CN105646634A - Preparation method of impurities of obeticholic acid - Google Patents
Preparation method of impurities of obeticholic acid Download PDFInfo
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- CN105646634A CN105646634A CN201610064314.7A CN201610064314A CN105646634A CN 105646634 A CN105646634 A CN 105646634A CN 201610064314 A CN201610064314 A CN 201610064314A CN 105646634 A CN105646634 A CN 105646634A
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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
Abstract
The invention relates to a synthesis method of three impurities of obeticholic acid. The method has important significance in synthesizing high-quality obeticholic acid. The method mainly studies 3 alpha,7 beta-dyhydroxyl-6-ethyl-5 beta-cholane-24-acid (V), 3 alpha,7 beta-dyhydroxyl-6 alpha-ethyl-5 beta-cholane-24-alcohol (VI) and 3,7-dicarbonyl-6 alpha-ethyl-5 beta-cholane-24-acid (VII). The synthesis route is shown in the description.
Description
Technical field
The preparation method that the present invention relates to shellfish cholic acid impurity difficult to understand.
Background technology
Shellfish cholic acid (Obeticholicacid, I) difficult to understand, chemical name: 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-acid, structural formula is as follows. It is a kind of method Buddhist nun's ester X receptor (FXR) agonist, 6-derivatized product for chenodeoxycholic acid, developed by American I ntercept drugmaker, for the treatment of the liver such as primary biliary cirrhosis (PBC) and non-alcoholic stellato-hepatitis and intestinal tract disease in clinical research, current Yuan Yan company has submitted the application of registration listing to for PBC indication to FDA and EMA.
The synthesis dominant response route of shellfish cholic acid (I) difficult to understand is as follows:
(1) with chenodeoxycholic acid for raw material; aoxidize through pyridinium chloro-chromate, then through 3,4-dihydro-2H-pyrans, 3-hydroxyl is protected; carrying out 6 ethylizations under LDA, n-BuLi catalysis, finally under sodium borohydride effect, reduction prepares shellfish cholic acid (I) difficult to understand.
(2) with 3-hydroxyl-7-ketone-5 ��-cholane-24-acid for raw material; through 3; 3-hydroxyl is protected by 4-dihydro-2H-pyrans; with LDA for catalyst; 6 alkylated reactions are carried out at-78 DEG C; carrying out carboxyl esterization reaction again under hydrochloric acid catalysis and prepare intermediate, intermediate is after sodium borohydride reduction, and hydrolysis obtains shellfish cholic acid (I) difficult to understand in the basic conditions.
(3) with 3-hydroxyl-7-ketone-5 ��-cholane-24-acid for raw material; 7 hydroxyls are aoxidized with sodium hypochlorite for oxidant; under cesium carbonate effect, carboxy protective is carried out again with bromobenzyl; n-BuLi is catalyst; adopt trim,ethylchlorosilane respectively to 3 at-78 DEG C; 7 hydroxyls carry out silanization protection; with boron trifluoride ether solution for catalyst; ethylidene replacement is carried out to 6 at-60 DEG C; carry out 7 carbonyl reductions with sodium borohydride again, finally with Pd/C 6 ethylidene are reduced and take off benzyl simultaneously and prepare shellfish cholic acid (I) difficult to understand.
(4) with 3-hydroxyl-7-ketone-5 ��-cholane-24-acid for initiation material; carboxy protective is carried out through esterification; again with trim,ethylchlorosilane to 3; 7 hydroxyls carry out silanization protection; with boron trifluoride diethyl etherate for catalyst; reacting with anhydrous acetaldehyde, then hydrolysis obtains 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid (II) in the basic conditions, obtains end-product Austria shellfish cholic acid (I) through Pd/C catalytic hydrogenation and sodium borohydride reduction after.
Wherein, shellfish cholic acid synthesis difficult to understand it is critical only that the control of impurity, and therefore the study on the synthesis of shellfish cholic acid impurity difficult to understand is significant. Document points out that shellfish cholic acid difficult to understand needs the impurity of research to include: 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid (II); 3 Alpha-hydroxy-6 ��-ethyl-7-ketone-5 ��-cholane-24-acid (III);3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-acid (IV); 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V). The impurity additionally needing research in technical study process includes: 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI); 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII). Synthesis report document for shellfish cholic acid impurity difficult to understand is less both at home and abroad.
Summary of the invention
The present invention relates to three impurity of shellfish cholic acid difficult to understand: 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V); 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI); 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII). The synthetic route of the present invention is as follows:
Impurity (V) is with 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid (II) for raw material, and impurity (VI) and (VII) are with shellfish cholic acid (I) difficult to understand for raw material. Wherein 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid (II) is the key intermediate of synthesis shellfish cholic acid (I) difficult to understand.
The synthesis step of the present invention:
The preparation of (1) 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V)
1. 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V) is with 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid (II) for raw material, it is hydrogenated with by palladium hydrogenated carbon, then 7 carbonyl reductions obtain, hydrogenation conditions is atmospheric pressure at room, reduction temperature is-25 DEG C��-30 DEG C, and preparation liquid phase separation obtains.
2. 3 ��, in the preparation method of 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), hydrogenation solvent for use is selected from methanol, ethanol, isopropanol, n-butyl alcohol, acetone, butanone, oxolane, dichloromethane, chloroform, acetonitrile, ethyl acetate, nafoxidine, pyridine, piperidines, N-Methyl pyrrolidone, N, dinethylformamide, water, sodium hydrate aqueous solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, sodium bicarbonate aqueous solution, wet chemical, potassium bicarbonate aqueous solution, and two kinds or above mixed solution. The present invention preferentially selects the mixed solution of methanol and sodium hydrate aqueous solution as solvent.
In the preparation method of 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), the w/v of 3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid (II) and solvent is 1: 25��35.
3. 3 ��, in the preparation method of 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), reducing agent used is selected from N ��, K, stannous chloride, sodium borohydride, potassium borohydride, red aluminum, Lithium Aluminium Hydride, three tertiary butyoxy aluminum lithiums, cerous chloride, and sodium borohydride, potassium borohydride etc. and Louis acid complex reducing agent. The present invention preferentially selects potassium borohydride and cerous chloride as reducing agent.
In the preparation method of 4. 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid adopts preparation liquid phase separation.
The preparation of (2) 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI)
1. 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI) is with shellfish cholic acid (I) difficult to understand for raw material, in acid condition through being esterified to obtain carboxyl ester compound, and esterification reaction temperature 20��150 DEG C, prepare then through reduction.
2. 3 ��, in the preparation method of 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), esterification solvent for use choosing esterification solvent for use is selected from methanol, ethanol, isopropanol, n-butyl alcohol, sec-butyl alcohol, neopentyl alcohol, benzyl alcohol, ethylene glycol, glycerol. Prioritizing selection methanol as solvent of the present invention is esterified.
In the preparation method of ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), the w/v of shellfish cholic acid (I) difficult to understand and solvent is 1: 5��15;
3. through reducing 3 prepared �� after being esterified under acid condition, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), wherein, the kind of described acid and consumption can be all Conventional solvents and the consumption of this type of reaction of this area, the consumption of the preferred following acid of the present invention and acid: wherein, described acid is preferably hydrochloric acid, sulphuric acid, methanesulfonic acid; The consumption of described acid is preferably 0.2��0.4 equivalent, regulates solution �� H to 1��2.
4. through reducing 3 prepared �� after being esterified under acid condition, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), wherein, reducing agent used is selected from Na, K, stannous chloride, sodium borohydride, potassium borohydride, red aluminum, Lithium Aluminium Hydride, three tertiary butyoxy aluminum lithiums, cerous chloride, and sodium borohydride, potassium borohydride etc. and Louis acid complex reducing agent. The present invention preferentially selects Lithium Aluminium Hydride as reducing agent.
5. shellfish cholate compound difficult to understand is through reducing 3 prepared ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), extracts solvent for use selected from n-butyl alcohol, isopropanol, ethanol, methanol, ethyl acetate, toluene, acetone, dichloromethane, chloroform, acetonitrile, oxolane. Ethyl acetate solvent of the present invention.
6. 3 ��, in the preparation method of 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI) is refining adopts silica gel column chromatography method, eluant adopts petrol ether/ethyl acetate system, it is preferable that ethyl acetate: petroleum ether=1: 4��6.
(3) 3, the preparation of 7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII)
1. 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII) are with shellfish cholic acid (I) difficult to understand for raw material, oxidized obtain, reaction temperature-10��30 DEG C.
2., in the preparation method of 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII), oxidising agent used is selected from NBS, hydrogen peroxide, peracetic acid, sodium dichromate, chromic acid, nitric acid, potassium permanganate, Ammonium persulfate., sodium hypochlorite. The present invention preferentially selects Jones reagent (chromic acid).
3. 3, in the preparation method of 7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII), solvent for use is selected from acetone, oxolane, dichloromethane, chloroform, acetonitrile, ethyl acetate, nafoxidine, triethylamine, pyridine, piperidines, N-Methyl pyrrolidone, N, dinethylformamide, N, N-dimethyl acetylamide, the preferred acetone of the present invention is as solvent. The present invention preferentially selects acetone solvent.
In the preparation method of 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII), the w/v of shellfish cholic acid (I) difficult to understand and solvent is 1: 15��25.
4. Jones reagent oxidation prepare 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII), extracts solvent for use selected from n-butyl alcohol, isopropanol, ethanol, methanol, ethyl acetate, toluene, acetone, dichloromethane, chloroform, acetonitrile, oxolane. Ethyl acetate solvent of the present invention.
5. 3, in the preparation method of 7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII), 3,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII) is refining adopts silica gel column chromatography method, eluant adopts ethanol/methylene system, it is preferable that methanol: dichloromethane=1: 20��30.
Detailed description of the invention
Following Examples further illustrates the present invention, but the present invention is not intended to be limited thereto.
Prepared by embodiment 1:3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V)
2.0g3 Alpha-hydroxy-6-ethylidene-7-ketone-5 ��-cholane-24-acid is placed in 100ml single port bottle, adds 50ml methanol-30% sodium hydrate aqueous solution (2: 1) mixed solution, stirring and dissolving, add 0.2g5% �� d/C, pass into H2, stirring reaction at 25 DEG C, normal pressure inhales hydrogen to reacting completely, elimination palladium charcoal, and filtrate is adjusted to acidity with phosphoric acid, when being concentrated into white solid, pours in 20ml frozen water, stands and precipitates out solid, and sucking filtration is dry, obtains white solid 1.25g.
Under nitrogen protection, by above-mentioned white solid 0.95g, CeCl30.85g, dissolve with the mixed solution (v/v=1/1) of 10ml methanol oxolane, it is cooled to-25 DEG C after entirely molten, it is then quickly added into potassium borohydride, TLC monitoring reaction disappears to raw material, add 10% aqueous hydrochloric acid solution cancellation, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate dries, and filters, and concentrate obtains white foam solid 0.43g through column chromatography, target product 3 �� is obtained, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V) 0.12g then through preparation liquid phase separation.
Its Structural Identification data are as follows:
1H-NMR (300Mz, DMSO-d6) ��: 0.60 (s, 3H), 2.06-2.18 (m, 1H), 2.22-2.26 (m, 1H), 3.11 (m, 1H), 3.48 (s, 1H), 4.06 (d, J=4.7Hz, 1H), 4.31 (d, J=4.4Hz, 1H), 11.97 (s, 1H).
ESI-MS (m/z): 443.3 [M+Na]+, 419.25 [M-H]-��
The preparation of embodiment 23 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI)
Austria shellfish cholic acid 2.0g is placed in 25ml reaction bulb, adds 10ml methanol stirring and dissolving, add 0.1ml concentrated hydrochloric acid, (25-30 DEG C) 24h, TLC monitoring is stirred at room temperature complete to raw material reaction, adjusts about pH7 with 2M sodium hydroxide solution, concentrating under reduced pressure, residue adds methylene chloride dissolving, separatory, saturated common salt water washing, anhydrous sodium sulfate dries, filtering, filtrate reduced in volume is extremely dry, get Ao Bei Methyl cholate 1.8g;
-10 DEG C, reaction bulb adds the 20ml oxolane dried, 0.35g lithium aluminium hydride reduction; nitrogen protection, is maintained under-10 DEG C of conditions, is slowly added dropwise oxolane (10ml) solution of shellfish Methyl cholate (1.8g) difficult to understand; drip and finish, rise to room temperature reaction 10h. Being slowly added dropwise 1ml water, 1ml15% sodium hydrate aqueous solution successively, 3ml water carries out cancellation, filters, filtrate adds 15ml ethyl acetate, separatory, saturated common salt water washing, anhydrous sodium sulfate dries, and filters, and concentrate obtains white foaming solid 0.85g through column chromatography for separation.
Its Structural Identification data are as follows:
1H-NMR (300Mz, CDCl3) ��: 0.66 (S, 3H), 0.87-0.92 (m, 6H), 0.95 (d, J=6.5Hz, 3H), 3.35-3.45 (m, 1H), 3.61 (t, J=6.2Hz, 2H) 3.70 (s, 1H).
ESI-MS (m/z): 429.4 [M+Na]+, 405.4 [M-H]-��
The preparation of embodiment 33,7-diketone-6 ��-ethyl-5 ��-cholane-24-acid (VII)
3.75g Austria shellfish cholic acid is placed in 250ml single port bottle, adds 75ml acetone, stirring and dissolving, nitrogen protection under room temperature, under ice-water bath, be slowly added dropwise 7mlJones reagent, drip and finish, be slowly increased to room temperature, continue stirring 2h. Being slowly added dropwise 30ml isopropanol and carry out cancellation, filter, filtrate concentrates, and residue adds 40ml ethyl acetate, and saturated sodium bicarbonate washs, saturated common salt water washing, and anhydrous sodium sulfate dries, and filters, and concentrate obtains off-white color solid 1.52g through column chromatography for separation.
Its Structural Identification data are as follows:
1H-NMR (300Mz, CDCl3) ��: 0.69 (S, 3H), 0.80 (t, J=7.3Hz, 3H), 0.94 (d, J=6.3Hz, 3H), 1.48-1.77 (m, 6H), 2.3-2.5 (m, 2H), 2.73 (m, 1H).
ESI-MS (m/z): 439.3 [M+Na]+, 415.3 [M-H]-��
Claims (9)
1. the preparation method of shellfish cholic acid impurity difficult to understand, it is characterized in that with 3 Alpha-hydroxy-6-ethylidene-7-carbonyl-5 ��-cholane-24-acid (II) for raw material, 3 �� are obtained, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V) by catalytic hydrogenation, reduction;With shellfish cholic acid (I) difficult to understand for raw material, obtain 3 �� by carboxyl esterification, then reduction in acid condition, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI); Shellfish cholic acid (I) difficult to understand obtains 3,7-dicarbapentaborane-6 ��-ethyl-5 ��-cholane-24-acid (VII) by oxidation.
2. 3 �� according to claim 1, the preparation method of 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), 3 ��, 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V) is prepared by with 3 Alpha-hydroxy-6-ethylidene-7-carbonyl-5 ��-cholane-24-acid (II) for raw material, when atmospheric pressure at room by palladium charcoal catalytic hydrogenation, then 7 carbonyl reductions at-25 DEG C��-30 DEG C, obtain finally by preparation liquid phase separation.
3. 3 �� according to claim 2, the preparation method of 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), hydrogenation solvent for use is selected from methanol, ethanol, isopropanol, n-butyl alcohol, acetone, butanone, oxolane, dichloromethane, chloroform, acetonitrile, ethyl acetate, nafoxidine, pyridine, piperidines, N-Methyl pyrrolidone, N, dinethylformamide, water, sodium hydrate aqueous solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, sodium bicarbonate aqueous solution, wet chemical, potassium bicarbonate aqueous solution, and two kinds or above mixed solution, the present invention preferentially selects the mixed solution of methanol and sodium hydrate aqueous solution, the w/v of 3 Alpha-hydroxy-6-ethylidene-7-carbonyl-5 ��-cholane-24-acid (II) and solvent is 1: 25��35.
4. 3 �� according to claim 2, the preparation method of 7 beta-dihydroxy-6-ethyl-5 ��-cholane-24-acid (V), reducing agent is selected from Na, K, stannous chloride, sodium borohydride, potassium borohydride, red aluminum, Lithium Aluminium Hydride, three tertiary butyoxy aluminum lithiums, cerous chloride and sodium borohydride, potassium borohydride etc. and Louis acid complex reducing agent. The present invention preferentially selects potassium borohydride and cerous chloride as reducing agent.
5. impurity 3 �� according to claim 1, the preparation method of 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), 3 ��, the preparation of 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI) is with shellfish cholic acid (1) difficult to understand for raw material, under acid part, obtain carboxyl ester compound with alcohol esterification, then prepare then through reduction. The kind of described acid and consumption can be all the conventional organic acid of this type of reaction of this area or mineral acid and consumption, the preferred following acid of the present invention and sour consumption: wherein, described acid is preferably hydrochloric acid, sulphuric acid, methanesulfonic acid; The consumption of described acid is preferably 0.2��0.4 equivalent, regulates pH value of solution to 1��2. Esterification alcohol used is selected from methanol, ethanol, isopropanol, n-butyl alcohol, sec-butyl alcohol, neopentyl alcohol, benzyl alcohol, ethylene glycol, glycerol. Prioritizing selection methanol of the present invention is esterified. The w/v of shellfish cholic acid (I) difficult to understand and methanol is 1: 5��15; Esterification reaction temperature 20��150 DEG C.
6. impurity 3 �� according to claim 5, the preparation method of 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), reducing agent is selected from Na, K, stannous chloride, sodium borohydride, potassium borohydride, red aluminum, Lithium Aluminium Hydride, three tertiary butyoxy aluminum lithiums, cerous chloride and sodium borohydride, potassium borohydride etc. and Louis acid complex reducing agent. The present invention preferentially selects Lithium Aluminium Hydride as reducing agent. Reduzate extracts solvent for use selected from n-butyl alcohol, isopropanol, ethanol, methanol, ethyl acetate, toluene, acetone, dichloromethane, chloroform, acetonitrile, oxolane.Ethyl acetate solvent of the present invention extracts.
7. impurity 3 �� according to claim 6, the preparation method of 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI), refining 3 ��, 7 alpha-dihydroxy-6 ��-ethyl-5 ��-cholane-24-alcohol (VI) adopts silica gel column chromatography method, eluant adopts petrol ether/ethyl acetate system, it is preferable that ethyl acetate: petroleum ether=1: 4��6.
8. impurity 3 according to claim 1, the preparation method of 7-dicarbapentaborane-6 ��-ethyl-5 ��-cholane-24-acid (VII), 3, the preparation of 7-dicarbapentaborane-6 ��-ethyl-5 ��-cholane-24-acid (VII) is with shellfish cholic acid (I) difficult to understand for raw material, oxidized obtain, reaction temperature-10��30 DEG C. Oxidising agent is selected from NBS, hydrogen peroxide, peracetic acid, sodium dichromate, chromic acid, nitric acid, potassium permanganate, Ammonium persulfate., sodium hypochlorite. The present invention preferentially selects Jones reagent (chromic acid); Solvent for use is selected from acetone, oxolane, dichloromethane, chloroform, acetonitrile, ethyl acetate, nafoxidine, triethylamine, pyridine, piperidines, N-Methyl pyrrolidone, N, dinethylformamide, N, N-dimethyl acetylamide, the preferred acetone of the present invention is as solvent; The w/v of shellfish cholic acid (I) difficult to understand and solvent is 1: 15��25.
9. according to claim 83, the preparation method of 7-dicarbapentaborane-6 ��-ethyl-5 ��-cholane-24-acid (VII), 3 prepared, 7-dicarbapentaborane-6 ��-ethyl-5 ��-cholane-24-acid (VII), extract solvent for use selected from n-butyl alcohol, ethyl acetate, toluene, dichloromethane, chloroform, acetonitrile, oxolane, ethyl acetate solvent of the present invention; Refining 3,7-dicarbapentaborane-6 ��-ethyl-5 ��-cholane-24-acid (VII) adopts silica gel column chromatography method, and eluant adopts ethanol/methylene system, it is preferable that methanol: dichloromethane=1: 20��30.
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| CN106977571A (en) * | 2017-04-24 | 2017-07-25 | 重庆东得医药科技有限公司 | A kind of shellfish cholic acid analogue difficult to understand and its preparation method and application |
| WO2020025942A1 (en) | 2018-07-30 | 2020-02-06 | NZP UK Limited | Fluorinated bile acid derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106977571A (en) * | 2017-04-24 | 2017-07-25 | 重庆东得医药科技有限公司 | A kind of shellfish cholic acid analogue difficult to understand and its preparation method and application |
| CN106977571B (en) * | 2017-04-24 | 2019-01-08 | 重庆东得医药科技有限公司 | A kind of Austria's shellfish cholic acid analogue and its preparation method and application |
| WO2020025942A1 (en) | 2018-07-30 | 2020-02-06 | NZP UK Limited | Fluorinated bile acid derivatives |
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Application publication date: 20160608 |