CN108794559A - A method of using hyodesoxycholic acid as Material synthesis lithocholic acid - Google Patents
A method of using hyodesoxycholic acid as Material synthesis lithocholic acid Download PDFInfo
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- CN108794559A CN108794559A CN201810856645.3A CN201810856645A CN108794559A CN 108794559 A CN108794559 A CN 108794559A CN 201810856645 A CN201810856645 A CN 201810856645A CN 108794559 A CN108794559 A CN 108794559A
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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 organic chemistry fileds, are related to a kind of synthetic method of lithocholic acid, and in particular to a method of using hyodesoxycholic 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 hyodesoxycholic 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 pig
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 content is low, limited source, cannot meet the market demand, and artificial
Synthetic route is rarely reported, therefore it is necessary to develop a novelty, practical synthetic route.
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, has used expensive PtO2 in final step reaction, has limited
Its industrialized production.
Patent of invention in 2017 discloses one kind using hyodesoxycholic acid as starting material, by 6 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
Hyodesoxycholic 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 aoxidized to obtain by hyodesoxycholic acid 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,
Occur at hydrazone reaction, then through reduction reaction with unifor after first starting material hyodesoxycholic acid cheap and easy to get is aoxidized
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 and hydrazine class compound shown in Formulas I is 1 in step 1):1~3.
As a preferred embodiment, the molar ratio of compound and hydrazine class compound 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 hyodesoxycholic 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：
1.95g (5mmol) compound of formula I is dissolved in 20mL acetic acid, and 1.86g (10mmol) unifor is added,
Room temperature reaction 12 hours.TLC detects raw material after the reaction was complete, pours into ice water, the solid being obtained by filtration is dissolved with ethyl acetate.
Ethyl acetate layer 5%Na2CO3Solution washs, and is washed with water and washs to neutrality, is finally concentrated to dryness.Residue isopropanol
Recrystallize to obtain formula Π compound 2.5g, yield 89.3%.
2) synthesis of formula Ш compounds：
2g (3.56mmol) formula Π compounds are dissolved in the acetic acid of 50mL at room temperature, are controlled interior temperature and are divided within 60 DEG C
It criticizes and 1.35g (35.6mmol) sodium borohydride is added.It is stirred at room temperature 6 hours and reacts.Obtained mixture pours into trash ice, mistake
Filter.Obtained solid recrystallizing methanol obtains lithocholic acid 1.2g shown in formula Ш, yield 90%.
Embodiment 2
1) synthesis of formula Π compounds：
1.95g (5mmol) compound of formula I is dissolved in 20mL acetic acid, and 2.79g (15mmol) unifor is added,
Room temperature reaction 10 hours.TLC detects raw material after the reaction was complete, pours into cold water, obtained solid product is extracted with dichloromethane.
Organic phase 5%Na2CO3Solution washs, and is washed with water and washs to neutrality, is finally evaporated to dryness.Residue with Ethyl acetate recrystallizes
Obtain formula Π compound 2.4g, yield 85.7%.
2) synthesis of formula Ш compounds：
2g (3.56mmol) formula Π compounds are dissolved in the acetic acid of 50mL at room temperature, are gradually added into batches under ice-water bath
2g (53.4mmol) sodium borohydride.It is stirred at room temperature 4 hours and reacts.Obtained mixture pours into trash ice, filtering., obtain
Solid obtain lithocholic acid 1.15g shown in formula Ш, yield 86% with recrystallizing methanol.
Comparative example
According to the conjunction of lithocholic acid disclosed in Jiangsu Jiaerke Pharmaceuticals Group Co., Ltd.'s patent CN106977572 embodiments one
At method, 7- Ketolithocholsaeures 586mg 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 540mg.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 compound shown in Formulas I and hydrazine chemical combination in step 1)
The molar ratio of object 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 step 1) is acetic acid, propionic acid with solvent in step 2)
One or two.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109154016A (en) * | 2017-12-29 | 2019-01-04 | 邦泰生物工程(深圳)有限公司 | A kind of method of chemo-enzymatic process preparation ursodesoxycholic acid |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD272854A1 (en) * | 1988-06-02 | 1989-10-25 | Jenapharm Veb | METHOD FOR PRODUCING 3 BETA-SUBSTITUTED (20S) -20-ARYL-SULFONYLMETHYL-PREGNA-5,7-DIENES |
| CN1106611A (en) * | 1993-02-19 | 1995-08-09 | 西姆法有限公司 | Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them |
| CN1520295A (en) * | 2001-04-25 | 2004-08-11 | ����˹�ж�-����˹˹������˾ | Indole, azaindole and related heterocyclic amidopiperazine derivatives |
| CN106977572A (en) * | 2017-06-01 | 2017-07-25 | 江苏佳尔科药业集团有限公司 | A kind of method using hyodesoxycholic acid as Material synthesis lithocholic acid |
| 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 |
| CN107325146A (en) * | 2017-06-28 | 2017-11-07 | 李建恒 | A kind of synthetic method of the β alcohol of 17 5,16 diene of (3 pyridine radicals) androstane 3 |
| CN109154016A (en) * | 2017-12-29 | 2019-01-04 | 邦泰生物工程(深圳)有限公司 | A kind of method of chemo-enzymatic process preparation ursodesoxycholic acid |
-
2018
- 2018-07-31 CN CN201810856645.3A patent/CN108794559A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD272854A1 (en) * | 1988-06-02 | 1989-10-25 | Jenapharm Veb | METHOD FOR PRODUCING 3 BETA-SUBSTITUTED (20S) -20-ARYL-SULFONYLMETHYL-PREGNA-5,7-DIENES |
| CN1106611A (en) * | 1993-02-19 | 1995-08-09 | 西姆法有限公司 | Substituted phosphonates, the processes for their preparation and pharmaceutical compositions containing them |
| CN1520295A (en) * | 2001-04-25 | 2004-08-11 | ����˹�ж�-����˹˹������˾ | Indole, azaindole and related heterocyclic amidopiperazine derivatives |
| CN106977572A (en) * | 2017-06-01 | 2017-07-25 | 江苏佳尔科药业集团有限公司 | A kind of method using hyodesoxycholic acid as Material synthesis lithocholic acid |
| 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 |
| CN107325146A (en) * | 2017-06-28 | 2017-11-07 | 李建恒 | A kind of synthetic method of the β alcohol of 17 5,16 diene of (3 pyridine radicals) androstane 3 |
| CN109154016A (en) * | 2017-12-29 | 2019-01-04 | 邦泰生物工程(深圳)有限公司 | A kind of method of chemo-enzymatic process preparation ursodesoxycholic acid |
Non-Patent Citations (3)
| Title |
|---|
| 《简明化学试剂手册》编写组 编: "《简明化学试剂手册》", 31 January 1991, 上海科学技术出版社 * |
| TAKASHI IIDA 等: "Improved Conditions for Preparation and Reductive Cleavage of Steroidal Ketone Tosylhydrazones", 《SYNTHESIS》 * |
| 雷燕 等: "《实用化工材料手册-合成材料及其助剂》", 31 May 1994, 广东科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109154016A (en) * | 2017-12-29 | 2019-01-04 | 邦泰生物工程(深圳)有限公司 | A kind of method of chemo-enzymatic process preparation ursodesoxycholic acid |
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Effective date of registration: 20181213 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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