CN108218942A - A kind of preparation method of 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid - Google Patents
A kind of preparation method of 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid Download PDFInfo
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- CN108218942A CN108218942A CN201711360094.3A CN201711360094A CN108218942A CN 108218942 A CN108218942 A CN 108218942A CN 201711360094 A CN201711360094 A CN 201711360094A CN 108218942 A CN108218942 A CN 108218942A
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- 0 C[C@](CC*)C(CC1)[C@@](C)(CC[C@@]2[C@@](C)(CC[C@](C3)O)N3C3)[C@@]1[C@]2(*)[C@]3O Chemical compound C[C@](CC*)C(CC1)[C@@](C)(CC[C@@]2[C@@](C)(CC[C@](C3)O)N3C3)[C@@]1[C@]2(*)[C@]3O 0.000 description 2
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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 discloses a kind of new methods for preparing 3 α hydroxyls of high-purity, 7 oxo, 5 β cholanic acids, this method is using sodium hypochlorite cheap and easy to get as oxidant, aoxidize chenodeoxycholic acid, barium salt is first made in purification, barium is sloughed again, it is finally recrystallized with first alcohol and water, 3 α hydroxyls of high-purity, 7 oxo, 5 β cholanic acids is made.The features such as preparation method of the present invention is mild, safe with reaction condition, easy to operate, controllable, at low cost, high income, low stain, has wide development and application prospect.
Description
Technical field
The invention belongs to technical field of medicine synthesis.More particularly to a kind of preparation of -5 β of 3 Alpha-hydroxy -7- oxos-cholanic acid
Method.
Background technology
Ursodesoxycholic acid (its structure is as shown in formula I) can promote the secretion of endogenous bile acid, protect liver plasma membrane；Dissolving
Cholesterol calculus；And with immunoregulation effect.Medically for increasing bile acid secretion, and change bile component, drop
Low bile cholesterol and cholesterol ester, the cholesterol be conducive in gall stone gradually dissolve.
Artificial synthesized ursodesoxycholic acid becomes the developing direction of modern medicine, has important practical significance.
Chenodeoxycholic acid (its structure is as shown in formula II) is a kind of natural cholic acid, is primarily present in people and ox, goose, chicken, pig
In the bile for waiting animals.Wherein in chicken bile, chenodeoxycholic acid is about 80% so that the extraction of chenodeoxycholic acid, which has, stablizes, is honest and clean
The raw material of valency.
Chenodeoxycholic acid and ursodesoxycholic acid structure are only that the chirality of 7 hydroxyls is different, therefore one in chemical synthesis
Synthetic route is using chenodeoxycholic acid as starting material, and 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid is obtained, then also through peroxidating
Original obtains ursodesoxycholic acid.Since the 1980s, people begin to study emphatically can be used for the reaction it is mild, safe,
Highly effective oxidizer and reducing agent.
Common chenodeoxycholic acid oxidation has：(1) using acetone, water as medium N- bromo-succinimides (NBS) oxygen
Change method.The major defect of the method is that organic wastewater is more, and is difficult to control oxidation reaction terminal.(2) electrochemical oxidation process.The method
Major defect be the electrolytic cell for needing Special Category, electrolytic process is influenced by many factors, such as voltage, electric current, electrode kind
Class etc., and its industrial wastewater is more, high energy consumption.(3) sodium hypochlorite oxidization.The major defect of the method is that hypochlorous acid receives aqueous solution
It is poor with the intermiscibility of raw material and organic solvent, it is unfavorable for the progress of reaction.(4) Organic Chromium salt oxidizing agent oxidizing process.The method
Major defect be that the reaction heat effect is big, poor selectivity.
The present invention is directed to the shortcomings that sodium hypochlorite oxidization, and suitable catalysts and solvents is selected to aoxidize chenodeoxycholic
Acid, while 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid in order to obtain, are optimized the post processing of crude product.
Invention content
For the above situation, the invention discloses a kind of new sides for preparing 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid
Method, for this method using sodium hypochlorite cheap and easy to get as oxidant, barium salt is first made in oxidation chenodeoxycholic acid in purification, then
Barium is sloughed, is finally recrystallized with first alcohol and water, 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid is made.
Specifically, it includes the following steps：
(1) according to chenodeoxycholic acid：Alcohols solvent：Acid catalyst=1:5~10:1~4 mass ratio, to reaction vessel
Middle addition chenodeoxycholic acid, alcohols solvent and acid catalyst are stirred at room temperature to being completely dissolved, and kept for 0.5~1 hour；
(2) after being cooled to -50~0 DEG C, according to chenodeoxycholic acid：10% sodium hypochlorite=1:1~3 mass ratio is added dropwise
Liquor natrii hypochloritis after being added dropwise, reacts 0.5~5 hour in less than -10 DEG C；
(3) after completion of the reaction, filter, wash, being dried to obtain the crude product of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid；
(4) crude product of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid is dissolved in ethanol solution, NaOH aqueous solutions is added to make pH value of solution
=7~10, BaCl is added dropwise2Or CaCl2Aqueous solution, is evaporated off part ethyl alcohol, and cool down crystallization, filtering, obtain 3 Alpha-hydroxy -7- oxos -
The barium salt or calcium salt of 5 β-cholanic acid；
(5) barium salt of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid is suspended in water, adds sodium carbonate agitating and heating reflux 0.5
~5 hours, dilute hydrochloric acid (10%, v/v) was added dropwise to pH=1~4 in cooling, and filtering, washing, drying obtain solid, use methanol：Water
=1:1~3 (v/v) is recrystallized, and obtains purity up to 99.6% 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid.
Preferably, in above-mentioned preparation method step 1, chenodeoxycholic acid purity is more than 98%.
Preferably, in above-mentioned preparation method step 1, chenodeoxycholic acid：Alcohols solvent：Acid catalyst=1:5~6:3
~4 mass ratio.
Preferably, in above-mentioned preparation method step 1, the acid catalyst is acetic acid, formic acid, tartaric acid, citric acid
In any one, preferred acetic acid.
Preferably, in above-mentioned preparation method step 2, the chenodeoxycholic acid, 10% sodium hypochlorite mass ratio be
1:2。
Preferably, in above-mentioned preparation method step 2, system temperature control during the dropwise addition -10 DEG C with
Under, and kept for 0.5 hour.
Preferably, in above-mentioned preparation method step 4, the dropwise addition BaCl2、CaCl2Any one in aqueous solution,
It is preferred that BaCl2Aqueous solution.
Preferably, in above-mentioned preparation method step 5, the dropwise addition dilute hydrochloric acid (10%, v/v) is excellent to pH=1~4
Select pH=2~3.
Preferably, in above-mentioned preparation method step 5, solvent volume ratio preferably 1 when the methanol, water recrystallize:1.
Description of the drawings
Fig. 1 is the reaction side that 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid is used to prepare in the embodiment of the present invention 1
Formula.
Specific embodiment
Embodiment 1：The preparation of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid
At room temperature, chenodeoxycholic acid (100g, 98%) is added in into three-necked flask, adds methanol (500mL) and acetic acid
(350mL) after stirring and dissolving, is refrigerated to -15 DEG C, NaClO solution (200g, 10%) is added dropwise.Drop finishes, and stirs 30min, TLC prisons
The reaction was complete for control.NaHSO is added dropwise3(5%, 200mL) aqueous solution stirs 1h, stops cooling.Filtering, water (2*500mL) are washed, drum
It air-dries dry (70 DEG C, 18h), obtains off-white powder (93.20g), purity 92%.
Embodiment 2：The preparation of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid
At room temperature, chenodeoxycholic acid (100g, 98%) is added in into three-necked flask, adds methanol (500mL) and acetic acid
(350mL) after stirring and dissolving, is refrigerated to 0 DEG C, NaClO solution (200g, 10%) is added dropwise.Drop finishes, and stirs 30min, TLC monitoring
The reaction was complete.NaHSO is added dropwise3(5%, 200mL) aqueous solution stirs 1h, stops cooling.Filtering, water (2*500mL) are washed, air blast
Dry (70 DEG C, 18h), obtain off-white powder (85g), purity 82%.
Embodiment 3：The preparation of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid
At room temperature, chenodeoxycholic acid (100g, 98%) is added in into three-necked flask, adds methanol (500mL) and formic acid
(350mL) after stirring and dissolving, is refrigerated to -15 DEG C, NaClO solution (200g, 10%) is added dropwise.Drop finishes, and stirs 30min, TLC prisons
The reaction was complete for control.NaHSO is added dropwise3(5%, 200mL) aqueous solution stirs 1h, stops cooling.Filtering, water (2*500mL) are washed, drum
It air-dries dry (70 DEG C, 18h), obtains off-white powder (87g), purity 81%.
Embodiment 4：The preparation of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid
At room temperature, chenodeoxycholic acid (100g, 98%) is added in into three-necked flask, adds methanol (500mL) and winestone
Sour (18g) after stirring and dissolving, is refrigerated to -15 DEG C, NaClO solution (200g, 10%) is added dropwise.Drop finishes, and stirs 30min, TLC prisons
The reaction was complete for control.NaHSO is added dropwise3(5%, 200mL) aqueous solution stirs 1h, stops cooling.Filtering, water (2*500mL) are washed, drum
It air-dries dry (70 DEG C, 18h), obtains off-white powder (90g), purity 88%.
Embodiment 5：The purifying of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid
At room temperature, 3-5 β of Alpha-hydroxy-7- oxos-cholane acid crude (93.20g) is suspended in 95% ethyl alcohol (900mL),
NaOH aqueous solutions (10mol/L) are added with stirring to pH=8~9, suspension becomes solution.Add 5% activated carbon, be heated to reflux
30min, filtering, filtrate continue agitating and heating reflux 30min.BaCl is added dropwise2(10%, 900mL) aqueous solution.Drop, which finishes, to be stirred at reflux
1h distills and a little crystal grain is hung on ethyl alcohol to bottle wall, stops heating.The lower Temperature fall crystallization of stirring, overnight.Filtering, 50% ethyl alcohol
Aqueous solution (2*200mL) washs filter cake, forced air drying (70 DEG C, 18h).Dried barium salt is suspended in water (1000mL),
Add sodium carbonate (18g), agitating and heating reflux 30min, filtering stands and is cooled to room temperature.At room temperature, dilute salt is added dropwise while stirring
Sour (10%, v/v) is filtered, water (2*200mL) is washed, forced air drying (70 DEG C, 18h) to pH=2~3.Dry product first
Alcohol and water (1000mL, 1:1, v/v) 0.5h is heated to reflux, is filtered while hot.Filtrate reheats reflux 0.5h, is stored at room temperature, mistake
Filter, water (2*300mL) are washed, and forced air drying (70 DEG C, 6h) obtains white crystalline product (51.2g), yield 51.5%, purity
99.6%.
Embodiment 6：The purifying of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid
At room temperature, 3-5 β of Alpha-hydroxy-7- oxos-cholane acid crude (93.20g) is suspended in 95% ethyl alcohol (900mL),
NaOH aqueous solutions (10mol/L) are added with stirring to pH=8~9, suspension becomes solution.Add 5% activated carbon, be heated to reflux
30min, filtering, filtrate continue agitating and heating reflux 30min.CaCl is added dropwise2(10%, 900mL) aqueous solution.Drop, which finishes, to be stirred at reflux
1h distills and a little crystal grain is hung on ethyl alcohol to bottle wall, stops heating.The lower Temperature fall crystallization of stirring, overnight.Filtering, 50% ethyl alcohol
Aqueous solution (2*200mL) washs filter cake, forced air drying (70 DEG C, 18h).Dried barium salt is suspended in water (1000mL),
Add sodium carbonate (18g), agitating and heating reflux 30min, filtering stands and is cooled to room temperature.At room temperature, dilute salt is added dropwise while stirring
Sour (10%, v/v) is filtered, water (2*200mL) is washed, forced air drying (70 DEG C, 18h) to pH=2~3.Dry product first
Alcohol and water (1000mL, 1:1, v/v) 0.5h is heated to reflux, is filtered while hot.Filtrate reheats reflux 0.5h, is stored at room temperature, mistake
Filter, water (2*300mL) are washed, and forced air drying (70 DEG C, 6h) obtains white crystalline product (38.1g), yield 38.3%, purity
98.1%.
Claims (8)
1. a kind of new method for preparing 3-5 β of Alpha-hydroxy-7- oxos of high-purity-cholanic acid, includes the following steps：
（1）According to chenodeoxycholic acid：Alcohols solvent：Acid catalyst=1:5~10:1 ~ 4 mass ratio, goose is added in into reaction vessel
Deoxycholic aicd, alcohols solvent and acid catalyst are stirred at room temperature to being completely dissolved, and are kept for 0.5 ~ 1 hour；
（2）After being cooled to -50 ~ 0 DEG C, according to chenodeoxycholic acid：10% sodium hypochlorite=1:Sodium hypochlorite is added dropwise in 1 ~ 3 mass ratio
Solution after being added dropwise, reacts 0.5 ~ 5 hour in less than -10 DEG C；
（3）After completion of the reaction, filter, wash, being dried to obtain the crude product of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid；
（4）The crude product of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid is dissolved in ethanol solution, add NaOH aqueous solutions make pH value of solution=7 ~
10, BaCl is added dropwise2Or CaCl2Part ethyl alcohol is evaporated off in aqueous solution, and cool down crystallization, and filtering obtains 3-5 β of Alpha-hydroxy-7- oxos-courage
The barium salt or calcium salt of alkanoic acid；
（5）The barium salt of 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid is suspended in water, adds sodium carbonate agitating and heating reflux 0.5 ~ 5
Hour, dilute hydrochloric acid is added dropwise in cooling（10%, v/v）To pH=1 ~ 4, filtering, washing, drying obtain solid, use methanol：Water=1:1~3
(v/v) it recrystallizes, obtains purity up to 99.6% 3-5 β of Alpha-hydroxy-7- oxos-cholanic acid.
2. the preparation method according to claim 1, it is characterised in that：Step（1）In, chenodeoxycholic acid：Alcohols solvent：
Acid catalyst=1:5~6:3 ~ 4 mass ratio.
3. the preparation method according to claim 1, it is characterised in that：Step（1）In, the acid catalyst is acetic acid, first
Any one in acid, tartaric acid, citric acid, preferably acetic acid.
4. the preparation method according to claim 1, it is characterised in that：Step（2）In, the chenodeoxycholic acid, 10% time
The mass ratio of sodium chlorate is 1:2.
5. the preparation method according to claim 1, it is characterised in that：Step（2）In, the system during the dropwise addition
Temperature control is at -10 DEG C hereinafter, and being kept for 0.5 hour.
6. the preparation method according to claim 1, it is characterised in that：Step（4）In, the dropwise addition BaCl2、CaCl2Water
Any one in solution, preferably BaCl2Aqueous solution.
7. the preparation method according to claim 1, it is characterised in that：Step（5）In, the dropwise addition dilute hydrochloric acid（10%, v/
v）To pH=1 ~ 4, preferably pH=2 ~ 3.
8. the preparation method according to claim 1, it is characterised in that：Step（5）In, it is described to be recrystallized with first alcohol and water
When, solvent volume ratio preferably 1:1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233961A (en) * | 2020-04-14 | 2020-06-05 | 苏州敬业医药化工有限公司 | Preparation method of ursodeoxycholic acid |
| CN111455400A (en) * | 2020-05-28 | 2020-07-28 | 福建省南仹生物科技有限公司 | 7-ketolithocholic acid product and preparation method thereof |
| CN115806578A (en) * | 2021-09-15 | 2023-03-17 | 成都百泉生物医药科技有限公司 | Nor-UDCA intermediate, nor-UDCA and preparation method of Nor-UDCA intermediate |
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| CN1869044A (en) * | 2006-06-09 | 2006-11-29 | 沈阳化工学院 | Separation purification preparation method of chenodeoxycholic acid in pig's bile |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111233961A (en) * | 2020-04-14 | 2020-06-05 | 苏州敬业医药化工有限公司 | Preparation method of ursodeoxycholic acid |
| CN111455400A (en) * | 2020-05-28 | 2020-07-28 | 福建省南仹生物科技有限公司 | 7-ketolithocholic acid product and preparation method thereof |
| CN111455400B (en) * | 2020-05-28 | 2021-07-23 | 福建省南仹生物科技有限公司 | 7-ketolithocholic acid product and preparation method thereof |
| CN115806578A (en) * | 2021-09-15 | 2023-03-17 | 成都百泉生物医药科技有限公司 | Nor-UDCA intermediate, nor-UDCA and preparation method of Nor-UDCA intermediate |
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