent comprising Polysaccharide Carbamate The invention relates to a separation agent which comprises a polysaccharide carbamate and an optional carrier. The separation agent of the invention is useful for separation of various chemical substance, especially optical resolution of. optical isomers. fIn addition, it serves for separation of geometrical isomers and polymers having different molecular weight ranges from each other. They have not easily been separated in the state of arts. As is well-known, optical isomers usually exhibit different effects upon living organisms though they are chemically identical to each other. Therefore in order to improve the effectiveness of a medicine or an agricultural chemical per a unit dose or to prevent side effects or damages caused by it in the fields of medicines, agricultural chemicals and biochemistry-related industries, the preparation of optically pure compounds is an important task. Although a preferential crystallization method or a diastereomer method has heretofore been used to perform separation between optical isomers, the optical resolution, these methods are applicable to rather limited kinds of compounds and frequently require a long time and much labor. Therefore, there has been a demand for a technique of effecting the optical resolution by a more practical chromatographic method. Studying on the optical resolution by chromatography have long been sade. However, it has been difficult to apply resolving agents developed heretofore satisfactorily to the optical resolution of all of the compounds, because there are various problems in that they have poor resolution efficiencies, that compounds to be resolved must have special functional groups, and that the resolving agents have poor stability. ¯ objects of the Invention# It is therefore an abject of the present - invention to provide a resolving agent which has a chemical structure different from those of the existing resolution agents and, therefore, has resolution characteristics different from those of the latter or has a higher discriminating power for optical isomers. EConstitution of the Invention3 In this invention, the above object can be attained by utilizing a resolving agent comprising a carbamate derivative of a polysaccharide, except an aromatic carbamate of cellulose, as an effective component. This resolving agent can exhibit different adsorptive powers for isomers preferably having a certain optical isomerism. The polysaccharide of this invention is selected from the group consisting of cellulose, amylose, chitosan, dextran, xylan and inulin, which are easily available as higly pure polysaccharides. It is preferred that the number-average degree of polymerization (the average number of pyranose of furanose rings per molecule) of these polysaccharides are at least 5, preferably at least 10, and that they are not higher than 500, because of easiness of handling, though there is no special upper limit. The carbamoyl groups of the polysaccharide carbamate derivative of the present invention are N-substituted charbamoyl groups of 2 to 30, preferably 2 to 20, atoms and the substituent on N atoms includeEaromatic groups such as phenyl, a-or S- naphthyl, 4-nitrophenyl, etc., heteroaromatic groups; substituted derivatives thereof; aliphatic (alicyclic) groups such as methyl; and substituted derivatives thereof, etc. In said carbamate derivatives, 30 to 100%, preferably 85 to 100%, on the average, of the total hydroxyl groups of the corresponding polysaccharides form urethane bonds together with said carbamoyl groups. Although the hydroxyl groups other than the above may be free hydroxyl groups, they may be esterified, carbamoylated or etherified to an extent not detrimental to the isoner resolving power of said carbanate derivatives. For the synthesis of said carbamate derivatives, a common reaction for forming a urethane from an alcohol and an isocyanate can be applied directly. For example, they can be obtained by reacting polysaccharides with the corresponding isocyanates by using a catalyst comprising a Lewis base such as a tertiary amine or a Lewis acid such as a tin compound. When the resolving agent of the present invention is used in resolving a compound or its optical isomers, it is a general practice to resort to chromatographic means such as gas chromatography, liquid chromatography, or thin layer chromatography, but it is also possible to perform membrane separation. When the resolving agent of the present invention is applied to liquid chromatography, use is made of methods such as one in which the agent in the form of powder is packed in a column, one in which the agent is applied to a capillary column as a coating, one in which the agent is formed into capillaries to utilize their inside walls, and one in which the agent is spun into fiber and a bundle of the fibers is used as a column. Among these methods, the powder method is most general. When said resolving agent is formed into powder, it is preferable to grind it or to form into beads. Although the particle size varies with the size of a column or a plate used, it is 1 um to 10 mm, preferably 1 Wm to 300 urn, and it is preferable that the particles are porous. In order to improve the ressure durability of the resolving agent, to prevent its swelling or shrinkage caused by solvent replacement, and to improve the number of thoretical plates, it is preferable to support said separation agent on a carrier. Although the suitable size of a carrier varies with the size of a column or a plate used, it is generally 1 urn to 10 mm, preferably 1 um to 300 pm. The carrier is preferably porous, and the average pore diameter is 10 to 100 vm, preferably 50 to 50,000 . The amount of said resolving agent supported is 1 to 100 wt.%, preferably 5 to 50 wt.%, based on a carrier. The method for supporting said resolving agent on a carrier nay be chemical or physical one. Examples of the physical methods include one comprising dissolving said resolving agent in a solvent in which the agent is soluble, thoroughly mixing the solution with a carrier, and distilling off the solvent from the mixture by evacuation or passing an air stream with heating and one comprising dissolving said resolving agent in a solvent in which the agent is soluble, thoroughly mixing the solution with a carrier, and dispersing the mixture by agitation in a liquid incompatible with said solvent to diffuse said solvent into the liquid. When crystallizing said resolving agent supported on the carrier in this way, it is possible to treat it by, for example, heating. It is also possible to modify the state of supporting and, in its turn, its resolving power by swelling or dissolving said resolving agent in a small amount of a solvent and distilling off the solvent again. The carriers which can be mentioned include porous organic and inorganic carriers, among which the latter is preferable. Examples of the porous organic carriers which can be suitably used include high-molecular substances such as polystyrene, polyacrylamide, and polyacrylate. Examples of the porous inorganic carriers which can be suitably used include synthetic and natural substances such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin, and it is possible to subject them to a surface treatment to improve their affinities for said resolving agent. Examples of the surface treatments include a silane treatment in which an oraganosilane is used and a surface treatment by plasma polymerization. When said resolving agent is applied to the separation of compounds or the resolution of optical isomers, even resolving agents which are chemically the same frequently show different separation characteristics if they differ in physical properties such as molecular weight, crystallinity, and orientability. Therefore, when said resolving agent is applied according to any of the above-mentioned processes, it is possible to modify the separation characteristics so as to meet the intended use by selecting solvents used in the process, or performing heat-treatment or etching after the process, or physical treatment such as swelling with a liquid. There is no particular limitation on developing solvents which are used in performing liquid or thin layer chromatography, except that those liquids which dissolve said resolving agent or react therewith must be excluded. There is no particular limitation on developing solvents except that reactive liquids must be excluded, when said resolving agent is bonded to a carrier by a chemical method, or it is insolubilized by crosslinking. Since the separation characteristics of compounds or optical isomers are, of course, affected by a developing solvent used, it is desirable. to select a suitable 'developing solvent according to the purpose. In performing thin layer chromatography, it is desirable to coat a support with a 0.1 to 100 mmthick layer comprising said resolving agent in the form of particles of a diameter of 0.1 urn to 0.1 mm and, if necessary, a small amount of a binder. When performing membrane separation, the resolving agent is used in the form of hollow yarn or film. The resolving agent of the present invention comprising a carbamate derivative of a polysaccharide as an effective component is effective for the separation of a variety of compounds, and especially extremely effective for the resolution of optical isomers which are heretofore very difficultly separated. One of the optical isomers of a compound to be resolved will be adsorbed more strongly than the other on the resolving agent of the invention. The present invention will now be described in detail with reference to examples, but it should be noted that the present invention is by no means limited thereto. The definitions of the terms used in the examples are as follows: EMI9.1 (void volume) capacity ratio of enantiomer separation adsorbed ratio of more strongly factor lc} capacity ratio of enantiomer adsorbed less strongly I 2 x (distance between peaks of more strongly adsorbed enantiomer and resolution (s) = more weakly adsorbed enantiomer) total of band widths of both peaks Synthesis Example 1 (synthesis of cellulose trimethyl carbamate) An excess (10 ml) of methyl isocyanate was added to a mixture (1 g:l.5 g: :l5 g:l g) of cellulose, LiCl, N,N-diinethylacetarnide and pyridine, and the resulting mixture was kept at about 80 CC to complete the reaction. The reaction product was precipitated from a large amount of methanol, and the precipitate was filtered through a glass filter, washed with methanol and dried in vacuo. Elementary analysis %C %H %N Found: 43.02 5.88 14.90 Calculated: 43.24 5.75 . 12.61 Synthesis Example 2 (synthesis of amylose trisphenyl carbamate) 1 g of amylose and 8 ml of phenyl isocyanate were added to 50 ml of pyridine, and the mixture was kept at about 110 C to complete the reaction. The reaction product was precipitated from a large amount of methanol, and the precipitate was filtered through a glass filter, washed with methanol and dried in vacuo. Elementary analysis %C %H %N Found: 61.20 4.70 7.95 Calculated: 62.42 4.85 8.09 Synthesis Examples 3 through 6 Xylan, chitosan, dextran, or inulin was reacted in the same way as in Example 2. Results of the elementary analysis of xylan bisphenylcarbamate(Synthesis Example 3) %C %H %N Found: 59.07 5.20 6.88 Calculated: 61.62 4.90 7.56 Results of the elementary analysis of chitosan trisphenylcarbamate (Synthesis Example 4) %C %H %N Found: 61.50 4.51 10.18 Calculated 62.54 5.05 10.81 Results of the elementary analysis of dextran trisphenylcarbamate(Synthesis Example 5) Found: 60.39 4.78 7.61 Calculated: (62.42) (4.85) (8.09) Results of the elementary analysis of inulin trisphenylcarbamate (Synthesis Example 6) %C %H %N Found: 62.00 4.84 8.09 Calculated: 62.42 4.85 8.09 Examples 1 through 6 A mixture (10 g:50 g:l g:2 g) of silica gel (trademark Lichrospher SI-4000 la product of Merck), benzene dried over metallic sodium, pyridine, and y-aminopropyltriethoxysilane was reacted at 80 0C for 16 hours under a stream of nitrogen. The reac tion mixture was poured into methanol, and the precipitate was filtered, washed with methanol and dried. Elementary analysis C: 0.23%, H: 0.07%, N: 0.09%. 750 mg of each of the polysaccharide derivatives obtained in Synthesis Examples 1 through 6 was dis solved in 10 ml of a solvent shown below, and the solution was mixed with the silane-treated silica gel obtained in Synthesis Example 7. The solvent 'was distilled off to prepare a supported resolving agent. Example No. Polysaccharide derivative Solvent 1. cellulose trismethylcarbamate N,N-dimethyl acetamide 2. amylose trisphenylcarbamate dioxane 3. chitosan trisphenylcarbamate chloroform/form aldehyde (10:1.5) 4. xylan bisphenylcarbamate N,N-dimethyl acetamide 5. dextran trisphenylcarbamate N,N-dimethyl acetamide 6. inulin trisphenylcarbamate dimethyl sulfoxide Application Example 1 Each of the resolving agents obtained in Examples 1 through 6 was packed in a stainless steel column (25 cm x 0.46 (i.d.) cm) by a slurry filling method. The number of theoretical plates for the compound having a smaller adsorptive power was 4,000 to 7,000. The high performance liquid chromatograph used was Trirotor-Il (a product of Japan Spectroscopic Co.), the detector was uVIDEC-100-III (a product of Japan Spectroscopic Co.), and the polarimeter used was DIP-181 (cell: 5 cm x 0.3 cm (i.d.), a product of Japan Spectroscopic Co.). The flow rate was 0.5 ml/min and the temperature was 250C. The results of the resolution are summarized in Tables 1 through 5. Table I (Resolving agent of Example 1) EMI14.1 <tb> <SEP> separation <tb> <SEP> Racemates <SEP> factor <SEP> Eluent <tb> <SEP> a <tb> <SEP> . < <tb> <SEP> M)ffi(o## <SEP> 1 <SEP> hexane/2-propanol <tb> 99:1 <tb> I <SEP> 128 <SEP> hexane <SEP> /2 <SEP> -propanol <tb> ss <SEP> < <SEP> C0y <SEP> pr <SEP> 90:10 <tb> <SEP> c?NE#1L <SEP> hexane/2-propanol <tb> <SEP> 1.19 <SEP> 90: :10 <tb> Table 2 (Resolving agent of Example 2) EMI15.1 <tb> <SEP> capacity <SEP> separation <SEP> Resolution <tb> kj <SEP> Racefnates <SEP> ratio <SEP> actora <tb> <SEP> ki <SEP> ratio <SEP> factor <SEP> Rs <tb> <SEP> N <tb> O.77(+) <SEP> 1.28 <SEP> 1.10 <tb> <SEP> 0 <tb> I <tb> <SEP> CoCacac)3 <SEP> cc( C)3 <SEP> 1.80(-) <SEP> 1.28 <SEP> 0.87 <tb> 1 <tb> <SEP> Cr(acac)3 <SEP> 1.73(+) <SEP> 1.32 <SEP> 1.24 <tb> <SEP> Cr <tb> <SEP> CON#P# <SEP> 0.92(-) <SEP> 1.48 <SEP> l#20 <tb> <SEP> CONEY'^ <tb> <SEP> C <SEP> OCOR- <SEP> 0.89t-) <SEP> 1.14 <SEP> 0.66 <tb> <SEP> OCOPh <tb> r <SEP> CONE#-#fi <tb> t <SEP> LL <SEP> 1.86(+) <SEP> 1,22 <SEP> 0.72 <tb> <SEP> CONEB"a <tb> <SEP> C <SEP> ON-Ph <tb> &verbar; <SEP> < <SEP> c <SEP> O <SEP> ¯ <SEP> 2 <SEP> F <SEP> 1. <SEP> 83(+) <SEP> 1r.52 <SEP> ¯ <tb> Eluent: hexane/2-propanol (9:1) Table 3 (Resolving agent of Example 4) EMI16.1 <tb> Separation <SEP> Resolution <tb> <SEP> Racemates <SEP> Racemates <SEP> taifactor <SEP> | <SEP> Rs <tb> k; <SEP> ar <SEP> a <tb> 5.28(-) <SEP> 1.11 <tb> <SEP> I <tb> g <SEP> 0.67(-) <SEP> 1.26 <SEP> 1.00 <tb> <SEP> Co(acae)3 <SEP> 3.27(-) <SEP> 1.17 <SEP> 0.72 <tb> <SEP> Cr(acac)3 <SEP> 2.83(-) <SEP> 1.18 <SEP> 0.73 <tb> <SEP> CONHPh <tb> L <SEP> 0.#41+) <SEP> 1.79 <SEP> 1,43 <tb> <SEP> vCO <SEP> t <SEP> o <tb> <SEP> (CrOCOPh <SEP> 3.96(-) <SEP> %I <tb> <SEP> OCOPto <SEP> t <tb> <SEP> imC0O0#: :#Th## <SEP> l.68(+) <SEP> 1.28 <SEP> 0.80 <tb> <SEP> I <SEP> 1.68(+) <SEP> 1.28 <SEP> 0,80 <tb> <SEP> l <tb> <SEP> I <SEP> I <tb> <SEP> C-C <SEP> ¯ <SEP> 2.66(+) <SEP> i <SEP> 1.14 <SEP> 0.95 <tb> <SEP> I <SEP> 1 <SEP> I <tb> <SEP> Oil <SEP> 0 <SEP> 1 <tb> Eluent: hexane/2-propanol (9:1) Table 4 (Resolving agent of Example 3) EMI17.1 <tb> F <SEP> Racemates <SEP> a <SEP> Eluent <tb> <SEP> factor <SEP> Eluent <tb> 1 <SEP> 1.08 <SEP> 70 <SEP> 30 <tb> <SEP> Q <SEP> Pn <SEP> 1.22 <SEP> ethanol <SEP> water <tb> I <SEP> CONRPh <tb> <SEP> 0 <SEP> t <SEP> | <SEP> 1.37 <SEP> hexane <SEP> 2-propanol <SEP> | <tb> <SEP> I <SEP> H <tb> <SEP> ethanol/water <tb> <SEP> CF3 <SEP> 1.41 <SEP> 70: :30 <tb> Table 5 (Resolution agent of Example 5) EMI18.1 <tb> <SEP> capacity <SEP> Separation <SEP> Resolution <tb> <SEP> Racemates <SEP> | <SEP> ratio <SEP> 1 <SEP> ffactor <tb> <SEP> or <SEP> a <SEP> Re <tb> JAM <SEP> I <SEP> 0.67(+) <SEP> 1.13 <SEP> 0.49 <tb> <SEP> I <tb> <SEP> Co(acac)3 <SEP> | <SEP> 3.39(-) <SEP> 12.32 <SEP> 2.64 <tb> <SEP> Cr(acac)3 <SEP> 2.94(+) <SEP> 1.81 <SEP> 2.19 <tb> <SEP> CO#P,3tr <tb> <SEP> ¯¯ <SEP> 0.49 <SEP> s-} <SEP> 1.33 <SEP> o <SEP> .82 <tb> = <SEP> 1.33 <SEP> 0.82 <tb> <SEP> CON-fi## <tb> <SEP> O.64(+) <SEP> 1.47 <SEP> 1.04 <tb> <SEP> I <tb> <SEP> CONE?h <tb> Eluent: hexane/2-propanol (9:1)

Claims: The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: A method of separating a chemical substance from a mixture containing the same, which comprises the step of treating said mixture with a carbamate derivative of a polysaccharide selected from the group consisting of cellulose, amylose, chitosan, xylan, dextran and inulin, except for an aromatic carbamate of cellulose. A method as claimed in Claim 1, in which' said carbamate derivative has a substitution ratio by the carbamoyl group of 85 percent or more. A separating agent which comprises particles having a size of 1 micron to 10 mm and essentially consisting of the carbamate derivative of a polysaccharide as defined in Claim 1. A separating agent which comprises a carrier having a particle size of 1 micron to 10 mm and a pore size of 10 A to 100 microns and the carbamate derivative of a polysaccharide as defined in Claim 1. A method as claimed in Claim 1 which applies to the optical resolution of a mixture of optical isomers. A method as claimed in Claim 1, in which the method is conducted through a chromatographic column or layer.

Inventors: HATADA, KOICHI, OKAMOTO, YOSHIO
Applicants: DAICEL CHEMICAL INDUSTRIES, LTD.
Application year: 1985
Main classification: C07B57
IPC codes: B01J20, B01D15, B01D71, C07B63, C09K3, C07B57, C07C67, G01N30, C07C45, C07B31