CN108822177A - A kind of preparation method of Austria's shellfish cholic acid intermediate - Google Patents
A kind of preparation method of Austria's shellfish cholic acid intermediate Download PDFInfo
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- CN108822177A CN108822177A CN201811016651.4A CN201811016651A CN108822177A CN 108822177 A CN108822177 A CN 108822177A CN 201811016651 A CN201811016651 A CN 201811016651A CN 108822177 A CN108822177 A CN 108822177A
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- cholic acid
- shellfish cholic
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- acid intermediate
- reaction temperature
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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
Disclosed by the invention is a kind of preparation method of shellfish cholic acid intermediate difficult to understand, solves when preparing the intermediate using chenodeoxycholic acid in the prior art, usually occurs the case where 3 hydroxyls of simultaneous oxidation in oxidation process, the problem for causing yield and purity not high.The present invention includes step 1, chenodeoxycholic acid is dissolved in methanol solvate, mixed solution is made, and sodium bromide is added into mixed solution and is configured to electrolysis system；Electrolysis system is added in the undivided cell of graphite electrode by step 2, and the 10~12h that is persistently powered obtains oxidation product, and electric current is 3~5A in undivided cell, and reaction temperature is -5~5 DEG C；Dilution heat of sulfuric acid is added dropwise into oxidation product for step 3, reacts 30min or more, and reaction temperature is 20~60 DEG C；The gas that reaction generates, which extend into react in NaOH solution with NaOH solution, is made sodium bromide；Shellfish cholic acid intermediate difficult to understand is made in step 4, purification.The advantages such as the present invention has yield and purity is high, and production cost is low.
Description
Technical field
The present invention relates to a kind of chemical synthesis process, and in particular to be a kind of shellfish cholic acid intermediate difficult to understand preparation method.
Background technique
Shellfish cholic acid category farnesoid X receptor agonist difficult to understand inhibits cytochromes 7A1 by activating farnesoid X receptor indirectly
(CYP7A1) gene expression.Since CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, shellfish cholic acid difficult to understand can inhibit cholic acid
Synthesis, for treating primary biliary cirrhosis (PBC) and non-alcohol fatty liver.Shellfish cholic acid difficult to understand as PBC two
Line therapeutic agent responds insufficient or does not tolerate patient for ursodesoxycholic acid, is expected to replace the treatment status of ursodesoxycholic acid.It is difficult to understand
Shellfish cholic acid is researched and developed successfully by Intercept drugmaker of the U.S., is first over 20 years research and develop for treating cholestatic liver
The drug of disease, market potential are huge.
For synthesizing 3-5 β of Alpha-hydroxy-7- ketone group of an intermediate-cholanic acid of shellfish cholic acid difficult to understand, as shown in formula one, usually
It is to be prepared using chenodeoxycholic acid as raw material.
Formula one：
When preparing the intermediate using chenodeoxycholic acid, usually occur 3 hydroxyls of simultaneous oxidation in oxidation process
Situation, the problem for causing yield and purity not high.
Summary of the invention
When it is an object of the invention to solve to prepare the intermediate using chenodeoxycholic acid in the prior art, in oxidation process
In usually there is the case where 3 hydroxyls of simultaneous oxidation, the problem for causing yield and purity not high；One to solve the above problems is provided
The preparation method of kind shellfish cholic acid intermediate difficult to understand.
In order to achieve the above objectives, technical scheme is as follows：
A kind of preparation method of Austria's shellfish cholic acid intermediate, including：
Chenodeoxycholic acid is dissolved in methanol solvate and mixed solution is made by step 1, and sodium bromide is added into mixed solution
It is configured to electrolysis system；
Electrolysis system is added in the undivided cell of graphite electrode by step 2, and the 10~12h that is persistently powered obtains oxygen
Change product, electric current is 3~5A in undivided cell, and reaction temperature is -5~5 DEG C；
Dilution heat of sulfuric acid is added dropwise into oxidation product for step 3, reacts 30min or more, and reaction temperature is 20~60 DEG C；Instead
The gas that should be generated, which extend into react in NaOH solution with NaOH solution, is made sodium bromide；
Shellfish cholic acid intermediate difficult to understand is made in step 4, purification.
By above-mentioned setting, it can effectively realize that 7 hydroxyls individually aoxidize completely, 3 hydroxyls will not be aoxidized, reach selectivity
The purpose of oxidation, improves purity and yield, effect are very significant.
The present invention can not only achieve the purpose that selective oxidation, moreover, the bromo element in the present invention can repeat to make
With, that is, low-boiling hydrogen bromide can effectively be displaced using high boiling dilution heat of sulfuric acid, the hydrogen bromide displaced is added
Into NaOH solution, raw material sodium bromide can also be made again by drying, and then achieve the purpose that recycling, production cost
It is lower.
Further, the molar ratio of the sodium bromide in the step 2 and the dilute sulfuric acid of step 3 kind is 2.1~2.3 ︰ 1.Institute
The reaction temperature for stating step 2 is 0~5 DEG C.The reaction temperature of the step 3 is 40~50 DEG C.
In order to reach better purity, the method for the purification is：Solution after step 3 reaction is filtered, with pure water,
Liquid separation, dry, finished product is made in reduced pressure.
By above-mentioned setting, better yield and purity can be effectively obtained, yield can achieve 95% or more, and purity can
To reach 98% or more, effect is very significant.
Compared with prior art, the present invention having the following advantages that and beneficial effect：
1, the present invention can effectively realize that 7 hydroxyls individually aoxidize completely, will not aoxidize 3 hydroxyls, reach selective oxidation
Purpose；
2, the bromo element in the present invention may be reused, that is, can effectively be replaced using high boiling dilution heat of sulfuric acid
The hydrogen bromide displaced is added in NaOH solution by low-boiling hydrogen bromide out, and raw material can also be made again by drying
Sodium bromide, and then achieve the purpose that recycling, production cost is lower；
3, yield of the invention can achieve 90% or more, and purity can achieve 98% or more, and effect is very significant.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail, embodiments of the present invention are not limited thereto.
Embodiment 1
A kind of preparation method of Austria's shellfish cholic acid intermediate, including：
100g chenodeoxycholic acid is dissolved in 1000mL methanol solvate and mixed solution is made, into mixed solution by step 1
Sodium bromide 1.03g is added and is configured to electrolysis system；
Electrolysis system is added in the undivided cell of graphite electrode by step 2, and persistently energization 12h obtains oxidation and produces
Object, electric current is 4A in undivided cell, and reaction temperature is 2 DEG C；
Step 3, the dilution heat of sulfuric acid that dropwise addition 7.19g mass fraction is 30% into oxidation product, reaction time 1h,
Reaction temperature is 45 DEG C；The gas that reaction generates is passed into the bottom end of NaOH solution, reacts gas with NaOH solution and bromine is made
Change sodium solution, raw material sodium bromide is made after sodium bromide solution is dry；
Shellfish cholic acid intermediate difficult to understand described in formula one is made in step 4, purification.
Above-mentioned finished product is detected, testing result is shown：The yield of finished product has reached 97%, and purity has reached 99%,
Effect is very significant.
Embodiment 2
The present embodiment the difference from embodiment 1 is that, the response parameter of step is different in the present embodiment, and specific setting is such as
Under：
200g chenodeoxycholic acid is dissolved in 1500mL methanol solvate and mixed solution is made, into mixed solution by step 1
Sodium bromide 2.10g is added and is configured to electrolysis system；
Electrolysis system is added in the undivided cell of graphite electrode by step 2, and persistently energization 12h obtains oxidation and produces
Object, electric current is 3A in undivided cell, and reaction temperature is 5 DEG C；
Step 3, the dilution heat of sulfuric acid that dropwise addition 15.42g mass fraction is 30% into oxidation product, reaction time 1h,
Reaction temperature is 40 DEG C；
Step 4 filters, and with pure water, liquid separation is dry, and finished product described in formula one is made in reduced pressure；
Formula one：
Above-mentioned finished product is detected, testing result is shown：The yield of finished product has reached 95%, and purity has reached 98%.
Embodiment 3
The present embodiment the difference from embodiment 1 is that, the response parameter of step is different in the present embodiment, and specific setting is such as
Under：
100g chenodeoxycholic acid is dissolved in 1000mL methanol solvate and mixed solution is made, into mixed solution by step 1
Sodium bromide 1.10g is added and is configured to electrolysis system；
Electrolysis system is added in the undivided cell of graphite electrode by step 2, and persistently energization 12h obtains oxidation and produces
Object, electric current is 5A in undivided cell, and reaction temperature is 0 DEG C；
Step 3, the dilution heat of sulfuric acid that dropwise addition 9.42g mass fraction is 30% into oxidation product, reaction time 1h,
Reaction temperature is 35 DEG C；
Step 4 filters, and with pure water, liquid separation is dry, and finished product described in formula one is made in reduced pressure；
Formula one：
Above-mentioned finished product is detected, testing result is shown：The yield of finished product has reached 91%, and purity has reached 95%.
Above-described embodiment is merely a preferred embodiment of the present invention, and it is not intended to limit the protection scope of the present invention, as long as using
Design principle of the invention, and the non-creative variation worked and made is carried out on this basis, it should belong to of the invention
Within protection scope.
Claims (5)
1. a kind of preparation method of Austria's shellfish cholic acid intermediate, including：
Chenodeoxycholic acid is dissolved in methanol solvate and mixed solution is made by step 1, and sodium bromide configuration is added into mixed solution
At electrolysis system；
Electrolysis system is added in the undivided cell of graphite electrode by step 2, and the 10~12h that is persistently powered obtains oxidation and produces
Object, electric current is 3~5A in undivided cell, and reaction temperature is -5~5 DEG C；
Dilution heat of sulfuric acid is added dropwise into oxidation product for step 3, reacts 30min or more, and reaction temperature is 20~60 DEG C；Reaction produces
Raw gas, which extend into react in NaOH solution with NaOH solution, is made sodium bromide；
Shellfish cholic acid intermediate difficult to understand is made in step 4, purification.
2. a kind of preparation method of shellfish cholic acid intermediate difficult to understand according to claim 1, which is characterized in that in the step 2
Sodium bromide and step 3 kind dilute sulfuric acid molar ratio be 2.1~2.3 ︰ 1.
3. a kind of preparation method of shellfish cholic acid intermediate difficult to understand according to claim 1, which is characterized in that the step 2
Reaction temperature is 0~5 DEG C.
4. a kind of preparation method of shellfish cholic acid intermediate difficult to understand according to claim 2 or 3, which is characterized in that the step
Three reaction temperature is 40~50 DEG C.
5. a kind of preparation method of shellfish cholic acid intermediate difficult to understand according to claim 1, which is characterized in that the side of the purification
Method is：Solution after step 3 is reacted is filtered, with pure water, liquid separation is dry, and finished product is made in reduced pressure.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811016651.4A CN108822177A (en) | 2018-09-03 | 2018-09-03 | A kind of preparation method of Austria's shellfish cholic acid intermediate |
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| CN201811016651.4A CN108822177A (en) | 2018-09-03 | 2018-09-03 | A kind of preparation method of Austria's shellfish cholic acid intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1912192A (en) * | 2006-07-27 | 2007-02-14 | 华东理工大学 | Preparation method of 7-keto lithocholic acid |
| CN106916196A (en) * | 2017-03-30 | 2017-07-04 | 成都绿林科技有限公司 | A kind of synthetic method of shellfish cholic acid intermediate difficult to understand |
-
2018
- 2018-09-03 CN CN201811016651.4A patent/CN108822177A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1912192A (en) * | 2006-07-27 | 2007-02-14 | 华东理工大学 | Preparation method of 7-keto lithocholic acid |
| CN106916196A (en) * | 2017-03-30 | 2017-07-04 | 成都绿林科技有限公司 | A kind of synthetic method of shellfish cholic acid intermediate difficult to understand |
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Application publication date: 20181116 |
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