CN102746359A - Novel synthesizing method for preparing ursodesoxycholic acid (UDCA) from chenodeoxycholic acid - Google Patents
Novel synthesizing method for preparing ursodesoxycholic acid (UDCA) from chenodeoxycholic acid Download PDFInfo
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- CN102746359A CN102746359A CN2012102626538A CN201210262653A CN102746359A CN 102746359 A CN102746359 A CN 102746359A CN 2012102626538 A CN2012102626538 A CN 2012102626538A CN 201210262653 A CN201210262653 A CN 201210262653A CN 102746359 A CN102746359 A CN 102746359A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a novel method for preparing UDCA from chenodeoxycholic acid. The method includes taking the chenodeoxycholic acid as a raw material, performing protection on carboxyl and selective protection on 3-carboxyl, then subjecting carboxyl at position 7 to a reaction through Mitsunobu or producing ester from paratoluensulfonyl chloride, methanesulfonyl chloride and paranitrobenzenesulfonyl chloride, and stripping off a protecting group to prepare the UDCA. Compared with other processes, the method has the advantages of being mild in reaction condition, simple in operation, high in efficiency, yield and optical purity and the like, and provided with a bright industrial production prospect.
Description
One, technical field
The present invention relates to a kind of preparation method who treats gallbladdergallstonecholetithiasis, liver protecting medicine, prepare the new synthetic method of ursodesoxycholic acid by Chenodiol.
Two, background technology
The ursodesoxycholic acid chemical name is: 3a, and 7 beta-dihydroxyies-5 β-cholestane-24-acid, identical with the molecular formula of Chenodiol, cattle and sheep bile acid, three-dimensional arrangement is different, chemically calls isomers to the structural relation of these two kinds of compounds.These article are white crystalline powder, odorless, bitter.Be soluble in ethanol, Glacial acetic acid min. 99.5, sig water; Slightly be dissolved in ether, be insoluble in the acid of water and rare ore deposit, 203 ℃ of fusing points; Ursodesoxycholic acid (UDCA) is the hydrophilic cholic acid of a kind of nontoxicity; Can suppress competitively the absorption of toxicity endogenous cholic acid at ileum, through activating the signal network that calcium ion, protein kinase C are formed, and strengthen the hepatocellular secretion capacity of cholestasis through activating the mitotic activity protein kinase; 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 molecule on cytolemma and the organoid competitively, prevents that liver cell and bile duct cell from receiving 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 simultaneously, non-alcoholic fatty liver disease, benign recurrent intrahepatic cholestasis disease, congenital interior bile duct cystic dilatation disease.
Ursodesoxycholic acid (UDCA) is the effective constituent in the Fel Ursi, first ursodesoxycholic acid separation of pure article crystallization of the positive field of nineteen twenty-seven Japanese, nineteen thirty-seven clear and definite chemical structure.
At present both at home and abroad the starting raw material of synthetic ursodesoxycholic acid has two kinds of Chenodiol and cattle and sheep bile acids, and adopts the synthetic ursodesoxycholic acid of which kind of raw material all need produce 7-ketone Deoxycholic Acid earlier, and the process hydro-reduction obtains ursodesoxycholic acid again.
Great majority are to adopt alcohol+sodium Metal 99.5 system to carry out the hydro-reduction reaction now; This system stereoselectivity when carrying out the hydro-reduction reaction is relatively poor; Probably have only 80% 7-ketone Deoxycholic Acid to be reduced into ursodesoxycholic acid; Other 20% is reduced into Chenodiol, and reaction also need be carried out separation and purification after accomplishing, and the ursodeoxycholic acid product that obtains at last probably has only 60% of Chenodiol.
Three, summary of the invention
The objective of the invention is in order to overcome weak point of the prior art, provide a kind of produce that route is short, yield is high, optical purity is good a kind of with 7 hydroxyls after the Mitsunobu reaction, configuration reversal prepares the method for ursodesoxycholic acid.Ursodesoxycholic acid synthetic route of the present invention is following:
Embodiment
Through following examples with better explanation the present invention.But the present invention does not receive the restriction of following embodiment.
Embodiment 1
Synthesizing of Chenodiol methyl esters
(39.2g 0.1mol) is dissolved in the 100ml methyl alcohol Chenodiol, adds the 1ml vitriol oil, and reflux stirs 10h; After reacting completely, after concentrating, add 200ml ETHYLE ACETATE, water 100ml; Regulate pH to neutral with the unsaturated carbonate potassium solution, obtain organic layer, washing, anhydrous sodium sulfate drying; Decompression and solvent recovery, recrystallization get white solid 37.2g, yield 91.6%; Mp:156-157 ℃; NMR (CDCl
3300MHz) δ ppm 0.63 (3H, s, C-18Me), 0.94 (3H, s, C-19Me), 3.66 (3H, s, COOMe), 3.65 (2H, brm, C-3 and C-7 C
HOH) all the other are cholic acid parent nucleus peak.
Embodiment 2
Synthesizing of 3-ethyl carbonate ester-Chenodiol methyl esters
The Chenodiol methyl esters (20.3g, 0.05mol), 20ml methylene dichloride, pyridine 6ml, 0-5 ℃ drips the 6g Vinyl chloroformate; Behind the stirring at room 2h, add the entry dilution, use dichloromethane extraction; Merge organic layer, use 10% hydrochloric acid, water washing successively, anhydrous sodium sulfate drying; Decompression and solvent recovery gets pale solid 17.6g, yield 73.6%; Mp136-137 ℃; NMR (CDCl
3300MHz) δ ppm:0.66 (3H, s, C-18 Me), 0.91 (3H, s, C-19Me) 1.28 (3H, t, OCOCH
2C
H 3 ) 3.64 (3H, s, COOMe) 3.82 (1H, m, C-7CHOH), 4.14 (2H, q, OCOC
H 2CH
3), 4.44 (1H, brm, C-3
CHOCOCH
2CH
3) all the other are cholic acid parent nucleus peak.
Embodiment 3
Synthesizing of 3-ethyl carbonate ester-7-methanesulfonates-Chenodiol methyl esters
(4.78g 0.01mol) is dissolved in the 5ml pyridine 3-ethyl carbonate ester-Chenodiol methyl esters, and room temperature slowly drips (8g, 0.011mol) methylsulfonyl chloride; Stirred overnight after reaction finishes, is poured in the frozen water, with 50ml dichloromethane extraction 2 times; Merge organic layer, use 10% hydrochloric acid, 5% sodium hydrogen carbonate solution, water washing successively, anhydrous sodium sulfate drying, decompression and solvent recovery is to doing; Recrystallization gets prism-shaped needle 4.6g, yield 82.7%, mp107-108 ℃; NMR (CDCl
3300MHz) δ ppm:0.67 (3H, s, C-18Me), 0.94 (3H, s, C-19Me), 1.33 (3H, t, OCOCH2C
H 3 ), 3.04 (3H, s, SO
2Me), 3.61 (3H, s, COOMe), 4.17 (2H, q, OCOC
H 2CH
3), 4.43 (1H, brm, C-3
CHOCOEt), 4.89 (1H, brm, C-7
CHOSO
2CH
3) all the other are cholic acid parent nucleus peak.
Embodiment 3
Synthesizing of ursodesoxycholic acid
(2.78g 0.005mol) adds among the 10mlDMF, potassium acetate 1g 3-ethyl carbonate ester-7-methanesulfonates-Chenodiol methyl esters, is heated to 65 ℃, stirs 10h, is cooled to room temperature; Add the dilution of 20ml water, with ETHYLE ACETATE 50ml extraction 2 times, merge organic layer, washing; Anhydrous sodium sulfate drying, be evaporated to do after, add 20ml methyl alcohol, water 10ml, sodium hydroxide 2g stirring at room 24h, after reacting completely; Regulate pH6-7 with 6mol/L hydrochloric acid, the reclaim under reduced pressure organic solvent, with 100ml ethyl acetate extraction 2 times, the merging organic layer; Washing and drying, decompression and solvent recovery gets white solid, and re-crystallizing in ethyl acetate gets white needle 1.2g, yield 61.2%; 203-204 ℃; NMR (CDCl
3-DMSO-d
6300MHz) δ ppm:0.68 (3H, s, C-18 Me), 0.95 (3H, s, C-19 Me), 3.63 (2H, brm, C-3 and C-7 C
HOH) all the other are cholic acid parent nucleus peak.
Being merely embodiments of the invention in sum, is not to be used for limiting practical range of the present invention.Be that all equivalences of doing according to the content of claim of the present invention change and modification, all should be technological category of the present invention.
Claims (4)
1. one kind prepares the novel method that is prepared ursodesoxycholic acid by Chenodiol, and this process step is following:
A, carboxylic acid in the Chenodiol is processed compound 1, structural formula is following:
B, again 3-position hydroxyl in the compound in the A step-1 is adopted hydroxyl protection reagent, the selective protection hydroxyl, reaction makes compound-2;
C, with the 7-position hydroxyl in the compound-2, adopt configuration reversal reagent, preparation compound 3 is finally sloughed the protection base and is obtained ursodesoxycholic acid.
Wherein:
Compound-1 is a chenodeoxycholic acid ester, and R representes a protection base that is easy to the deprotection carboxyl in the ester;
Compound-2 is the chenodeoxycholic acid ester of 3 hydroxyl protections, R
1Represent a protection base that is easy to the deprotection hydroxyl;
Compound-3 is the chenodeoxycholic acid ester of 3 hydroxyl protection-7 hydroxy esterifications, R
2Represent a protection base that is easy to the deprotection hydroxyl.
Fig.1. the structural formula of above-claimed cpd.
2. a kind of novel method that is prepared ursodesoxycholic acid by Chenodiol for preparing according to claim 1 is characterised in that: carboxy protective groups such as R methyl, ethyl, benzyl in the formula.
3. a kind of novel method that is prepared ursodesoxycholic acid by Chenodiol for preparing according to claim 1 is characterised in that: it is basic that step B meta hydroxyl protection adopts ethers protection base, ester class to protect, first-selected chloro-formic ester class protection base.
4. a kind of preparation according to claim 1 is prepared the novel method of ursodesoxycholic acid by Chenodiol; Be characterised in that: step C meta hydroxyl configuration reversal, adopt DEAD-triphen phosphorus system (Mitsunobu reaction) Phenylsulfonic acid system such as tosic acid (Ts), methylsulfonic acid (Ms), p-nitrophenyl sulfonic acid to refer to that systems such as (Ns) prepares ursodesoxycholic acid.
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| CN201210262653.8A CN102746359B (en) | 2012-07-26 | 2012-07-26 | A kind of synthetic method being prepared ursodesoxycholic acid by Chenodiol |
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| CN201210262653.8A CN102746359B (en) | 2012-07-26 | 2012-07-26 | A kind of synthetic method being prepared ursodesoxycholic acid by Chenodiol |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503987A (en) * | 2015-12-28 | 2016-04-20 | 成都市新功生物科技有限公司 | Method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through copper-carrying active carbon catalytic oxidation-reduction method |
| CN108299540A (en) * | 2017-12-28 | 2018-07-20 | 广州市盈宇医药科技有限公司 | A kind of synthetic method of Tauro ursodesoxy cholic acid |
| CN108864237A (en) * | 2018-07-25 | 2018-11-23 | 江苏佳尔科药业集团有限公司 | 3 hydroxyl configuration reversal methods of steroidal compounds |
-
2012
- 2012-07-26 CN CN201210262653.8A patent/CN102746359B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| AJAY K. BOSE，ET AL.，: "Steroids. IX. Facile Inversion of Unhindered Sterol Configuration", 《TETRAHEDRON LETTERS》 * |
| TAKASHI IIDA，ET AL.，: "Potential Bile Acid Metabolites: IV Inversion of 7α-Hydroxyl; Ursodeoxycholic Acid", 《LIPIDS》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503987A (en) * | 2015-12-28 | 2016-04-20 | 成都市新功生物科技有限公司 | Method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through copper-carrying active carbon catalytic oxidation-reduction method |
| CN105503987B (en) * | 2015-12-28 | 2017-05-31 | 成都市新功生物科技有限公司 | A kind of Activated Carbon with Cu catalytic oxidation-reduction method synthesizes the method for urso with chenodeoxycholic acid |
| CN108299540A (en) * | 2017-12-28 | 2018-07-20 | 广州市盈宇医药科技有限公司 | A kind of synthetic method of Tauro ursodesoxy cholic acid |
| CN108864237A (en) * | 2018-07-25 | 2018-11-23 | 江苏佳尔科药业集团有限公司 | 3 hydroxyl configuration reversal methods of steroidal compounds |
| CN108864237B (en) * | 2018-07-25 | 2021-06-11 | 江苏佳尔科药业集团股份有限公司 | Method for overturning 3-hydroxy configuration of steroid compound |
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