CN106046094A - Obeticholic acid dimer impurities and preparation method thereof - Google Patents
Obeticholic acid dimer impurities and preparation method thereof Download PDFInfo
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- 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 relates to obeticholic acid dimer impurities and a preparation method thereof. The preparation method sequentially includes the steps of S1, preparing a beticholic acid dimer impurity coarse compound; S2, performing column chromatography separation and purification on the beticholic acid dimer impurity coarse compound. The preparation method has the advantages that the method is used for preparing the dimer impurities generated during the synthesizing and degrading process of obeticholic acid, the quality of the obeticholic acid can be well controlled, and medicine safety can be increased.
Description
Technical field
The present invention relates to a kind of shellfish cholic acid dimer impurity difficult to understand and preparation method thereof, belong to medicinal chemistry arts.
Background technology
Shellfish cholic acid (OCA) difficult to understand is a kind of semi-synthetic chenodeoxycholic acid, is also method Buddhist nun's ester derivant X receptor (FXR) agonist,
Zoopery proves that it improves insulin resistant and alleviates the effect of hepatic fat content.
The structural formula of shellfish cholic acid difficult to understand is as follows:
Ying Te Sept company of the U.S. is envisaged for primary biliary cirrhosis (PBC) and non-alcoholic stellato-hepatitis
(NASH).The NDA that is in of primary biliary cirrhosis (PBC) indication evaluates stage, non-alcoholic stellato-hepatitis
(NASH) indication is in III phase clinical stage.
Authorization Notice No. is that the Chinese patent literature of CN101203526B discloses preparation 3 Α (Β)-7 Α (Β)-dihydroxy
The method of base-6 Α (Β)-alkyl-5 Β-cholanic acid (shellfish cholic acid difficult to understand), but the not open dimeric preparation side of shellfish cholic acid difficult to understand
Method；Application publication number is that the Chinese patent literature of CN104781272A discloses the preparation of shellfish cholic acid difficult to understand, purposes and solid form
And the control of the limit of dimer impurity, but the preparation method of undisclosed dimer impurity.
For preferably quality research to shellfish cholic acid difficult to understand, it is highly desirable to obtain the standard substance of this impurity.Be easy to qualitative and
Carry out the analysis and research of impurity quantitatively, and controlled, within a safety, rational limits, will be directly connected to
The quality of shellfish cholic acid difficult to understand and safety.Thereby may be ensured that the quality of medicine, significant to safe medication.
Summary of the invention
In order to solve above-mentioned technical problem, it is an object of the invention to prepare institute in shellfish cholic acid synthesis difficult to understand and degradation process
The dimer impurity produced, can preferably control the quality of shellfish cholic acid difficult to understand, improve the safety of medicine.
Further object is that and a kind of method preparing shellfish cholic acid dimer impurity difficult to understand is provided.
Technical scheme is as follows:
Scheme one
The shellfish cholic acid dimer impurity structural formula difficult to understand of the present invention is as follows:
Scheme two
A kind of preparation method preparing shellfish cholic acid dimer impurity difficult to understand, the step carried out including next coming in order:
S1: the preparation of shellfish cholic acid dimer impurity crude compound difficult to understand；It includes the sub-step that next coming in order are carried out:
S1-1: shellfish cholic acid difficult to understand is added to the organic solvent of 20～40 volume times amount, and drips catalyst；
S1-2: stir and be heated to reflux band water, insulation reaction at 65～120 DEG C, the water yield collected of weighing is about theory
The water yield 80% time, be cooled to 30～35 DEG C, weight ÷ 420.63 ÷ 2 × 18 of described theoretical water=input shellfish cholic acid difficult to understand；
Its chemical equation is as follows:
S1-3: add the sodium bicarbonate solution of 5%, agitator treating 10 minutes, stratification；
S1-4: organic layer evaporated under reduced pressure get Ao Bei cholic acid dimer impurity crude compound；
S2: shellfish cholic acid dimer impurity crude compound column chromatography for separation difficult to understand purifies；It includes the son that next coming in order are carried out
Step:
S2-1: the shellfish cholic acid dimer impurity crude compound difficult to understand of step S1-4 gained is added 3～the oil of 6 volume times amount
Ether dissolves；
S2-2: add 200～300 mesh silica gel, rotation steaming is quicksand like to solid；
S2-3: the most again add 200～300 mesh silica gel as fixing to petroleum ether, be stirring evenly and then adding into
In glass chromatography column；
S2-4: the sample loading that step S2-3 is mixed to glass chromatography column, molten with the mixing of petroleum ether by ethyl acetate
Liquid, as flowing phase, is collected impact point solution and decompression is spin-dried for obtaining shellfish cholic acid dimer impurity difficult to understand.
Wherein, one or more in organic solvent employing normal hexane, toluene, the petroleum ether of step S1-1 is any
Ratio mixes.
Wherein, the reaction temperature of step S1-2 is 68-72 DEG C or 110-115 DEG C.
Wherein, step S1-1 catalyst uses sulphuric acid, phosphoric acid, and one or more the arbitrary proportion in hydrochloric acid mixes
Close.
Wherein, the insulation reaction time of step S1-2 is 4～8h.
Wherein, the fixing phase 15-20 weight times sample size of step S2-3.
Wherein, in step S2-4, the ratio of the mixed solvent of ethyl acetate and petroleum ether is 1:1.
There is advantages that
1) present invention can preferably control the quality of shellfish cholic acid difficult to understand, improves the safety of medicine.
2) present invention prepares shellfish cholic acid dimer impurity purity difficult to understand more than 99.0%, highly purified dimer impurity for
Need to use impurity reference substance concentration curve to for carrying out the shellfish cholic acid difficult to understand of limit of impurities detection, there is very important meaning
Justice.
3) the shellfish cholic acid dimer impurity product difficult to understand of the present invention is good with magazins' layout degree, and product purity is high.
Accompanying drawing explanation
Fig. 1 is Austria of the present invention shellfish cholic acid dimer impurity structural formula；
Fig. 2 is the chemical equation that the present invention generates shellfish cholic acid dimer impurity difficult to understand；
Fig. 3 is the mass spectrum of Austria of the present invention shellfish cholic acid dimer impurity；
Fig. 4 is the hydrogen spectrogram of Austria of the present invention shellfish cholic acid dimer impurity；
Fig. 5 is the carbon spectrogram of Austria of the present invention shellfish cholic acid dimer impurity.
Detailed description of the invention
(1) detailed description of the invention is as follows:
A kind of dimeric preparation method of shellfish cholic acid difficult to understand, the step carried out including next coming in order:
S1: the preparation of shellfish cholic acid dimer impurity crude compound difficult to understand；It includes the sub-step that next coming in order are carried out:
S1-1: shellfish cholic acid difficult to understand is added to the normal hexane of 20～40 volume times amount or toluene or petroleum ether,
S1-2: stir and be heated to reflux band water, insulation reaction 4～8h at 65～120 DEG C, the water yield collected of weighing is about
Theoretical water 80% time, be cooled to 30～35 DEG C, weight ÷ 420.63 ÷ of described theoretical water=input shellfish cholic acid difficult to understand 2 ×
18；
S1-3: add the sodium bicarbonate solution of 5%, agitator treating 10 minutes, stratification；
S1-4: organic layer evaporated under reduced pressure get Ao Bei cholic acid dimer impurity crude compound；
S2: shellfish cholic acid dimer impurity crude compound column chromatography for separation difficult to understand purifies, and it includes the son that next coming in order are carried out
Step:
S2-1: the dimeric crude compound of step S1-3 gained is added 3～dissolves in the petroleum ether of 6 volume times amount；
S2-2: add 200～300 mesh silica gel, rotation steaming is quicksand like to solid in bottle；
S2-3: the most again add 200～300 mesh silica gel as fixing to petroleum ether, be stirring evenly and then adding into
In glass chromatography column；
S2-4: by the sample loading mixed to glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1 is made
For flowing phase, collect impact point solution and decompression is spin-dried for obtaining shellfish cholic acid dimer impurity difficult to understand.
(2) embodiment is as follows:
It is next with specific embodiment below in conjunction with the accompanying drawings that the present invention will be described in detail.
Embodiment 1 (most preferred embodiment):
Equipped with agitator, water knockout drum, thermometer there-necked flask in, add difficult to understand shellfish cholic acid 12g, normal hexane 360ml, dense
1, sulphuric acid, at 70 ± 2 DEG C, the lower reflux dewatering 6h of stirring, is cooled to room temperature, and the 100ml that adds water washs, and discards water layer, 5% bicarbonate
Sodium solution 50ml washs, and discards sodium bicarbonate water layer, is decompressed to dry get Ao Bei cholic acid dimer impurity rough at organic layer 50 DEG C
Compound；Shellfish cholic acid dimer impurity crude compound 11g difficult to understand of gained is added 55ml petroleum ether dissolution, add 20g 200～
300 mesh silica gel, rotation steaming is quicksand like to solid in bottle.Meanwhile, using 250g 200～300 mesh silica gel as fixing be added to
In 500ml petroleum ether, it is stirring evenly and then adding into glass chromatography column, pressurizes and glass chromatography column is compacted, the sample that will mix
Loading is to glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1, as flowing phase, collects impact point solution also
Decompression is spin-dried for obtaining 4.0g Austria shellfish cholic acid dimer impurity, yield 35%, purity 99.5%.
Embodiment 2 (preferred embodiment):
Equipped with agitator, water knockout drum, thermometer there-necked flask in, add shellfish cholic acid 12g difficult to understand, toluene 360ml, phosphorus
Acid 1, at 112 ± 2 DEG C, the lower reflux dewatering 6h of stirring, is cooled to room temperature, and the 100ml that adds water washs, and discards water layer, 5% bicarbonate
Sodium solution 50ml washs, and discards sodium bicarbonate water layer, is decompressed to dry get Ao Bei cholic acid dimer impurity rough at organic layer 55 DEG C
Compound；Shellfish cholic acid dimer impurity crude compound 12g difficult to understand of gained is added 55ml petroleum ether dissolution, add 20g 200～
300 mesh silica gel, rotation steaming is quicksand like to solid in bottle.Meanwhile, using 250g 200～300 mesh silica gel as fixing be added to
In 500ml petroleum ether, it is stirring evenly and then adding into glass chromatography column, pressurizes and glass chromatography column is compacted, the sample that will mix
Loading is to glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1, as flowing phase, collects impact point solution also
Decompression is spin-dried for obtaining 3.7g Austria shellfish cholic acid dimer impurity, yield 32%, purity 99.1%.
Embodiment 3:
Equipped with agitator, water knockout drum, thermometer there-necked flask in, add difficult to understand shellfish cholic acid 12g, petroleum ether 360ml, dense
1, sulphuric acid, at 70 ± 2 DEG C, the lower reflux dewatering 6h of stirring, is cooled to room temperature, and the 100ml that adds water washs, and discards water layer, 5% bicarbonate
Sodium solution 50ml washs, and discards sodium bicarbonate water layer, is decompressed to dry get Ao Bei cholic acid dimer impurity rough at organic layer 50 DEG C
Compound；Shellfish cholic acid dimer impurity crude compound 11g difficult to understand of gained is added 55ml petroleum ether dissolution, add 20g 200～
300 mesh silica gel, rotation steaming is quicksand like to solid in bottle.Meanwhile, using 250g 200～300 mesh silica gel as fixing be added to
In 500ml petroleum ether, it is stirring evenly and then adding into glass chromatography column, pressurizes and glass chromatography column is compacted, the sample that will mix
Loading is to glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1, as flowing phase, collects impact point solution also
Decompression is spin-dried for obtaining 4.0g Austria shellfish cholic acid dimer impurity, yield 35%, purity 99.0%.
Embodiment 4:
Equipped with agitator, water knockout drum, thermometer there-necked flask in, add difficult to understand shellfish cholic acid 12g, normal hexane 360ml, dense
1, sulphuric acid, at 70 ± 2 DEG C, the lower reflux dewatering 8h of stirring, is cooled to room temperature, and the 100ml that adds water washs, and discards water layer, 5% bicarbonate
Sodium solution 50ml washs, and discards sodium bicarbonate water layer, is decompressed to dry get Ao Bei cholic acid dimer impurity rough at organic layer 50 DEG C
Compound；Shellfish cholic acid dimer impurity crude compound 11g difficult to understand of gained is added 55ml petroleum ether dissolution, add 20g 200～
300 mesh silica gel, rotation steaming is quicksand like to solid in bottle.Meanwhile, using 250g 200～300 mesh silica gel as fixing be added to
In 500ml petroleum ether, it is stirring evenly and then adding into glass chromatography column, pressurizes and glass chromatography column is compacted, the sample that will mix
Loading is to glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1, as flowing phase, collects impact point solution also
Decompression is spin-dried for obtaining 4.0g Austria shellfish cholic acid dimer impurity, yield 35%, purity 98.5%.
Embodiment 5:
Equipped with agitator, water knockout drum, thermometer there-necked flask in, add shellfish cholic acid 12g difficult to understand, toluene 360ml, phosphoric acid
1, at 112 ± 2 DEG C, the lower reflux dewatering 8h of stirring, is cooled to room temperature, and the 100ml that adds water washs, and discards water layer, 5% sodium bicarbonate
Solution 50ml washs, and discards sodium bicarbonate water layer, is decompressed to dry get Ao Bei cholic acid dimer impurity roughization at organic layer 55 DEG C
Compound；Shellfish cholic acid dimer impurity crude compound 12g difficult to understand of gained is added 55ml petroleum ether dissolution, adds 20g 200～300
Mesh silica gel, rotation steaming is quicksand like to solid in bottle.Meanwhile, 250g 200～300 mesh silica gel is added to 500ml as fixing
In petroleum ether, it is stirring evenly and then adding into glass chromatography column, pressurizes and glass chromatography column is compacted, by the sample loading mixed extremely
Glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1, as flowing phase, collects impact point solution rotation of reducing pressure
Dry obtain 3.7g Austria shellfish cholic acid dimer impurity, yield 32%, purity 98.1%.
Embodiment 6:
Equipped with agitator, water knockout drum, thermometer there-necked flask in, add difficult to understand shellfish cholic acid 12g, normal hexane 360ml, dense
1, sulphuric acid, at 70 ± 2 DEG C, the lower reflux dewatering 6h of stirring, is cooled to room temperature, and the 100ml that adds water washs, and discards water layer, 5% bicarbonate
Sodium solution 50ml washs, and discards sodium bicarbonate water layer, is decompressed to dry get Ao Bei cholic acid dimer impurity rough at organic layer 50 DEG C
Compound；Shellfish cholic acid dimer impurity crude compound 11g difficult to understand of gained is added 55ml petroleum ether dissolution, add 20g 200～
300 mesh silica gel, rotation steaming is quicksand like to solid in bottle.Meanwhile, using 250g 200～300 mesh silica gel as fixing be added to
In 500ml petroleum ether, it is stirring evenly and then adding into glass chromatography column, pressurizes and glass chromatography column is compacted, the sample that will mix
Loading is to glass chromatography column, by ethyl acetate: the mixed solvent of petroleum ether=1:1, as flowing phase, collects impact point solution also
Decompression is spin-dried for obtaining 4.0g Austria shellfish cholic acid dimer impurity, yield 35%, purity 95%.
Through the test of each step to each embodiment, experimental data is respectively as shown in herein below:
(1) experimental data (shellfish cholic acid density=1.091 difficult to understand) of the shellfish each embodiment of cholic acid dissolution phase difficult to understand
1, the screening (normal hexane, toluene and petroleum ether) of organic solvent and its consumption
Shellfish cholic acid dissolution phase matched group difficult to understand chooses the normal hexane of 10 times, 20 times volume times amount respectively；Will shellfish cholic acid difficult to understand
It is added separately in the normal hexane of 10,20 volume times amount.
Organic at different amounts (volume times amount) of the shellfish cholic acid difficult to understand of the table one shellfish each embodiment of cholic acid dissolution phase difficult to understand
Solvent dissolves situation (reaction effect)
Table 1
| Project | Solvent species | Consumption | Reaction effect |
| Matched group | Normal hexane | 10 times | Major part is dissolved |
| Matched group | Normal hexane | 20 times | There is little granule undissolved |
| The embodiment of the present invention 1 | Normal hexane | 30 times | Molten clearly |
| The embodiment of the present invention 2 | Toluene | 30 times | Molten clearly |
| The embodiment of the present invention 3 | Petroleum ether | 30 times | Molten clearly |
From the experimental data of table one this it appears that: dissolution phase, in the experiment of matched group, the consumption of normal hexane exists
During 10 volume times amount of shellfish cholic acid difficult to understand, reaction effect be that major part is dissolved, the consumption of normal hexane shellfish cholic acid difficult to understand 20 volumes again
During amount, the least granule is undissolved；And the consumption of the organic solvent (normal hexane or toluene or petroleum ether) in each embodiment
When reaching 30 volume times amount of shellfish cholic acid difficult to understand, reaction effect be molten clearly.From this it can be concluded that in dissolution phase, used
30 volume times amount organic solvent (normal hexane or toluene or petroleum ether) when consumption is shellfish cholic acid difficult to understand.
(2) the reflux dewatering stage collects the experimental data (weight of theoretical water=input shellfish cholic acid difficult to understand of theoretical water
÷420.63÷2×18)
Table two response time, the screening of reaction temperature
Wherein, the matched group response time in reflux dewatering stage is respectively 3h and 4h.
Table 2-1: when selecting normal hexane to make solvent: the reflux dewatering stage collects the experimental data of theoretical water
| Project | Reaction temperature | Response time | Reaction effect |
| Matched group | 68-72℃ | 3h | Collect about the 73% of theoretical water |
| Matched group | 68-72℃ | 4h | Collect about the 83% of theoretical water |
| The embodiment of the present invention 1 | 68-72℃ | 6h | Collect about the 85% of theoretical water |
| The embodiment of the present invention 4 | 68-72℃ | 8h | Collect about the 85% of theoretical water |
Table 2-2: when selecting toluene to make solvent: the reflux dewatering stage collects the experimental data of theoretical water
| Project | Reaction temperature | Response time | Reaction effect |
| Matched group | 110-115℃ | 3h | Collect about the 75% of theoretical water |
| Matched group | 110-115℃ | 4h | Collect about the 85% of theoretical water |
| The embodiment of the present invention 2 | 110-115℃ | 6h | Collect about the 87% of theoretical water |
| The embodiment of the present invention 5 | 110-115℃ | 8h | Collect about the 87% of theoretical water |
Wherein, the product colour selecting toluene to prepare is deeper, in light yellow.
From the experimental data of table two this it appears that: in the reflux dewatering stage, select normal hexane when making solvent, reaction temperature
Degree for 68-72 DEG C time, along with the growth in response time, the water yield collected rises the most therewith, when reacted between reach 6 hours
Time, collect about the 85% of theoretical water, continue to extend the response time, when reacted between when reach 8 hours, collect
The water yield maintain an equal level with response time of 6 hours, be still about the 85% of theoretical water, by table 2-1 it can be seen that on reflux dewatering rank
Section, when selecting normal hexane to make solvent, when reaction temperature is 68-72 DEG C, optimum reacting time is 6 hours.
(3) experimental data of the column chromatography effect of column chromatography stage each embodiment
The fixing silica gel using 200-300 mesh mutually of column chromatography stage matched group 1, flowing employing dichloromethane mutually and methanol 1:
The mixed solution of 1；
The fixing silica gel using 200-300 mesh mutually of matched group 2, flowing uses the mixing of ethyl acetate and petroleum ether 2:1 mutually
Solution；
The fixing silica gel using 100-200 mesh mutually of matched group 3, flowing uses the mixing of ethyl acetate and petroleum ether 1:1 mutually
Solution；
The column chromatography effect of table three step 2 column chromatography stage each embodiment
Table 3: fixing phase and the selection of flowing phase in column chromatography procedure
| Project | Fixing phase | Flowing phase | Column chromatography effect |
| Matched group 1 | Silica gel 200-300 mesh | Dichloromethane: methanol=1:1 | Product cannot be gone out |
| The embodiment of the present invention 1 | Silica gel 200-300 mesh | Ethyl acetate: petroleum ether=1:1 | Product is good with magazins' layout degree, and product purity is high |
| Matched group 2 | Silica gel 200-300 mesh | Ethyl acetate: petroleum ether=2:1 | Flowing out very fast, product has with impurity and intersects |
| Matched group 3 | Silica gel 100-200 mesh | Ethyl acetate: petroleum ether=1:1 | Product has with impurity and intersects |
From the experimental data of table three this it appears that: use the present invention optimisation technique scheme, purity can be prepared
The dimer impurity reference substance of more than 95.0%.
Mass spectrum, hydrogen spectrogram and carbon measured by shellfish cholic acid dimer impurity difficult to understand prepared by each embodiment of the present invention
Spectrogram is respectively as shown in accompanying drawing 3, accompanying drawing 4 and accompanying drawing 5, it was demonstrated that the shellfish cholic acid dimer difficult to understand prepared by each embodiment of the present invention
The structural formula of impurity is as follows:
The foregoing is only embodiments of the invention, not thereby limit the scope of the claims of the present invention, every utilize this
Equivalent structure or equivalence flow process that bright description and accompanying drawing content are made convert, or are directly or indirectly used in other relevant skills
Art field, is the most in like manner included in the scope of patent protection of the present invention.
Claims (8)
1. a shellfish cholic acid dimer impurity difficult to understand, it is characterised in that: structural formula is as follows:
2. the preparation method preparing shellfish cholic acid dimer impurity difficult to understand, it is characterised in that: include the step that next coming in order are carried out:
S1: the preparation of shellfish cholic acid dimer impurity crude compound difficult to understand；It includes the sub-step that next coming in order are carried out:
S1-1: shellfish cholic acid difficult to understand is added to the organic solvent of 20～40 volume times amount, and drips catalyst；
S1-2: stir and be heated to reflux band water, insulation reaction at 65～120 DEG C, the water yield collected of weighing is about theoretical water
80% time, be cooled to 30～35 DEG C, weight ÷ 420.63 ÷ 2 × 18 of described theoretical water=input shellfish cholic acid difficult to understand；It is changed
Reaction equation is as follows:
S1-3: add the sodium bicarbonate solution of 5%, agitator treating 10 minutes, stratification；
S1-4: organic layer evaporated under reduced pressure get Ao Bei cholic acid dimer impurity crude compound；
S2: shellfish cholic acid dimer impurity crude compound column chromatography for separation difficult to understand purifies；It includes the sub-step that next coming in order are carried out:
S2-1: the shellfish cholic acid dimer impurity crude compound difficult to understand of step S1-4 gained is added 3～in the petroleum ether of 6 volume times amount
Dissolve；
S2-2: add 200～300 mesh silica gel, rotation steaming is quicksand like to solid；
S2-3: addition 200～300 mesh silica gel are as fixing to petroleum ether the most again, are stirring evenly and then adding into glass
In chromatographic column；
S2-4: sample loading step S2-3 mixed to glass chromatography column, makees with the mixed solution of ethyl acetate with petroleum ether
For flowing phase, collect impact point solution and decompression is spin-dried for obtaining shellfish cholic acid dimer impurity difficult to understand.
The preparation method of a kind of shellfish cholic acid dimer impurity difficult to understand the most as claimed in claim 2, it is characterised in that: step S1-1
Organic solvent uses one or more the arbitrary proportion mixing in normal hexane, toluene, petroleum ether.
The preparation method of a kind of shellfish cholic acid dimer impurity difficult to understand the most as claimed in claim 2, it is characterised in that: step S1-2
Reaction temperature is 68-72 DEG C or 110-115 DEG C.
The preparation method of a kind of shellfish cholic acid dimer impurity difficult to understand the most as claimed in claim 2, it is characterised in that: step S1-1 is urged
Agent uses sulphuric acid, phosphoric acid, one or more the arbitrary proportion mixing in hydrochloric acid.
The preparation method of a kind of shellfish cholic acid dimer impurity difficult to understand the most as claimed in claim 2, it is characterised in that: step S1-2
The insulation reaction time is 4～8h.
7. the preparation method of the shellfish cholic acid dimer impurity a kind of difficult to understand as described in any one of claim 2-6, it is characterised in that: step
The fixing phase 15-20 times weight of rapid S2-3 is in sample size.
The preparation method of a kind of shellfish cholic acid dimer impurity difficult to understand the most as claimed in claim 7, it is characterised in that: in step S2-4
Ethyl acetate is 1:1 with the ratio of the mixed solvent of petroleum ether.
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| CN111440223A (en) * | 2020-04-09 | 2020-07-24 | 江苏海悦康医药科技有限公司 | Preparation method of obeticholic acid impurity |
| WO2023048453A1 (en) * | 2021-09-27 | 2023-03-30 | (주) 테라베스트 | Nanoparticles comprising drug dimers, and use thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017170854A1 (en) * | 2016-03-31 | 2017-10-05 | 大日本住友製薬株式会社 | Film-coated tablet having high chemical stability of active ingredient |
| US11331273B2 (en) | 2016-03-31 | 2022-05-17 | Intercept Pharmaceuticals, Inc. | Film-coated tablet having high chemical stability of active ingredient |
| CN111440223A (en) * | 2020-04-09 | 2020-07-24 | 江苏海悦康医药科技有限公司 | Preparation method of obeticholic acid impurity |
| WO2023048453A1 (en) * | 2021-09-27 | 2023-03-30 | (주) 테라베스트 | Nanoparticles comprising drug dimers, and use thereof |
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