CN105541953A - Recrystallization purification method for high-purity obeticholic acid - Google Patents
Recrystallization purification method for high-purity obeticholic acid Download PDFInfo
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- CN105541953A CN105541953A CN201610149202.1A CN201610149202A CN105541953A CN 105541953 A CN105541953 A CN 105541953A CN 201610149202 A CN201610149202 A CN 201610149202A CN 105541953 A CN105541953 A CN 105541953A
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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 discloses a recrystallization purification method for high-purity obeticholic acid. Obeticholic acid and organic amine are salified and then re-crystallized in an organic solvent to obtain high-purity obeticholic acid. The method includes the specific steps that crude obeticholic acid reacts with organic amine in the organic solvent to obtain obeticholic acid organic amine salt; the obeticholic acid organic amine salt is subjected to acid adjustment to be re-crystallized in an obeticholic acid mode. According to the purification method, high-purity (purity is larger than 98.5% and the individual impurity rate is smaller than 0.1%) obeticholic acid can be obtained, the steps of column chromatography and the like which cannot produce a large amount of high-purity obeticholic acid are not needed for the method, and therefore the purification method can better adapt to industrial production.
Description
Technical field
Embodiments of the present invention relate to biomedicine field, and more specifically, embodiments of the present invention relate to the recrystallization purifying method of a kind of high purity shellfish cholic acid difficult to understand.
Background technology
Shellfish cholic acid obeticholicacid difficult to understand is a kind of new drug for the treatment of cholestasis type liver cirrhosis, is applied to clinical bulk drug purity requirement higher, and in synthesis preparation process, usually can introduces the impurity of other similar structures, have impact on the purity of product it.Prior art patent US2008/0214515A1 discloses the method adopting ethyl acetate to carry out recrystallization and carries out purifying.Document JMC2014,57,937-954 also use the report of column chromatography method purifying; The industrial applications of column chromatography is more limited; Directly adopt the method for butylacetate crystallization also not thorough to single assorted removal, therefore the defect of prior art needs to be overcome, to obtain better production technique simultaneously.
Summary of the invention
Instant invention overcomes the deficiencies in the prior art, provide the recrystallization purifying method of a kind of high purity shellfish cholic acid difficult to understand, to expect to make the purification process of shellfish cholic acid difficult to understand be more suitable for suitability for industrialized production.
For solving above-mentioned technical problem, one embodiment of the present invention by the following technical solutions:
A recrystallization purifying method for high purity shellfish cholic acid difficult to understand, it is by recrystallization and obtain the method for high purity Austria shellfish cholic acid in organic solvent after shellfish cholic acid difficult to understand and organic amine salify.
The recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand specifically comprises the following steps:
Step one, shellfish cholic acid crude product difficult to understand reacted with organic amine in organic solvent obtain shellfish cholic acid organic amine salt difficult to understand;
Step 2, described shellfish cholic acid organic amine salt difficult to understand carried out acid and adjust, make it with shellfish cholic acid form recrystallization difficult to understand.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, the concrete operation method of described step one is: be dissolved in the organic solvent of 3 ~ 5 times of weight by shellfish cholic acid crude product difficult to understand, and add the organic amine of 5 ~ 20wt%, back flow reaction 2 ~ 5h, then 10 ~ 20 DEG C are cooled to, crystallization shellfish cholic acid difficult to understand organic amine salt, filters and obtains shellfish cholic acid organic amine salt difficult to understand.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, the concrete operation method of described step 2 is: by soluble in water for shellfish cholic acid organic amine salt difficult to understand, adding mineral acid to pH value is wherein 2.0 ~ 3.0, filtered and recycled shellfish cholic acid difficult to understand, again shellfish cholic acid difficult to understand to be joined in organic solvent and heating for dissolving, then be cooled to 20 DEG C, recrystallization separates out high purity shellfish cholic acid difficult to understand.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, described organic amine is aniline, pentanoic, phenylethylamine, triethylamine, quadrol, dicyclohexyl amine, diisopropylethylamine or diethyl ethanamine.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, organic solvent described in step one is acetone, ethyl acetate, butylacetate or sec-butyl alcohol.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, organic solvent described in step 2 is acetic acid alkane ester, such as ethyl acetate, butylacetate, propyl acetate etc.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, described mineral acid is sulfuric acid or hydrochloric acid.
In the recrystallization purifying method of above-mentioned high purity shellfish cholic acid difficult to understand, described high purity shellfish cholic acid difficult to understand refers to the shellfish cholic acid difficult to understand of purity > 98.5%, single assorted < 0.1%.
Compared with prior art, one of beneficial effect of the present invention is: purification process of the present invention can obtain the shellfish cholic acid difficult to understand of high purity (purity > 98.5%, single assorted < 0.1%), and method is without the need to adopting column chromatography etc. can not the step of in a large number production high purity shellfish cholic acid difficult to understand, therefore purification process of the present invention more can adapt to suitability for industrialized production.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Embodiment 1
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 100g purity 89.6%, add acetone by 3 times of its weight and add triethylamine by 20% of its weight, after reflux 2h, starting slow cooling to 10 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.0 by being acidified to pH value with the dilute hydrochloric acid that mass percent is 10wt% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid ethyl acetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallize out, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 98.7%, and the rate of recovery is 84.5%.
Embodiment 2
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 100g purity 89.6%, add ethyl acetate by 4 times of its weight and add quadrol by 5% of its weight, after reflux 3h, starting slow cooling to 15 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.5 by being acidified to pH value with the dilute sulphuric acid of shellfish cholic acid organic amine salt mass percent 10% difficult to understand after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid butylacetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallize out, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 98.9%, and the rate of recovery is 85.3%.
Embodiment 3
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 100g purity 89.6%, add sec-butyl alcohol by 5 times of its weight and add phenylethylamine by 10% of its weight, after reflux 4h, starting slow cooling to 20 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 3.0 by being acidified to pH value with the dilute sulphuric acid of shellfish cholic acid organic amine salt mass percent 60% difficult to understand after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid propyl acetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 99.1%, and the rate of recovery is 82.3%.
Embodiment 4
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 200g purity 89.6%, add butylacetate by 4 times of its weight and add dicyclohexyl amine by 20% of its weight, after reflux 5h, starting slow cooling to 10 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.5 by being acidified to pH value with the dilute sulphuric acid of its mass percent 35% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid ethyl acetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 98.8%, and the rate of recovery is 84.7%.
Embodiment 5
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 200g purity 89.6%, add ethyl acetate by 3 times of its weight and add aniline by 15% of its weight, after reflux 4h, starting slow cooling to 10 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.5 by being acidified to pH value with the dilute hydrochloric acid of its mass percent 10% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid butylacetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 98.7%, and the rate of recovery is 83.3%.
Embodiment 6:
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 200g purity 89.6%, add butylacetate by 4.5 times of its weight and add diisopropylethylamine by 20% of its weight, after reflux 4h, start slow cooling to 15 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.0 by being acidified to pH value with the dilute sulphuric acid acid of its mass percent 10% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid propyl acetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 99.2%, and the rate of recovery is 82.6%.
Embodiment 7:
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 500g purity 90.4%, add ethyl acetate by 3.5 times of its weight and add pentanoic by 20% of its weight, after reflux 4h, starting slow cooling to 15 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.0 by being acidified to pH value with the dilute hydrochloric acid of its mass percent 10% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid butylacetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 98.8%, and the rate of recovery is 84.3%.
Embodiment 8:
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 500g purity 90.4%, add butylacetate by 4 times of its weight and add diethyl ethanamine by 20% of its weight, after reflux 3h, start slow cooling to 15 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.0 by being acidified to pH value with the dilute hydrochloric acid of its mass percent 10% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid ethyl acetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 98.9%, and the rate of recovery is 84.5%.
Embodiment 9:
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 5kg purity 90.4%, add butylacetate by 4 times of its weight and add triethylamine by 20% of its weight, after reflux 4h, starting slow cooling to 10 DEG C, crystallization, filters and obtains shellfish cholic acid organic amine salt difficult to understand crystallization.
Be 2.0 by being acidified to pH value with the dilute hydrochloric acid of its mass percent 10% after this shellfish cholic acid organic amine salt crystallization dissolved in purified water difficult to understand, filtration drying must refine shellfish cholic acid difficult to understand.
By this refining shellfish cholic acid butylacetate heating for dissolving difficult to understand, be then cooled to 20 DEG C, crystallization, filtration drying can obtain the recrystallization shellfish cholic acid difficult to understand (single mixing is less than 0.1%) that purity is 99.1%, and the rate of recovery is 85.1%.
Comparative example:
Disclosed in US2008/0214515A1, existing method (Example1, stepg) is tested.
Get the shellfish cholic acid crude product difficult to understand (single mixing is greater than 2%) of 100g purity 89.6%, add 85% phosphoric acid solution by 1 times of its weight and doubly add ethyl acetate by its weight 2, be heated to 70 DEG C of dissolvings, then 20 DEG C of crystallize outs are cooled to, filter and wash by ethyl acetate, 65 DEG C of dryings can obtain the shellfish cholic acid difficult to understand (single mixing is greater than 0.3%) that purity is 94.3%, and the rate of recovery is 89.2%.
Although with reference to explanatory embodiment of the present invention, invention has been described here, but, should be appreciated that, those skilled in the art can design a lot of other amendment and embodiment, these amendments and embodiment will drop within spirit disclosed in the present application and spirit.More particularly, in scope disclosed in the present application, multiple modification and improvement can be carried out to the building block of subject combination layout and/or layout.Except the modification of carrying out building block and/or layout is with except improvement, to those skilled in the art, other purposes also will be obvious.
Claims (9)
1. a recrystallization purifying method for high purity shellfish cholic acid difficult to understand, is characterized in that it is by recrystallization and obtain the method for high purity Austria shellfish cholic acid in organic solvent after shellfish cholic acid difficult to understand and organic amine salify.
2. the recrystallization purifying method of high purity according to claim 1 shellfish cholic acid difficult to understand, is characterized in that it comprises the following steps:
Step one, shellfish cholic acid crude product difficult to understand reacted with organic amine in organic solvent obtain shellfish cholic acid organic amine salt difficult to understand;
Step 2, described shellfish cholic acid organic amine salt difficult to understand carried out acid and adjust, make it with shellfish cholic acid form recrystallization difficult to understand.
3. the recrystallization purifying method of high purity according to claim 2 shellfish cholic acid difficult to understand, it is characterized in that the concrete operation method of described step one is: be dissolved in the organic solvent of 3 ~ 5 times of weight by shellfish cholic acid crude product difficult to understand, and add the organic amine of 5 ~ 20wt% of shellfish cholic acid crude product difficult to understand, back flow reaction 2 ~ 5h, then 10 ~ 20 DEG C are cooled to, crystallization shellfish cholic acid difficult to understand organic amine salt, filters and obtains shellfish cholic acid organic amine salt difficult to understand.
4. the recrystallization purifying method of high purity according to claim 2 shellfish cholic acid difficult to understand, it is characterized in that the concrete operation method of described step 2 is: by soluble in water for shellfish cholic acid organic amine salt difficult to understand, adding mineral acid to pH value is wherein 2.0 ~ 3.0, filtered and recycled shellfish cholic acid difficult to understand, again shellfish cholic acid difficult to understand to be joined in organic solvent and heating for dissolving, then be cooled to 20 DEG C, recrystallization separates out high purity shellfish cholic acid difficult to understand.
5. the recrystallization purifying method of high purity according to claim 2 shellfish cholic acid difficult to understand, is characterized in that described organic amine is aniline, pentanoic, phenylethylamine, triethylamine, quadrol, dicyclohexyl amine, diisopropylethylamine or diethyl ethanamine.
6. the recrystallization purifying method of high purity according to claim 3 shellfish cholic acid difficult to understand, is characterized in that described organic solvent is acetone, ethyl acetate, butylacetate or sec-butyl alcohol.
7. the recrystallization purifying method of high purity according to claim 4 shellfish cholic acid difficult to understand, is characterized in that described organic solvent is acetic acid alkane ester.
8. the recrystallization purifying method of high purity according to claim 4 shellfish cholic acid difficult to understand, is characterized in that described mineral acid is sulfuric acid or hydrochloric acid.
9. the recrystallization purifying method of the shellfish cholic acid difficult to understand of the high purity according to claim 1 or 4, is characterized in that described high purity shellfish cholic acid difficult to understand refers to the shellfish cholic acid difficult to understand of purity > 98.5%, single assorted < 0.1%.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017008773A1 (en) * | 2015-07-16 | 2017-01-19 | 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 |
| CN107674107A (en) * | 2017-09-30 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of process for purification of shellfish cholic acid difficult to understand |
| EP3293196A1 (en) * | 2016-09-09 | 2018-03-14 | Hexal AG | Process for purifying obeticholic acid |
| CN108948117A (en) * | 2017-05-19 | 2018-12-07 | 杭州源昶医药科技有限公司 | A kind of synthetic method of Austria's shellfish cholic acid |
| WO2020039449A1 (en) * | 2018-08-24 | 2020-02-27 | Solara Active Pharma Sciences Limited | An improved process for the preparation of obeticholic acid and intermediates used in the process thereof |
| CN111032623A (en) * | 2017-08-25 | 2020-04-17 | 维生源知识产权有限责任公司 | Process for purifying long-chain amino acid |
| 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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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017008773A1 (en) * | 2015-07-16 | 2017-01-19 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
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| EP3414256B1 (en) | 2016-02-10 | 2022-01-19 | Dr. Reddy's Laboratories Limited | Purification process involving amine salt of obeticholic acid |
| EP3293196A1 (en) * | 2016-09-09 | 2018-03-14 | Hexal AG | Process for purifying obeticholic acid |
| CN108948117A (en) * | 2017-05-19 | 2018-12-07 | 杭州源昶医药科技有限公司 | A kind of synthetic method of Austria's shellfish cholic 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 |
| CN111032623A (en) * | 2017-08-25 | 2020-04-17 | 维生源知识产权有限责任公司 | Process for purifying long-chain amino acid |
| CN111032623B (en) * | 2017-08-25 | 2023-02-03 | 维生源知识产权有限责任公司 | Process for purifying long-chain amino acid |
| CN107674107A (en) * | 2017-09-30 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of process for purification of shellfish cholic acid difficult to understand |
| WO2020039449A1 (en) * | 2018-08-24 | 2020-02-27 | Solara Active Pharma Sciences Limited | An improved 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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| CN105541953B (en) | 2017-11-21 |
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