CN108676051A - A method of using chenodeoxycholic acid as Material synthesis lithocholic acid - Google Patents
A method of using chenodeoxycholic acid as Material synthesis lithocholic acid Download PDFInfo
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- CN108676051A CN108676051A CN201810856674.XA CN201810856674A CN108676051A CN 108676051 A CN108676051 A CN 108676051A CN 201810856674 A CN201810856674 A CN 201810856674A CN 108676051 A CN108676051 A CN 108676051A
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- synthetic method
- acid
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- lithocholic acid
- reducing agent
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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 belongs to organic chemistry fileds, are related to a kind of synthetic method of lithocholic acid, and in particular to a method of using chenodeoxycholic acid as Material synthesis lithocholic acid.The synthetic method of the present invention occurs to obtain lithocholic acid at hydrazone reaction, then through reduction reaction after oxidized using chenodeoxycholic acid as raw material.Starting material is cheap and easy to get in the synthetic method of the present invention, and synthesis step is short, is a completely new synthetic route；Its required reagent is easy to preserve, is safe and non-toxic, and reaction condition is mild, post-processing is simple, and efficiency and total recovery are high, are suitable for industrialized production.
Description
Technical field
The invention belongs to organic chemistry fileds, are related to a kind of synthetic method of lithocholic acid, and in particular to one kind is deoxygenated with goose
Cholic acid is the method for Material synthesis lithocholic acid.
Background technology
Lithocholic acid also known as 3-5 β of Alpha-hydroxy-cholanic acid are a kind of secondary bile acids, shown in structure such as formula (i).Study table
Alum cholic acid and its derivative have a variety of physiological activity.Protein tyrosine phosphate 1B (PTP1B) is insulin in human body
The negative regulatory factor of signal is the potential target for treating diabetes, and lithocholic acid can obviously inhibit the activity of PTP1B, and lithocholic acid can
Neuroblastoma cell is killed with selectivity, and to normal cell almost without toxicity (Oncotarget2 (10) (2011) 761-
782)；Lithocholic acid amino acid derivativges are EphA2 antagonists, have blood vessel formation against function, can be used as novel antitumor examination
Agent.
Lithocholic acid mainly extracts from the bile of animal, and artificial synthesized route is rarely reported, therefore develops novelty, a reality
Synthetic route is necessary.
The synthesis report in relation to lithocholic acid is seldom at present.Report following synthetic route within 1940：With deoxycholic acid methyl esters
For starting material, it is oxidized to carbonyl, 12- carbonyls and semicarbazides through 3 α-OH selective protections, 12 α-OH and is condensed and restores, hydrolyzes
And etc., synthesize lithocholic acid, total recovery 50%.
Metal sodium reduction is used in final step in the synthetic route, and danger coefficient is larger, is unfavorable for industrializing, and total recovery
It is relatively low.
A nineteen forty-six other document report is using deoxycholic acid as original raw material, through 24- esterifications, selective protection 3
α-OH, 3 α-OH protecting groups of 12 α-OH and then selectively removing, hydrolysis, hydrogenation are protected again, altogether 7 steps reaction synthesis lithocholic acid
(Journal of Biological Chemistry,1946,162,555-563).Reaction route is as follows：
The synthetic route step is partially long, and total recovery is relatively low, and expensive PtO has been used in final step reaction2, limitation
Its industrialized production.
Patent of invention in 2017 discloses one kind using chenodeoxycholic acid as starting material, by 7 α-OH selectivity oxygen
Change, the method for Huang Min-lon reduction synthesis lithocholic acid.Reaction route is as follows：
The synthetic route total recovery is relatively low, and second step reaction required temperature is high, efficiency is low, and required reagent hydration hydrazine is high poison
Class compound is unfavorable for industrialized production.
Therefore it needs to develop that a kind of synthesis step is short, required reagent safety is nontoxic, and post-processes that simple, total recovery is high, fit
A kind of synthetic method of lithocholic acid used in industrial production.
Invention content
In view of this, the purpose of the present invention is to provide a kind of synthetic method of lithocholic acid, the synthetic method starting material
Chenodeoxycholic acid is cheap and easy to get, and required reagent safety is nontoxic, and synthesis step is short, and post-processing is simple, and total recovery is high, is suitable for industry
Metaplasia is produced.
To achieve the above object, the technical scheme is that：
A kind of synthetic method of lithocholic acid, includes the following steps：
1) using compound shown in Formulas I as raw material, occur to obtain formula at hydrazone reaction in a solvent with tolysulfonyl hydrazine compound
Compound shown in Π；
2) compound shown in formula Π reacts with reducing agent in a solvent, obtains compound shown in formula Ш；
Formulas I compound represented can be obtained by chenodeoxycholic acid oxidase according to a conventional method.
Synthetic method starting material provided by the invention is cheap and easy to get, and synthesis step is short, is a completely new synthetic route,
It will first occur at hydrazone reaction, then through reduction reaction with unifor after starting material chenodeoxycholic acid oxidase cheap and easy to get
Lithocholic acid is obtained, required reagent safety is nontoxic in method of the invention, and reaction condition is mild, post-processing is simple, and total recovery is high, fits
For industrialized production.
Further, compound and the molar ratio of unifor shown in Formulas I are 1 in step 1):1~5.
As a preferred embodiment, the molar ratio of compound unifor shown in Formulas I is 1 in step 1):1~3.
As a preferred embodiment, the molar ratio of compound and unifor shown in Formulas I is 1 in step 1)：2.
Further, the temperature reacted in step 1) is 0~50 DEG C, the reaction time is 1~for 24 hours.
As a preferred embodiment, reaction temperature is room temperature, reaction time 12h in step 1).
Further, compound and the molar ratio of reducing agent shown in Π are 1 in step 2):1~20.
As a preferred embodiment, the molar ratio of compound and reducing agent shown in Π is 1 in step 2):1~15.
As a preferred embodiment, the molar ratio of compound and reducing agent shown in Π is 1 in step 2):10.
Further, reducing agent is sodium borohydride, potassium borohydride, zinc borohydride, sodium cyanoborohydride, triacetyl in step 2)
Oxygroup sodium borohydride, lithium aluminium hydride reduction it is one or more.
Further, reducing agent is sodium borohydride in step 2).
To stablize under sodium borohydride normal temperature and pressure, there is stronger selective reduction, relatively other reducing agents are cheap and easy to get,
Industrially can largely it provide.
Further, the temperature reacted in step 2) is 0~50 DEG C.
As a preferred embodiment, the temperature reacted in step 2) is 15~30 DEG C.
As a preferred embodiment, the temperature reacted in step 2) is 25 DEG C.
Further, step 1) and the one or two that solvent in step 2) is acetic acid, propionic acid.
As a preferred embodiment, step 1) is acetic acid with solvent in step 2).
The beneficial effects of the present invention are：
1) provided by the invention using chenodeoxycholic acid as the method for Material synthesis lithocholic acid, starting material is cheap and easy to get, closes
It is short at step, it is a completely new synthetic route, post-processing is simple, and total recovery is high, is suitable for industrialized production.
2) reagent needed for being reacted in synthetic method of the invention is easy to preserve, is safe and non-toxic.
3) reaction temperature is low in synthetic method of the invention, and efficiency is high, is conducive to industrialized production.
Specific implementation mode
It detailed description of a preferred embodiment of the present invention will be given below.The reality of actual conditions is not specified in preferred embodiment
Proved recipe method, usually according to normal condition, illustrated embodiment are but not to be to preferably be illustrated to present disclosure
Present disclosure is only limitted to illustrated embodiment.So those skilled in the art according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
Embodiment 1
1) synthesis of formula Π compounds：
7.8g (0.02mol) compound of formula I is dissolved in 150mL acetic acid, and 7.5g (0.04mol) tolysulfonyl is added
Hydrazine is reacted at room temperature 12 hours, is poured into cold water, obtained solid product is extracted with ethyl acetate.Organic phase 5%Na2CO3It is molten
Liquid washs, and is washed with water and washs to neutrality, ethyl acetate layer is concentrated to dryness, residue recrystallizing methanol.Obtain formula Π compounds
10.1g, yield 90%.
2) synthesis of formula Ш compounds：
5.6g (0.01mol) formula Π compounds are dissolved in the acetic acid of 100mL at room temperature, are controlled interior temperature and are no more than 60 DEG C
3.78g (0.1mol) sodium borohydride is added portionwise, is stirred at room temperature 6 hours and reacts.Obtained mixture pours into trash ice, mistake
Filter.Obtained solid is washed with water to neutrality, dry to obtain lithocholic acid 3.46g shown in formula Ш, yield 92% with recrystallizing methanol.
Embodiment 2
1) synthesis of formula Π compounds：
7.8g (0.02mol) compound of formula I is dissolved in 150mL acetic acid, and 3.75g (0.02mol) tolysulfonyl is added
Hydrazine reacts at room temperature 18 hours.It pours into cold water, obtained semi-solid product is extracted with ethyl acetate.Organic phase 5%Na2CO3
Solution washs, and is washed with water and washs to neutrality, last evaporation drying.Silica gel column purification on oiliness residue obtains formula Π compounds
8.4g, yield 75%.
2) synthesis of formula Ш compounds：
5.6g (0.01mol) formula Π compounds are dissolved in (at room temperature) in the acetic acid of 100mL, are controlled interior temperature and are no more than 60
DEG C, it is gradually added into 1.89g (0.05mol) sodium borohydride in batches.It is stirred at room temperature 8 hours and reacts.Obtained mixture pours into
In trash ice, filtering.Obtained solid is washed with water to neutrality, dry.Recrystallizing methanol obtains lithocholic acid 3.2g, yield shown in formula Ш
It is 85%.
Comparative example
According to the conjunction of lithocholic acid disclosed in Jiangsu Jiaerke Pharmaceuticals Group Co., Ltd.'s patent CN107200763 embodiments one
At method, 1 compound 586mg of formula is dissolved in diethylene glycol 10ml, 98% hydrazine hydrate 0.75ml is added, is heated to 120
DEG C stirring 2 hours, be cooled to 80 DEG C, add potassium hydroxide 840mg be warming up to 200 DEG C react 6 hours.It is cooling after having reacted
It to room temperature, is poured into water, 2N hydrochloric acid condition PH to 2 is added, water phase is extracted with dichloromethane, saturated common salt washing, anhydrous slufuric acid
Sodium is dried, and concentration, column chromatography obtains lithocholic acid 532mg.The technique uses deadly poisonous compound hydrazine hydrate, and reaction temperature is high, no
It is suitble to industry amplification.
Finally illustrate, the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although with reference to compared with
Good embodiment describes the invention in detail, it will be understood by those of ordinary skill in the art that, it can be to the skill of the present invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the right of invention.
Claims (8)
1. a kind of synthetic method of lithocholic acid, which is characterized in that include the following steps：
1) using compound shown in Formulas I as raw material, occur, at hydrazone reaction, to obtain chemical combination shown in formula Π in a solvent with unifor
Object；
2) compound shown in formula Π reacts with reducing agent in a solvent, obtains compound shown in formula Ш；
2. synthetic method according to claim 1, which is characterized in that in step 1) compound shown in Formulas I with to toluene sulphur
The molar ratio of hydrazides is 1:1~5.
3. synthetic method according to claim 1, which is characterized in that the temperature reacted in step 1) is 0~50 DEG C, reaction
Time be 1~for 24 hours.
4. synthetic method according to claim 1, which is characterized in that compound and reducing agent shown in Π rubs in step 2)
You are than being 1:1~20.
5. synthetic method according to claim 1, which is characterized in that reducing agent is sodium borohydride, hydroboration in step 2)
Potassium, zinc borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium aluminium hydride reduction it is one or more.
6. synthetic method according to claim 5, which is characterized in that reducing agent is sodium borohydride in step 2).
7. synthetic method according to claim 1, which is characterized in that the temperature reacted in step 2) is 0~50 DEG C.
8. synthetic method according to claim 1, which is characterized in that solvent is acetic acid, propionic acid in step 1) step 2)
It is one or two kinds of.
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| CN201810856674.XA CN108676051A (en) | 2018-07-31 | 2018-07-31 | A method of using chenodeoxycholic acid as Material synthesis lithocholic acid |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928123A (en) * | 2015-12-30 | 2017-07-07 | 上海迪赛诺药业有限公司 | A kind of preparation method of Telaprevir intermediate |
| CN107200763A (en) * | 2017-06-01 | 2017-09-26 | 江苏佳尔科药业集团有限公司 | A kind of method using chenodeoxycholic acid as Material synthesis lithocholic acid |
-
2018
- 2018-07-31 CN CN201810856674.XA patent/CN108676051A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928123A (en) * | 2015-12-30 | 2017-07-07 | 上海迪赛诺药业有限公司 | A kind of preparation method of Telaprevir intermediate |
| CN107200763A (en) * | 2017-06-01 | 2017-09-26 | 江苏佳尔科药业集团有限公司 | A kind of method using chenodeoxycholic acid as Material synthesis lithocholic acid |
Non-Patent Citations (2)
| Title |
|---|
| TAKASHI IIDA ET AL.: "Potential Bile Acid Metabolites. 3. A New Route to Chenodeoxycholic Acid", 《J. ORG. CHEM.》 * |
| 胡祥正等: "鹅去氧胆酸及其衍生物的制备和应用", 《化学进展》 * |
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Inventor after: Shen Dandan Inventor after: Zhou Yuqi Inventor after: Jiang Quanke Inventor after: Xiao Bo Inventor after: Lai Kaizhi Inventor before: Zhou Yuqi Inventor before: Shen Dandan Inventor before: Jiang Quanke Inventor before: Xiao Bo Inventor before: Lai Kaizhi |
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Effective date of registration: 20181219 Address after: 400030 No. 1, Phase II Skirt Tower, No. 1, Asia Pacific Road, Nanan District, Chongqing City - No. 155, Commerce Applicant after: Chongqing wave science and Technology Development Co., Ltd. Applicant after: CHONGQING INSTITUTE FOR FOOD AND DRUG CONTROL Address before: 400030 No. 1, Phase II Skirt Tower, No. 1, Asia Pacific Road, Nanan District, Chongqing City - No. 155, Commerce Applicant before: Chongqing wave science and Technology Development Co., Ltd. |
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Application publication date: 20181019 |