CN105541953B - A kind of recrystallization purifying method of high-purity Austria shellfish cholic acid - Google Patents
A kind of recrystallization purifying method of high-purity Austria shellfish cholic acid Download PDFInfo
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- CN105541953B CN105541953B CN201610149202.1A CN201610149202A CN105541953B CN 105541953 B CN105541953 B CN 105541953B CN 201610149202 A CN201610149202 A CN 201610149202A CN 105541953 B CN105541953 B CN 105541953B
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- cholic acid
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- 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 discloses a kind of recrystallization purifying method of high-purity Austria shellfish cholic acid, it is that concrete operations are that shellfish cholic acid crude product difficult to understand first is obtained into shellfish cholic acid organic amine salt difficult to understand with organic amine reaction in organic solvent into the method for recrystallizing in organic solvent and obtaining high-purity Austria shellfish cholic acid after salt by shellfish cholic acid difficult to understand and organic amine；The shellfish cholic acid organic amine salt difficult to understand is subjected to sour tune again, it is recrystallized in the form of shellfish cholic acid difficult to understand.Purification process of the present invention can obtain high-purity (purity ＞ 98.5%, single miscellaneous ＜ 0.1%) shellfish cholic acid difficult to understand, and method the step of high-purity Austria shellfish cholic acid can not need not largely being produced using column chromatography etc., therefore purification process of the present invention is suitable for industrialized production.
Description
Technical field
Embodiments of the present invention are related to biomedicine field, more specifically, embodiments of the present invention are related to a kind of height
The recrystallization purifying method of purity Austria shellfish cholic acid.
Background technology
Shellfish cholic acid obeticholic acid difficult to understand are a kind of new drugs for treating cholestasis type hepatic sclerosis, are applied in facing
The bulk drug purity requirement of bed is higher, and during synthetically prepared, the impurity of other similar structures can be usually introduced, have impact on
The purity of product.Prior art patent US2008/0214515 A1 are disclosed the method recrystallized using ethyl acetate and entered
Row purifying.Document JMC 2014,57,937-954 also use the report of column chromatography method purifying；The industrial applications of column chromatography
Compare limited；While it is directly also not thorough to single miscellaneous removal using the method for butyl acetate crystallization, therefore prior art is scarce
Sunken needs are overcome, to obtain more preferable production technology.
The content of the invention
Instant invention overcomes the deficiencies in the prior art, there is provided a kind of recrystallization purifying method of high-purity Austria shellfish cholic acid, with
The purification process for it is expected that shellfish cholic acid difficult to understand can be made is more suitable for industrialized production.
To solve above-mentioned technical problem, one embodiment of the present invention uses following technical scheme：
A kind of recrystallization purifying method of high-purity Austria shellfish cholic acid, it be by shellfish cholic acid difficult to understand and organic amine into after salt organic
The method for being recrystallized in solvent and obtaining high-purity Austria shellfish cholic acid.
The recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid specifically includes following steps：
Step 1: shellfish cholic acid crude product difficult to understand is obtained into shellfish cholic acid organic amine salt difficult to understand with organic amine reaction in organic solvent；
Step 2: the shellfish cholic acid organic amine salt difficult to understand is carried out into sour tune, it is set to be recrystallized in the form of shellfish cholic acid difficult to understand.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, the concrete operation method of the step 1 is：By Austria
Shellfish cholic acid crude product is dissolved in the organic solvent of 3~5 times of weight, and 5~20wt% of addition organic amine, 2~5h of back flow reaction, so
After be cooled to 10~20 DEG C, crystallization separates out shellfish cholic acid organic amine salt difficult to understand, is filtrated to get shellfish cholic acid organic amine salt difficult to understand.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, the concrete operation method of the step 2 is：By Austria
Shellfish cholic acid organic amine salt is soluble in water, and it is 2.0~3.0 to add inorganic acid to pH value thereto, and shellfish cholic acid difficult to understand is recovered by filtration, then will
Shellfish cholic acid difficult to understand is added in organic solvent and dissolved by heating, and is then cooled to 20 DEG C, recrystallization separates out high-purity Austria shellfish cholic acid.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, the organic amine be aniline, diphenylamines, phenyl ethylamine,
Triethylamine, ethylenediamine, dicyclohexyl amine, diisopropylethylamine or diethyl ethanamine.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, organic solvent described in step 1 is acetone, acetic acid second
Ester, butyl acetate or sec-butyl alcohol.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, organic solvent described in step 2 is acetic acid alkyl ester, example
Such as ethyl acetate, butyl acetate, propyl acetate.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, the inorganic acid is sulfuric acid or hydrochloric acid.
In the recrystallization purifying method of above-mentioned high-purity Austria shellfish cholic acid, high-purity Austria shellfish cholic acid refers to purity ＞
98.5%th, single miscellaneous ＜ 0.1% shellfish cholic acid difficult to understand.
Compared with prior art, one of beneficial effects of the present invention are：Purification process of the present invention can obtain height
The shellfish cholic acid difficult to understand of purity (purity ＞ 98.5%, single miscellaneous ＜ 0.1%), and method can not need not largely produce height using column chromatography etc.
The step of purity Austria shellfish cholic acid, therefore purification process of the present invention is suitable for industrialized production.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 100g purity 89.6% is taken, acetone is added by 3 times of its weight and presses
The 20% of its weight adds triethylamine, after being heated to reflux 2h, starts slow cooling to 10 DEG C, separates out crystallization, be filtrated to get Ao Bei
Cholic acid organic amine salt crystallizes.
The shellfish cholic acid organic amine salt crystallization difficult to understand is sour with the watery hydrochloric acid for being 10wt% with mass percent after dissolved in purified water
It is 2.0 to change to pH value, and filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with ethyl acetate, is then cooled to 20 DEG C, separates out crystal, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 98.7%, the rate of recovery 84.5%.
Embodiment 2
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 100g purity 89.6% is taken, ethyl acetate are added by 4 times of its weight
Ethylenediamine is added with by the 5% of its weight, after being heated to reflux 3h, starts slow cooling to 15 DEG C, separates out crystallization, be filtrated to get Austria
Shellfish cholic acid organic amine salt crystallizes.
By after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with shellfish cholic acid organic amine salt mass percent difficult to understand
It is 2.5 that 10% dilute sulfuric acid, which is acidified to pH value, and filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with butyl acetate, is then cooled to 20 DEG C, separates out crystal, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 98.9%, the rate of recovery 85.3%.
Embodiment 3
Take the shellfish cholic acid crude product difficult to understand (single miscellaneous is more than 2%) of 100g purity 89.6%, by 5 times of its weight add sec-butyl alcohols and
Phenyl ethylamine is added by the 10% of its weight, after being heated to reflux 4h, starts slow cooling to 20 DEG C, separates out crystallization, be filtrated to get Austria
Shellfish cholic acid organic amine salt crystallizes.
By after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with shellfish cholic acid organic amine salt mass percent difficult to understand
It is 3.0 that 60% dilute sulfuric acid, which is acidified to pH value, and filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with propyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 99.1%, the rate of recovery 82.3%.
Embodiment 4
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 200g purity 89.6% is taken, butyl acetates are added by 4 times of its weight
Dicyclohexyl amine is added with by the 20% of its weight, after being heated to reflux 5h, starts slow cooling to 10 DEG C, separates out crystallization, filter
Crystallized to shellfish cholic acid organic amine salt difficult to understand.
It will be acidified after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with the dilute sulfuric acid of its mass percent 35%
It is 2.5 to pH value, filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with ethyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 98.8%, the rate of recovery 84.7%.
Embodiment 5
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 200g purity 89.6% is taken, ethyl acetate are added by 3 times of its weight
Aniline is added with by the 15% of its weight, after being heated to reflux 4h, starts slow cooling to 10 DEG C, separates out crystallization, be filtrated to get Austria
Shellfish cholic acid organic amine salt crystallizes.
It will be acidified after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with the watery hydrochloric acid of its mass percent 10%
It is 2.5 to pH value, filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with butyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 98.7%, the rate of recovery 83.3%.
Embodiment 6：
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 200g purity 89.6% is taken, acetic acid fourths are added by 4.5 times of its weight
Ester and the 20% addition diisopropylethylamine by its weight, after being heated to reflux 4h, start slow cooling to 15 DEG C, separate out crystallization,
It is filtrated to get shellfish cholic acid organic amine salt crystallization difficult to understand.
By the dilute sulfuric acid acid acid after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with its mass percent 10%
It is 2.0 to change to pH value, and filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with propyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 99.2%, the rate of recovery 82.6%.
Embodiment 7：
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 500g purity 90.4% is taken, acetic acid second are added by 3.5 times of its weight
Ester and the 20% addition diphenylamines by its weight, after being heated to reflux 4h, start slow cooling to 15 DEG C, separate out crystallization, filter
Crystallized to shellfish cholic acid organic amine salt difficult to understand.
It will be acidified after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with the watery hydrochloric acid of its mass percent 10%
It is 2.0 to pH value, filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with butyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 98.8%, the rate of recovery 84.3%.
Embodiment 8：
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 500g purity 90.4% is taken, butyl acetates are added by 4 times of its weight
Diethyl ethanamine is added with by the 20% of its weight, after being heated to reflux 3h, starts slow cooling to 15 DEG C, separates out crystallization, filtering
Obtain shellfish cholic acid organic amine salt crystallization difficult to understand.
It will be acidified after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with the watery hydrochloric acid of its mass percent 10%
It is 2.0 to pH value, filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with ethyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 98.9%, the rate of recovery 84.5%.
Embodiment 9：
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 5kg purity 90.4% is taken, butyl acetates are added by 4 times of its weight
Triethylamine is added with by the 20% of its weight, after being heated to reflux 4h, starts slow cooling to 10 DEG C, separates out crystallization, be filtrated to get
Shellfish cholic acid organic amine salt crystallization difficult to understand.
It will be acidified after the shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand with the watery hydrochloric acid of its mass percent 10%
It is 2.0 to pH value, filtration drying must refine shellfish cholic acid difficult to understand.
This is refined into shellfish cholic acid difficult to understand to be dissolved by heating with butyl acetate, is then cooled to 20 DEG C, separates out crystallization, filtration drying can
Obtain recrystallization Austria shellfish cholic acid (list is miscellaneous to be less than 0.1%) that purity is 99.1%, the rate of recovery 85.1%.
Comparative example：
Existing method (Example 1, step g) is tested according to disclosed in US2008/0214515A1.
The shellfish cholic acid crude product difficult to understand (list is miscellaneous to be more than 2%) of 100g purity 89.6% is taken, 85% phosphoric acid is added by 1 times of its weight
Solution and by 2 times of its weight addition ethyl acetate, is heated to 70 DEG C of dissolvings, is then cooled to 20 DEG C of precipitation crystal, filtering is used in combination
Ethyl acetate washs, and 65 DEG C of dryings can obtain the shellfish cholic acid difficult to understand (list is miscellaneous to be more than 0.3%) that purity is 94.3%, and the rate of recovery is
89.2%.
Although reference be made herein to invention has been described for explanatory embodiment of the invention, however, it is to be understood that ability
Field technique personnel can be designed that a lot of other modifications and embodiment, and these modifications and embodiment will fall in the application public affairs
Within the spirit and spirit opened.More specifically, can be to the group of theme combination layout in the range of disclosure
A variety of variations and modifications are carried out into part and/or layout.In addition to the variations and modifications carried out to building block and/or layout,
To those skilled in the art, other purposes also will be apparent.
Claims (2)
- A kind of 1. recrystallization purifying method of high-purity Austria shellfish cholic acid, it is characterised in that it is into salt by shellfish cholic acid difficult to understand and organic amine The method for recrystallizing in organic solvent afterwards and obtaining high-purity Austria shellfish cholic acid, comprise the following steps：Step 1: shellfish cholic acid crude product difficult to understand is obtained into shellfish cholic acid organic amine salt difficult to understand with organic amine reaction in organic solvent；Step 2: the shellfish cholic acid organic amine salt difficult to understand is carried out into sour tune, it is set to be recrystallized in the form of shellfish cholic acid difficult to understand；The concrete operation method of the step 1 is：Shellfish cholic acid crude product difficult to understand is dissolved in the organic solvent of 3~5 times of weight, and added Enter 5~20wt% of shellfish cholic acid crude product difficult to understand organic amine, 2~5h of back flow reaction, be then cooled to 10~20 DEG C, crystallization separates out difficult to understand Shellfish cholic acid organic amine salt, it is filtrated to get shellfish cholic acid organic amine salt difficult to understand；The concrete operation method of the step 2 is：Shellfish cholic acid organic amine salt difficult to understand is soluble in water, add inorganic acid extremely thereto PH value is 2.0~3.0, and shellfish cholic acid difficult to understand is recovered by filtration, then shellfish cholic acid difficult to understand is added in organic solvent and dissolved by heating, and is then dropped For temperature to 20 DEG C, recrystallization separates out high-purity Austria shellfish cholic acid；The organic amine is aniline, diphenylamines, phenyl ethylamine, triethylamine, ethylenediamine, dicyclohexyl amine, diisopropylethylamine or diethyl Base ethamine；Organic solvent is acetone, ethyl acetate, butyl acetate or sec-butyl alcohol in the step 1；Organic solvent is acetic acid alkyl ester in the step 2；The inorganic acid is sulfuric acid or hydrochloric acid.
- 2. the recrystallization purifying method of high-purity Austria shellfish cholic acid according to claim 1, it is characterised in that the high-purity Shellfish cholic acid difficult to understand refers to purity ＞ 98.5%, single miscellaneous ＜ 0.1% shellfish cholic acid difficult to understand.
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| CZ2015504A3 (en) * | 2015-07-16 | 2017-01-25 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
| WO2017137931A1 (en) | 2016-02-10 | 2017-08-17 | Dr. Reddy’S Laboratories Limited | Amine salt of obeticholic acid |
| EP3293196A1 (en) * | 2016-09-09 | 2018-03-14 | Hexal AG | Process for purifying obeticholic acid |
| CN108948117B (en) * | 2017-05-19 | 2020-09-18 | 杭州源昶医药科技有限公司 | Synthetic method of obeticholic acid |
| US10239823B2 (en) * | 2017-08-25 | 2019-03-26 | Vitaworks Ip, Llc | Process for purifying long chain amino acids |
| CN107674107B (en) * | 2017-09-30 | 2020-09-15 | 上海博志研新药物技术有限公司 | Method for refining obeticholic acid |
| US20210261599A1 (en) * | 2018-08-24 | 2021-08-26 | Solara Active Pharma Sciences Limited | Process for the Preparation of Obeticholic Acid and Intermediates Used In the Process Thereof |
| CN114644670A (en) * | 2020-12-17 | 2022-06-21 | 四川弘远药业有限公司 | Eutectic crystal of obeticholic acid and p-aminobenzoic acid and preparation method thereof |
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| EP1392714B1 (en) * | 2001-03-12 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Steroids as agonists for fxr |
| ITMI20050912A1 (en) * | 2005-05-19 | 2006-11-20 | Erregierre Spa | PROCESS OF PREPARATION OF ACIDS 3-A-YA (B) -DIDROSSI-6-A (B) -ALCHIL-5B-COLANICI |
| SG11201408501UA (en) * | 2012-06-19 | 2015-01-29 | Intercept Pharmaceuticals Inc | Preparation, uses and solid forms of obeticholic acid |
| CN103772465B (en) * | 2014-01-16 | 2015-09-23 | 中山百灵生物技术有限公司 | Preparation method of high-purity hyodeoxycholic acid |
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