KR101809943B1 - Preparation method of trihydroxyethyl rutoside - Google Patents
Preparation method of trihydroxyethyl rutoside Download PDFInfo
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Abstract
The present invention relates to a process for the production of trihydroxyethyl rutoside, which comprises first preparing rutin with 7-monohydroxyethyl rutoside having a weight content of at least 98% Subsequently, hydroxyethylated to 7-monohydroxyethylrutoside to obtain troxerutin having a non-hydroxyethylated rutose derivative impurity of less than 2% , The weight content of 7,3 ', 4'-trihydroxyethylrutoside in the trocetrone is greater than 80%, and the product is continuously purified to give 7,3', 4'-trihydro Roxy ethyl rutoside can be obtained.
Description
The present invention relates to a method for preparing a drug compound, and more particularly, to a method for producing trihydroxyethyl rutoside.
Troxerutin is also known as venoruton, and its chemical name is 7,3 ', 4'-trihydroxyethyl rutoside ("trihydroxyethyl rutoside" And the molecular formula is C 33 H 42 O 19 , CAS No. 7085-55-4, the molecular weight is 742.69, and the structural formula is as follows.
Tromethorphine is an anti-coagulant and a thrombolytic agent and its preparation usually proceeds from the synthesis of tromethorphine under base catalysis by using rutin and ethylene oxide as raw materials, methanol and water as a medium. In the present market, the conventional drug substance of trocseutin is sold, and its content is 60%, 80%, and 88%, respectively.
The higher the content of the active ingredient, the higher the quality of the trihydroxyethylrutose in the tromethyleutine, but the technical means is not ideal for producing the highly pure trometroutine in the prior art.
Commercially available tromethorphine products include tromethorphan injection, tromethorphan oral solution, and tromethorphine capsules. In particular, in the case of the troxerutin injection, the impurity contained in the prior art, which is not ideal in the purity of the troxerutin, gives a relatively large safety risk to the clinical drug. In fact, when the drug is injected, There are many. Thus, increasing the purity of the TROXERRUTINE, especially obtaining the purity of the major active ingredient, trihydroxyethylrutoside, has been the direction of many researchers.
The conventional process for preparing the trocetrone is a single-step reaction process in which the rutin is immediately hydroxymethylated to complete the reaction. The hydroxyethylation reaction such as the change of factors such as the hydroxyethylating reagent, the reaction solvent, the catalyst, There are various processes depending on the burning conditions, as follows.
1. In Patent BG2888B1, trihydroxyethylrutoside having a purity of 85.8% is obtained by using water as a solvent, ammonia water as a catalyst, and ethylene oxide as a hydroxyethylating reagent.
2. In patent CN1331697 (US6855697), trihydroxyethylrutoside having a purity of 92% is obtained by using water as a solvent, an alkali metal as a catalyst, ethylene oxide as a hydroxyethylating agent and controlling the crystallization conditions.
3. In patent US3420815, sodium hydroxide is used as a catalyst. The chromatographic purity of the obtained trometachlorin is 87.4%, the content is 85.3%, and the melting point is 181 to 183 ° C.
4. In patent CN1554353, an organic solvent (methanol, ethanol) is used as a solvent and pyridine is used as a catalyst to obtain trihydroxyethylrutoside having a content of 90%.
5. Patent CN1814613 adopts a resin to control the pH value of reaction liquid and obtain trihydroxyethylrutoside with 85% content.
One of the reasons that it is difficult to obtain monomeric trihydroxyethylrutoside is that all four active hydroxy groups in the routine can be hydroxyethylated and the resulting reaction products are a mixture. Another important cause is that it is difficult to obtain a high-purity routine by a conventional method because it is difficult to purify the routine because the routines derived from nature are very similar in structure to the impurities. The patent CN200810007927.2 relates to a method for purifying the routine, and it is only by using a complicated countercurrent distribution chromatography that a routine of 98% purity in gram (g) grade can be obtained. Actually, conventionally produced trocseutrines are all commercially available routines with a relatively low purity as raw materials. In the case of these raw materials, the contained impurities can also participate in the hydroxyethylation reaction and the trihydroxyethylrutoside And the properties are very similar to each other. The production of the high purity trihydroxyethylrutoside is very difficult and it is difficult to obtain purified high purity trihydroxyethylrutoside in the form of purified liquid chromatographic separation of purified product of Lixin et al. ], A trihydroxyethylrutoside monomer was prepared in an amount of 98% or more by a conventional method except that a trihydroxyethylrutoside control product of 99% was obtained. Even if a commercially available product was promoted to be 99% pure, the production method was not disclosed and the product was not supplied. The chromatographic purity is only 96-97%, even though it is the trihydroxyethylrutoside control product which has been made by solvent recrystallization several times by adopting the prior art.
In order to solve the problems existing in the prior art, the present invention proposes a method for producing tromethylein having a low impurity content, more specifically, And a process for preparing trihydroxyethyl rutoside monomers having a content of more than 98%. The essence of the present invention is to adopt a two-step synthesis method to prepare trihydroxyethylrutoside and purify the reaction intermediate to obtain a high-purity final product.
The present invention relates to a novel process for preparing troxerutin,
1) preparing the rutin with 7-monohydroxyethyl rutoside;
2) purifying the 7-monohydroxyethyl rutose;
3) preparing trihydroxyethyl rutoside using the purified 7-monohydroxyethyl rutoside; And
4) purifying the trihydroxyethylrutoside.
In the present invention, the reaction intermediates of rutin and rutin are prepared. Since the 7-monohydroxyethylrutoside and other components in the reactant differ significantly in the impurity properties contained in the raw materials, By using the difference in properties between hydroxyethyl rutose and impurities to purify the 7-monohydroxyethylrutoside, it is possible to obtain the high purity 7-hydroxyethyl rutosaide (content greater than 98%), and the final product After removing impurities having a small property difference from trihydroxyethylrutoside at this stage, the 7-monohydroxyethylrutoside thus purified is continuously subjected to hydroxyethylation, and the reaction product is further purified and purified to give purity Gt; 98% < / RTI > of trihydroxyethyl rutoside can be obtained.
Compared to the prior art, the present invention can use a conventional purification method. In particular, since a recrystallization method can be used, a special equipment and an expensive chromatographic column are not needed, and thus the production cost can be reduced drastically, and monomer trihydroxyethyl It opens up the possibility of mass production of rutoside. However, when the method of the prior art is used, the difference in properties between the impurities and the final product is small, so that even when the final product is recrystallized by using the recrystallization method, high purity trihydroxyethylrutoside can not be obtained.
The reaction process of the present invention is as follows.
In the production method of the present invention,
The 7-monohydroxyethylrutoside preparation of step 1) above uses conventional techniques. The technique of U.S. Patent No. 4,153,788 may be employed, for example, using borax to protect
In the production process, the hydroxy group is protected using a hydroxy-protecting reagent, and then the hydroxyethylating reagent is added to conduct the reaction in a solvent. Here, the routine may be a commercially available one, wherein the hydroxyl group-protecting reagent is borax, the hydroxyethylating reagent is ethylene oxide, and the reaction solvent may be selected from the group consisting of water, methanol and ethanol, Is 30 to 50 ° C. and the reaction time is 4 to 12 hours. After completion of the reaction, the reaction solution is allowed to stand or stand at a low temperature. If necessary, the pH value of the solution can be adjusted to acidic. You can proceed.
The 7-monohydroxyethylrutocide purification of step 2) above may employ any method suitable for industrial application, for example, a recrystallization method. Herein, the 7-monohydroxyethylrutoside is purified to 95% or more purity and then the raw material is added, preferably 98% or more, and most preferably 99% or more.
The solvent used in the recrystallization method is selected from the group consisting of water, methanol, ethanol, isopropanol or a mixture thereof, and the step of recrystallization includes a step of dissolution, crystallization, and filtration.
Preparation of the trihydroxyethylrutoside using the purified 7-monohydroxyethylrutoside of step 3) above may employ conventional hydroxyethylation processes. For example, the 7-monohydroxyethylrutoside is further subjected to hydroxyethylation using a hydroxyethylating reagent such as an epoxy oxide, and the reaction solution obtained after completion of the reaction is desalted through a cation resin or an anion resin, After removing the impurities through the resin, proceed to step 4).
In the above process, the 7-monohydroxyethyl rutose is dissolved or suspended in a solvent, and the reaction is carried out by adding the hydroxyethylating reagent, wherein the hydroxyethylating reagent is an epoxy oxide , And the reaction solvent is selected from the group consisting of water, methanol, ethanol, pyridine, or a mixture thereof. The reaction temperature is 50 to 80 ° C, and the reaction time is 3 to 8 hours. The pH value of the solution can be adjusted to an acidic state, and the obtained reaction solution can be used immediately in the next step.
In the cation resin and the anionic resin, the cation resin is a strongly acidic styrene type cation exchange resin selected from the group consisting of 007 × 7 (732), 001 × 12, 001 × 14, 001 × 16 And the anionic resin is selected from the group consisting of 201 × 4 (711) and 201 × 7 (717) as a strong alkaline styrenic anion exchange resin, and the resin may be passed through the following method. That is, the reaction solution is passed through each of the resin columns, or the resin is added to the reaction solution, stirred, and separated to obtain a crude product solution of trihydroxyethyl rutosaide.
The macroporous resin is purified by a conventional method selected from among D101, D201, DAB-8 and D301, that is, after filtration of the reactant aqueous solution, the macroporous resin is immediately passed through a saponification column, washed with purified water, The organic solvent is ethanol, and the obtained product is a trihydroxyethylrutocide crude product solution. After the crude product solution is concentrated and dried, recrystallization can be carried out in the next step.
The purification in step 4) can be carried out by recrystallization to obtain pure trihydroxyethylrutoside, and the solvent used for recrystallization is selected from the group consisting of water, methanol, ethanol, isopropanol or a mixture thereof, The steps include the steps of dissolution, crystallization, and filtration.
Except where otherwise noted, all specific gravity values and percentages are percentages by mass, and the chromatographic purity is the test results obtained in accordance with the component testing method under the European Pharmacopoeia, version 7.0 Trouble Routine section, .
The advantages of the present invention are as follows.
In the prior art, high purity trihydroxyethylrutoside with a content greater than 98% can only be obtained using laboratory chromatography, which is costly and limited to laboratory research, making mass production and widespread use impossible . However, when the method of the present invention is used, highly pure trihydroxyethylrutoside can be obtained by a relatively simple process, which is low in cost and excellent in practicality.
Compared with the prior art, the present invention greatly reduces the production cost. In particular, the purification method which is common to the purification of trihydroxyethylrutoside has been adopted to greatly reduce the production cost, and related experimental data are as follows.
98% of trihydroxyethylrutoside can not be obtained by the method described in document US3420815. The chromatographic purity of the obtained product is 87.4%, the content is 84.2%, the color of the product is dark yellow, The point was 178 to 182 캜, and the cost was 400 to 500 yuan / kg. Separation by purification chromatography yielded 99% trihydroxyethylrutoside, but the cost greatly increased, which was about 5000 to 10,000 yuan / g.
Comparative data of the manufacturing process according to the document method are as follows.
According to the method of US6855697, 98% of trihydroxyethylrutoside could not be obtained, and the obtained product had a measured chromatographic purity of 92.1%, a content of 90.3%, a product of yellow color, and a melting point Was 179 to 183 占 폚, and the cost was 500 to 800 yuan / kg. Separation by purification chromatography yielded 99% trihydroxyethylrutoside, but the cost greatly increased, which was about 5000 to 10,000 yuan / g.
The 98% trihydroxyethylrutoside obtained in the present invention has a pale yellow color of the product and has a melting point of 185 to 187 ° C and a cost of 2000 to 3000 yuan / kg.
The 99% trihydroxyethylrutoside obtained in the present invention has a pale yellow color of the product and has a melting point of 186 to 188 ° C and a cost of 3000 to 5000 yuan / kg.
In the present invention, the results of the reaction products after completion of the
Footnote: R f is the duration of the impurity peak relative to the main peak.
As can be seen from the above table, the difference in physicochemical properties between 7-monohydroxyethylrutoside and the
In order to demonstrate the superiority of the present invention, the present invention is compared with the prior art closest to the present invention, as follows.
The method of US6855697 was adopted to prepare trihydroxyethylrutoside, and the method of separating and purifying trihydroxyethylrutoside in the reaction solution after completion of the reaction is as follows.
The reaction solution containing trihydroxyethylrutoside was desalted through a 732 cation resin column and a 717 anion resin column, followed by concentration under reduced pressure and spray drying. The reaction solution was heated and dissolved by adding 8000 ml of methanol, followed by addition of activated carbon for injection The filtrate was subjected to natural crystallization at room temperature for 6 hours, filtered by suction, and the solid was dried at 40 to 50 ° C to give trihydroxyethylrutoside And the detected content was 88.2%. The obtained solid was subjected to recrystallization purification and drying using 20-fold amount of methanol in the same manner, and the content of trihydroxyethylrutocide was 90.6%.
The reaction solution containing trihydroxyethylrutocide was desalted through a 732 cation resin column and 711 anion resin column, and then concentrated under reduced pressure and spray-dried. 7000 ml of methanol-water (37: 3) The filtrate was subjected to natural crystallization at room temperature for 6 hours, followed by suction filtration, and the solid was dried at 40 to 50 ° C to obtain a filtrate. Trihydroxyethyl < / RTI > rutoside was obtained, and the detected content was 90.1%. The obtained solid was subjected to recrystallization purification and drying using methanol-water (37: 3) in an amount of 20 times by the same method, and the content of trihydroxyethylrutoside was 91.60%.
The reaction solution containing trihydroxyethylrutocide was desalted through a 001X14 cationic resin column and a 717 anion resin column, and then concentrated under reduced pressure and spray-dried. 9000 ml of methanol-isopropanol (95: 5) was added and heated to dissolve The filtrate was subjected to natural crystallization at room temperature for 6 hours, followed by suction filtration, and the solid was dried at 40 to 50 ° C to obtain a filtrate. Trihydroxyethyl < / RTI > rutoside was obtained, and the detected content was 91.7%. The obtained solid was subjected to recrystallization purification and drying using a 20-fold amount of methanol-isopropanol (95: 5) in the same manner, and the content of trihydroxyethylrutocide was 92.4%.
The method of the present invention is adopted to prepare trihydroxyethylrutoside, and the trihydroxyethylrutoside in the reaction solution after the completion of the reaction is separated and purified.
The reaction solution containing trihydroxyethylrutoside was desalted through a 732 cation resin column and a 717 anion resin column, followed by concentration under reduced pressure and spray drying. The reaction solution was heated and dissolved by adding 8000 ml of methanol, followed by addition of activated carbon for injection The filtrate was subjected to natural crystallization at room temperature for 6 hours, filtered by suction, and the solid was dried at 40 to 50 ° C to give trihydroxyethylrutoside And the detected content was 92.4%. The obtained solid was subjected to recrystallization purification and drying using 20-fold amount of methanol in the same manner, and the content of trihydroxyethylrutocide was 98.2%.
The reaction solution containing trihydroxyethylrutocide was desalted through a 732 cation resin column and 711 anion resin column, and then concentrated under reduced pressure and spray-dried. 7000 ml of methanol-water (37: 3) The filtrate was subjected to natural crystallization at room temperature for 6 hours, followed by suction filtration, and the solid was dried at 40 to 50 ° C to obtain a filtrate. Trihydroxyethyl < / RTI > rutoside was obtained, and the detected content was 93.5%. The obtained solid was subjected to recrystallization purification and drying using methanol-water (37: 3) in an amount of 20 times by the same method, and the content of trihydroxyethylrutoside was 98.3%.
The reaction solution containing trihydroxyethylrutocide was desalted through a 001X14 cationic resin column and a 717 anion resin column, and then concentrated under reduced pressure and spray-dried. 9000 ml of methanol-isopropanol (95: 5) was added and heated to dissolve The filtrate was subjected to natural crystallization at room temperature for 6 hours, followed by suction filtration, and the solid was dried at 40 to 50 ° C to obtain a filtrate. Trihydroxyethyl < / RTI > rutose was obtained, and the detected content was 95.8%. The obtained solid was subjected to recrystallization purification and drying using a 20-fold amount of methanol-isopropanol (95: 5) in the same manner, and the content of trihydroxyethylrutocide was 98.6%.
As can be seen from the above comparison, when the purification is carried out by the same method, the purification effect of the process of the present invention is more excellent.
The trihydroxyethylrutoside having a purity of 91.3% prepared by the prior art, for example, US6855697, is continuously subjected to recrystallization purification several times using a mixed solvent of methanol and isopropanol (95: 5) in an amount of 20 to 25 times After repeating, we still could not get pure product, and the result is as follows.
1 is an HPLC chromatogram of 7-monohydroxyethyl rutoside reaction solution in the present invention;
Figure 2 is an HPLC chromatogram after 7-mono hydroxyethyl rutoside purification in the present invention;
Figure 3 is the final product trihydroxyethylrutocide (98%) HPLC chromatogram for the present invention;
Figure 4 is the final product trihydroxyethylrutoside (99%) HPLC chromatogram for the present invention;
Figure 5 is the final product trihydroxyethylrutose HPLC chromatogram for the method of document 6855697; And
FIG. 6 is a commercially available trihydroxyethylrutoside control (96%) HPLC chromatogram (Chinese Pharmacogenetics Assay 100416-200503).
The following does not limit the scope of protection of the present invention as an embodiment of the present invention.
Example 1:
1. 328 g, 0.86 mol borax (Na 2 B 4 O 7 .10H 2 O) was added to 2500 ml of deionized water and dissolved by stirring and then again 605 g, 0.82 mol of rutin added and 40 to 45 ≪ / RTI > until dissolved, and filtered to obtain a purified aqueous solution of rotoin-borax complex. The solution was kept at 40 to 45 DEG C, and 88 g of 2 mol ethylene oxide was poured into the reaction solution under stirring. The reaction time was about 6 hours, and the reaction proceeded until the HPLC detection reaction was completely completed. The pH value was adjusted to 2.0 using 5N hydrochloric acid, and the mixture was allowed to stand at 3 to 5 ° C for 12 hours. The mixture was subjected to suction filtration to obtain a solid filter cake. The contained 7-monohydroxyethyl rutoside was 504 g , And the yield is 95%.
2. 1460 g of the 7-monohydroxyethylrutoside water-containing solid obtained in 1 above was added to 4750 ml of deionized water and heated to 60 ° C under stirring to completely dissolve and then filtered, And the solid obtained by suction filtration was dried at 40 to 50 ° C for 12 hours to obtain 450 g of 7-monohydroxyethylrutoside. The content calculated according to anhydrous was 98.3%, and the chromatographic purity was 98.6% %, The yield is 89.3%, and the total yield is 84.8%.
0.7 mol, 490 g of 7-monohydroxyethylrutoside and 5.6 g of sodium hydroxide obtained in 3.2 were added to 1880 ml of deionized water, maintained at 75 to 80 캜 by stirring and heating, and 92 g of ethylene oxide (2.1 Mol) is poured into the reaction solution, and the reaction is maintained for 5 to 6 hours. When the specific gravity of trihydroxyethylrutoside reaches 75 to 78% by HPLC test, the addition of ethylene oxide is stopped, When the temperature dropped to 40 ° C or lower, 3N hydrochloric acid was added to adjust the pH value to 5.0 ± 0.2. The reaction solution was desalted through 732 cationic water column and 717 anion water index, and then concentrated under reduced pressure, By spray drying, 520 g of a solid powder was obtained. The trihydroxyethylrutocide content was 92.3%, the melting point was 180 to 183 캜, the yield was 98%, and the total yield was 83.1%.
500 g of the solid powder obtained in 4.3 was added, and 10000 ml of methanol was added and heated until dissolved. 1.0 g of activated carbon for injection was added and the mixture was stirred for 30 minutes. When heat was retained, suction filtration was carried out, Was subjected to natural crystallization at room temperature for 6 hours, filtered by suction, and the solid was dried at 40 to 50 DEG C to obtain 410 g of trihydroxyethylrutoside. The content was 96.8%, the yield was 82%, and the total yield was 68.1 %to be.
5.4 g of the solid powder obtained in 4) was added, and 9500 ml of methanol was added. The mixture was heated until dissolved and refluxed for 30 minutes. When heat was retained, suction filtration was carried out. The filtrate was subjected to natural crystallization at room temperature for 6 hours, The solid was vacuum-dried at 40 to 50 ° C to obtain 338 g of trihydroxyethylrutoside. The content was 98.2%, the chromatographic purity was 98.4%, the melting point was 184 to 186 ° C, and the yield was 82.5 %, And the total yield is 56%.
Example 2
1. 164g, 0.43 mole borax (Na 2 B 4 O 7 · 10H 2 O), 12g, 0.3 mol was added to sodium (NaOH) with 2000ml de-ionized water and hydroxide added thereto, followed by stirring, and then re-605g, 0.82 mol and dissolving the routine , The temperature was heated and maintained at 40 to 45 DEG C, and 88 g of 2 mol ethylene oxide was poured into the reaction solution under stirring. The reaction time was about 12 hours, and the reaction proceeded until the HPLC detection reaction was completely finished. The pH value was adjusted to 2.0 using hydrochloric acid, and the mixture was allowed to stand at 3 to 5 ° C for 12 hours. The solid filtration cake was obtained by suction extraction. The contained 7-monohydroxyethyl rutose was 510 g, and the yield was 96% .
2. 510 g of the 7-monohydroxyethylrutoside obtained in 1 above (total weight 1450, moisture content 940 g) was added to 2000 ml of deionized water, heated to 40 캜 under stirring, and a saturated aqueous solution of sodium hydrogencarbonate was added to solid The filtrate was adjusted to pH 4.0 with 0.1 molar hydrochloric acid and left overnight at 3 to 5 ° C. The solid obtained by suction filtration was subjected to filtration at 40 to 50 ° C for 12 433 g of 7-monohydroxyethyl rutose was obtained (total weight 470 g), and the calculated amount was 98.6%, the chromatographic purity was 98.8%, the yield was 85%, the total yield was 81.6% to be.
0.67 mol obtained in 3.2, 433 g of 7-monohydroxyethylrutoside and 5.6 g of ammonia water were taken and added to 1880 ml of deionized water, maintained at 75 to 80 캜 by stirring and heating, and 92 g (2.1 mol) of ethylene oxide ) Was poured into the reaction solution and the reaction was maintained for 5 to 6 hours. When the specific gravity of trihydroxyethylrutoside reached 75 to 78% in the HPLC test, the addition of ethylene oxide was stopped. At the same time, When the temperature dropped and the reaction solution dropped to 40 ° C or less, the reaction solution was directly purified by D101 macroporous resin pretreated. The resin volume was 20 kg. After completion of the addition of the sample, the washing solution was firstly neutralized with deionized water And the test solution was examined with silver nitrate test solution. After washing until the liquid became colorless with 60% ethanol, the washing solution was collected, and 2500 ml If concentration under reduced pressure, to obtain a solid powder by spray drying, 465g, tri-hydroxyethyl and ruto side content was 92%, and the yield was 86%, the total yield of 70.2%.
465 g of the solid powder obtained in 4. 3 was added and 8000 ml of methanol was added and heated until dissolved. 1.0 g of activated charcoal was added, and the mixture was stirred for 30 minutes. When heat remained, suction filtration was carried out, Was subjected to natural crystallization at room temperature for 6 hours, filtered by suction, and the solid was dried at 40 to 50 DEG C to obtain 381 g of trihydroxyethylrutoside. The content was 97.2%, the yield was 82%, and the total yield was 57.6 %to be.
The solid powder (381 g) obtained in 5.4 was taken and 10500 ml of methanol was added. The mixture was heated until dissolved and refluxed for 30 minutes. When the heat remained, suction filtration was carried out. The filtrate was subjected to natural crystallization at room temperature for 6 hours, The solid was vacuum-dried at 40 to 50 DEG C to obtain 314 g of trihydroxyethylrutoside. The content was 98.3%, the chromatographic purity was 98.3%, the melting point was 184 to 186 DEG C, and the yield was 82.5 %, And the total yield is 47.5%.
Example 3
1. Add 328 g, 0.86 mol of borax (Na 2 B 4 O 7 · 10 H 2 O) to 2000 ml of deionized water and dissolve with stirring, then add 605 g, 0.82 moles of rutin, and dissolve at 40-45 ° C After stirring, the solution is filtered to obtain a purified aqueous solution of rhodium-borax complex. The solution was maintained at 40 to 45 캜, and 88 g of 2 mol ethylene oxide was poured into the reaction solution under stirring. The reaction time was about 6 hours, and the reaction proceeded until the HPLC detection reaction was completely completed. , And the resin volume was 25 kg. After completion of the sample addition, the filtrate was washed with deionized water until the pH value of the effluent was close to neutrality. First, 2000 ml of 10% ethanol Washed with 10000 ml of 60% ethanol, thoroughly washed with 90% ethanol, collected in a 60% ethanol effluent, concentrated in vacuo until the alcohol odor was removed, water was added to 12000 ml, The filtrate cake was washed with ice water to obtain 473 g of 7-monohydroxyethylrutoside (total weight 1440 g), and the content calculated according to the anhydrous amount And 99.3%, chromatographic purity is 99.3%, yield of 89.3%.
1440 g of the 7-monohydroxyethylrutoside water-containing solid obtained in 2.1 was taken, and 4750 ml of deionized water was added. The mixture was heated to 60 ° C under stirring, completely dissolved and filtered, and the filtrate was washed with 3N hydrochloric acid The pH was adjusted to 2.0, and the mixture was allowed to stand at 3 to 5 ° C overnight. The solid obtained by suction filtration was dried at 40 to 50 ° C for 12 hours to obtain 463 g of 7-monohydroxyethylrutoside (moisture content: 8% ), The calculated content according to anhydride was 99.5%, the chromatographic purity was 99.5%, the yield was 90.1%, and the total yield was 80.5%.
0.71 mol obtained in 3.2, 463 g of 7-monohydroxyethylrutoside and 5.6 g of sodium hydroxide are taken and added to 1880 ml of deionized water, maintained at 75 to 80 캜 by stirring and heating, and 92 g of ethylene oxide (2.1 Mol) is poured into the reaction solution, and the reaction is maintained for 5 to 6 hours. When the specific gravity of trihydroxyethylrutoside reaches 75 to 78% by HPLC test, the addition of ethylene oxide is stopped, When the reaction solution dropped to 40 ° C or less, 3N hydrochloric acid was added to adjust the pH value to 5.0 ± 0.2. The reaction solution was desalted through a 732 cation resin column and a 717 anion resin column, and then concentrated under reduced pressure. By spray drying, 531 g of a solid powder was obtained. The trihydroxyethylrutocide content was 85%, the melting point was 180 to 183 ° C, the yield was 85%, and the total yield was 68.4%.
531 g of the solid powder obtained in 4.3 was added and 8000 ml of methanol was added and heated until dissolved. 1.0 g of activated charcoal was added, and the mixture was stirred for 30 minutes. When heat remained, suction filtration was carried out. Was subjected to natural crystallization at room temperature for 6 hours, filtered by suction, and the solid was dried at 40 to 50 DEG C to obtain 435 g of trihydroxyethylrutoside. The content was 95.8%, the yield was 82%, the total yield was 56 %to be.
435 g of the solid powder obtained in 5.4 was taken and 10500 ml of methanol was added. The mixture was heated until dissolved and refluxed for 30 minutes. When heat was retained, suction filtration was carried out. The filtrate was subjected to natural crystallization at room temperature for 6 hours, The solid was vacuum-dried at 40 to 50 DEG C to obtain 354 g of trihydroxyethylrutoside. The content was 98.4%, the chromatographic purity was 98.4%, the melting point was 184 to 186 DEG C, and the yield was 81.5 %, And the total yield is 45.6%.
Example 4
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
0.71 mol obtained in 2.1, 510 g of 7-monohydroxyethylrutoside and 5.6 g of sodium hydroxide were added to a mixed solution of 1000 ml of deionized water and 800 ml of ethanol, stirred and heated to 70 to 75 캜 (2.1 mol) of ethylene oxide was poured into the reaction solution, and the reaction was carried out for 10 to 13 hours. When the specific gravity of trihydroxyethylrutoside reached 75 to 78% by HPLC test, the addition of ethylene oxide was stopped, When the reaction solution dropped to 40 ° C or less, 3N hydrochloric acid was added to adjust the pH value to 5.0 ± 0.2, and the ethanol was recovered under reduced pressure. The reaction solution contained 732 cationic resin, 717 And then spray drying was performed to obtain 480 g of a solid powder. The trihydroxyethylrutocide content was 93.4%, the melting point was 181 to 184 ° C, and the yield was 85% All.
3. The obtained solid was recrystallized twice using methanol according to the method of Example 1 to obtain 323 g of trihydroxyethylrutoside. The chromatographic purity was 98.6%, the content was 98.5%, the melting point was 185 - 186 < 0 > C, and the total yield is 53.5%.
Example 5
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
0.71 mol obtained in 2.1, 510 g of 7-monohydroxyethylrutoside and 5.6 g of sodium hydroxide were added to a mixed solution of 1000 ml of deionized water and 800 ml of methanol, stirred, heated to 60 to 70 캜 to maintain the temperature (2.1 mol) of ethylene oxide was poured into the reaction solution, and the reaction was carried out for 10 to 13 hours. When the specific gravity of trihydroxyethylrutoside reached 75 to 78% by HPLC test, the addition of ethylene oxide was stopped, When the reaction solution dropped to 40 ° C or below, the pH value was adjusted to 5.0 ± 0.2 by adding 3N hydrochloric acid. The reaction solution contained 732 cationic resin and 717 anionic resin, respectively, Methanol was recovered under reduced pressure and spray drying was conducted to obtain 474 g of a solid powder. The trihydroxyethylrutocide content was 94.5%, the melting point was 181 to 184 ° C, and the yield was 84% All.
3. The obtained solid was recrystallized twice using methanol according to the
Example 6
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
2. To a 5000 ml autoclave were added 0.71 mole of 1 obtained in 1, 510g of 7-monohydroxyethylrutoside and 10 ml of triethylamine, 2000 ml of methanol, and finally 132 g (3.0 mole) of ethylene oxide After the addition, the mixture was immediately sealed and stirred. When the temperature was raised to 75 ° C to 80 ° C and the reaction was continued for 2 to 3 hours, the temperature was lowered to 40 ° C or less. Pressure was released. The reaction solution was filtered, After passing through a cationic water column and a 717 negative ion column, the pH value is adjusted to 5.0 ± 0.2 using 5N hydrochloric acid, and the solution is allowed to stand at room temperature for 6 to 8 hours. The crystals are filtered to obtain a 380 g filter cake.
3. The filtrate cake was further heated to dissolve using 20 times methanol, filtered for 30 minutes, and the filtrate was allowed to stand at room temperature for 6 to 8 hours. The crystals were filtered and dried at 40 to 50 DEG C And dried in vacuo to obtain 304 g of a solid powder. The trihydroxyethylrutocide content was 98.1%, the melting point was 184 to 186 ° C, and the yield was 58%.
Example 7
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
2. Add 0.71 moles of 1, 7 g of monohydroxyethyl rutoside and 12 ml of triethylamine, 2000 ml of methanol, obtained in 1 to a 5000 ml autoclave, add 132 g (3.0 moles) of ethylene oxide at the end and immediately seal When the temperature dropped to 40 ° C or lower, the pressure was released. The reaction solution was filtered, and further washed with 732 cation resin, 717 anion After passing through a water column, the pH value is adjusted to 5.0 ± 0.2 using 5N hydrochloric acid and left at room temperature for 6 to 8 hours. The crystals are filtered to obtain a 375 g filter cake.
3. The filter cake was further heated to dissolve using a 20-fold amount of methanol-isopropanol (37: 3), refluxed for 30 minutes and filtered. The filtrate was left at room temperature for 6 to 8 hours, Filtration and vacuum drying at 40 to 50 ° C yielded 302 g of a solid powder with a trihydroxyethylrutocide content of 98.3%, melting point of 184 to 186 ° C and a yield of 57%.
Example 8
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
2. To a 5000 ml autoclave, 0.71 mol obtained in 1, 510 g of 7-monohydroxyethylrutoside, 30 ml of ammonia water, 2000 ml of methanol and 154 g (3.5 mol) of ethylene oxide were added and immediately sealed and stirred, When the temperature was lowered to 40 ° C or lower, the pressure was released. The reaction solution was filtered, and the reaction solution was further passed through a 732 cation resin column and a 717 anion resin column After adjusting the pH value to 5.0 ± 0.2 using 5N hydrochloric acid, the mixture is allowed to stand at room temperature for 6 to 8 hours, and the crystals are filtered to obtain a 360 g filter cake.
3. The filtrate cake was further heated to dissolve using 20 times methanol, filtered for 30 minutes, and the filtrate was allowed to stand at room temperature for 6 to 8 hours. The crystals were filtered and dried at 40 to 50 DEG C And dried in vacuo to obtain 290 g of a solid powder. The trihydroxyethylrutocide content was 98.2%, the melting point was 184 to 186 ° C, and the yield was 55%.
Example 9
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
2. Add 5000 ml of an autoclave to 0.71 mole of the 7 obtained from 1, 510 g of 7-monohydroxyethylrutoside and 10 ml of pyridine, 1600 ml of methanol and 400 ml of ethanol, finally add 154 g (3.5 moles) of ethylene oxide, The reaction solution was filtered, and the reaction solution was again subjected to filtration to obtain 717 anion water. Then, the reaction solution was filtered, After passing through a column, the pH value is adjusted to 5.0 ± 0.2 using 5N hydrochloric acid and left at room temperature for 6 to 8 hours. Crystals are filtered to obtain a 420 g filter cake.
3. The filtrate cake was further heated to dissolve using methanol-ethanol (95: 5) of 20 times the volume, and the solution was stirred for 30 minutes and then filtered. The filtrate was allowed to stand at room temperature for 6 to 8 hours, Filtration and vacuum drying at 40 to 50 ° C yielded 336 g of a solid powder with a trihydroxyethylrutocide content of 98.2%, a melting point of 184 to 186 ° C, and a yield of 64%.
Example 10
1. Preparation of 7-monohydroxyethylrutoside is the same as in Example 1.
2. Add a solution of 0.71 mol obtained in 1, 510 g of 7-monohydroxyethyl rutoside and 10 ml of pyridine, 2000 ml of methanol to a 5000 ml autoclave, finally add 154 g (3.5 moles) of ethylene oxide and immediately seal and stir The reaction solution was adjusted to pH 5.0 ± 0.2 using 5N hydrochloric acid. The pH was adjusted to 5.0 ± 0.2, and the pH was adjusted to 5.0 ± 0.2 , Left at room temperature for 6 to 8 hours, and the crystals are filtered to obtain a 410 g filter cake.
3. The filtrate cake was further heated to dissolve using 20 times methanol, filtered for 30 minutes, and the filtrate was allowed to stand at room temperature for 6 to 8 hours. The crystals were filtered and dried at 40 to 50 DEG C And dried in vacuo to obtain 310 g of a solid powder. The trihydroxyethylrutocide content was 98.3%, the melting point was 184 to 186 캜, and the yield was 61%.
Example 11
1. 100 g of 98.7% trihydroxyethylrutoside obtained in Example 5 was added, 3000 ml of methanol-ethanol (50: 50) was added, and the mixture was heated and refluxed for 30 minutes. When heat was retained, Was subjected to natural crystallization at room temperature for 6 hours. After suction filtration, the solid was vacuum dried at 40 to 50 ° C to obtain 80.2 g of trihydroxyethylrutoside. The chromatographic purity was 98.8%, the content was 98.8% The melting point is 186 to 188 캜.
(80: g) of 98.8% of trihydroxyethylrutoside obtained in 2.1 was added with 2400 ml of methanol-isopropanol (95: 5), and the mixture was heated and refluxed for 30 minutes. When heat was retained, After 6 hours of natural crystallization, the solid was vacuum dried at 40 to 50 ° C to obtain 64.3 g of trihydroxyethylrutoside. The chromatogram purity was 99.2%, the content was 99.2%, the melting point Lt; / RTI >
Claims (10)
2) purifying the 7-monohydroxyethylrutoside,
3) preparing trihydroxyethylrutoside using the purified 7-monohydroxyethylrutoside,
4) purifying said trihydroxyethylrutoside,
Here, in the step of preparing the 7-monohydroxyethylrutoside in the step 1), the hydroxy group is protected using a hydroxy-protecting reagent, and then the reaction is carried out in a solvent by adding a hydroxyethylating reagent , The hydroxyl group-protecting reagent is borax, the hydroxyethylating reagent is ethylene oxide, and the reaction solvent can be selected from the group consisting of water, methanol, and ethanol, the reaction temperature is 30 to 50 ° C, 4 to 12 hours;
Herein, the 7-monohydroxyethylrutoside purification of step 2) employs a recrystallization method and the recrystallization solvent is selected from the group consisting of water, methanol, ethanol, isopropanol or a mixture thereof, and the step of recrystallization Comprises the steps of dissolving, crystallizing, filtering;
Here, in the process of preparing trihydroxyethylrutoside using the purified 7-monohydroxyethylrutoside of step 3), the 7-monohydroxyethylrutoside is dispersed or dissolved in a solvent The hydroxyethylating reagent is ethylene oxide and the reaction solvent is selected from the group consisting of water, methanol, ethanol, pyridine, or a mixture thereof, and the catalyst is selected from the group consisting of hydroxyl Sodium and aqueous ammonia, the reaction temperature is 50 to 80 ° C, and the reaction time is 3 to 8 hours. After completion of the reaction, the cationic resin and the anionic resin are respectively passed through or treated with a macroporous resin;
Here, in passing through the cation resin and the anion resin, the cation resin is selected from strongly acidic styrene type cation exchange resins, and the anionic resin is selected from strongly alkaline styrenic anion exchange resins
Here, in the purification using the recrystallization method in the step 4), the recrystallization solvent is selected from the group consisting of water, methanol, ethanol, isopropanol or a mixture thereof, and the recrystallization step includes a step of dissolving, crystallizing, ≪ / RTI &
Wherein the 7-monohydroxyethylrutoside is purified at a purity of 95% by mass or more, and the raw material is further introduced.
Wherein the 7-monohydroxyethylrutoside is purified at a purity of 98% by mass or more, and the raw material is fed again.
Wherein the 7-monohydroxyethylrutoside is purified at a purity of 99% by mass or more, and the raw material is fed again.
In the 7-monohydroxyethylrutoside preparation of step 1), the hydroxy-protecting reagent is borax, the hydroxyethylating agent is ethylene oxide, and the reaction solvent is selected from the group consisting of water, methanol and ethanol , The reaction temperature is 30 to 50 占 폚, the reaction time is 4 to 12 hours,
In the recrystallization method for the 7-monohydroxyethylrutoside purification of step 2) above, the recrystallization solvent is selected from the group consisting of water, methanol, ethanol or a mixture thereof,
Wherein the hydroxyethylating reagent is ethylene oxide and the reaction solvent is selected from the group consisting of water, methanol, ethanol or a mixture thereof And the reaction time is 3 to 13 hours. After completion of the reaction, the reaction mixture is desalted through the cation resin and the anion resin, or the impurities are removed through the macroporous resin,
Wherein the recrystallization solvent is selected from the group consisting of water, methanol, ethanol, or a mixture thereof in adopting the recrystallization method in the purification of the step 4).
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| FR5072M (en) * | 1965-10-25 | 1967-05-16 | ||
| US4153788A (en) * | 1974-04-09 | 1979-05-08 | Zyma S.A. | Process of preparing mono-O-β-hydroxyethyl-7 rutoside |
| CH581127A5 (en) * | 1974-04-09 | 1976-10-29 | Zyma Sa | |
| US4393055A (en) * | 1982-05-03 | 1983-07-12 | American Cyanamid Company | Hydroxyalkyl ether derivatives of rutin poly(H-)sulfate and method of use |
| FR2787111B1 (en) * | 1998-12-11 | 2001-02-23 | Negma Lab | TROXERUTINE WITH HIGH TRIHYDROXY-ETHYL-RUTOSIDE CONTENT, HIGH WETABILITY, AND PREPARATION METHOD |
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| CN101891784B (en) * | 2010-07-17 | 2012-02-15 | 山西津华晖星制药有限公司 | Method for synthesizing 3',4',7-troxerutin |
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