CN103012532A - Method for producing ursodesoxycholic acid with 98.5 percent sodium cholate - Google Patents
Method for producing ursodesoxycholic acid with 98.5 percent sodium cholate Download PDFInfo
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- CN103012532A CN103012532A CN201210526902XA CN201210526902A CN103012532A CN 103012532 A CN103012532 A CN 103012532A CN 201210526902X A CN201210526902X A CN 201210526902XA CN 201210526902 A CN201210526902 A CN 201210526902A CN 103012532 A CN103012532 A CN 103012532A
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- 229960001661 ursodiol Drugs 0.000 title claims abstract description 36
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic 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-UZVSRGJWSA-N 0.000 title claims abstract description 30
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 15
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].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 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 title abstract 3
- 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 claims abstract description 33
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims abstract description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 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 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims description 95
- 230000008025 crystallization Effects 0.000 claims description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- 238000001291 vacuum drying Methods 0.000 claims description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 241000283690 Bos taurus Species 0.000 claims description 17
- 241001494479 Pecora Species 0.000 claims description 17
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000003613 bile acid Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 9
- 238000010792 warming Methods 0.000 claims description 9
- DLYVTEULDNMQAR-SRNOMOOLSA-N Cholic Acid Methyl Ester 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](C)CCC(=O)OC)[C@@]2(C)[C@@H](O)C1 DLYVTEULDNMQAR-SRNOMOOLSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 238000010790 dilution Methods 0.000 claims description 7
- 239000012895 dilution Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 229960004249 sodium acetate Drugs 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 235000017550 sodium carbonate Nutrition 0.000 claims description 7
- 239000001117 sulphuric acid Substances 0.000 claims description 7
- 235000011149 sulphuric acid Nutrition 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 230000003252 repetitive effect Effects 0.000 claims description 2
- 238000005201 scrubbing Methods 0.000 claims description 2
- 210000000941 bile Anatomy 0.000 abstract description 8
- 235000019416 cholic acid Nutrition 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 2
- -1 chenodeoxycholic acid compound Chemical class 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 239000002812 cholic acid derivative Substances 0.000 abstract 1
- 150000001842 cholic acids Chemical class 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 238000000926 separation method Methods 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
- 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 description 7
- 239000004380 Cholic acid Substances 0.000 description 7
- 229960002471 cholic acid Drugs 0.000 description 7
- 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 description 7
- 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 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 2
- 241000272814 Anser sp. Species 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 208000006154 Chronic hepatitis C Diseases 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000010923 batch production Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000000013 bile duct Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UYVVLXVBEQAATF-UHFFFAOYSA-N 4-(1,3,7,12-tetrahydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoic acid Chemical compound OC1CC2CC(O)CC(O)C2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 UYVVLXVBEQAATF-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000018672 Dilatation Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 201000001493 benign recurrent intrahepatic cholestasis Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
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- 231100000956 nontoxicity Toxicity 0.000 description 1
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Abstract
The invention relates to a method for producing ursodesoxycholic acid with 98.5 percent sodium cholate. The method comprises the following steps: conducting four steps including esterification, acetylation, oxidation and reduction on sodium cholate, so as to convert cholic acids which are isomers into structures of chenodeoxycholic acid, and generate a chenodeoxycholic acid compound; conducting reaction of chenodeoxycholic acid to obtain ursodesoxycholic acid; and carrying out separation with ethyl acetate, so as to obtain ursodesoxycholic acid of which the purity is 98.5 percent. The method has the advantages that the manufacturing process is simple; the production cost is low; the problem that bile of birds is too less to collect is solved; and the purity of the ursodesoxycholic acid obtained through synthetic production is high, and reaches international advanced level.
Description
Technical field
The present invention relates to a kind of preparation method of ursodesoxycholic acid, relate in particular to a kind of production method of producing ursodesoxycholic acid with the cattle and sheep bile acid of content 98.5%; Be a kind of dissolving cholesterol calculus medicine, also be used for the treatment of the liver protecting medicine of primary biliary cirrhosis (PBS), chronic hepatitis C, alcoholic liver disease, non-alcoholic fatty liver disease simultaneously.
Background technology
At first in goose bile, found this effective constituent of Chenodiol as far back as 1848, in this title of nineteen twenty-four called after Chenodiol (CDCA).Since nineteen thirty-seven, someone attempts with the mixture dissolving gallbladdergallstonecholetithiasis that contains Chenodiol, found again afterwards that Chenodiol had the saturated bile effect of the cholesterol of correction, Britain has formally opened up the treatment of dissolving cholesterol calculus in 1972, correct the medicine of saturated bile and dissolving gallbladdergallstonecholetithiasis as first.
The chemical name of Chenodiol is 3 α, 7 alpha-dihydroxy-s-5 β-ursodeoxycholic acid, is white, needle-shaped crystals, and is tasteless, dissolves in methyl alcohol, ethanol, chloroform, acetone, Glacial acetic acid and sig water.Water insoluble, petroleum acid and benzene, fusing point 141-142 ℃ [α].+11.50°。
The ursodesoxycholic acid chemical name: 3 α, 7 beta-dihydroxyies-5 β-ursodeoxycholic acid are identical with the molecular formula of Chenodiol, cattle and sheep bile acid, three-dimensional arrangement is different, chemically the structural relation of these two kinds of compounds is called isomers, and this product is white crystalline powder, odorless, bitter.Be soluble in ethanol, chloroform, Glacial acetic acid, sig water, slightly be dissolved in ether, be insoluble in the acid of water and rare ore deposit, 203 ℃ of fusing points, [α].+ 57 ℃ of ursodesoxycholic acids are the hydrophilic cholic acid of a kind of nontoxicity, can suppress competitively toxicity endogenous cholic acid in the absorption of ileum, even the signal network by calcium ion, protein kinase C composition, and strengthen the hepatocellular secretion capacity of cholestasis by activating the isolating active proteins kinases, endogenous vegetables water cholic acid concentration in blood and the liver cell is reduced, reach the effect of anti-cholestasis.Ursodesoxycholic acid can also replace the toxicity cholic acid molecules on cytolemma and the organoid competitively, prevents that liver cell and bile duct cell are subject to the infringement of more toxicity cholic acid.Clinically, ursodesoxycholic acid is mainly used in dissolving cholesterol type hepatobiliary calculus, primary biliary cirrhosis (PBC), chronic hepatitis C also are used for alcoholic liver disease, non-alcoholic fatty liver disease, benign recurrent intrahepatic cholestasis disease, congenital interior bile duct cystic dilatation disease simultaneously.
In the prior art, the medicine of producing ursodesoxycholic acid all is to use from poultry bile 86% the Chenodiol that separates, extracts, is purified into to change into ursodesoxycholic acid by chemical process usually, but because it is less to exist the poultry bile amount, the problem that is difficult to collect, so cause present bear gall medicinal material rare, be difficult to satisfy people's demand.
Summary of the invention
The present invention is directed to above-mentioned problems of the prior art, by a large amount of groping and Test Summary, provide a kind of production method of producing ursodesoxycholic acid with the ox oxycholic acid of content 98.5%; Solved the rare problem of bear gall medicinal material in the prior art, and technique of the present invention is simple, cost is low, has improved the purity of ursodesoxycholic acid, is fit to batch production.
Technical scheme of the present invention comprises the steps:
Get methyl alcohol 50-60kg, add the cattle and sheep bile acid 20-30kg of content 98.5%, heated 1-2 hour, placing room temperature had crystallization after 6-8 hour, filter, and filtrate methyl alcohol to be recycled, the crystallization petroleum ether gets Methyl cholate 70 ℃ of vacuum-dryings;
Get toluene 10-20kg, adding the 2-4kg pyridine drops in the reactor, and then the Methyl cholate 2-4kg that adds above-mentioned crystallization at room temperature stirred 40-50 minute, then add water 120-150kg, again stirred 40-50 minute, then leave standstill 5-6 hour after, reclaim after isolating toluene, crystallization, crystallization is 70 ℃ of lower vacuum-dryings; Crystallization gets 3 α, 7 α-diacetyl Methyl cholate with the sherwood oil repetitive scrubbing;
Get above-mentioned 3 α, 7 α-diacetyl Methyl cholate 1-3kg, add the 2-4kg sodium-acetate, adding 10-15kg methyl alcohol refluxed 30 minutes, treat to add when temperature reaches 5-10 ℃ clorox 1kg, continue to stir 4-5 hour, then add in the 100kg water, rear filtration to be crystallized, crystallization is 70 ℃ of lower vacuum-dryings; Crystallization is 3 α-7 α-diacetoxy-12-ketone group ursodeoxycholic acid methyl esters;
Get 3 α-7 α-diacetoxy-12-ketone group ursodeoxycholic acid methyl esters 20-30kg and add ethylene glycol 200-250kg, hydrazine hydrate solvent 20-30kg backflow 12-15 hour, and then be warming up to 195-200 ℃ and refluxed again 3-4 hour, then stopping to heat up is cooled to room temperature, adds the dilution of 500-700kg water again, then regulates PH2.0 with dilute sulphuric acid, treat crystallization, filter, crystallization is 70 ℃ of vacuum-dryings, and crystallization is content 98.5% Chenodiol;
The Chenodiol 10-20kg that gets above-mentioned content 98.5% is raw material, adds the methyl alcohol of 10-15 times of weight of raw material, heats 60-80 ℃, dissolves 3-7 hour, gets solution A;
Mentioned solution A temperature is down to 5-10 ℃, then adds clorox, the weight of clorox is the 6%-15% of solution A weight, 5-10 ℃ of lower reaction 8-10 hour, gets reaction solution B;
Above-mentioned reaction solution B is warmed to 50-60 ℃ again, then adds yellow soda ash 30-40kg, add water 100-150 kg and filter, discard filtered liquid, crystallization gets 7-ketone 70 ℃ of vacuum-dryings;
Get above-mentioned 7-ketone 8-12kg, add sec-butyl alcohol 30-40kg, be warming up to 60-70 ℃ of dissolving, add sodium Metal 99.5 3-8kg, stirred 2-3 hour at 90-100 ℃, then stop to stir, filter, crystallization is 70 ℃ of vacuum-dryings;
Get above-mentioned dried crystallization product 8-12kg, add the 30-50kg ethyl acetate, add again the 1.0-3kg triethylamine 50-75 ℃ of dissolving, and stirred 1-3 hour, then regulate about PH2.0 with HCl, filter, filtrate discards, and crystallization gets ursodesoxycholic acid 70 ℃ of vacuum-dryings.
Advantage of the present invention and beneficial effect are as follows:
The present invention adopts cattle and sheep bile acid through four steps such as over-churning, acetylize, oxidation, reduction, the cholic acid of isomers is changed into the structure of Chenodiol, formed the compound of Chenodiol, the recycling Chenodiol is by obtaining ursodesoxycholic acid after the reaction; Overcome the limitation that can only extract Chenodiol from the fowl courage, in addition, the bile of fowl courage is less, and the bile of cattle and sheep is large and more, cattle and sheep bile acid is changed into goose go the explained hereafter cost of cholic acid low, is fit to produce in enormous quantities; And the ursodesoxycholic acid purity that is fit to production is high, has reached international advanced level.
The present invention has not only solved the rare problem of bear gall medicinal material in the prior art, and production technique is simple, and raw material sources are easy to get, and cost is low, has improved the purity of ursodesoxycholic acid, and production and transport stores without any risk, has wide market outlook.
Embodiment
Embodiment 1
Get the cattle and sheep bile acid 25kg of content 98.5%, add methyl alcohol 55kg, after the reflux 1.5 hours, place 7 hours under the room temperature to producing crystallization, filter, crystallization model 90-120 petroleum ether, get dry product 70 ℃ of vacuum-drying crystallizations, then get dry product 3kg, get toluene 15kg, get pyridine 3kg and put into together retort, at room temperature stirred 45 minutes, then add 135kg water and again stirred 45 minutes, then leave standstill 5.5 hours after, isolate toluene and reclaim, crystallization, crystallization is with repeated multiple times 3 α that wash to get of model 90-120 sherwood oil, 7 α-diacetyl Methyl cholate 70 ℃ of vacuum-dryings, get dry product 2kg and add the 3kg sodium-acetate, then getting 13kg methyl alcohol puts into together retort and refluxed together 30 minutes, then cool the temperature to 8 ℃ and add clorox 1kg, continue to stir 4.5 hours, then add water 100kg, continue to stir after 30 minutes, crystallization filters, and crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 25 kg and add ethylene glycol 225kg, the hydrazine hydrate 25kg of content 85% refluxed 13 hours in 130 ℃, and then be warming up to 198 ℃ and refluxed again 3.5 hours, then stop to add again the dilution of 600kg water after intensification is cooled to room temperature, then transfer PH2.0 behind crystallization, to filter with dilute sulphuric acid, crystallization is 70 ℃ of vacuum-dryings, and crystallization is the Chenodiol of content 98.5%.
Get content and be 98.5% Chenodiol 15kg, the methyl alcohol that adds 13 times of weight of CDCA acid starting material dissolved 5 hours at 70 ℃, cooled the temperature to 8 ℃ after the dissolving again, then added clorox, the weight of clorox is 9% of solution A weight, stirred 9 hours at 8 ℃, then temperature is elevated to 55 ℃, add yellow soda ash 35kg, add water 125 kg and produce precipitation, filter, crystallization obtains 7-ketone 70 ℃ of vacuum-dryings 8 hours; Get 7-ketone 10kg, add sec-butyl alcohol 35 kg, then dissolving when 65 ℃ of temperature adds the 5kg sodium Metal 99.5, stirs 2.5 hours at 95 ℃, then stops to stir, and filters, and crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 10kg, add the 40kg ethyl acetate, add again the 2kg triethylamine 60 ℃ of dissolvings, and stirred 2 hours, then regulate about PH2.0 with HCl, filter, crystallization, 70 ℃ of vacuum-dryings namely get purity at the ursodesoxycholic acid more than 98.5%.
Embodiment 2
Get content at the cattle and sheep bile acid 20kg more than 98.5%, add methyl alcohol 50kg, after the reflux 1 hour, place 6 hours under the room temperature to producing crystallization, filter, crystallization model 90-120 petroleum ether, 70 ℃ of vacuum-drying crystallizations, then get dry product 2kg, get toluene 10kg, get pyridine 2kg and put into together retort, at room temperature stirred 40 minutes, then add 120kg water and again stirred 40 minutes, then leave standstill 5 hours after, isolate toluene and reclaim, crystallization, crystallization is with repeated multiple times 3 α that wash to get of model 90-120 sherwood oil, 7 α-diacetyl Methyl cholate 70 ℃ of vacuum-dryings, get dry product 1kg and add the 2kg sodium-acetate, then getting 10kg methyl alcohol puts into together retort and refluxed together 30 minutes, then cool the temperature to 5 ℃ and add clorox 3kg, continue to stir 4 hours, then add water 100kg, continue to stir after 30 minutes, crystallization filters, and crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 20 kg and add ethylene glycol 200kg, the hydrazine hydrate 20kg of content 85% refluxed 12 hours in 130 ℃, and then be warming up to 195 ℃ and refluxed again 3 hours, then stop to add again the dilution of 500kg water after intensification is cooled to room temperature, then transfer PH2.0 behind crystallization, to filter with dilute sulphuric acid, crystallization is 70 ℃ of vacuum-dryings, and crystallization is the Chenodiol of content 98.5%.
Get content and be 98.5% Chenodiol 10kg, the methyl alcohol that adds 10 times of weight of CDCA acid starting material dissolved 3 hours at 60 ℃, cooled the temperature to 5 ℃ after the dissolving again, then added clorox, the weight of clorox is 12% of solution A weight, stirred 8 hours at 5 ℃, then temperature is elevated to 50 ℃, add yellow soda ash 30kg, add water 100 kg and produce precipitation, filter, crystallization obtains 7-ketone 70 ℃ of vacuum-dryings 8 hours; Get 7-ketone 8kg, add sec-butyl alcohol 30 kg, dissolve when temperature 60 C, then add the 3kg sodium Metal 99.5, stirred 2 hours at 90 ℃, then stop to stir, filter, crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 8kg, add the 30kg ethyl acetate, add again the 1.0kg triethylamine 50 ℃ of dissolvings, and stirred 1 hour, then regulate about PH2.0 with HCl, filter, crystallization, 70 ℃ of vacuum-dryings namely get purity at the ursodesoxycholic acid more than 98.5%.
Embodiment 3
Get content at the cattle and sheep bile acid 30kg more than 98.5%, add methyl alcohol 60kg, after the reflux 2 hours, place 8 hours under the room temperature to producing crystallization, filter, crystallization model 90-120 petroleum ether, 70 ℃ of vacuum-drying crystallizations and get final product, then get dry product 4kg, get toluene 20kg, get pyridine 4kg and put into together retort, at room temperature stirred 50 minutes, then add 150kg water and again stirred 50 minutes, then leave standstill 6 hours after, isolate toluene and reclaim, crystallization, crystallization is with repeated multiple times 3 α that wash to get of model 90-120 sherwood oil, 7 α-diacetyl Methyl cholate 70 ℃ of vacuum-dryings, get dry product 3kg and add the 4kg sodium-acetate, then getting 15kg methyl alcohol puts into together retort and refluxed together 30 minutes, then cool the temperature to 10 ℃ and add clorox 4kg, continue to stir 5 hours, then add water 100kg, continue to stir after 30 minutes, crystallization filters, and crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 30 kg and add ethylene glycol 250kg, the hydrazine hydrate 30kg of content 85% refluxed 15 hours in 130 ℃, and then be warming up to 200 ℃ and refluxed again 4 hours, then stop to add again the dilution of 700kg water after intensification is cooled to room temperature, then transfer PH2.0 behind crystallization, to filter with dilute sulphuric acid, crystallization is 70 ℃ of vacuum-dryings, and crystallization is the Chenodiol of content 98.5%.
Get content and be 98.5% Chenodiol 20kg, the methyl alcohol that adds 15 times of weight of CDCA acid starting material dissolved 7 hours at 60 ℃, cooled the temperature to 10 ℃ after the dissolving again, then added clorox, the weight of clorox is 12% of solution A weight, stirred 10 hours at 10 ℃, then temperature is elevated to 60 ℃, add yellow soda ash 40kg, add water 150 kg and produce precipitation, filter, crystallization obtains 7-ketone 70 ℃ of vacuum-dryings 8 hours; Get 7-ketone 12kg, add sec-butyl alcohol 40 kg, dissolve when temperature 70 C, then add the 8kg sodium Metal 99.5, stirred 3 hours at 100 ℃, then stop to stir, filter, crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 12kg, add the 50kg ethyl acetate, add again the 3kg triethylamine 75 ℃ of dissolvings, and stirred 3 hours, then regulate about PH2.0 with HCl, filter, crystallization, 70 ℃ of vacuum-dryings namely get purity at the ursodesoxycholic acid more than 98.5%.
Implement 4
Get the cattle and sheep bile acid 27kg of content 98.5%, add methyl alcohol 58kg, after the reflux 2 hours, place 7 hours under the room temperature to producing crystallization, filter, crystallization model 90-120 petroleum ether, get Methyl cholate 70 ℃ of vacuum-drying crystallizations, then get Methyl cholate 3kg, get toluene 18kg, get pyridine 4kg and put into together retort, at room temperature stirred 50 minutes, then add 145kg water and again stirred 48 minutes, then leave standstill 6 hours after, isolate toluene and reclaim, crystallization, crystallization is with repeated multiple times 3 α that wash to get of model 90-120 sherwood oil, 7 α-diacetyl Methyl cholate 70 ℃ of vacuum-dryings, get above-mentioned dried 3 α, 7 α-diacetyl Methyl cholate 2.8kg adds the 3.5kg sodium-acetate, then getting 14kg methyl alcohol puts into together retort and refluxed together 30 minutes, then cool the temperature to 10 ℃ and add clorox 4kg, continue to stir 5 hours, then add water 100kg, continue to stir after 30 minutes, crystallization filters, and crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 28kg and add ethylene glycol 240kg, the hydrazine hydrate 26kg of content 85% refluxed 15 hours in 130 ℃, and then be warming up to 200 ℃ and refluxed again 4 hours, then stop to add again the dilution of 650kg water after intensification is cooled to room temperature, then transfer PH2.0 behind crystallization, to filter with dilute sulphuric acid, crystallization is 70 ℃ of vacuum-dryings, and crystallization is the Chenodiol of content 98.5%.
Get content and be 98.5% Chenodiol 18kg, the methyl alcohol that adds 12 times of weight of CDCA acid starting material dissolved 6 hours at 60 ℃, cooled the temperature to 10 ℃ after the dissolving again, then added clorox, the weight of clorox is 15% of solution A weight, stirred 10 hours at 10 ℃, then temperature is elevated to 60 ℃, add yellow soda ash 40kg, add water 150 kg and produce precipitation, filter, crystallization obtains 7-ketone 70 ℃ of vacuum-dryings 8 hours; Get 7-ketone 12kg, add sec-butyl alcohol 40 kg, dissolve when temperature 70 C, then add the 8kg sodium Metal 99.5, stirred 3 hours at 100 ℃, then stop to stir, filter, crystallization is 70 ℃ of vacuum-dryings.Get above-mentioned dry product 11kg, add the 45kg ethyl acetate, add again the 3kg triethylamine 75 ℃ of dissolvings, and stirred 3 hours, then regulate about PH2.0 with HCl, filter, crystallization, 70 ℃ of vacuum-dryings namely get purity at the ursodesoxycholic acid more than 98.5%.
All technical of the present invention and beneficial effect have carried out comprehensive and systematic check with reference to national standard, and its detected result is listed in table 1 for ease of reference.
Conclusion: comprehensive above-mentioned comparison and detection that all technical of the present invention is undertaken by national standard as can be known, the equal conformance with standard of all technical of the present invention.And it is high to enrich proof ursodesoxycholic acid purity of the present invention, is fit to batch production.
Claims (4)
1. a production method of producing ursodesoxycholic acid with the cattle and sheep bile acid of content 98.5% is characterized in that comprising the steps:
Get methyl alcohol 50-60kg, add the cattle and sheep bile acid 20-30kg of content 98.5%, heated 1-2 hour, placing room temperature had crystallization after 6-8 hour, filter, and filtrate methyl alcohol to be recycled, the crystallization petroleum ether gets Methyl cholate 70 ℃ of vacuum-dryings;
Get toluene 10-20kg, adding the 2-4kg pyridine drops in the reactor, and then the Methyl cholate 2-4kg that adds above-mentioned crystallization at room temperature stirred 40-50 minute, then add water 120-150kg, again stirred 40-50 minute, then leave standstill 5-6 hour after, reclaim after isolating toluene, crystallization, crystallization is 70 ℃ of lower vacuum-dryings; Crystallization gets 3 α, 7 α-diacetyl Methyl cholate with the sherwood oil repetitive scrubbing;
Get above-mentioned 3 α, 7 α-diacetyl Methyl cholate 1-3kg, add the 2-4kg sodium-acetate, adding 10-15kg methyl alcohol refluxed 30 minutes, treat to add when temperature reaches 5-10 ℃ clorox 1kg, continue to stir 4-5 hour, then add in the 100kg water, rear filtration to be crystallized, crystallization is 70 ℃ of lower vacuum-dryings; Crystallization is 3 α-7 α-diacetoxy-12-ketone group ursodeoxycholic acid methyl esters;
Get 3 α-7 α-diacetoxy-12-ketone group ursodeoxycholic acid methyl esters 20-30kg and add ethylene glycol 200-250kg, hydrazine hydrate solvent 20-30kg backflow 12-15 hour, and then be warming up to 195-200 ℃ and refluxed again 3-4 hour, then stopping to heat up is cooled to room temperature, adds the dilution of 500-700kg water again, then regulates PH2.0 with dilute sulphuric acid, treat crystallization, filter, crystallization is 70 ℃ of vacuum-dryings, and crystallization is content 98.5% Chenodiol;
The Chenodiol 10-20kg that gets above-mentioned content 98.5% is raw material, adds the methyl alcohol of 10-15 times of weight of raw material, heats 60-80 ℃, dissolves 3-7 hour, gets solution A;
Mentioned solution A temperature is down to 5-10 ℃, then adds clorox, the weight of clorox is the 6%-15% of solution A weight, 5-10 ℃ of lower reaction 8-10 hour, gets reaction solution B;
Above-mentioned reaction solution B is warmed to 50-60 ℃ again, then adds yellow soda ash 30-40kg, add water 100-150 kg and filter, discard filtered liquid, crystallization gets 7-ketone 70 ℃ of vacuum-dryings;
Get above-mentioned 7-ketone 8-12kg, add sec-butyl alcohol 30-40kg, be warming up to 60-70 ℃ of dissolving, add sodium Metal 99.5 3-8kg, stirred 2-3 hour at 90-100 ℃, then stop to stir, filter, crystallization is 70 ℃ of vacuum-dryings;
Get above-mentioned dried crystallization product 8-12kg, add the 30-50kg ethyl acetate, add again the 1.0-3kg triethylamine 50-75 ℃ of dissolving, and stirred 1-3 hour, then regulate about PH2.0 with HCl, filter, filtrate discards, and crystallization gets ursodesoxycholic acid 70 ℃ of vacuum-dryings.
2. production method of producing ursodesoxycholic acid with the cattle and sheep bile acid of content 98.5% according to claim 1 is characterized in that comprising the steps:
Get the cattle and sheep bile acid 27kg of content 98.5%, add methyl alcohol 58kg, after the reflux 2 hours, place 7 hours under the room temperature to producing crystallization, filter, crystallization model 90-120 petroleum ether, get Methyl cholate 70 ℃ of vacuum-drying crystallizations, then get Methyl cholate 3kg, get toluene 18kg, get pyridine 4kg and put into together retort, at room temperature stirred 50 minutes, then add 145kg water and again stirred 48 minutes, then leave standstill 6 hours after, isolate toluene and reclaim, crystallization, crystallization is with repeated multiple times 3 α that wash to get of model 90-120 sherwood oil, 7 α-diacetyl Methyl cholate 70 ℃ of vacuum-dryings, get above-mentioned dried 3 α, 7 α-diacetyl Methyl cholate 2.8kg adds the 3.5kg sodium-acetate, then getting 14kg methyl alcohol puts into together retort and refluxed together 30 minutes, then cool the temperature to 10 ℃ and add clorox 4kg, continue to stir 5 hours, then add water 100kg, continue to stir after 30 minutes, crystallization filters, and crystallization is 70 ℃ of vacuum-dryings;
Get above-mentioned dry product 28kg and add ethylene glycol 240kg, the hydrazine hydrate 26kg of content 85% refluxed 15 hours in 130 ℃, and then be warming up to 200 ℃ and refluxed again 4 hours, then stop to add again the dilution of 650kg water after intensification is cooled to room temperature, then transfer PH2.0 behind crystallization, to filter with dilute sulphuric acid, crystallization is 70 ℃ of vacuum-dryings, and crystallization is the Chenodiol of content 98.5%;
Get content and be 98.5% Chenodiol 18kg, the methyl alcohol that adds 12 times of weight of CDCA acid starting material dissolved 6 hours at 60 ℃, cooled the temperature to 10 ℃ after the dissolving again, then added clorox, the weight of clorox is 15% of solution A weight, stirred 10 hours at 10 ℃, then temperature is elevated to 60 ℃, add yellow soda ash 40kg, add water 150 kg and produce precipitation, filter, crystallization obtains 7-ketone 70 ℃ of vacuum-dryings 8 hours; Get 7-ketone 12kg, add sec-butyl alcohol 40 kg, dissolve when temperature 70 C, then add the 8kg sodium Metal 99.5, stirred 3 hours at 100 ℃, then stop to stir, filter, crystallization is 70 ℃ of vacuum-dryings;
Get above-mentioned dry product 11kg, add the 45kg ethyl acetate, add again the 3kg triethylamine 75 ℃ of dissolvings, and stirred 3 hours, then regulate about PH2.0 with HCl, filter, crystallization, 70 ℃ of vacuum-dryings namely get purity at the ursodesoxycholic acid more than 98.5%.
3. production method of producing ursodesoxycholic acid with the cattle and sheep bile acid of content 98.5% according to claim 1 is characterized in that described sherwood oil is model 100-120 sherwood oil.
4. production method of producing ursodesoxycholic acid with the cattle and sheep bile acid of content 98.5% according to claim 1 is characterized in that the hydrazine hydrate solvent that described hydrazine hydrate solvent is content 85%.
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