CN115724897A - Oxidation impurity removal method for cholestanic acid and derivatives thereof - Google Patents
Oxidation impurity removal method for cholestanic acid and derivatives thereof Download PDFInfo
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- CN115724897A CN115724897A CN202111017557.2A CN202111017557A CN115724897A CN 115724897 A CN115724897 A CN 115724897A CN 202111017557 A CN202111017557 A CN 202111017557A CN 115724897 A CN115724897 A CN 115724897A
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- cholesteric
- potassium permanganate
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- 239000002253 acid Substances 0.000 title claims abstract description 131
- 239000012535 impurity Substances 0.000 title claims abstract description 97
- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 25
- 230000003647 oxidation Effects 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 57
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 33
- 230000003098 cholesteric effect Effects 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 230000006378 damage Effects 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 21
- 229960002471 cholic acid Drugs 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 11
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 18
- XIIAYQZJNBULGD-LDHZKLTISA-N cholestane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XIIAYQZJNBULGD-LDHZKLTISA-N 0.000 description 18
- 238000001514 detection method Methods 0.000 description 15
- 238000005070 sampling Methods 0.000 description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 229960003080 taurine Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000007857 degradation product Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 4
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- -1 3 α Chemical compound 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical group C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- HIAJCGFYHIANNA-QIZZZRFXSA-N 3b-Hydroxy-5-cholenoic acid Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 HIAJCGFYHIANNA-QIZZZRFXSA-N 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- RPKLZQLYODPWTM-KBMWBBLPSA-N cholanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 RPKLZQLYODPWTM-KBMWBBLPSA-N 0.000 description 1
- 150000001837 cholestane derivatives Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
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Abstract
The invention discloses an oxidation impurity removal method for cholestanic acid and derivatives thereof, relates to the technical field of impurity removal of the cholestanic acid and the derivatives thereof, solves the problem that no report is provided for specially removing 22-alkene-cholestanic acid impurities at present, and comprises the following steps: mixing the cholesteric acid and/or the cholesteric acid derivative with a solvent and alkali, adjusting the pH value to be =7.0-14, adding a potassium permanganate or potassium permanganate solution under stirring, stirring and reacting for 2-120 minutes, and removing 22-alkene-cholesteric acid impurities in the cholesteric acid or cholesteric acid derivative 22-alkene impurities in the cholesteric acid derivative through oxidation and destruction; under the specific solvent and pH, the invention selectively oxidizes the 22-alkene-cholestanic acid impurities by potassium permanganate, and meanwhile, the hydroxyl of the cholestanic acid cannot be oxidized and changed into impurities.
Description
Technical Field
The invention relates to the technical field of impurity removal of cholesteric acid and derivatives thereof, in particular to the technical field of biological impurity removal of cholesteric acid and derivatives thereof.
Background
Cholestan is an important pharmaceutical and chemical intermediate, and includes 3 α,7 α,12 α -trihydroxy-5 β -cholestan-24-oic acid (3 α,7 α,12 α -trihydroxy-5 β -cholelan-24-acid), 3 α,12 α -dihydroxy-5 β -cholestan-24-oic acid (3 α,12 α -dihydroxy-5 β -cholelan-24-acid), 3 α,7 α -dihydroxy-5 β -cholestan-24-oic acid (3 α,7 α -dihydroxy-5 β -cholelan-24-acid), and 3 α,7 β -dihydroxy-5 β -cholestan-24-oic acid (3 α,7 β -dihydroxy-5 β -cholelan-24-acid). The cholestric acid derivative comprises 3 alpha, 7 beta dihydroxy cholanyl-N-taurine and the like.
Wherein R is-OH or-NH-CH 2 -CH 2 -SO 3 H or-NH-CH 2 -COOH or alkoxy;
r1 is-H or-OH or = O;
r2 is-H or-OH or = O;
r3 is-H or-OH or = O;
r4 is-H or-OH or = O or-CH 2CH3 or = CHCH3.
The cholestanic acid is mainly extracted or semi-synthesized from animal bile, a single bond between carbon atoms No. 22 and No. 23 of a cholestanic acid chemical structure is changed into a double bond, and the chemical structure of a 22-alkene-cholestanic acid impurity is shown, the cholestanic acid usually contains the impurity, the cholestanic acid contains the 22-alkene-cholestanic acid impurity, a cholestanic acid derivative contains a cholestanic acid derivative 22-alkene impurity, and metabolites of the impurity comprise a genotoxic impurity warning structure, so that the research and control of the impurity are important points. There is no report of specific removal of 22-ene-cholanic acid impurities.
Disclosure of Invention
The invention aims to: in order to solve the technical problems, the invention provides an oxidation impurity removal method for the cholestanic acid and the derivatives thereof.
The invention specifically adopts the following technical scheme for realizing the purpose:
an oxidation impurity removal method for cholestanic acid and derivatives thereof comprises the following steps: mixing the cholesteric acid and/or the cholesteric acid derivative with a solvent and alkali, adjusting the pH =7.0-14, adding a potassium permanganate or potassium permanganate solution under stirring, stirring and reacting for 2-120 minutes (the stirring and reacting is qualified until the impurity limit is reached), and oxidizing and destroying 22-alkene-cholesteric acid impurities in the cholesteric acid or 22-alkene impurities in the cholesteric acid derivative.
In the technical scheme of the application, the 22-alkene-cholestanic acid impurity is selectively oxidized by potassium permanganate under specific solvent and pH, namely, the cholestanic acid and/or the cholestanic acid derivative is oxidized and decontaminated by potassium permanganate in an alkaline solution, and meanwhile, hydroxyl of the cholestanic acid is not oxidized and decontaminated.
The 22-alkene-cholesteryl acid impurity has one more double bond than the chemical structure of the cholesteryl acid, theoretically, the impurity can be removed by a reduction or oxidation method, but the reduction method generally needs to use expensive noble metals such as palladium carbon and the like as catalysts, the reaction is carried out under the condition of hydrogen pressurization, namely, the dangerous cost is high, the cholesteryl acid has larger steric hindrance, the impurity can not be removed by reduction, because the cholesteryl acid and the derivative thereof both contain hydroxyl groups, the double bond is removed by oxidation through the oxidation method, the side reaction that the hydroxyl group of the cholesteryl acid is oxidized at the same time is easy to occur, and the product is changed into the impurity. Potassium permanganate is a strong oxidant which is cheap and easy to obtain, and generally recognizes that active groups such as hydroxyl, double bonds and the like can be oxidized. The invention considers that the steric hindrance of the cholesteric acid is larger, guesses that some cheap and traditional non-selective strong oxidants can also differentiate the oxidation of hydroxyl and double bonds of the cholesteric acid, and finally discovers that potassium permanganate can selectively oxidize the double bond structure on 22-alkene-cholesteric acid impurities under the condition of alkaline aqueous solution without damaging hydroxyl active groups on the cholesteric acid through screening of a large amount of oxidants and oxidation conditions. The 22-alkene-cholalic acid impurity is oxidized and destroyed by potassium permanganate to be removed to form impurity oxidation degradation products (the chemical structures of the impurity oxidation degradation products are shown as chemical structures 1 and 2), the impurity oxidation degradation products and the cholalic acid have larger structural difference and are easy to separate, for example, the cholalic acid is separated out by directly regulating acid and crystallizing, and the impurity oxidation degradation products are left in the filtrate to be removed. The separation of the cholesterin and the impurity oxidation degradation products can also be realized by extraction, resin adsorption and other modes.
Preferably, the solvent is water.
Preferably, the base is sodium hydroxide or potassium hydroxide.
Preferably, the weight ratio of the cholenic acid to the potassium permanganate is 100.
Preferably, the weight ratio of the cholestanic acid derivative to the potassium permanganate is 100.
Preferably, the pH is adjusted to 8.5-13.
Preferably, the reaction is stirred for 30 minutes.
Preferably, the cholesteric acid and/or the cholesteric acid derivative is butyl acetate or ethyl acetate solution containing the cholesteric acid and/or the cholesteric acid derivative, sodium hydroxide aqueous solution is added until the pH of an aqueous layer is =7.0-12, liquid separation is carried out, potassium permanganate or potassium permanganate solution is added into the aqueous layer, stirring reaction is carried out for 2-120 minutes, and 22-alkene-cholesteric acid impurities in the cholesteric acid or 22-alkene impurities in the cholesteric acid derivative are removed through oxidative destruction.
Preferably, after the impurity removal is finished, adding ethanol and activated carbon, continuously stirring, filtering the reaction solution, adjusting the pH value of the filtrate by using acid, filtering, washing the filter cake by using water, and drying to obtain the refined product of the cholesteryl acid and/or the cholesteryl acid derivative.
Preferably, the acid is hydrochloric acid, sulfuric acid or acetic acid.
In the technical scheme of the application:
after the potassium permanganate or the potassium permanganate solution is added under stirring, stirring reaction can be carried out to remove impurities as long as the water is kept in a liquid temperature range;
stirring for 2-120 min, stirring or standing for several hours for post-treatment after the impurity limit is qualified, and has no negative effect on product quality.
The invention has the following beneficial effects:
1. in the invention, HPLC ultraviolet detection of 22-alkene-cholestic acid impurities in natural cholestic acid is carried out, the impurities account for about 14 percent, the method can specifically remove the impurities or cholestic acid derivative 22-alkene impurities in the cholestic acid derivative, and the yield is high;
2. the potassium permanganate is low in use amount, and the impurity removal cost is low, about 1 yuan/kg;
3. the invention has no generation of dangerous gas and is relatively safer;
4.100 kg of cholestanic acid corresponding waste residue is about 0.011-1.09 kg, and the waste residue amount is low;
5. the impurity removal reaction time is 20-60 minutes, the time is short, and the efficiency is high;
6. the invention can adopt water as solvent, and is easy to be embedded into the existing extraction process of the cholestanic acid;
7. the invention does not need hydrogen pressurization catalytic hydrogenation, is safer and is easy to be applied in scale.
Drawings
FIG. 1 is a HPLC chart of crude 3 α,7 α -dihydroxy-5 β -cholestane-24-oic acid of example 9 of this invention;
FIG. 2 is a HPLC chart of the impurity-removed reaction solution in example 9.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. The components of embodiments of the present invention generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations.
Thus, the following detailed description of the embodiments of the present invention, presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Example 1
An oxidation impurity removal method for cholestanic acid and derivatives thereof comprises the following steps:
100g of crude 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid [ (22-ene-cholestane impurity)/(cholestane) =15% (peak area ratio of HPLC ultraviolet detector) ], 10g of sodium hydroxide, 500g of water and pH =10.2 are added into a reaction bottle. Adding 1g of potassium permanganate while stirring, stirring at room temperature for reaction for 30 minutes, sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-ene-cholestanic acid impurity)/(cholestanic acid) =0.2%, adding 5g of ethanol and 1g of activated carbon into a reaction bottle, continuing stirring at room temperature for 2 hours, filtering the reaction solution, adjusting the pH of the filtrate to =3 with hydrochloric acid, filtering, washing the filter cake with water, and drying to obtain 99g of refined 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid product with the weight yield of 99%.
Comparative example 1
Adding 100g of crude 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid [ (22-ene-cholestane impurity)/(cholestane) =15% ] into a reaction bottle, 10g of sodium hydroxide and 500g of water, dropwise adding 10g of 10% sodium hypochlorite solution while stirring, stirring and reacting at room temperature for about 30 minutes, and sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-ene-cholalic acid impurity)/(cholalic acid) =14.0%, there is no impurity removal effect, and a large amount of unknown impurities are detected.
Comparative example 2
Adding 100g of crude 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid [ (22-ene-cholestane impurity)/(cholestane) =15% ] into a reaction bottle, 16g of acetic acid and 500g of methanol, dropwise adding 10g of 10% sodium hypochlorite solution under stirring, stirring and reacting at room temperature for about 30 minutes, and sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-ene-cholestane contaminant)/(cholestane) =14%, there was no decontaminating effect, and 9% of 3 α,7 α -dihydroxy-5 β -cholestane-24-acid was converted to 3 α -hydroxy-7-keto-5 β -cholestane-24-acid contaminant, 2% of 3 α,7 α -dihydroxy-5 β -cholestane-24-acid was converted to 3 α,7 α -dihydroxy-5 β -cholestane-24-acid methyl ester contaminant.
Comparative example 3
Adding 100g of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid crude product [ (22-ene-cholestane impurity)/(cholestane) =15% ] into a reaction bottle, 10g of sodium hydroxide and 500g of water, adding 1g of hydrogen peroxide in batches under stirring, stirring and reacting for about 30 minutes at room temperature, and sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: the (22-alkene-cholestanic acid impurity)/(cholestanic acid) ratio is unchanged, and the product is also unchanged.
Comparative example 4
Adding 100g of crude 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid [ (22-ene-cholestane impurities)/(cholestane) =15% ]100g, 10g of sodium hydroxide and 500g of water into a reaction bottle, adding 1g of sodium bromate in batches under stirring, stirring and reacting for about 30 minutes at room temperature, and sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: the (22-ene-cholalic acid impurity)/(cholalic acid) =14.6%, the proportion is basically unchanged, the peak of the product is degraded by 7%, and a plurality of impurities are generated simultaneously.
Comparative example 5
Adding 100g of crude 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid [ (22-ene-cholestane impurity)/(cholestane) =15% ] and 500g of water into a reaction bottle, adding sodium hydroxide to adjust the pH to 6.5, adding 1g of potassium permanganate in batches under stirring, stirring at room temperature for reaction for about 30 minutes, taking a suspension sample, and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-ene-cholanic acid impurity)/(cholanic acid) =14.7%, and a small amount of impurity is generated.
Statistics of the results of example 1 and comparative examples 1-5 are shown in table 1, and it is known from table 1 that only example 1 is effective in removing 22-ene-cholanic acid impurities and the product does not become contaminated.
TABLE 1 statistical Table of results for example 1 and comparative examples 1-5
Example 2
Adding 1000g of 10% 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid crude product [ (22-alkene-cholestane impurity)/(cholestane) =15% ] butyl acetate solution into a reaction bottle, adding 1% sodium hydroxide aqueous solution until the pH of a water layer is =9, separating, adding 0.5g of potassium permanganate into a water layer, stirring and reacting for about 30 minutes, and sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-ene-cholesteric acid impurity)/(cholesteric acid) =0.01%; filtering the reaction solution, adjusting the pH of the filtrate to 3 by using 50% sulfuric acid, heating to 45 ℃, stirring for 30 minutes, filtering, washing a filter cake by using water, and drying to obtain 98.5g of a refined product of the 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid with the weight yield of 98.5%.
Example 3
Adding 800g of ethyl acetate solution of 12.5% concentration 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid crude product [ (22-ene-cholestane impurity)/(cholestane) =13% ] into a reaction bottle, adding 1000g of water, adjusting the pH to be water layer pH =8.9 by using 30% sodium hydroxide aqueous solution, separating, distilling and concentrating the water layer to 800g under reduced pressure, stirring and separating, adding 0.2g of potassium permanganate in batches, stirring and reacting for about 30 minutes at room temperature, sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-ene-cholesteric acid impurity)/(cholesteric acid) =0.2%; filtering the reaction solution, adjusting the pH of the filtrate to 3 by using 50% sulfuric acid, heating to 45 ℃, stirring for 30 minutes, filtering, washing a filter cake by using water, and drying to obtain 98.5g of a refined product of the 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid with the weight yield of 98.5%.
Example 4
Adding 100kg of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-acid crude product [ (22-ene-cholestane impurity)/(cholestane) =9% ] and 700kg of water into a reaction bottle, adding sodium hydroxide to adjust the pH value to 12, stirring for 1 hour, adding 0.3g of potassium permanganate while stirring, stirring for reacting for 30 minutes, sampling by an HPLC (ultraviolet detector), and displaying a detection result: (22-ene-cholalic acid impurity)/(cholalic acid) =0.2%, adding 1kg of sodium sulfite into the reaction bottle, and continuing stirring at room temperature for 2 hours; filtering the reaction liquid, adjusting the pH value of the filtrate to 3 by hydrochloric acid, filtering, washing a filter cake by water, and drying to obtain 99.5kg of refined 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-acid with the weight yield of 99.5 percent.
Example 5
100g of crude 3 alpha, 7 beta-dihydroxy-5 beta-cholestane-24-acid [ (22-ene-cholestane impurity)/(cholestane) =4% ] and 800g of water are added into a reaction bottle, and sodium hydroxide is added to adjust the pH value to 10.5 and the mixture is stirred for 2 hours. 10g of potassium permanganate solution with the concentration of 1% is dropwise added under stirring, the reaction is carried out for 1 hour under stirring at room temperature, the sampling HPLC (ultraviolet detector) is adopted, and the detection result shows that: (22-ene-cholalic acid impurity)/(cholalic acid) =0.1%, adding 1g of ethanol and 1g of activated carbon into a reaction bottle, and continuing stirring at room temperature for 2 hours; filtering the reaction solution, adjusting the pH value of the filtrate to 3 by hydrochloric acid, filtering, washing the filter cake by water, and drying to obtain 99g of refined 3 alpha, 7 beta-dihydroxy-5 beta-cholestane-24-acid product with the weight yield of 99 percent.
Example 6
100g of crude 3 alpha, 7 beta dihydroxycholanyl-N-taurine [ (22-ene-cholalic acid derivative impurity)/(cholalic acid derivative) =3% ] and 200g of water are added into a reaction bottle, and sodium hydroxide is added to adjust the pH value to 9 and stir for 2 hours. Adding 0.3g of potassium permanganate (adding in batches) under stirring, stirring at room temperature for reaction for 0.5 hour, sampling and detecting by HPLC (ultraviolet detector), and detecting results show that: (22-alkene-cholesterin derivative impurities)/(cholesterin derivatives) =0.05%, 1g of ethanol is added into a reaction bottle, 1g of activated carbon is added, the mixture is continuously stirred for 1 hour at room temperature, the reaction liquid is filtered, the filtrate is heated to 70-80 ℃, the pH value is adjusted to 1, the mixture is stirred and cooled to 0-5 ℃, crystal washing is carried out for 30-40 hours, the mixture is filtered, ice water is used for leaching after the filtration is carried out, the mixture is dried at 40-60 ℃ and normal pressure until the moisture is 6.2-7.2%, and qualified 3 alpha, 7 beta dihydroxyl cholanyl-N-taurine is obtained.
Example 7
100g of crude 3 alpha, 7 alpha dihydroxycholanyl-N-taurine [ (22-ene-cholalic acid derivative impurity)/(cholalic acid derivative) =16% ] and 200g of water are added into a reaction bottle, and sodium hydroxide is added to adjust the pH value to 9 and stir for 2 hours. Adding 0.5g of potassium permanganate while stirring, reacting for 0.5 hour while stirring, sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-alkene-cholesterin derivative impurities)/(cholesterin derivatives) =0.01%, adding 1g of ethanol and 1g of activated carbon into a reaction bottle, continuously stirring for 1 hour, filtering the reaction solution, heating the filtrate to 70-80 ℃, adjusting the pH to 1, stirring and cooling to 0-5 ℃, washing crystals for 30-40 hours, filtering, leaching with ice water after draining, drying at 40-50 ℃ under normal pressure until the water content is 6.2-7.2%, and obtaining qualified 3 alpha, 7 alpha dihydroxycholanyl-N-taurine.
Example 8
Adding 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid crude product [ (22-ene-cholestane impurity)/(cholestane) =15% ]50g,3 alpha, 7 alpha dihydroxy cholanyl-N-taurine crude product [ (22-ene-cholestane derivative impurity)/(cholestane derivative) =15% ]50g and water 300g into a reaction bottle, adding sodium hydroxide to adjust the pH value to 12, and stirring for 2 hours. Adding 0.6g of potassium permanganate while stirring, stirring at room temperature for reaction for 0.5 hour, sampling and detecting by HPLC (ultraviolet detector), wherein the detection result shows that: (22-alkene-cholestanic acid and derivative impurities)/(cholestanic acid and derivatives) =0.1%, adding 1g of ethanol into a reaction bottle, adding 1g of activated carbon, continuously stirring at room temperature for 1 hour, filtering the reaction liquid, heating the filtrate to 70-80 ℃, adjusting the pH to 1, stirring and cooling to 0-5 ℃, washing crystals for 30-40 hours, filtering, leaching with ice water after draining, and drying at 40-60 ℃ under normal pressure to obtain a qualified mixture of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid and 3 alpha, 7 beta-dihydroxy cholanyl-N-taurine, which is one of the mixtures of cholestanic acid and cholestanic acid derivatives.
Example 9
As shown in fig. 1 and 2, crude product [ (22-ene-cholestane impurity)/(cholestane) = 6.98%; see fig. 1]100g of 3 α,7 α -dihydroxy-5 β -cholestane-24-carboxylic acid, 10g of sodium hydroxide, and 500g of water were added to a reaction flask, and the mixture was stirred at room temperature to be dissolved. Adding 0.5g of potassium permanganate into the mixture in batches under stirring, stirring the mixture at room temperature for reaction for about 30 minutes, sampling and detecting by using an HPLC (ultraviolet detector), and displaying the detection result (see a figure 2): (22-ene-cholalic acid impurity)/(cholalic acid) =0.13%, adding 2g of ethanol into the reaction bottle, and continuing stirring at room temperature for 2 hours; filtering the reaction solution, adjusting pH of the filtrate to 3 with hydrochloric acid, heating to 43 deg.C, stirring for 30 min, filtering, washing the filter cake with water, and oven drying to obtain refined 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid product 99.1g with weight yield of 99.1%
Table 2 shows peaks corresponding to HPLC chart of crude 3 alpha, 7 alpha-dihydroxy-5 beta-cholestane-24-acid
Table 3 shows peaks corresponding to HPLC chart of the reaction solution after impurity removal
Fig. 1 and table 2 show chromatogram and peak table of HPLC (ultraviolet detector) detection of crude 3 α,7 α -dihydroxy-5 β -cholestane-24-acid, peak with retention time of 34.954min is peak of 22-ene-cholestane impurity, peak with retention time of 398.443min is peak of cholestane (i.e. 3 α,7 α -dihydroxy-5 β -cholestane-24-acid), and peak area ratio between the two is (22-ene-cholestane impurity)/(cholestane) =22.30/319.52=6.98%.
Fig. 2 and table 3 show chromatograms and peak tables of HPLC (ultraviolet detector) detection of the impurity removal reaction solution, where the peak with retention time of 34.800min is the peak of 22-ene-cholestane impurity, the peak with retention time of 39.492min is the peak of cholestane (i.e., 3 α,7 α -dihydroxy-5 β -cholestane-24-acid), and the peak area ratio between the two is (22-ene-cholestane impurity)/(cholestane) =0.66/492.36=0.13%. The content ratio of 22-alkene-cholestanic acid impurities is obviously reduced and removed.
Claims (9)
1. An oxidation impurity removal method for cholestanic acid and derivatives thereof is characterized by comprising the following steps: mixing the cholesteric acid and/or the cholesteric acid derivative with a solvent and alkali, adjusting the pH value to be =7.0-14, adding a potassium permanganate or potassium permanganate solution under stirring, stirring and reacting for 2-120 minutes, and removing 22-alkene-cholesteric acid impurities in the cholesteric acid or cholesteric acid derivative 22-alkene impurities in the cholesteric acid derivative through oxidation and destruction.
2. The method of claim 1, wherein the solvent is water.
3. The method of claim 1, wherein the alkali is sodium hydroxide or potassium hydroxide.
4. The oxidation impurity removal method for the cholestic acid and the derivatives thereof according to claim 1, wherein the weight ratio of the cholestic acid to the potassium permanganate is 100.
5. The oxidation impurity removing method for the cholestic acid and the derivatives thereof according to claim 1, wherein the weight ratio of the cholestic acid derivatives to the potassium permanganate is 100.
6. The method of claim 1, wherein the pH is adjusted to 8.5-13.
7. The method for removing impurities by oxidation of cholalic acid and its derivatives according to claim 1, wherein the reaction is stirred for 30 minutes.
8. A method for removing impurities of cholestic acid and its derivatives by oxidization according to claim 1, wherein the cholestic acid and/or its derivatives is butyl acetate or ethyl acetate solution containing cholestic acid and/or its derivatives, aqueous solution of sodium hydroxide is added until pH =7.0-12 in aqueous layer, liquid separation is carried out, aqueous layer is taken in potassium permanganate or potassium permanganate solution, stirring reaction is carried out for 2-120 min, and 22-ene-cholestic acid impurities in cholestic acid or 22-ene-cholestic acid derivatives in cholestic acid derivatives are removed by oxidization.
9. An oxidation process for removing impurities from cholestic acid and its derivatives as claimed in claim 1-8, which includes adding alcohol and activated carbon, stirring, filtering, regulating pH value, filtering, washing filter cake with water, and baking.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH460752A (en) * | 1958-04-12 | 1968-08-15 | Philips Nv | Process for the production of new 9B, 10a-bisnorchol-22-aldehydes |
| CN101492488A (en) * | 2009-03-13 | 2009-07-29 | 淮北煤炭师范学院 | Method of preparing dihydrogen cholesterol and choleste alkyl ketone |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH460752A (en) * | 1958-04-12 | 1968-08-15 | Philips Nv | Process for the production of new 9B, 10a-bisnorchol-22-aldehydes |
| CN101492488A (en) * | 2009-03-13 | 2009-07-29 | 淮北煤炭师范学院 | Method of preparing dihydrogen cholesterol and choleste alkyl ketone |
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