CN1912192A - Preparation method of 7-keto lithocholic acid - Google Patents
Preparation method of 7-keto lithocholic acid Download PDFInfo
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Abstract
The invention relates to 7-alkone lithocholic acid preparing method. It includes the following steps: dissolving the compound into the organic solvent to form electrolyte, electrolyzing the electrolyte by constant current at oxidizing medium condition to gain the object. The electrolyzing current density is 47.6A/m2-190.4A/m2. The invention has the advantages of moderate operation condition, green, simplifying ursodesoxycholic acid preparing steps.
Description
Technical Field
The invention relates to a preparation method of 7-ketolithocholic acid, in particular to a method for preparing 7-ketolithocholic acid by adopting an electrolytic method.
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). Ursodeoxycholic acid is the main effective component of rare traditional Chinese medicine bear gall, but bear gall is a very scarce resource and is difficult to meet the requirements of clinical application.
Since the 50 s, chemical synthesis methods using animal cholic acid substances as raw materials have appeared. Japanese patent (JP 0161496) reports that bovine and ovine cholic acids are used as raw materials, the 3-position hydroxyl is selectively protected by methyl esterification, and then (NH) is used4)2Ce(NO3)3Oxidizing 7-hydroxy with NaBr to obtain 7-ketocholanic acid, and reacting with MeSO2Cl reaction to obtain 12 α -methanesulfonyl ester on organic amine Me2After 60 years, research on synthesis of ursodeoxycholic acid has been mainly devoted to stereoselective reduction of 7-ketolithocholic acid, namely reduction of 7-ketolithocholic acid with alkali metal in lower alcohol, reported by Saito et al (JP 52007950) in 1977, reduction of 7-ketolithocholic acid with metallic potassium in t-butanol, selective reduction of the 7-carbonyl to the 7-hydroxy β, to prepare ursodeoxycholic acid with a yield of 99.9% and a purity of 96.1%, m.p. of 196 ℃, Japanese patent (JP 05032692) reported that 7-ketolithocholic acid was treated with KOH in propanol, refluxed for 2H, and then treated with H to obtain methyl Δ 11-3 α -7-carbonyl cholanate, which was hydrogenolyzed with metallic sodium in n-butanol to obtain Δ 11-3 α, 7 β -dihydroxycholanate, and Pd/C to obtain ursodeoxycholic acid by catalytic hydrogenation of Pd/C2Raney Ni was reacted at 80 ℃ under 4.9X 105Pa for 3.5 hours to obtain 99.0% ursodeoxycholic acid mixture containing cholic acid, with a reduction yield of 97.7%, a selectivity of 7 β of 92.5%, Zhouweishan et al (proceedings of chemistry 1998, 46 (11): 1150) reported in 1988 as the main component in pig bileThe method comprises the steps of taking hyodeoxycholic acid as a raw material, converting 6-hydroxyl into 7-hydroxyl by utilizing 1, 2-keto shift reaction, wherein the total yield of the method is about 15%, 1991, Wangchun et al (Chinese science (B edition): 1991, (7): 680) report that hyodeoxycholic acid is taken as a raw material, a compound with a 4-en-3-one structure is synthesized, then 6, 7-position dehydrogenation, epoxidation and catalytic hydrogenation are carried out to achieve the purpose of reconstructing 5-position β hydrogen configuration, and 7-position hydroxyl is obtained, and then ursodeoxycholic acid is further synthesized.
In summary, the chemical synthesis method has the disadvantages of multiple synthesis steps, harsh operation conditions, low yield, easy environmental pollution and the like.
After 80 s, methods such as microbial fermentation, enzymatic chemical methods, electrochemical synthesis, etc. have also been developed. Sawada (appl. environ. Microbial.1982, 44 (6): 1249-1252) et al reported a 50% yield process for the preparation of ursodeoxycholic acid from lithocholic acid by Fusarium equisetum equiseti M-41 in Fusarium in 1980. In 1981, Hirano (J.lipid. Res.1981, 22 (7): 1060-. In 1985 Kole et al (FEMS Microbiol. Lett., 1985, 28(1), 69-72) first conducted the search for the conversion of ursodeoxycholic acid using immobilized cells of C.absomonum, and overall, the conversion rate was too low, only about 20%.
The main problems of the microbial fermentation method are that stable and efficient strains are difficult to screen, and the fermentation product is complex and difficult to separate.
The research direction of the electrochemical synthesis method is mainly to search for a suitable stereoselective reduction catalyst. Japanese patent (JP06002184) reports that 7-ketolithocholic acid can be converted into ursodeoxycholic acid by electrochemical reduction in lower alcohol, and the influence of different current densities and energization times on the yield of ursodeoxycholic acid is studied. U.S. Pat. No. 3, 4,547,271 reports that ursodeoxycholic acid can be obtained in high yield by adding a weakly acidic bipolar compound such as dimethyl sulfoxide, tetramethylurea, etc. to an electrolyte containing lower alcohol, electrochemically reducing 7-ketolithocholic acid to ursodeoxycholic acid using ruthenium-coated titanium alloy and mercury as electrodes, and selecting a suitable electrolyte system. The method is relatively simple and safe.
In conclusion, the electrochemical synthesis method has unique advantages in the preparation of ursodeoxycholic acid (UDCA). Therefore, if the electrochemical synthesis method can be used for preparing the 7-ketolithocholic acid, the defects of long preparation steps, low efficiency, difficult product separation, harsh operation conditions, easy environmental pollution and the like in the existing ursodeoxycholic acid preparation method can be overcome.
Disclosure of Invention
The invention aims to provide a method for preparing 7-ketolithocholic acid by adopting an electrolytic method.
The invention adopts an electrolytic method to indirectly oxidize chenodeoxycholic acid (CDCA) which is relatively cheap and easy to obtain in an oxidation medium and has a structure shown in a formula (2) to prepare the 7-ketolithocholic acid (an important intermediate for synthesizing ursodeoxycholic acid).
The method for preparing 7-ketolithocholic acid is characterized by comprising the following main steps: dissolving a compound with a structure shown as a formula (2) in an organic solvent to form an electrolyte, and electrolyzing the electrolyte at constant current in the presence of an oxidizing medium to obtain a target object [ with a structure shown as a formula (1)]]Wherein: the current density of electrolysis was 47.6A/m2～190.4A/m2(preferred electrolytic Current Density is 95.2A/m2)。
In the present invention, it is recommended that the organic solvent used is C1～C3The monohydric alcohol or acetonitrile of (1), preferably acetonitrile, methanol or ethanol; the preferred oxidizing medium used is a water-soluble bromide, most preferably potassium bromide.
Taking potassium bromide as an oxidation medium as an example, the main reaction equation of the invention is as follows:
electrode reaction of the anode:
according to the technical scheme, the method has the advantages of mild operation conditions, environmental friendliness, simplification of preparation steps of ursodeoxycholic acid (UDCA) and the like.
Detailed Description
The electrolysis of the invention can be carried out in a diaphragm type or non-diaphragm type electrolytic cell, and is divided into the following parts:
I. in a diaphragm type electrolytic cell, the present invention comprises the steps of:
(1) respectively dissolving 0.4g of KBr in 13ml of deionized water, dissolving 1.0-2.5 g (preferably 2.0-2.5 g) of chenodeoxycholic acid (CDCA) in 50ml of acetonitrile, methanol or ethanol, and then uniformly mixing the two solutions and putting the mixture into an anode chamber to be used as an anolyte; 63ml of 20% dilute sulfuric acid is used as catholyte; with PbO2Ti mesh electrode, titaniumThe ruthenium reticular electrode or the graphite plate electrode is used as an anode, and the stainless steel plate is used as a cathode; HF-101 strongly acidic cation exchange membrane (Shanghai Huaqia science and technology trade company) is used as diaphragm, and constant current electrolysis is carried out by controlling current during electrolysis with DC voltage-stabilizing and current-stabilizing power supply, wherein the current density of electrolysis is 47.6A/m2～190.4A/m2Judging the end point of the reaction by Thin Layer Chromatography (TLC) (wherein the used spreading agent is chloroform/methanol/glacial acetic acid, the volume ratio is 40: 2: 1, the color developing agent is 20% phosphomolybdic acid ethanol solution, and the color developing temperature is about 100 ℃), and stopping electrolysis when the raw material point disappears after the thin layer chromatography;
(2) and (2) carrying out suction filtration on the anolyte electrolyzed in the step (1), slowly adding the filtrate into about 700ml of deionized water under stirring, standing, separating out a precipitate, filtering, and drying a filter cake to obtain the target product (7-ketolithocholic acid).
In a non-diaphragm cell, the invention comprises the steps of:
(1) respectively dissolving 0.4g of KBr in 13ml of deionized water, dissolving 1.0-2.5 g (preferably 2.0-2.5 g) of CDCA in 50ml of acetonitrile, methanol or ethanol, and then uniformly mixing the two solutions and putting the two solutions into an electrolytic cell to serve as electrolyte; with PbO2The Ti reticular electrode, the titanium ruthenium reticular electrode or the graphite plate electrode is taken as an anode, and the stainless steel plate is taken as a cathode; controlling current during electrolysis with DC voltage-stabilizing and current-stabilizing power supply to perform constant current electrolysis with current density of 47.6A/m2～190.4A/m2TLC is adopted to judge the reaction end point (the used spreading agent and the proportion thereof as well as the color developing agent and the color developing temperature are the same as above), and when the raw material point disappears, the electrolysis is stopped;
(2) and (2) carrying out suction filtration on the electrolyte electrolyzed in the step (1), slowly adding the filtrate into about 700ml of deionized water under stirring, standing, separating out a precipitate, filtering, and drying a filter cake to obtain the target product (7-ketolithocholic acid).
The invention is further illustrated by the following examples, which are intended only for a better understanding of the invention and do not limit the scope of the invention:
in the following examples, the product (7-ketolithocholic acid) was quantitatively analyzed by High Performance Liquid Chromatography (HPLC). The HPLC detection conditions were, unless otherwise specified: the chromatographic column is an RP C18 reversed phase column, the mobile phase is acetonitrile with the volume ratio of 70: 30 and phosphate buffer solution with the pH value of 3.0, the flow rate is 1.0ml/min, the column temperature is room temperature, and the ultraviolet detection wavelength is 208 nm.
Example 1
0.4g of KBr is dissolved in 13ml of secondary deionized water, 2.0g of CDCA is weighed and dissolved in 50ml of acetonitrile, and the two solutions are uniformly mixed and then are placed in an anode chamber of an H-shaped diaphragm electrolytic cell to serve as an anolyte. 63ml of 20% dilute sulfuric acid were used as catholyte. The HF-101 strong acid type cation exchange membrane is a diaphragm. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 95.2A/m2And when the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is 2.5 h. 1.697g of crude 7K-LCA is obtained, the HPLC content being 90.4%. Calculated yield and current efficiency were 77.1% and 84.2%, respectively. The product is purified by column chromatography and recrystallization, and the melting point is measured as follows: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃). 1H NMR analysis results: delta 0.5 to 1.8, 2.1, 2.2(33H, m, -CH)2-，-CH2CH3，-CH2CH2-)δ1.9(1H，d，-CH-)，δ2.4(1H，t，-COCH)，δ2.8(1H，q，-CHCHCH2-)，δ4.5(1H，s，-OH)，δ11.4(1H，s，-COOH)。
Example 2
0.4g of KBr is dissolved in 13ml of secondary deionized water, 2.0g of CDCA is weighed and dissolved in 50ml of ethanol, and the two solutions are uniformly mixed and then are placed in an anode chamber of an H-type diaphragm electrolytic cell to serve as an anolyte. 63ml of 20% dilute sulfuric acid were used as catholyte. The HF-101 strong acid type cation exchange membrane is a diaphragm. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 95.2A/m2When the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is about 4.5 h. To obtainTo 7g of crude 7K-LCA 1.652g, the HPLC content was 89.5%. Calculated yield and current efficiency74.3% and 45.5%, respectively. After purification of the product, the melting point was determined: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃).
Example 3
0.4g of KBris dissolved in 13ml of secondary deionized water, 2.0g of CDCA is weighed and dissolved in 50ml of acetonitrile, and the two solutions are uniformly mixed and then are placed in an anode chamber of an H-shaped diaphragm electrolytic cell to serve as an anolyte. 63ml of 20% dilute sulfuric acid were used as catholyte. The HF-101 strong acid type cation exchange membrane is a diaphragm. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 190.4A/m2And when the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is 2.25 h. 1.423g of crude 7K-LCA are obtained, the HPLC content being 87.9%. Calculated product yield and current efficiency were 62.8% and 38.1%, respectively. After purification of the product, the melting point was determined: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃).
Example 4
0.4g of KBr is dissolved in 13ml of secondary deionized water, 2.0g of CDCA is weighed and dissolved in 50ml of acetonitrile, and the two solutions are uniformly mixed and then are placed in an anode chamber of an H-shaped diaphragm electrolytic cell to serve as an anolyte. 63ml of 20% dilute sulfuric acid were used as catholyte. The HF-101 strong acid type cation exchange membrane is a diaphragm. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 47.6A/m2And when the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is 4.5 h. 1.589g of crude 7K-LCA are obtained, the HPLC content being 86.7%. Calculated product yield and current efficiency were 69.2% and 84.0%, respectively. After purification of the product, the melting point was determined: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃).
Example 5
0.4g of KBr is dissolved in 13ml of secondary deionized water, 2.5g of CDCA is weighed and dissolved in 50ml of acetonitrile, and the two solutions are uniformly mixed and then are placed in an anode chamber of an H-shaped diaphragm electrolytic cell to serve as an anolyte. 63ml of 20% dilute sulfuric acid were used as catholyte. HF-101 the strong acid type cation exchange membrane is a diaphragm. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 95.2A/m2And when the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is 3.5 h. 1.678g of crude 7K-LCA is obtained with an HPLC content of 86.4%. Calculated product yield and current efficiency were 58.3% and 56.9%, respectively. After purification of the product, the melting point was determined: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃).
Example 6
0.4g of KBr is dissolved in 13ml of secondary deionized water, 2.0g of CDCA is weighed and dissolved in 50ml of acetonitrile, and the two solutions are uniformly mixed and then are placed in an anode chamber of an H-shaped diaphragm electrolytic cell to serve as an anolyte. 63ml of 20% dilute sulfuric acid were used as catholyte. The HF-101 strong acid type cation exchange membrane is a diaphragm. Graphite plate-like electrodes were used as anodes, and stainless steel plates were used as cathodes. The current density used was 95.2A/m2When the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is about 3.3 h. 1.597g of crude 7K-LCA are obtained, the HPLC content being 88.7%. Calculated product yield and current efficiency were 71.2% and 58.6%, respectively.
Example 7
0.4g KBr is dissolved in 13ml secondary deionized water, 2.0g CDCA is weighed and dissolved in 50ml acetonitrile, and the two solutions are evenly mixed and then put into a diaphragm-free electrolytic cell to be used as electrolyte. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 95.2A/m2When the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is about 3.8 h. 1.519g of crude 7K-LCA with 89.7% HPLC content is obtained. Calculated product yield and current efficiency were 68.4% and 48.8%, respectively. After purification of the product, the melting point was determined: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃).
Example 8
0.4g KBr was dissolved in 13ml of secondary deionized water, and 2.0g CDC was weighedDissolving A in 50ml ethanol, mixing the two solutions uniformly, and placing the mixture into a diaphragm-free electrolytic cell to be used as an electrolyte. With PbO2the/Ti mesh electrode is an anode, and the stainless steel plate is a cathode. The current density used was 95.2A/m2When the CDCA basically finishes the reaction through TLC detection, the electrolysis is stopped, and the electrifying time is about 8.4 h. 1.627g of 7K-LCA crude product is obtained, the HPLC content is 88.4%. Calculated product yield and current efficiency were 72.3% and 23.4%, respectively. After purification of the product, the melting point was determined: m.p.200 to 203 ℃ (literature value: 201 to 203 ℃).
Claims (9)
1. A preparation method of 7-ketolithocholic acid is characterized by comprising the following main steps: dissolving a compound with a structure shown as a formula (2) in an organic solvent to form an electrolyte,
electrolyzing said electrolyte in the presence of an oxidizing medium at constant current to obtain the target, wherein: the current density of electrolysis was 47.6A/m2～190.4A/m2。
2. The method according to claim 1, wherein the organic solvent is C1～C3Monohydric alcohol or acetonitrile.
3. The method according to claim 2, wherein the organic solvent is acetonitrile, methanol or ethanol.
4. The method of claim 1, wherein the oxidizing medium is a water-soluble bromide.
5. The method of claim 4, wherein said oxidizing agent is potassium bromide.
6. The method according to any one of claims 1 to 5, wherein the method comprises the steps of:
(1) respectively dissolving 0.4g of KBr in 13ml of deionized water, dissolving 1.0-2.5 g of chenodeoxycholic acid in 50ml of acetonitrile, methanol or ethanol, uniformly mixing the two solutions, and putting the mixture into an anode chamber to serve as an anolyte; 63ml of 20% dilute sulfuric acid is used as catholyte; with PbO2The Ti reticular electrode, the titanium ruthenium reticular electrode or the graphite plate electrode is taken as an anode, and the stainless steel plate is taken as a cathode; HF-101 strong acid type cation exchange membrane is used as diaphragm, and the current during electrolysis is controlled by DC voltage-stabilizing current-stabilizing power supply to perform constant current electrolysis with current density of 47.6A/m2～190.4A/m2After thinlayer chromatography, when the raw material point disappears, the electrolysis is stopped;
(2) and (2) carrying out suction filtration on the electrolyzed anolyte obtained in the step (1), slowly adding the filtrate into about 700ml of deionized water under stirring, standing, separating out a precipitate, filtering, and drying a filter cake to obtain the target product.
7. The method according to claim 6, wherein the current density of electrolysis is 95.2A/m2。
8. The method according to any one of claims 1 to 5, wherein the method comprises the steps of:
(1) respectively dissolving 0.4g of KBr in 13ml of deionized water, dissolving 1.0-2.5 g of chenodeoxycholic acid in 50ml of acetonitrile, methanol or ethanol, uniformly mixing the two solutions, and putting the mixed solution into an electrolytic cell to serve as electrolyte; with PbO2The Ti reticular electrode, the titanium ruthenium reticular electrode or the graphite plate electrode is taken as an anode, and the stainless steel plate is taken as a cathode; controlling current during electrolysis with DC voltage-stabilizing and current-stabilizing power supply to perform constant current electrolysis with current density of 47.6A/m2～190.4A/m2After thin layer chromatography, when the raw material point disappears, the electrolysis is stopped;
(2) and (2) carrying out suction filtration on the electrolyte electrolyzed in the step (1), slowly adding the filtrate into about 700ml of deionized water under stirring, standing, separating out a precipitate, filtering, and drying a filter cake to obtain the target product.
9. The method according to claim 8, wherein the current density of electrolysis is 95.2A/m2。
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| CN102660755A (en) * | 2012-06-04 | 2012-09-12 | 华东理工大学 | Method for preparing ursodesoxycholic acid by electro-reduction |
| CN104328454A (en) * | 2014-09-29 | 2015-02-04 | 华东理工大学 | Method for stereo-selectively preparing ursodesoxycholic acid |
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| CN106868534A (en) * | 2016-11-16 | 2017-06-20 | 成都市新功生物科技有限公司 | Technique of Nano Pd electro-catalysis chenodeoxycholic acid synthesizes the method for urso |
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| CN111455400A (en) * | 2020-05-28 | 2020-07-28 | 福建省南仹生物科技有限公司 | 7-ketolithocholic acid product and preparation method thereof |
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| FR1391735A (en) * | 1963-10-17 | 1965-03-12 | Tetsuo Sato | Process for preparing ursodesoxycholic acid |
| US4147601A (en) * | 1977-07-28 | 1979-04-03 | Ppg Industries, Inc. | Electrolytic production of hydrobromic acid |
| FR2653126B1 (en) * | 1989-10-17 | 1994-12-09 | Sanofi Sa | PROCESS FOR THE PREPARATION OF DIACETOXYCHOLANATES. |
| US6811679B2 (en) * | 2003-03-28 | 2004-11-02 | Council Of Scientific & Industrial Research | Process for electrochemical oxidation of bromide to bromine |
| CN1771353B (en) * | 2003-03-31 | 2010-06-09 | 科学和工业研究委员会 | A process for electrochemical oxidation of bromide to bromine |
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| CN104350157A (en) * | 2012-05-28 | 2015-02-11 | 化学药品与食品产品股份公司 | Process for the selective reduction of bile acids, salts or derivatives thereof, in biphasic system |
| CN102660755A (en) * | 2012-06-04 | 2012-09-12 | 华东理工大学 | Method for preparing ursodesoxycholic acid by electro-reduction |
| CN102660755B (en) * | 2012-06-04 | 2016-08-03 | 华东理工大学 | Electroreduction prepares the method for ursodesoxycholic acid |
| CN104328454A (en) * | 2014-09-29 | 2015-02-04 | 华东理工大学 | Method for stereo-selectively preparing ursodesoxycholic acid |
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| CN108822177A (en) * | 2018-09-03 | 2018-11-16 | 四川百特芳华医药科技有限公司 | A kind of preparation method of Austria's shellfish cholic acid intermediate |
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