CN109535216A - A kind of preparation method of unformed shellfish cholic acid difficult to understand and unformed shellfish cholic acid difficult to understand - Google Patents
A kind of preparation method of unformed shellfish cholic acid difficult to understand and unformed shellfish cholic acid difficult to understand Download PDFInfo
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- CN109535216A CN109535216A CN201710864145.XA CN201710864145A CN109535216A CN 109535216 A CN109535216 A CN 109535216A CN 201710864145 A CN201710864145 A CN 201710864145A CN 109535216 A CN109535216 A CN 109535216A
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- cholic acid
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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 belongs to drug crystal forms fields, and in particular to the preparation method of the unformed shellfish cholic acid difficult to understand of one kind, the unformed shellfish cholic acid difficult to understand by this method preparation and its purposes in terms of the drug of preparation prevention or the treatment receptor-mediated related disease of farnesol X.The preparation method of unformed shellfish cholic acid difficult to understand provided by the present invention, main includes following two step: will (a) crystallize shellfish cholic acid and water difficult to understand with quality (g): the ratio that volume (ml) is 1:1~1:100 mixes, and 0.5~48h is stirred at 20~80 DEG C；(b) it filters, it is dry, unformed shellfish cholic acid difficult to understand can be prepared.This process simplify operating procedures, avoid a large amount of uses of organic solvent, product yield is up to 98%-99%, and can prepare the good unformed shellfish cholic acid difficult to understand of purity high stability without further purification step.
Description
Technical field
The present invention relates to drug crystal forms fields, are specifically related to the preparation method of the unformed shellfish cholic acid difficult to understand of one kind and by the party
The unformed shellfish cholic acid difficult to understand of method preparation.
Background technique
Shellfish cholic acid (Obeticholic acid, OCA) difficult to understand also known as 6 one ethyl chenodeoxycholic acids, structural formula is as shown in Equation 1,
It is the analog of cholic acid, based on the molecular structure of natural cholic acid.Shellfish cholic acid difficult to understand belongs to the potent excitement of Farnesoid X receptor
Agent passes through first selective binding and activates Farnesoid X receptor (FXR), adjusts the expression of related gene, and then influence bile
Acid, blood lipid and glycometabolism, therefore can be used for treating FXR and mediate insufficiency of accommodation, cardiovascular disease, cholestatic liver disease and height
HDL cholesterol, high triglyceride and fibrosis conditions etc., including it is biliary atresia, cholestatic liver disease, chronic liver disease, non-
Alcoholic fatty liver inflammation (NASH), hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), due into
Row fibre modification, hepatic fibrosis and cardiovascular disease (including atherosclerosis, arteriosclerosis, hypercholesterolemia
And hyperlipemia) caused by hepatic disorder etc..
Shellfish cholic acid difficult to understand as a kind of novel drug candidate for treating primary biliary cirrhosis and nonalcoholic fatty liver,
It is researched and developed by Intercept drugmaker, the U.S., clinical research shows the patient that cannot be resistant to completely to ursodesoxycholic acid, leads to
The level that shellfish cholic acid difficult to understand can be obviously improved alkaline phosphatase and serum bilirubin of taking is crossed, the clinical effectiveness of shellfish cholic acid difficult to understand is prompted
It may be better than existing drug ursodesoxycholic acid.The said firm discloses Austria in its PCT Patent Application file WO20131920971A1
The preparation method and different crystal forms of unformed 1 type of shellfish cholic acid specifically include crystal form A type, crystal form c-type, crystal form D type, crystal form F type
With the analysis of physical and chemical property of crystal form G type, such as the difference of fusing point, stability, solubility, dissolution rate, hygroscopicity, and then it is evaluated
Drug effect and bioavilability, if the chemical conversion of easily separated and scale produces, if is suitable as drug ingedient.Wherein, crystal form A, C and D
For mixed type hydrate/solvated compounds crystal form containing water and a certain range organic solvent, make in crystalline form F, G preparation process
With nitromethane, second eyeball equal solvent, environment is polluted, is not suitable for being developed as drug ingedient.Preparation is without fixed in the patent document
The method of type Austria shellfish cholic acid is dissolved in using the shellfish cholic acid c-type crystal form difficult to understand by 6 step synthesis and purifying as synthetic intermediate
In NaOH aqueous solution and HCl is added, to prepare 1 type of shellfish cholic acid (armorphous) difficult to understand of purity is high.And in preparing crystal c-type
When mesosome, organic solvent is needed such as to crystallize from acetonitrile and recrystallize from nitromethane.
Chinese patent application CN105777836A discloses a kind of polymorph and preparation method thereof of shellfish cholic acid difficult to understand, including
Crystal form I and II.Wherein crystal form II is used dissolves shellfish cholic acid difficult to understand in organic solvent, flows back, cools down, cooling, precipitates crystal, mistake
Filter, drying can be obtained.A kind of wherein XRPD map salt free ligands peak of crystal form II, it is thus understood that polymorphic composition or unformed
Composition.
Chinese patent application CN105085597A discloses a kind of preparation method of unformed shellfish cholic acid difficult to understand, by by shellfish difficult to understand
Cholic acid is dissolved in organic solvent and is filtered, and obtains filtrate decompression concentration or spray drying to prepare unformed shellfish gallbladder difficult to understand
Acid.Wherein any one or two kind of the organic solvent in alcohol solvent, ketone solvent, esters solvent, halogenated hydrocarbon solvent
More than.
There are many crystal forms for shellfish cholic acid difficult to understand, its stability of different crystal forms and bioavilability then have larger difference, to preparation
It is affected, the bioactivity of drug can be seriously affected.Moreover, same drug is in different solvents, temperature and other processing items
Other crystal forms can be converted under part.Therefore the stability and drug effect of this newtype drug active constituent of unformed shellfish cholic acid difficult to understand are studied
Etc. properties it is very significant for the processing technology for preparing the pharmaceutical composition containing shellfish cholic acid difficult to understand.
But in the prior art include the unformed method that prepared disclosed in above-mentioned Patent Application Publication, step is complicated,
A large amount of by-products are generated, difficulty is brought to isolating and purifying for product, or need to use organic solvent, exists in scale application
Many deficiencies.
In view of the above-mentioned defects in the prior art or shortcoming, present inventor are preparing unformed shellfish cholic acid difficult to understand
Further improvement has been done in method, has simplified operating procedure, avoids a large amount of uses of organic solvent, and without further
Purification step can prepare the unformed shellfish cholic acid difficult to understand of purity is high.
Summary of the invention
The present invention is intended to provide a kind of preparation method of unformed shellfish cholic acid difficult to understand, the unformed shellfish gallbladder difficult to understand by this method preparation
Acid and its purposes in terms of the drug for the related disease that preparation prevention or treatment farnesoid X receptor (FXR) mediate.
On the one hand, the present invention provides a kind of preparation method of unformed shellfish cholic acid difficult to understand, the method is comprised the steps of:
(a) shellfish cholic acid difficult to understand is mixed with water；
(b) it filters, it is dry, unformed shellfish cholic acid difficult to understand can be prepared.
The shellfish cholic acid difficult to understand mixed in the step (a) with water can be the shellfish cholic acid difficult to understand of any crystal habit.For example, shellfish difficult to understand
Cholic acid A crystal form, B crystal form, C crystal form, and optionally other crystal forms or the mixing crystal form of different crystal forms formation.
The mass volume ratio of Austria shellfish cholic acid and water described in the step (a) is preferably 1:1~1:100；More preferably 1:5
~1:80；More preferably 1:5~1:40.
After mixing shellfish cholic acid difficult to understand with water in the step (a), preferably stirred at 20~80 DEG C；More preferably 40~70
It is stirred at DEG C.
After shellfish cholic acid difficult to understand is mixed with water in the step (a), mixing time be 0.5~for 24 hours, preferably 1~15h, more
It is preferred that 3~10h.
One of drying condition in the step (b) temperature is 20~100 DEG C, preferably 30~80 DEG C；More preferably 40
~80 DEG C.
The present invention also provides a kind of preparation method of unformed shellfish cholic acid difficult to understand, the method is comprised the steps of:
(a) shellfish cholic acid difficult to understand is mixed with water by mass volume ratio 1:1~1:100, at 20~80 DEG C stir 0.5~for 24 hours；
(b) it filters, it is dry at 20~100 DEG C, unformed shellfish cholic acid difficult to understand can be prepared.
Invention further provides a kind of preparation method of unformed shellfish cholic acid difficult to understand, the method is comprised the steps of:
(a) shellfish cholic acid difficult to understand is mixed with water by mass volume ratio 1:5~1:40,3~10h is stirred at 40~70 DEG C；
(b) it filters, it is dry at 40~80 DEG C, unformed shellfish cholic acid difficult to understand can be prepared.
It, can be according to need about the drying in the preparation method step (b) of unformed shellfish cholic acid difficult to understand provided by the present invention
It wants, reduces vacuum degree by conventional means, such as vacuumized using water pump, oil pump, vacuum degree is -0.06Mpa~-0.095Mpa.
One of drying condition vacuum degree is preferably -0.08Mpa~-0.09Mpa in the step (b).
On the other hand, the present invention also provides a kind of using unformed Austria shellfish gallbladder prepared by either method of the present invention
Acid.
By the unformed shellfish cholic acid difficult to understand of above method preparation, purity reaches 99.8% or more, and yield reaches 98%-
99%.
In addition, unformed shellfish cholic acid difficult to understand of the present invention can be applied to preparation for preventing or treating farnesoid X receptor
(FXR) drug of the related disease mediated.Especially prepare for prevent or treat cardiovascular disease, cholestatic liver disease and
The drug of high HDL cholesterol, high triglyceride and fibrosis conditions etc..More specifically, can be applicable to preparation prevention or
Treat biliary atresia, cholestatic liver disease, chronic liver disease, nonalcoholic fatty liver disease (NASH), hepatitis C infection, wine
Essence hepatopathy, primary biliary cirrhosis (PBC), due to progressive fibre modification, hepatic fibrosis and cardiovascular disease (example
Such as, atherosclerosis, arteriosclerosis, hypercholesterolemia and hyperlipemia etc.) caused by hepatic disorder etc.
Drug.
The preparation method of unformed shellfish cholic acid difficult to understand of the present invention greatly simplifies unformed shellfish gallbladder difficult to understand in the prior art
The preparation method of acid avoids preparing using organic solvent or using acid, the defect of alkali preparation.The unformed shellfish cholic acid difficult to understand of the present invention
Preparation method do not need any organic solvent, do not need acid-base reagent, and process is few, easy to operate yet, high income, and make
Standby unformed shellfish cholic acid stability difficult to understand is good, purity is high.
Detailed description of the invention
Fig. 1 is X-ray diffraction (XRD) map of unformed shellfish cholic acid difficult to understand.
Specific embodiment
Technical solution of the present invention is further explained With reference to embodiment, but not with any side
The formula limitation present invention, under the premise of without departing substantially from inventive concept and technical solution of the invention, to of the art general
For logical technical staff, any change, transformation or the equivalent replacement method that can be realized fall within right of the invention and want
It asks in range.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is unless otherwise specified embodiment institute obtained by commercially available purchase
Shellfish cholic acid difficult to understand can refer to the method preparation reported in existing literature.
Embodiment 1
The shellfish cholic acid difficult to understand obtained from recrystallize with dichloromethane is selected, methylene chloride residual 0.4% weighs Austria's shellfish cholic acid
5g is added 50ml purified water, stirs 5h at 50 DEG C, filters, be about -0.06Mpa~-0.095Mpa, temperature 50 C in vacuum degree
Under, filtering obtained solid is 8 hours dry or more, unformed shellfish cholic acid 4.95g difficult to understand is obtained, identifies that Austria's shellfish cholic acid is solid through XRD
Body is unformed, yield 99.0%, HPLC purity 99.91%, moisture content 0.1%.
Embodiment 2
The shellfish cholic acid difficult to understand obtained from re-crystallizing in ethyl acetate is selected, ethyl acetate residual 0.55% weighs Austria's shellfish cholic acid
200ml purified water is added in 5g, and 40 DEG C of stirring 10h form homogenous suspension, filters, in vacuum degree is about -0.06Mpa by solid
Under~-0.095Mpa, temperature is drying at 40 DEG C, obtains powdery Austria shellfish cholic acid solid 4.92g, identifies Austria's shellfish cholic acid through XRD
Solid is unformed, yield 98.4%, HPLC purity 99.90%, moisture content 0.09%.
Embodiment 3
Selecting Austria's shellfish cholic acid disclosed in the prior art is raw material, weighs shellfish cholic acid 5g difficult to understand, 60ml purified water is added, 60 DEG C are stirred
3h is mixed, is filtered, solid is obtained into powdery Austria shellfish cholic acid in 55 DEG C of dryings of vacuum in the case where vacuum degree is -0.08Mpa~-0.09Mpa
Solid 4.93g identifies that Austria's shellfish cholic acid solid is unformed, yield 98.6%, HPLC purity 99.89%, moisture content through XRD
0.1%.
Embodiment 4
Selecting Austria shellfish cholic acid disclosed in the prior art is raw material, weighs shellfish cholic acid 5g difficult to understand, addition 100ml purified water, 70 DEG C
6.5h is stirred, and filtering is -0.06Mpa~-0.095Mpa in vacuum degree, solid is dried under temperature 60 C, obtain powdery Austria shellfish
Cholic acid solid 4.90g identifies that Austria's shellfish cholic acid solid is unformed, yield 98.0%, HPLC purity 99.92%, moisture through XRD
Content 0.08%.
With above-described embodiment the method, by the mixing of raw material Austria shellfish cholic acid and purified water, wherein the quality of shellfish cholic acid difficult to understand
When with the volume ratio of purified water being 1:5,1:80 and 1:100, can also prepare yield as embodiment 1-4 high-purity without
Sizing shellfish cholic acid difficult to understand.
Comparative example 1
The embodiment referring to disclosed in Chinese patent application CN105085597A, 10g Austria shellfish cholic acid C crystal form is dissolved in
500ml dehydrated alcohol obtains clarifying shellfish cholic acid solution difficult to understand after filtering；Spray drying removes solvent, and it is solid to obtain white shellfish cholic acid difficult to understand
Body 9.25g, yield 92.5% identify that Austria's shellfish cholic acid solid is unformed, HPLC purity 99.8% through XRD.
Comparative example 2
10g Austria shellfish cholic acid C crystal form is dissolved in 50ml acetone, obtains clarifying shellfish cholic acid solution difficult to understand after filtering；In rotary evaporation
Subtract on instrument and solvent is evaporated off, then 50 DEG C of dryings of vacuum, obtain white shellfish cholic acid solid 9.70g difficult to understand, yield 97.0% reflects through XRD
Fixed Austria's shellfish cholic acid solid is unformed.
Comparative example 3
10g Austria shellfish cholic acid C crystal form is dissolved in 100ml butyl acetate, is filtered, is subtracted solvent is evaporated off on a rotary evaporator,
Again in 60 DEG C of dryings of vacuum, white shellfish cholic acid solid 9.53g difficult to understand is obtained, yield 95.3% identifies Austria's shellfish cholic acid solid through XRD
It is unformed.
Dissolvent residual measurement
Next, the shellfish cholic acid sample difficult to understand prepared to above-described embodiment and comparative examples carries out dissolvent residual measurement.Its
In, specific dissolvent residual measuring method is as described below:
Chromatographic column: use commercially available -94% dimethylchlorosilane of 6% cyanogen propyl phenyl for the capillary chromatographic column of fixer
Capillary chromatographic column similar in (30m × 0.32mm × 1.8 μm) or polarity.
Temperature programming:, keeping 6min by 45 DEG C of initial temperature, is warming up to 80 DEG C with 5 DEG C of rate per minute, maintains 2 minutes,
220 DEG C are warming up to 30 DEG C of rate per minute again, is maintained 2 minutes；
Injector temperature: 160 DEG C
Detector temperature: 260 DEG C
Linear velocity: 19.6cm/s
Split ratio: 10:1
Head space condition: 90 DEG C balance 30 minutes
Measurement result is as shown in table 1.
| Dissolvent residual (%) | |
| Embodiment 1-4 | Solvent-free infinity |
| Comparative example 1 | Ethyl alcohol: 0.65 |
| Comparative example 2 | Acetone: 0.57 |
| Comparative example 3 | Butyl acetate: 0.55 |
Table 1
Dissolvent residual measurement result is as shown in table 1, using the unformed shellfish cholic acid difficult to understand of the method described in the present invention preparation
Dissolvent residual is not above limit 0.1%, and the dissolvent residual value difference in the unformed shellfish cholic acid difficult to understand in comparative examples
It is 0.65%, 0.57% and 0.55%.As shown in 1 measurement result of table, unformed shellfish cholic acid dissolvent residual difficult to understand of the present invention is non-
It is often low, be conducive to the unformed shellfish cholic acid difficult to understand as active pharmaceutical ingredient and be used to prepare drug, and this method step is simple, nothing
The step of the removing solvent such as need to distill can reach the requirement as active pharmaceutical ingredient, to be prepared into different dosage forms medicine group
Close the drug that object is used to prevent or treat the related disease of farnesoid X receptor (FXR) mediation.
Stability Determination
Originally according to material medicine and preparation stability test direction principle (Chinese Pharmacopoeia version general rule 9001 in 2015) measurement
The shellfish cholic acid difficult to understand (being measured at 40 DEG C) prepared in application embodiment 1-4.The results are shown in Table 2 for Stability Determination.
Table 2
Thus illustrate that the unformed shellfish cholic acid difficult to understand that the application preparation method obtains has excellent stability.
With described in above-described embodiment, those skilled in the art select the quality of shellfish cholic acid difficult to understand and the ratio of purifying water volume is
When 1:5,1:80 and 1:100 are mixed, it can also equally be prepared that dissolvent residual is few, unformed Austria of excellent in stability
Shellfish cholic acid.
Claims (10)
1. a kind of preparation method of unformed shellfish cholic acid difficult to understand, which is characterized in that the method comprises the steps of:
(a) shellfish cholic acid difficult to understand is mixed with water；
(b) it filters, it is dry, unformed shellfish cholic acid difficult to understand can be prepared.
2. the method according to claim 1, wherein the quality of Austria shellfish cholic acid and water described in the step (a)
Volume ratio is 1:1~1:100；More preferably 1:5~1:80；More preferably 1:5~1:40.
3. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, which is characterized in that will in the step (a)
After shellfish cholic acid difficult to understand is mixed with water, preferably stirred at 20~80 DEG C；More preferably stirred at 40~70 DEG C.
4. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, which is characterized in that will in the step (a)
After shellfish cholic acid difficult to understand is mixed with water, mixing time is preferably 0.5~for 24 hours；Preferably 1~15h；More preferable 3~10h.
5. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, which is characterized in that done in the step (b)
Dry temperature is 20~100 DEG C.
6. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, which is characterized in that done in the step (b)
Dry temperature is preferably 30~80 DEG C；More preferably 40~80 DEG C.
7. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, the Ao Bei that is mixed in the step (a) with water
Cholic acid is to crystallize shellfish cholic acid difficult to understand.
8. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, which is characterized in that the method includes following
Step:
(a) shellfish cholic acid difficult to understand is mixed with water by mass volume ratio 1:1~1:100, at 20~80 DEG C stir 0.5~for 24 hours；
(b) it filters, it is dry at 20~100 DEG C, unformed shellfish cholic acid difficult to understand can be prepared.
9. the preparation method of unformed shellfish cholic acid difficult to understand according to claim 1, which is characterized in that the method includes following
Step:
(a) shellfish cholic acid difficult to understand is mixed with water by mass volume ratio 1:5~1:40,3~10h is stirred at 40~70 DEG C；
(b) it filters, it is dry at 40~80 DEG C, unformed shellfish cholic acid difficult to understand can be prepared.
10. a kind of unformed shellfish cholic acid difficult to understand of preparation of any one of -9 the methods according to claim 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710864145.XA CN109535216B (en) | 2017-09-22 | 2017-09-22 | Preparation method of amorphous obeticholic acid and amorphous obeticholic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710864145.XA CN109535216B (en) | 2017-09-22 | 2017-09-22 | Preparation method of amorphous obeticholic acid and amorphous obeticholic acid |
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| CN109535216A true CN109535216A (en) | 2019-03-29 |
| CN109535216B CN109535216B (en) | 2022-09-16 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085597A (en) * | 2015-08-28 | 2015-11-25 | 成都百裕科技制药有限公司 | Preparation method of non-shaped obeticholic acid |
| WO2017008773A1 (en) * | 2015-07-16 | 2017-01-19 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
| CN106632564A (en) * | 2015-10-30 | 2017-05-10 | 苏州泽璟生物制药有限公司 | Obeticholic acid salt and amorphous material thereof, and pharmaceutical composition |
| CN106810587A (en) * | 2015-12-01 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | The method for preparing unformed shellfish cholic acid difficult to understand |
-
2017
- 2017-09-22 CN CN201710864145.XA patent/CN109535216B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017008773A1 (en) * | 2015-07-16 | 2017-01-19 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
| CN105085597A (en) * | 2015-08-28 | 2015-11-25 | 成都百裕科技制药有限公司 | Preparation method of non-shaped obeticholic acid |
| CN106632564A (en) * | 2015-10-30 | 2017-05-10 | 苏州泽璟生物制药有限公司 | Obeticholic acid salt and amorphous material thereof, and pharmaceutical composition |
| CN106810587A (en) * | 2015-12-01 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | The method for preparing unformed shellfish cholic acid difficult to understand |
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