CN106916195A - The purification process of shellfish cholic acid intermediate difficult to understand - Google Patents
The purification process of shellfish cholic acid intermediate difficult to understand Download PDFInfo
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- CN106916195A CN106916195A CN201510999011.XA CN201510999011A CN106916195A CN 106916195 A CN106916195 A CN 106916195A CN 201510999011 A CN201510999011 A CN 201510999011A CN 106916195 A CN106916195 A CN 106916195A
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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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Abstract
The invention provides the purification process of shellfish cholic acid intermediate difficult to understand, the method includes being contacted the mixed solution of rudimentary alcohol and water with crude compound shown in formula 1.- 5 β of Alpha-hydroxy-6- ethylidene-7- oxos of shellfish cholic acid intermediate difficult to understand 3-cholanic acid can be efficiently purified using the method, the content that 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid impurity can effectively be controlled and the content for reducing other unknown impurities, so that for the synthesis of shellfish cholic acid difficult to understand provides qualified raw material.
Description
Technical field
The present invention relates to the field of chemical synthesis, specifically, the method the present invention relates to purify shellfish cholic acid intermediate difficult to understand.
Background technology
Shellfish cholic acid (OCA) difficult to understand belongs to farnesoid X receptor activator, can selectively activate bile acid nuclear receptor FXR.It is clinical
Preceding and clinical research prompting, it has the effect of preferable anti-cholestasis, anti-inflammatory and anti-fibrosis.Shellfish cholic acid difficult to understand is one
The analog of semi-synthetic primary bile acid chenodeoxycholic acid (CDCA) is planted, it synthesizes the pure of initiation material chenodeoxycholic acid
Degree is difficult to ensure that.The synthesis complexity of Cholic acids compound, and synthesize the similitude of each step intermediate, cause its part residual
The extremely difficult purifying of impurity is stayed, wherein the intermediate KLCA (compound shown in formula 2) for remaining influences larger to subsequent step, and
The content of KLCA is up to 5% or so in the shellfish cholic acid intermediate difficult to understand of most of market purchase and the synthesis of current technique, so that derivative
When being reacted to final Austria's shellfish cholic acid product, KLCA and its derivative impurity are difficult to purify and remove, so needing in intermediate
Preparation process in just strict control impurity content so that KLCA and its derivative impurity can be controlled in finished product
Less than 0.15%, to reach medicine quality control standard.
3-5 β of Alpha-hydroxy-6- ethylidene-7- oxos-cholanic acid (compound, OCA-E shown in formula 1) synthesizes as shellfish cholic acid difficult to understand
Important intermediate, its good purity is of great significance to ensureing the purity tool of final reactive compound Austria shellfish cholic acid.
The useful ethyl acetate of purifying of 3-5 β of Alpha-hydroxy-6- ethylidene-7- oxos-cholanic acid is purified in the prior art, so
And Expected Results is unable to reach to many impurity and KLCA.
Therefore, the purification process of -5 β of current 3 Alpha-hydroxy -6- ethylidene -7- oxos-cholanic acid still has much room for improvement.
The content of the invention
It is contemplated that at least solving one of technical problem in correlation technique to a certain extent or providing a kind of useful business
Selection.Therefore, the method it is an object of the present invention to propose shellfish cholic acid intermediate difficult to understand shown in a kind of purifying formula 1.Utilize
The method can efficiently purify-5 β of Alpha-hydroxy-6- ethylidene-7- oxos of shellfish cholic acid intermediate difficult to understand 3-cholanic acid, can effectively control
The content of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid (KLCA) impurity (compound shown in formula 2) and to reduce other unknown miscellaneous
The content of matter, so that for the synthesis of shellfish cholic acid difficult to understand provides qualified raw material.
A fermentation of the invention, the method that the present invention proposes shellfish cholic acid intermediate difficult to understand shown in a kind of purifying formula 1, including
The mixed solution of rudimentary alcohol and water is contacted with crude compound shown in formula 1.
Some embodiments of the invention, the operating procedure that the present invention is used is few, and purifying process is succinct, and effect is obvious, institute
Few with quantity of solvent, production efficiency is high, low cost, and gained finished product yield, purity are high, and accessory substance is few, three industrial wastes
It is easily processed, safety and environmental protection.Be conducive to the industrialized production of pure compounds shown in formula 1.Side according to embodiments of the present invention
Method, the total recovery of compound shown in purifying formula 1 can reach 70% or so, and product purity can reach 99.5~99.7%, KLCA
Content is controlled 0.3% or so, thus after subsequent reactions, may be such that KLCA and its derivative Control of Impurities are arrived in finished product
Less than 0.15%, reach medicine quality control standard.By contrast, the technique of re-crystallizing in ethyl acetate of the prior art, yield is only
60%, purity is also only between 98~99%, KLCA contents 1.5% or so, in subsequent reactions after this, it is difficult to will be eventually
KLCA and its derivative Control of Impurities are to less than 0.15% in product, it is impossible to reach medicine control standard.
Term " contact " used herein should be interpreted broadly, and it can be any energy so that at least two reactants occur
The mode of chemical reaction, for example, can be to be mixed two kinds of reactants under suitable condition.Herein, " compound
Herein otherwise referred to as " compound shown in formula N ", N herein is 1~2 arbitrary integer, such as " compound to N "
2 " it is referred to as herein " compound shown in formula 2 ".
In the description of the invention, it is to be understood that term " first ", " second " are only used for describing purpose, without being understood that
To indicate or implying relative importance or the implicit quantity for indicating indicated technical characteristic.Thus, " first ", " are defined
Two " one or more this feature can be expressed or be implicitly included to feature.In the description of the invention, " multiple "
Two or more are meant that, unless otherwise expressly limited specifically.
The method of compound shown in the purifying formula 1 of embodiments of the invention is described below in detail.
Some embodiments of the invention, the purification process includes：
(1) mixed solution of crude compound shown in the formula 1 and the rudimentary alcohol and water, decolorising agent are contacted, stirring plus
Heat, backflow；
(2) decolorising agent is filtered off while hot, and purified water is slowly added dropwise to gained filtrate；
(3) stir, slow cooling, add crystal seed, crystallization；
(4) continue to stir cooling, filtering obtains pure compounds shown in formula 1.
It is possible thereby to compound shown in the formula 1 of prepared high-purity.
Some embodiments of the invention, the lower alcohol be selected from least one in ethanol, isopropanol and butanol, it is excellent
Elect ethanol as.It is possible thereby to compound shown in the formula 1 of prepared high-purity.
Some embodiments of the invention, the mixed solution of the rudimentary alcohol and water and crude compound shown in the formula 1
Volume/mass ratio is 4.4ml/g~6ml/g, preferably 5ml/g.It is possible thereby to fully dissolving, and suppress lower alcohol and formula simultaneously
Compound shown in 1 generates ester impurity, and unlikely excessive and influence subsequent purification purity and yield.
Some embodiments of the invention, lower alcohol is with the volume ratio of the water in the mixed solution of the rudimentary alcohol and water
2:1~10:1, preferably 4:1.It is possible thereby to fully dissolving, and suppress the generation of ester impurity, and unlikely excess and shadow simultaneously
Ring subsequent purification purity and yield.
Some embodiments of the invention, decolorising agent described in the step (1) and crude compound shown in the formula 1
Mass ratio is 1:10~1:25, preferably 1:20.It is possible thereby to the effect decolourized and adsorb is reached, while not interfering with receipts again
Rate.
According to a particular embodiment of the invention, the decolorising agent is selected from activated carbon, diatomite, molecular sieve, atlapulgite
At least one, preferably activated carbon.
The amount and compound shown in the formula 1 of the purified water being added dropwise in some embodiments of the invention, the step (2)
The volume/mass ratio of crude product is 1ml/g~2ml/g, preferably 1.5ml/g.It is possible thereby to meet that supersaturated critical point is reached, together
When do not result in too fast crystallization again and influence purity.
Some embodiments of the invention, the speed that the step (2) is slowly added dropwise purified water is 1ml/min~4ml/min,
Preferably 1.5ml/min~3ml/min..Thus it can be prevented that water droplet acceleration too fast and cause local cooling and reach supersaturation,
Product is set to separate out too early.
Some embodiments of the invention, the speed of step (3) slow cooling is 0.2 DEG C/min~1.2 DEG C/min, excellent
Elect 0.4 DEG C/min as.
Some embodiments of the invention, step (3) is slow cooling to 65~80 degrees Celsius, preferably 70 degrees Celsius, this
When side adds crystal seed.It is possible thereby to be that the addition of crystal seed and crystallization create suitable condition.
Some embodiments of the invention, the step (4) is continued stirring and is cooled to 10~30 degrees Celsius, preferably 20~30
Degree Celsius.It is possible thereby to ensure to leach the yield of solid, while reducing impurity content.
Some embodiments of the invention, the step (4) filter after solid, further washed with ethyl acetate.
Pure compounds shown in formula 1 are further vacuum dried by some embodiments of the invention.
Some embodiments of the invention, vacuum drying temperature is 30~50 degrees Celsius, preferably 45 degrees Celsius.Thus
Can fully dry while not influenceing product property.
Some embodiments of the invention, the vacuum drying time is 8~16 hours, preferably 12 hours.It is possible thereby to
Fully dry does not influence product property simultaneously.
The method of compound can realize at least one following advantages shown in purifying formula 1 according to embodiments of the present invention：
1st, the method for compound shown in purifying formula 1 according to embodiments of the present invention, can efficiently compound shown in formula 1
Sterling；
2nd, the operating procedure of the method for compound shown in the purifying formula 1 of the embodiment of the present invention is succinct, and step is few, easy to control, can
Improve production efficiency, low cost, and safety and environmental protection, are conducive to industrial mass production；
3rd, the product color that the method for compound shown in purifying formula 1 according to embodiments of the present invention is prepared is good, yield and pure
Degree is greatly improved, and impurity is few, is conducive to the industrialized production of the product, and with market value very high；
4th, the method for compound shown in the purifying formula 1 of the embodiment of the present invention solves prior art by the efficiently removal impurity of formula 2
Problem, Promote Technology；
5th, the mixed solution of the method lower alcohol of compound and purified water shown in the purifying formula 1 of the embodiment of the present invention substitutes acetic acid
Ethyl ester, has broken 3-5 β of Alpha-hydroxy-6- ethylidene-7- oxos-difficult deadlock of cholanic acid purifying, and effectively reduce 3 Alpha-hydroxy-6-
Impurity component in -5 β of ethylidene -7- oxos-cholane acid product.
6th, the method for compound shown in the purifying formula 1 of the embodiment of the present invention provides the target product of very high-purity, is its life
When producing new drug, impurity in product is reduced, control drug quality provides safeguard.
Additional aspect of the invention and advantage will be set forth in part in the description, and partly will from the following description become bright
It is aobvious, or recognized by practice of the invention.
Brief description of the drawings
Of the invention above-mentioned and/or additional aspect and advantage will be apparent from description of the accompanying drawings below to embodiment is combined
Be readily appreciated that, wherein：
Fig. 1 is the detection of 3-5 β of the Alpha-hydroxy-6- ethylidene-7- oxos-cholane acid crude according to the embodiment of the present invention 1 before purification
Collection of illustrative plates；
Fig. 2 is the detection collection of illustrative plates of 3-5 β of the Alpha-hydroxy-6- ethylidene-7- oxos-cholanic acid according to the embodiment of the present invention 1 after purification；
Fig. 3 is the detection collection of illustrative plates of 3-5 β of the Alpha-hydroxy-6- ethylidene-7- oxos-cholanic acid according to the embodiment of the present invention 3 after purification.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention,
And be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to document in the art
Described technology or condition are carried out according to product description.Agents useful for same or the unreceipted production firm person of instrument, are
Can by city available from conventional products.
Raw material：
3-5 β of Alpha-hydroxy-6- ethylidene-7- oxos-cholane acid crude (purity 95% or so, detection KLCA contents 4.2% or so), from
System；
Ethanol (industrial pharmaceutical grade)；
Water (purified water)；
Activated carbon (industrial pharmaceutical grade).
Analytical and testing instrument：
The HPLC of Agilent 1260 band ELSD380 detectors
Chromatographic column：Thermo BDS C18(4.6×150mm,5um),004THE001
The purifying process of-5 β of Alpha-hydroxy-6- ethylidene-7- oxos of embodiment 1 3-cholanic acid
In equipped with mixer, thermometer, the 100ml there-necked flasks of dropping funel, medicinal alcohol 40ml and 10ml are added
Purified water, adds 3-5 β of Alpha-hydroxy-6- ethylidene-7- oxos-cholane acid crude 10g with stirring, heating stirring be back to it is molten clear,
Activated carbon 0.5g is added, is stirred 15 minutes, the activated carbon of filtering removal while hot.Filtrate be placed on equipped with mixer, thermometer,
In the 100ml there-necked flasks of dropping funel, under heating stirring backflow, purified water about 15ml is slowly added into dropping funel
To in flask, insulated and stirred continues to stir after 15 minutes, and slow cooling adds crystal seed, continues to stir when being cooled to 70 DEG C
Mix and be cooled to 25 DEG C, filter out solid, washed using a small amount of ethyl acetate, 45 DEG C dry 12h, obtain 6.8g purified products,
Yield 68%, wherein product purity 99.7%, KLCA impurity contents are 0.29%.
The purifying process of-5 β of Alpha-hydroxy-6- ethylidene-7- oxos of embodiment 2 3-cholanic acid
In equipped with mixer, thermometer, the 1000ml there-necked flasks of dropping funel, medicinal alcohol 400ml and 100ml are added
Purified water, adds 3-5 β of Alpha-hydroxy-6- ethylidene-7- oxos-cholane acid crude 100g with stirring, and heating stirring is back to molten
Clearly, activated carbon 5g is added, is stirred 15 minutes, the activated carbon of filtering removal while hot.Filtrate is placed on equipped with mixer, temperature
In meter, the 1000ml there-necked flasks of dropping funel, under heating stirring backflow, purified water is slowly added into about with dropping funel
To in flask, insulated and stirred continues to stir 150ml after 15 minutes, and slow cooling adds crystal seed when being cooled to 70 DEG C, after
Continuous stirring is cooled to 25 DEG C, filters out solid, is washed using a small amount of ethyl acetate, and 45 DEG C dry 12h, obtain 69.2g pure
Change product, yield 69%, product purity 99.6%, wherein KLCA impurity contents are 0.36%.
The purifying process of-5 β of Alpha-hydroxy-6- ethylidene-7- oxos of comparative example 1 3-cholanic acid
In equipped with mixer, the 1000ml there-necked flasks of thermometer, add ethyl acetate 800ml, add with stirring 3 α-
- 5 β of hydroxyl -6- ethylidene -7- oxos-cholane acid crude 100g, heating stirring is back to molten clear, addition activated carbon 5g, stirring
15 minutes, the activated carbon of filtering removal while hot.During filtrate is placed on equipped with mixer, the 1000ml there-necked flasks of thermometer,
Continue to stir, slow cooling adds crystal seed when being cooled to 65 DEG C, continue stirring and be cooled to 25 DEG C, filter out solid, use
A small amount of ethyl acetate washing, 45 DEG C dry 12h, obtain 61.1g purified products, yield 61%, product purity 98.3%, its
Middle KLCA contents are 1.6%.
It is demonstrated experimentally that compared to prior art, the application method can efficiently purify the Alpha-hydroxy -6- of shellfish cholic acid intermediate 3 difficult to understand
- 5 β of ethylidene-7- oxos-cholanic acid, can effectively control the content of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid impurity and reduce other
The content of unknown impuritie, so that for the synthesis of shellfish cholic acid difficult to understand provides qualified raw material.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example ",
Or the description of " some examples " etc. means to combine specific features, structure, material or feature bag that the embodiment or example are described
It is contained at least one embodiment of the invention or example.In this manual, to the schematic representation of above-mentioned term necessarily
It is directed to identical embodiment or example.And, the specific features of description, structure, material or feature can be any
Combined in an appropriate manner in individual or multiple embodiments or example.Additionally, in the case of not conflicting, the skill of this area
Can be combined for the feature of the different embodiments or example described in this specification and different embodiments or example by art personnel
And combination.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment be it is exemplary,
It is not considered as limiting the invention, one of ordinary skill in the art within the scope of the invention can be to above-described embodiment
It is changed, changes, replacing and modification.
Claims (10)
1. the method for the shellfish cholic acid intermediate difficult to understand shown in a kind of purifying formula 1, it is characterised in that the mixing of rudimentary alcohol and water is molten
Liquid is contacted with crude compound shown in formula 1.
2. method according to claim 1, it is characterised in that methods described includes：
(1) mixed solution of crude compound shown in the formula 1 and the rudimentary alcohol and water, decolorising agent are contacted, stirring plus
Heat, backflow；
(2) decolorising agent is filtered off while hot, and purified water is slowly added dropwise to gained filtrate；
(3) stir, slow cooling, add crystal seed, crystallization；
(4) continue to stir cooling, filtering obtains pure compounds shown in formula 1.
3. method according to claim 1, it is characterised in that the lower alcohol is selected from ethanol, isopropanol and butanol
In at least one, preferably ethanol.
4. method according to claim 1, it is characterised in that the mixed solution of the rudimentary alcohol and water and the formula 1
The volume/mass ratio of shown crude compound is 4.4ml/g~6ml/g, preferably 5ml/g.
5. method according to claim 4, it is characterised in that in the mixed solution of the rudimentary alcohol and water lower alcohol with
The volume ratio of water is 2:1~10:1, preferably 4:1.
6. method according to claim 2, it is characterised in that decolorising agent and the formula 1 described in the step (1)
The mass ratio of shown crude compound is 1:10~1:25, preferably 1:20.
7. method according to claim 2, it is characterised in that the amount of the purified water being added dropwise in the step (2) with
The volume/mass ratio of crude compound shown in the formula 1 is 1ml/g~2ml/g, preferably 1.5ml/g；
Optional, the speed that the step (2) is slowly added dropwise purified water is 1ml/min~4ml/min, preferably 1.5ml/min
~3ml/min.
8. method according to claim 2, it is characterised in that the speed of step (3) slow cooling is 0.2 DEG C/min
~1.2 DEG C/min, preferably 0.4 DEG C/min；
Optional, step (3) is slow cooling to 65~80 degrees Celsius, preferably 70 degrees Celsius, now side's addition crystal seed.
9. method according to claim 2, it is characterised in that the step (4) is continued stirring and is cooled to 10~30
Degree Celsius, preferably 20~30 degrees Celsius.
10. method according to claim 2, it is characterised in that the step (4) filter after solid, further
Washed with ethyl acetate；
Optional, further pure compounds shown in the formula 1 are vacuum dried；
Optional, the vacuum drying temperature is 30~50 degrees Celsius, preferably 45 degrees Celsius；
Optional, the vacuum drying time is 8~16 hours, preferably 12 hours.
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| CN201510999011.XA CN106916195A (en) | 2015-12-25 | 2015-12-25 | The purification process of shellfish cholic acid intermediate difficult to understand |
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| CN201510999011.XA CN106916195A (en) | 2015-12-25 | 2015-12-25 | The purification process of shellfish cholic acid intermediate difficult to understand |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
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2015
- 2015-12-25 CN CN201510999011.XA patent/CN106916195A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
Non-Patent Citations (2)
| Title |
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| 中国科学院上海药物研究所: "《中草药有效成分提取与分离》", 31 July 1983 * |
| 杨其蒀: "《天然药物化学》", 31 January 2003 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| CN108680696B (en) * | 2018-05-15 | 2020-06-30 | 南京正大天晴制药有限公司 | Detection method of obeticholic acid starting material |
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