CN112321665A - Method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid - Google Patents
Method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid Download PDFInfo
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- CN112321665A CN112321665A CN202011383540.4A CN202011383540A CN112321665A CN 112321665 A CN112321665 A CN 112321665A CN 202011383540 A CN202011383540 A CN 202011383540A CN 112321665 A CN112321665 A CN 112321665A
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 239000004380 Cholic acid Substances 0.000 title claims abstract description 20
- 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 title claims abstract description 20
- 229960002471 cholic acid Drugs 0.000 title claims abstract description 20
- 235000019416 cholic acid Nutrition 0.000 title claims abstract description 20
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 title claims abstract description 20
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic 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)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 title claims abstract description 19
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 241000272525 Anas platyrhynchos Species 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- DLYVTEULDNMQAR-UHFFFAOYSA-N Methylallocholat Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(=O)OC)C1(C)C(O)C2 DLYVTEULDNMQAR-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229940099352 cholate Drugs 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 150000001717 carbocyclic compounds Chemical class 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- -1 carbocyclic organic compound Chemical class 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 150000001801 chenodeoxycholic acids Chemical class 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—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
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention belongs to the field of organic synthesis of carbocyclic compounds, and particularly relates to a method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid, wherein the purity of chenodeoxycholic acid obtained by synthesizing the duck cholic acid as a raw material is 97.6%; the comprehensive yield is 87.8 percent, high purity of the product is avoided when high-temperature reaction is carried out, and impurity removal at the later stage is simple and convenient.
Description
Technical Field
The invention belongs to the field of organic synthesis of carbocyclic compounds, and particularly relates to a method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid.
Background
Chenodeoxycholic acid (3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid) is a carbocyclic organic compound with a chemical formula of C24H40O4Colorless needle-like crystals. Is almost insoluble in water, soluble in ethanol, glacial acetic acid and slightly soluble in chloroform. The main effect is to reduce the saturation of cholesterol in the bile, and after most patients take CDCA (when CDCA accounts for 70% of bile salt in the bile), the lipid recovers micelle state, and the cholesterol is in unsaturated state, so that the cholesterol in the calculus is dissolved and dropped off. The large dose of CDCA (10-15 mg/kg per day) can inhibit the synthesis of cholesterol and increase the secretion of bile of patients with cholelithiasis, but the secretion amount of bile salt and phospholipid in the patients is kept unchanged. Is a marketable chemical raw material medicine.
In the prior art, 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid is synthesized by basically using cholic acid as a raw material, and the cholic acid is expensive and does not accord with the industrial production principle. The application numbers are: 20151100072
2.8, the Chinese patent of invention discloses a method for preparing chenodeoxycholic acid by taking ducholic acid as a raw material, but the method relates to a Huang Minlon reduction method, high-temperature and high-pressure reaction is adopted, the danger coefficient is higher, and the mild condition and the higher yield of the synthesis process developed by the invention are realized.
Disclosure of Invention
According to the method, the chenodeoxycholic acids are respectively obtained by taking the ducosacholic acids as raw materials through an autonomously researched and developed extraction process. The invention is realized by the following processes:
a method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid comprises the following steps:
(1) sequentially adding methanol, cholic acid of duck and concentrated sulfuric acid into a 500ml four-mouth bottle, carrying out reflux reaction at 70 ℃ for 2 hours, distilling under reduced pressure to remove the methanol, adding water and dichloromethane for extraction, combining organic phases, washing with 60ml of water, washing with saturated NaCl, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3a,7a, 23-trihydroxy-methyl cholate;
(2) sequentially adding 3a,7a, 23-trihydroxy-methyl cholate, dissolving in dichloromethane and triethylamine, adding acetic anhydride and DMAP, reacting for 2 hours at 20-25 ℃, decompressing after the reaction is finished, removing the solvent, adding water, extracting a water phase by using ethyl acetate, combining organic phases, washing by using hydrochloric acid, water and saturated NaCl respectively, drying by using anhydrous sodium sulfate, concentrating a crude product by using organic phase under reduced pressure, and recrystallizing by using methanol to obtain 3a,7a, 23-triacetoxy-methyl cholate;
(3) sequentially adding 3a,7a, 23-triacetoxy-methyl cholate, ethyl acetate and acetic acid obtained in the step (1) into a 500ml four-mouth bottle, dissolving the mixture in acetic acid, controlling the temperature to be 30-40 ℃, adding sodium bicarbonate, reacting for 1 hour at the temperature of 30-40 ℃, distilling an organic phase until a viscous residue is obtained, adding methanol, cooling to be-5-0 ℃ for crystallization, filtering, leaching with 9g of methanol, and filtering until no filtrate exists, so as to obtain 3a,7 a-diacetoxy-23-hydroxy methyl cholate;
(4) dissolving 3a,7 a-diacetyloxy-23-hydroxy cholic acid methyl ester in dichloromethane in sequence, controlling the temperature to be 20-40 ℃, dropwise adding methane sulfonyl chloride and triethylamine in sequence, reacting for 1h, distilling under reduced pressure to remove the solvent, washing with hydrochloric acid, water and saturated NaCl respectively, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, heating the crude product with methanol to dissolve and recrystallize to obtain 3a,7 a-diacetyloxy-23-methanesulfonyl cholic acid methyl ester;
(5) 3a,7 a-diacetyloxy-23-methylsulfonylcholic acid methyl ester is dissolved in TFA in sequence, and sodium borohydride is added for reaction for 1 h. The organic phase was distilled under reduced pressure. Adding methanol, heating to dissolve, and cooling to obtain white crystalline solid 3a,7 a-diacetyloxy-methyl cholate;
(6) sequentially adding 3a,7 a-diacetyloxy-methyl cholate, adding dichloromethane for dissolution, adding sodium hydroxide, controlling the temperature to be 20-30 ℃, reacting for 1h, adding sulfuric acid for acidification after the reaction is finished, evaporating the solvent to obtain a crude product, heating, refluxing, cooling and recrystallizing by using methanol, leaching the filter cake by using purified water, and filtering until no filtrate exists, thereby obtaining the chenodeoxycholic acid.
The preparation method comprises the following steps: methanol in step (1): d, duck cholic acid: the mass ratio of the concentrated sulfuric acid is as follows: 8: 5: 0.05, wherein the purity of the duck cholic acid is more than 96%.
The preparation method comprises the following steps: the mass of sodium bicarbonate added in the step (2) is 1/5-1/10 of 3a,7a, 23-triacetoxy-cholic acid methyl ester.
The invention has the advantages of
(1) And (3) replacing cholic acid with hydroxy-ducholic acid at the 23-position to synthesize chenodeoxycholic acid. The price of cholic acid is about 2 ten thousand and one ton, and the price of the duck cholic acid is about 2000 yuan and one ton. And accords with the industrial production principle.
(2) The reaction conditions of the invention are designed reasonably, high temperature reaction is avoided, the conditions are simple, the operation is easy, and the synthetic route is novel and unique.
Drawings
FIG. 1 is a scheme of the synthesis process of the present invention.
Detailed Description
Example 1
A method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid comprises the following steps:
(1) adding 32g of methanol, 20g of duck cholic acid (purity is 99%) and 0.2g of concentrated sulfuric acid into a 500ml four-mouth bottle in sequence, carrying out reflux reaction at 70 ℃ for 2 hours, distilling under reduced pressure to remove the methanol, adding 45ml of water, extracting with 40ml of dichloromethane by 3, combining organic phases, washing with 60ml of water respectively, washing with saturated NaCl, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3a,7a, 23-trihydroxy-methyl cholate;
(2) 10g of 3a,7a, 23-trihydroxy-methyl cholate is sequentially added, dissolved in 90ml of dichloromethane and 8.6ml of triethylamine, 6.3g of acetic anhydride and 0.14g of DMAP (4-dimethylaminopyridine) are added, the mixture is reacted for 2 hours at 20-25 ℃, and the solvent is removed under reduced pressure after the reaction is finished. Adding 35g water, extracting water phase with ethyl acetate 35ml 3, mixing organic phases, washing with hydrochloric acid 45ml, water 45ml and saturated NaCl 45ml, drying with anhydrous sodium sulfate, concentrating organic phase under reduced pressure, and recrystallizing with methanol to obtain 3a,7a, 23-triacetoxy-methyl cholate
(3) 3a,7a, 23-triacetoxy-cholic acid methyl ester, 30g of ethyl acetate and 0.2g of acetic acid were added in this order to dissolve them. The temperature is controlled between 30 ℃ and 40 ℃, and 5.3g of sodium bicarbonate is added. The reaction is carried out for 1 hour at the temperature of 30-40 ℃. Distilling the organic phase until a viscous residue is obtained, adding methanol, cooling to-5-0 ℃, crystallizing, filtering, leaching with 9g of methanol, and filtering until no filtrate exists, thereby obtaining the 3a,7 a-diacetyloxy-23-hydroxy cholic acid methyl ester.
(4) Dissolving 3a,7 a-diacetyloxy-23-hydroxy cholic acid methyl ester in dichloromethane in sequence, controlling the temperature to be 20-40 ℃, dropwise adding methane sulfonyl chloride and triethylamine in sequence, reacting for 1h, distilling under reduced pressure to remove the solvent, washing with 50ml of hydrochloric acid, 50ml of water and 50ml of saturated NaCl respectively, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, heating the crude product with methanol to dissolve and recrystallize to obtain the 3a,7 a-diacetyloxy-23-methyl sulfonyl cholic acid methyl ester.
(5) 3a,7 a-diacetyloxy-23-methylsulfonylcholic acid methyl ester is dissolved in TFA in sequence, and sodium borohydride is added for reaction for 1 h. The organic phase was distilled under reduced pressure. Adding methanol, heating to dissolve, and cooling to obtain white crystalline solid 3a,7 a-diacetyloxy-methyl cholate.
(6) Sequentially adding 3a,7 a-diacetyloxy-cholic acid methyl ester, adding dichloromethane for dissolution, and 1.57g of sodium hydroxide, controlling the temperature to be 20-30 ℃, and reacting for 1 h. After the reaction, 0.1g of sulfuric acid was added to acidify the reaction mixture. Evaporating the solvent to obtain a crude product, heating, refluxing and cooling the crude product by using methanol for recrystallization, leaching the filter cake by using 10g of purified water, and filtering until no filtrate exists, thereby obtaining the chenodeoxycholic acid. The purity is 97.6%; the overall yield is 87.8%.
Claims (3)
1. A method for synthesizing 3 alpha, 7 alpha-dihydroxy-5-beta-cholanic acid from duck cholic acid is characterized by comprising the following steps:
(1) sequentially adding methanol, cholic acid of duck and concentrated sulfuric acid into a 500ml four-mouth bottle, carrying out reflux reaction at 70 ℃ for 2 hours, distilling under reduced pressure to remove the methanol, adding water and dichloromethane for extraction, combining organic phases, washing with 60ml of water, washing with saturated NaCl, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3a,7a, 23-trihydroxy-methyl cholate;
(2) sequentially adding 3a,7a, 23-trihydroxy-methyl cholate, dissolving in dichloromethane and triethylamine, adding acetic anhydride and DMAP, reacting for 2 hours at 20-25 ℃, decompressing after the reaction is finished, removing the solvent, adding water, extracting a water phase by using ethyl acetate, combining organic phases, washing by using hydrochloric acid, water and saturated NaCl respectively, drying by using anhydrous sodium sulfate, concentrating a crude product by using organic phase under reduced pressure, and recrystallizing by using methanol to obtain 3a,7a, 23-triacetoxy-methyl cholate;
(3) sequentially adding 3a,7a, 23-triacetoxy-methyl cholate, ethyl acetate and acetic acid obtained in the step (1) into a 500ml four-mouth bottle, dissolving the mixture in acetic acid, controlling the temperature to be 30-40 ℃, adding sodium bicarbonate, reacting for 1 hour at the temperature of 30-40 ℃, distilling an organic phase until a viscous residue is obtained, adding methanol, cooling to be-5-0 ℃ for crystallization, filtering, leaching with 9g of methanol, and filtering until no filtrate exists, so as to obtain 3a,7 a-diacetoxy-23-hydroxy methyl cholate;
(4) dissolving 3a,7 a-diacetyloxy-23-hydroxy cholic acid methyl ester in dichloromethane in sequence, controlling the temperature to be 20-40 ℃, dropwise adding methane sulfonyl chloride and triethylamine in sequence, reacting for 1h, distilling under reduced pressure to remove the solvent, washing with hydrochloric acid, water and saturated NaCl respectively, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, heating the crude product with methanol to dissolve and recrystallize to obtain 3a,7 a-diacetyloxy-23-methanesulfonyl cholic acid methyl ester;
(5) dissolving 3a,7 a-diacetyloxy-23-methylsulfonyl cholic acid methyl ester in TFA, adding sodium borohydride to react for 1h,
distilling the organic phase under reduced pressure, adding methanol, heating to dissolve, and cooling to obtain white crystalline solid 3a,7 a-diacetyloxy-methyl cholate;
(6) sequentially adding 3a,7 a-diacetyloxy-methyl cholate, adding dichloromethane for dissolution, adding sodium hydroxide, controlling the temperature to be 20-30 ℃, reacting for 1h, adding sulfuric acid for acidification after the reaction is finished, evaporating the solvent to obtain a crude product, heating, refluxing, cooling and recrystallizing by using methanol, leaching the filter cake by using purified water, and filtering until no filtrate exists, thereby obtaining the chenodeoxycholic acid.
2. The method of claim 1, wherein: methanol in step (1): d, duck cholic acid: the mass ratio of the concentrated sulfuric acid is as follows: 8: 5: 0.05, wherein the purity of the duck cholic acid is more than 96%.
3. The method of claim 1, wherein: the mass of sodium bicarbonate added in the step (2) is 1/5-1/10 of 3a,7a, 23-triacetoxy-cholic acid methyl ester.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6461496A (en) * | 1987-08-28 | 1989-03-08 | Adeka Argus Chemical Co Ltd | Production of 5'-ursodeoxycholic acid |
| CN102942449A (en) * | 2012-11-23 | 2013-02-27 | 上海药明康德新药开发有限公司 | Synthetic method of 2,2-bis (trifluoroethyl) propanol |
| CN105418716A (en) * | 2015-12-25 | 2016-03-23 | 成都市新功生物科技有限公司 | Method for synthesizing chenodeoxycholic acid by using duck cholic acid extracted from duck bile |
| CN112300237A (en) * | 2020-04-13 | 2021-02-02 | 苏州恩泰新材料科技有限公司 | Preparation method and application of seal cholic acid |
| CN112724189A (en) * | 2020-12-31 | 2021-04-30 | 中国科学院成都有机化学有限公司 | Preparation method of chenodeoxycholic acid |
-
2020
- 2020-12-01 CN CN202011383540.4A patent/CN112321665A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6461496A (en) * | 1987-08-28 | 1989-03-08 | Adeka Argus Chemical Co Ltd | Production of 5'-ursodeoxycholic acid |
| CN102942449A (en) * | 2012-11-23 | 2013-02-27 | 上海药明康德新药开发有限公司 | Synthetic method of 2,2-bis (trifluoroethyl) propanol |
| CN105418716A (en) * | 2015-12-25 | 2016-03-23 | 成都市新功生物科技有限公司 | Method for synthesizing chenodeoxycholic acid by using duck cholic acid extracted from duck bile |
| CN112300237A (en) * | 2020-04-13 | 2021-02-02 | 苏州恩泰新材料科技有限公司 | Preparation method and application of seal cholic acid |
| CN112724189A (en) * | 2020-12-31 | 2021-04-30 | 中国科学院成都有机化学有限公司 | Preparation method of chenodeoxycholic acid |
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