CN111455400B - 7-ketolithocholic acid product and preparation method thereof - Google Patents
7-ketolithocholic acid product and preparation method thereof Download PDFInfo
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- CN111455400B CN111455400B CN202010466102.8A CN202010466102A CN111455400B CN 111455400 B CN111455400 B CN 111455400B CN 202010466102 A CN202010466102 A CN 202010466102A CN 111455400 B CN111455400 B CN 111455400B
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- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
The invention relates to a 7-ketolithocholic acid product and a preparation method thereof, wherein an electrochemical synthesis method is adopted, and the electrochemical synthesis method comprises electrolytic oxidation, precipitation and purification; the electrolytic oxidation is to perform circular electrolysis on electrolyte containing chenodeoxycholic acid, sodium ions, chloride ions and water, wherein redox reaction is performed in the electrolytic process, sodium hypochlorite is generated in the water by the sodium ions and the chloride ions, and 7-ketolithocholic acid is generated by oxidation reaction of the chenodeoxycholic acid and the sodium hypochlorite. The technical scheme has simple process, mild reaction conditions and easy control, avoids environmental pollution caused by organic solvents, and improves the production safety. The purity of the synthesized 7-ketolithocholic acid product is over 80 percent, and the product can be further refined and purified.
Description
Technical Field
The invention relates to the field of chemical industry, and particularly relates to a 7-ketolithocholic acid product and a preparation method thereof.
Background
7-ketolithocholic acid [7K-LCA, the structure of which is shown in formula (1) ] is an important intermediate for preparing ursodeoxycholic acid (UDCA). Ursodeoxycholic acid is mainly used for treating various biliary diseases (gallstone, cholecystitis), hepatitis, hyperlipidemia and other diseases, and is the only drug approved by FDA for treating Primary Biliary Cirrhosis (PBC).
The natural source of UDCA is that live bear takes bile or bear bile, the method is complex to operate, the humanity and animal protection principles are violated, and the source of the natural bear bile is gradually reduced, so that the artificial synthesis and semi-synthesis research of UDCA has important value and significance. At present, a mature ursodeoxycholic acid synthesis process takes chenodeoxycholic acid (CDCA) as a raw material, and 7-ketolithocholic acid (7K-LCA) is obtained after oxidation and then is reduced to obtain the ursodeoxycholic acid.
The existing electrochemical methods for preparing 7-ketolithocholic acid from chenodeoxycholic acid all need to adopt a low-alcohol organic solvent, and the invention provides a novel electrochemical method for preparing 7-ketolithocholic acid from chenodeoxycholic acid without using an organic solvent.
Disclosure of Invention
Therefore, the inventor provides a method for preparing 7-ketolithocholic acid by using water as an electrolyte solvent and a reactant, and the 7-ketolithocholic acid product with the purity of more than 80% can be prepared under electrochemical conditions.
The invention provides a preparation method of 7-ketolithocholic acid, which is characterized by comprising the following steps:
electrolytic oxidation: carrying out circular electrolysis on an electrolyte containing chenodeoxycholic acid, sodium ions, chloride ions and water, wherein redox reaction is carried out in the electrolysis process, sodium hypochlorite is generated in the water by the sodium ions and the chloride ions, and the chenodeoxycholic acid reacts with the sodium hypochlorite to generate 7-ketolithocholic acid;
and (3) precipitation: adding magnesium sulfate into the electrolyzed solution to perform precipitation reaction to obtain a 7-ketolithocholic acid magnesium salt precipitate;
and (3) purification: adding the 7-ketolithocholic acid magnesium salt precipitate into a sodium carbonate solution, dissolving and filtering; acidifying the filtrate with 10-20 wt% sulfuric acid and filtering to obtain solid 7-ketolithocholic acid crude product.
Further, the preparation of the electrolyte comprises the following steps: mixing chenodeoxycholic acid, sodium hydroxide and water, and adjusting the pH value to 7.0-8.0 by using 10-15 wt% of hydrochloric acid to obtain the electrolyte.
Furthermore, in the initial electrolyte, the mass ratio of chenodeoxycholic acid, sodium hydroxide and water is 64-72:11-13: 700-900.
Furthermore, a stainless steel electric plate is used as a cathode, a graphite plate is used as an anode, and the current intensity of electrolysis is 2.8A-3.2A.
Further, the electrolysis process is monitored in real time, and when chenodeoxycholic acid components cannot be detected in the electrolyte, the electrolysis is stopped immediately.
Furthermore, the mass ratio of the magnesium sulfate to the chenodeoxycholic acid is 20-30: 61-82.
Furthermore, the mass ratio of the sodium carbonate to the chenodeoxycholic acid is 15-20: 61-75.
Further, the method also comprises the following refining steps: recrystallizing the 7-ketolithocholic acid crude product with an alcohol reagent for 2 times to obtain a product with the content of more than 95 wt%.
The inventor also provides a 7-ketolithocholic acid product, wherein the 7-ketolithocholic acid product is prepared by any one of the preparation methods.
Further, the purity of the 7-ketolithocholic acid product is more than 80%.
Different from the prior art, the technical scheme provides that an electrochemical synthesis method is adopted, electrolyte containing chenodeoxycholic acid, sodium ions, chloride ions and water is subjected to circular electrolysis, redox reaction is carried out in the electrolysis process, sodium hypochlorite is generated in the water by the sodium ions and the chloride ions, and 7-ketolithocholic acid is generated by oxidation reaction of the chenodeoxycholic acid and the sodium hypochlorite. The technical scheme has simple process, mild reaction conditions and easy control, avoids environmental pollution caused by organic solvents, and improves the production safety. The purity of the synthesized 7-ketolithocholic acid product is over 80 percent, and the product can be further refined and purified.
Detailed Description
In order to explain technical contents, structural features, and objects and effects of the technical means in detail, the following detailed description is given with reference to specific embodiments.
EXAMPLE 17 preparation of Ketone lithocholic acid
Preparing an electrolyte: mixing 8kg of chenodeoxycholic acid with the content of 68 wt%, 0.96kg of sodium hydroxide and 64kg of water, heating for dissolving, and adjusting the pH value to 7.0-8.0 by using 10 wt% of hydrochloric acid to obtain an electrolyte;
electrolytic oxidation: the stainless steel electric plate is used as a cathode, the graphite plate is used as an anode, and the current intensity of electrolysis is 3.0A; putting the electrolyte into an electrolytic cell for circular electrolysis, wherein redox reaction is generated in the electrolysis process, sodium ions and chloride ions are electrolyzed in water to generate sodium hypochlorite, and chenodeoxycholic acid and sodium hypochlorite are subjected to redox reaction to generate 7-ketolithocholic acid; the electrolytic process is monitored in real time by TLC (thin layer chromatography), and when chenodeoxycholic acid components cannot be detected in the electrolyte, the electrolysis is stopped immediately, so that the generation of peroxidation and CDCA double oxide is avoided.
And (3) precipitation: adding 2kg of magnesium sulfate into the electrolyzed solution to perform precipitation reaction to obtain a 7-ketolithocholic acid magnesium salt precipitate;
and (3) purification: adding 7-ketolithocholic acid magnesium salt precipitate into sodium carbonate solution (weighing 1.6kg of sodium carbonate, adding 3 times of water of 7-ketolithocholic acid magnesium salt precipitate), heating for dissolving, and filtering; acidifying the filtrate with 10 wt% sulfuric acid, and filtering to obtain solid 7-ketolithocholic acid crude product with content of more than 80 wt%.
Recrystallizing the crude product of the 7-ketolithocholic acid for 2 times by using ethanol to obtain a product with the content of more than 95 wt%.
EXAMPLE 27 preparation of Ketone lithocholic acid
Preparing an electrolyte: mixing 68 wt% chenodeoxycholic acid 9.5kg, 1.1kg sodium hydroxide and 70kg water, heating for dissolving, and adjusting pH value to 7.0-8.0 with 15 wt% hydrochloric acid to obtain electrolyte;
electrolytic oxidation: the stainless steel electric plate is a cathode, the graphite plate is an anode, and the current intensity of electrolysis is 2.8A; putting the electrolyte into an electrolytic cell for circular electrolysis, wherein redox reaction is generated in the electrolysis process, sodium ions and chloride ions are electrolyzed in water to generate sodium hypochlorite, and chenodeoxycholic acid and sodium hypochlorite are subjected to redox reaction to generate 7-ketolithocholic acid; the electrolytic process is monitored in real time by TLC (thin layer chromatography), and when chenodeoxycholic acid components cannot be detected in the electrolyte, the electrolysis is stopped immediately, so that the generation of peroxidation and CDCA double oxide is avoided.
And (3) precipitation: adding 2kg of magnesium sulfate into the electrolyzed solution to perform precipitation reaction to obtain a 7-ketolithocholic acid magnesium salt precipitate;
and (3) purification: adding 7-ketolithocholic acid magnesium salt precipitate into sodium carbonate solution (weighing 1.6g of sodium carbonate, adding 3 times of water of 7-ketolithocholic acid magnesium salt precipitate), heating for dissolving, and filtering; acidifying the filtrate with 20 wt% sulfuric acid, and filtering to obtain solid crude product with 7-ketolithocholic acid content over 80 wt%.
Recrystallizing the crude product of the 7-ketolithocholic acid for 2 times by using methanol to obtain a product with the content of more than 95 wt%.
EXAMPLE 37 preparation of Ketone-lithocholic acid
Preparing an electrolyte: mixing 68 wt% chenodeoxycholic acid 10.5kg, 1.3kg sodium hydroxide and 90kg water, heating for dissolving, and adjusting pH value to 7.0-8.0 with 15 wt% hydrochloric acid to obtain electrolyte;
electrolytic oxidation: the stainless steel electric plate is a cathode, the graphite plate is an anode, and the current intensity of electrolysis is 3.2A; putting the electrolyte into an electrolytic cell for circular electrolysis, wherein redox reaction is generated in the electrolysis process, sodium ions and chloride ions are electrolyzed in water to generate sodium hypochlorite, and chenodeoxycholic acid and sodium hypochlorite are subjected to redox reaction to generate 7-ketolithocholic acid; the electrolytic process is monitored in real time by TLC (thin layer chromatography), and when chenodeoxycholic acid components cannot be detected in the electrolyte, the electrolysis is stopped immediately to avoid peroxidation and generate CDCA double oxide.
And (3) precipitation: adding 3kg of magnesium sulfate into the electrolyzed solution, and carrying out precipitation reaction to obtain a 7-ketolithocholic acid magnesium salt precipitate;
and (3) purification: adding 7-ketolithocholic acid magnesium salt precipitate into sodium carbonate solution (weighing sodium carbonate 2.0kg, adding water 4 times of the weight of 7-ketolithocholic acid magnesium salt precipitate), heating for dissolving, and filtering; acidifying the filtrate with 15 wt% sulfuric acid, and filtering to obtain solid crude product with 7-ketolithocholic acid content over 80 wt%.
Recrystallizing the crude product of the 7-ketolithocholic acid for 2 times by using glycerol to obtain a product with the content of more than 95 wt%.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or terminal that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or terminal. Without further limitation, an element defined by the phrases "comprising … …" or "comprising … …" does not exclude the presence of additional elements in a process, method, article, or terminal that comprises the element. Further, herein, "greater than," "less than," "more than," and the like are understood to exclude the present numbers; the terms "above", "below", "within" and the like are to be understood as including the number.
It should be noted that, although the above embodiments have been described herein, the invention is not limited thereto. Therefore, based on the innovative concepts of the present invention, the technical solutions of the present invention can be directly or indirectly applied to other related technical fields by making changes and modifications to the embodiments described herein or by using equivalent structures or equivalent processes performed in the present specification, and are included in the scope of the present invention.
Claims (5)
1. A preparation method of 7-ketolithocholic acid is characterized by comprising the following steps:
electrolytic oxidation: carrying out circular electrolysis on an electrolyte containing chenodeoxycholic acid, sodium ions, chloride ions and water, wherein redox reaction is carried out in the electrolysis process, sodium hypochlorite is generated in the water by the sodium ions and the chloride ions, and the chenodeoxycholic acid reacts with the sodium hypochlorite to generate 7-ketolithocholic acid;
and (3) precipitation: adding magnesium sulfate into the electrolyzed solution to perform precipitation reaction to obtain a 7-ketolithocholic acid magnesium salt precipitate;
and (3) purification: adding the 7-ketolithocholic acid magnesium salt precipitate into a sodium carbonate solution, dissolving and filtering; acidifying the filtrate by using 10-20 wt% of sulfuric acid, and filtering to obtain a solid 7-ketolithocholic acid crude product;
refining, namely recrystallizing the 7-ketolithocholic acid crude product for 2 times by using an alcohol solvent to obtain a 7-ketolithocholic acid product with the content of more than 95 wt%;
the preparation of the electrolyte comprises the following steps: mixing chenodeoxycholic acid, sodium hydroxide and water, heating for dissolving, and adjusting the pH value to 7.0-8.0 by using 10-15 wt% hydrochloric acid to obtain an electrolyte;
in the initial electrolyte, the mass ratio of chenodeoxycholic acid, sodium hydroxide and water is 64-72:11-13: 700-900; the stainless steel electric plate is used as a cathode, the graphite plate is used as an anode, and the current intensity of electrolysis is 2.8A-3.2A.
2. The method according to claim 1, wherein the chenodeoxycholic acid component is monitored immediately during the electrolysis, and the electrolysis is stopped immediately after the chenodeoxycholic acid component is not detected in the electrolyte.
3. The preparation method according to claim 1, wherein the mass ratio of magnesium sulfate to chenodeoxycholic acid is 20-30: 61-82.
4. The preparation method according to claim 1, wherein the mass ratio of sodium carbonate to chenodeoxycholic acid is 15-20: 61-75.
5. A7-ketolithocholic acid product, wherein the 7-ketolithocholic acid product is prepared by the preparation method of any one of claims 1 to 4.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1912192A (en) * | 2006-07-27 | 2007-02-14 | 华东理工大学 | Preparation method of 7-keto lithocholic acid |
| CN108218942A (en) * | 2017-12-18 | 2018-06-29 | 南京科技职业学院 | A kind of preparation method of 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1912192A (en) * | 2006-07-27 | 2007-02-14 | 华东理工大学 | Preparation method of 7-keto lithocholic acid |
| CN108218942A (en) * | 2017-12-18 | 2018-06-29 | 南京科技职业学院 | A kind of preparation method of 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid |
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