CN107011404B - A method of using cholic acid as Material synthesis lithocholic acid - Google Patents
A method of using cholic acid as Material synthesis lithocholic acid 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 discloses a kind of synthetic methods of lithocholic acid, use cholic acid for starting material, are oxidized to carbonyl, hydrolysis, Huang Min-lon reduction by 3 α-OH selective protections, 7 α-OH, 12 α-OH, totally 4 steps reaction synthesis lithocholic acid.This method starting material is easy to get, is inexpensive, and synthesis step is brief, and side reaction is few, and post-processing is simple, and total recovery is high, is suitable for industrialized production.
Description
Technical field
The invention belongs to organic chemistry fileds, and in particular to a method of using cholic acid as Material synthesis lithocholic acid.
Background technique
Lithocholic acid also known as 3-5 β of Alpha-hydroxy-cholanic acid are a kind of bile acids, shown in structure such as formula (i).Research shows that
Lithocholic acid and its derivative have a variety of physiological activity, such as antibacterial, antifungal activity (Farmaco Sci.39 (4) (1984)
305-315), anti-tumor activity (Proc.Natl.Acad.Sci.U S A.109 (42) (2012) 16906-16910), α -2,3-
Sialyltransferase inhibitory activity (Chem.Commun. (6) (2006) 629-631), protein-tyrosine-phosphatase 1B inhibit to live
Property (Bioorg.Med.Chem.Lett.22 (23) (2012) 7237-7242), TGR5 receptor activators (J.Med.Chem.51
(6) (2008) 1831-1841) etc..
The synthesis report in relation to lithocholic acid is seldom at present.Nineteen forty-six has been reported that using deoxycholic acid as starting material, through C-24
Esterification, 3 α-OH of selective protection, 12 α-OH, then 3 α-OH protecting group of selectively removing, hydrolysis, hydrogenation are protected again, altogether 7
Step synthesis lithocholic acid (Journal of Biological Chemistry, 1946,162,555-563).Reaction route is as follows:
In this synthetic route, total recovery only has 23%, and uses expensive platinum dioxide catalyst, and higher cost is uncomfortable
It shares in industrialized production.
Summary of the invention
In order to overcome the drawbacks described above of the prior art, the present invention provides a kind of synthetic method of lithocholic acid, this method is risen
Beginning raw material cholic acid is easy to get and inexpensively, and synthesis step is brief, and side reaction is few, and post-processing is simple, is suitable for industrialized production.
To achieve the above object, the synthetic method (semisynthesis) of lithocholic acid of the present invention, comprising the following steps:
Step a): in a solvent, using cholic acid shown in formula (1) as starting material, esterification, selectivity occurs with acid anhydrides
3 α-OH are protected, formula (2) compound is obtained；
Step b): in a solvent, under the action of oxidant oxidation reaction occurs for formula (2) compound, by aoxidizing 7 α-OH
It is carbonyl with 12 α-OH, obtains formula (3) compound；
Step c): in a solvent, hydrolysis occurs in the presence of alkali for formula (3) compound, obtains formula (4) compound；
Step d): in a solvent, Huang Min-lon reduction reaction occurs under the action of hydrazine hydrate and alkali for formula (4) compound, obtains
To lithocholic acid shown in formula (5)；
The reaction process is as shown in reaction formula (I):
Wherein, R is-(CH2)2COOH、-(CH2)3COOH、-(CH2)4COOH ,-PhCOOH etc..
In step a), the temperature range of the esterification is 25 DEG C~100 DEG C；It preferably, is 80 DEG C.
In step a), the time range of the esterification is 24~48 hours；Preferably, it is 43 hours.
In step a), the acid anhydrides is selected from succinic anhydride, glutaric anhydride, adipic anhydride and phthalic anhydride etc.；It is preferred that
Ground is succinic anhydride.
In step a), the molar ratio of the cholic acid and acid anhydrides is 1:(1~3)；It preferably, is 1:1.75.
In step a), the solvent is pyridine.
In a specific embodiment, the reaction condition in step a) of the present invention are as follows: cholic acid is dissolved in pyridine, is added
Enter acid anhydrides heating reaction, reaction process is detected by TLC, obtains formula (2) compound.
In step b), the oxidant is selected from PDC, PCC, CrO3、NBS、NCS、NaClO、Ca(ClO)2And H2O2In
It is one or more；Preferably, it is NBS (N- bromo-succinimide).
In step b), the temperature range of the oxidation reaction is 0 DEG C~60 DEG C；It preferably, is 40 DEG C.
In step b), the time range of the oxidation reaction is 0.5~12 hour；Preferably, it is 6 hours.
In step b), the molar ratio of formula (2) compound and oxidant is 1:(2~5)；It preferably, is 1:4.
In step b), the solvent is selected from one of tetrahydrofuran, acetone and water etc. or a variety of；Preferably, work as oxidation
Agent is PDC, PCC, CrO3When, the solvent is tetrahydrofuran；When oxidant is NBS, NCS, NaClO, Ca (ClO)2And H2O2
When, the solvent is acetone and water, wherein the volume ratio of the acetone and water is (1~5): 1, it is preferable that is 3:1.
In step b), preferably carried out under the conditions of being protected from light.
In a specific embodiment, the reaction condition in step b) of the present invention are as follows: formula (2) compound is dissolved in molten
In agent, oxidant reaction is added, reaction process is detected by TLC, obtains formula (3) compound.
In step c), the temperature range of the hydrolysis is 0 DEG C~75 DEG C；It preferably, is 25 DEG C of room temperature.
In step c), the time range of the hydrolysis is 1~24 hour；Preferably, it is 16 hours.
In step c), the solvent is selected from one of tetrahydrofuran, water etc. or a variety of；Preferably, for tetrahydrofuran and
The mixed solvent of water, wherein the volume ratio of tetrahydrofuran and water is (4~8): 1, it is preferable that be 6:1.
In step c), the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, potassium acetate, uncle
One of butanol potassium, sodium tert-butoxide and sodium ethoxide etc. are a variety of；It preferably, is lithium hydroxide；It is further preferred that being a water
Close lithium hydroxide.
In step c), the molar ratio of formula (3) compound and alkali is 1:(3~10)；It preferably, is 1:4.
In a specific embodiment, the reaction condition in step c) of the present invention are as follows: formula (3) compound is dissolved in water
With the in the mixed solvent of tetrahydrofuran, be added alkali, by TLC detect reaction process, after obtain formula (4) compound.
In step d), the alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium acetate and sodium ethoxide
Deng one of or it is a variety of；It preferably, is potassium hydroxide.
In step d), formula (4) compound is 1:5~20:5~20 with the molar ratio of hydrazine hydrate and potassium hydroxide；It is excellent
Selection of land is 1:10:10.
In step d), the solvent is selected from one of diglycol, ethylene glycol and glycerine etc. or a variety of；It is preferred that
Ground is diglycol.
In step d), the temperature range of the Huang Min-lon reduction reaction is 100 DEG C~200 DEG C；Preferably, for 120 DEG C~
200℃.It is further preferred that being 120 DEG C, 200 DEG C.
In step d), the time range of the Huang Min-lon reduction reaction is 3~24 hours；Preferably, it is 6 hours.
In a specific embodiment, the reaction condition in step d) of the present invention are as follows: formula (4) compound is dissolved in molten
In agent, hydrazine hydrate and alkali is added, is heated to 100~200 DEG C, reacts 3~24 hours, reaction process is detected by TLC, obtains formula
(5) lithocholic acid shown in.
In the present invention, the mechanism of the Huang Min-lon reduction reaction is as follows:
Hydrazone is generated with hydrazine reaction first containing carbonyls, then in the presence of alkali, sloughs the hydrogen on nitrogen, double bond is moved
Position.Finally, nitrogen is left away, carbanion captures the hydrogen in water again, and generation is reduced to methylene.
The beneficial effects of the present invention are: 1) starting material of the invention be easy to get, it is inexpensive, synthetic route is brief, by 4 steps
Lithocholic acid is synthesized, is a completely new synthetic route, so far without reporting similar synthetic method.2) three-step reaction is almost fixed before
Amount is completed, and side reaction is few, and post-processing is simple, and gross mass yield is up to 75%.
Specific embodiment
In conjunction with following specific embodiments, the present invention is described in further detail.Implement process of the invention, condition,
Experimental method etc. is in addition to what is specifically mentioned below the common sense of this field, and there are no special restrictions to content by the present invention.
In following embodiments, compound structure is measured by Nuclear Magnetic Resonance (Bruker, 400MHz)；Cholic acid is smooth by upper Haitai
Science and Technology Ltd. provides；Remaining conventional reagent is mainly provided by Shanghai traditional Chinese medicines chemical reagents corporation；Product mainly passes through silica gel
Column chromatographic purifying, silica gel (200-300 mesh) are provided by Haiyang Chemical Plant, Qingdao.
Embodiment one
1, the synthesis of formula (2 ') compound
Cholic acid (10g, 24.5mol) is dissolved in pyridine (50mL), is added succinic anhydride (3.43g, 34.3mmol), heating
It is reacted 17 hours to 80 DEG C, adds 300mg succinic anhydride, reacted 7 hours, add 300mg succinic anhydride, then react 7 hours, then
200mg succinic anhydride is added to react 12 hours.After TLC detects raw material fully reacting, reaction solution is cooled to room temperature, is poured into dilute
In HCL aqueous solution (55mL concentrated hydrochloric acid+500mL water), 100mL ethyl acetate is added and is stirred at room temperature 20 minutes.Liquid separation, water phase second
Acetoacetic ester extracts (40mL × 4).Merge organic phase, is successively washed with saturated salt solution (30mL × 1), anhydrous Na2SO4It is dry.Subtract
Pressure concentration, vacuum drying, obtain formula (2 ') crude compound (white solid, 12.4g), mass yield 124%.Product is without pure
Change, directly casts single step reaction.1H NMR(400MHz,DMSO-d6) δ 12.07 (s, 2H), 4.44 (s, 1H), 4.03 (d, J=
7.2Hz, 1H), 3.79 (s, 1H), 0.94 (t, J=11.8Hz, 5H), 0.84 (s, 3H), 0.59 (s, 3H)
2, the synthesis of formula (3 ') compound
Formula (2 ') crude compound (12.4g, 24.5mmol) is dissolved in acetone (180mL) and water (60mL) mixed solvent
In, it is added NBS (17.4g, 98mmol), interior temperature rise is protected from light 6 hours to 40 DEG C.TLC detects raw material almost after fully reacting,
It is cooled to room temperature, 30mL solution of sodium bisulfite is added, reaction is quenched.200mL water, water phase acetic acid second is added in liquid separation, water phase
Ester extracts (30mL × 4).Merge organic phase, is successively washed with saturated salt solution (30mL × 1), anhydrous Na2SO4It is dry.It depressurizes dense
It is reduced to dry, obtains formula (3 ') crude compound (white solid, 11g), mass yield 110% (relative to starting material cholic acid).It produces
Product directly cast single step reaction without purifying.1H NMR(400MHz,CDCl3) δ 4.70 (t, J=10.2Hz, 1H), 1.40-
1.22 (m, 9H), 1.03 (s, 3H), 0.84 (d, J=6.2Hz, 3H)
3, the synthesis of formula (4) compound
Formula (3 ') compound (1g, 2mmol) is dissolved in tetrahydrofuran (30mL) and water (5mL) in the mixed solvent, is added one
Reaction 16 hours is stirred at room temperature in hydronium(ion) lithia (332mg, 8mmol).TLC detects raw material fully reacting, and it is molten that 2N HCl is added
Mother liquor pH is adjusted to 2~3 by liquid.100mL water is added, water phase extracts (20mL × 4) with methylene chloride.Merge organic phase, successively
It is washed with saturated salt solution (30mL × 1), anhydrous Na2SO4It is dry.It is concentrated under reduced pressure, vacuum drying, obtains formula (4) compound (white
Solid, 0.78g), mass yield 78%.Product directly casts single step reaction without purifying.
4, the synthesis of formula (5) compound
Formula (4) compound (404mg, 1mmol) is dissolved in diglycol (10mL), and 98% hydrazine hydrate is added
(0.5mL, 10mmol), be heated to 120 DEG C stir 2 hours, be cooled to 70~80 DEG C, add potassium hydroxide (560mg,
200 DEG C are warming up to after 10mmol) to react 6 hours.After TLC detects raw material fully reacting, it is cooled to room temperature, is poured into water
2N salt acid for adjusting pH is added to 2~3 in (150mL).Water phase extracts (20mL × 5) with methylene chloride.Merge organic phase, successively uses
Saturated salt solution (20mL × 1) washing, anhydrous Na2SO4It is dry.It is concentrated under reduced pressure, silica gel column chromatography (DCM:MeOH=10:1) is pure
Change, obtains lithocholic acid shown in formula (5) (white solid, 356mg), mass yield 88%.1H NMR(400MHz,CD3OD)δ3.61–
3.46 (m, 1H), 0.95 (t, J=3.2Hz, 6H), 0.69 (s, 3H).13C NMR(100MHz,CD3OD)δ178.2,72.4,
57.9,57.5,49.0,43.9,43.6,41.9,41.5,37.3,37.2,36.7,36.5,35.7,32.3,32.0,31.2,
29.2,28.4,27.7,25.3,24.0,22.0,18.8,12.5。
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally
Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with appended claims be protect
Protect range.
Claims (10)
1. a kind of synthetic method of lithocholic acid, which is characterized in that the described method comprises the following steps:
Step a): in a solvent, using cholic acid shown in formula (1) as raw material, esterification occurs with acid anhydrides, obtains formula (2) chemical combination
Object, the solvent are pyridine；
Step b): in a solvent, under the action of oxidant oxidation reaction occurs for formula (2) compound, obtains formula (3) compound；
Step c): in a solvent, hydrolysis occurs in the presence of alkali for formula (3) compound, obtains formula (4) compound；
Step d): in a solvent, under the action of hydrazine hydrate and alkali huang-Minlon reaction occurs for formula (4) compound, obtains formula (5) institute
The lithocholic acid shown, the alkali are potassium hydroxide；
The reaction process is as shown in reaction formula (I):
Wherein: R is-(CH2)2COOH、-(CH2)3COOH、-(CH2)4COOH or-PhCOOH.
2. the method as described in claim 1, which is characterized in that in step a), the temperature range of the esterification is 25 DEG C
~100 DEG C；The molar ratio of the cholic acid and acid anhydrides is 1:(1~3).
3. the method as described in claim 1, which is characterized in that in step a), the acid anhydrides is selected from succinic anhydride, glutaric acid
Acid anhydride, adipic anhydride and phthalic anhydride.
4. the method as described in claim 1, which is characterized in that in step b), the oxidant is selected from PDC, PCC, CrO3、
NBS、NCS、NaClO、Ca(ClO)2And H2O2One of or it is a variety of；And/or the solvent is selected from tetrahydrofuran, acetone and water
One of or it is a variety of.
5. the method as described in claim 1, which is characterized in that in step b), the temperature range of the oxidation reaction is 0 DEG C~
60℃；And/or the molar ratio of formula (2) compound and oxidant is 1:(2~5).
6. the method as described in claim 1, which is characterized in that in step b), when oxidant is PDC, PCC, CrO3When, it is described
Solvent is tetrahydrofuran；When oxidant is NBS, NCS, NaClO, Ca (ClO)2And H2O2When, the solvent be acetone and water,
Described in the volume ratio of acetone and water be (1~5): 1.
7. the method as described in claim 1, which is characterized in that in step c), the temperature range of the hydrolysis is 0 DEG C~
75℃；And/or the molar ratio of formula (3) compound and alkali is 1:(3~10).
8. the method as described in claim 1, which is characterized in that in step c), the solvent in tetrahydrofuran, water one
Kind is a variety of；And/or the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, potassium acetate, tertiary fourth
One of potassium alcoholate, sodium tert-butoxide and sodium ethoxide are a variety of.
9. the method as described in claim 1, which is characterized in that in step d), the solvent is selected from diglycol, second two
One of pure and mild glycerine is a variety of.
10. the method as described in claim 1, which is characterized in that in step d), the temperature range of the Huang Min-lon reduction reaction
It is 100 DEG C~200 DEG C；And/or the molar ratio of formula (4) compound and hydrazine hydrate and potassium hydroxide be 1:5~20:5~
20。
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| CN108676049A (en) * | 2017-11-02 | 2018-10-19 | 华东师范大学 | A kind of preparation method of Austria's shellfish cholic acid, ursodesoxycholic acid and 7- Ketocholic acid |
| WO2021145458A1 (en) * | 2020-01-16 | 2021-07-22 | 学校法人慶應義塾 | Composition for producing bile acids |
| CN111560045A (en) * | 2020-06-23 | 2020-08-21 | 江苏佳尔科药业集团股份有限公司 | Method for synthesizing lithocholic acid by taking BA as raw material |
| CN112375117A (en) * | 2020-11-14 | 2021-02-19 | 湖南科瑞生物制药股份有限公司 | Preparation method of lithocholic acid and intermediate thereof |
| CN115716857A (en) * | 2022-10-28 | 2023-02-28 | 湖南科瑞生物制药股份有限公司 | Refining method of lithocholic acid |
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| WO2017035501A1 (en) * | 2015-08-27 | 2017-03-02 | Academia Sinica | Sialyltransferase inhibitors and uses thereof |
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Address after: 213111 Huzhuangtou 302, Sanhuangmiao Village Committee, Zhenglu Town, Tianning District, Changzhou City, Jiangsu Province Patentee after: Jiangsu Jiaerke Pharmaceutical Group Co., Ltd. Address before: 213111 Huzhuangtou 302, Sanhuangmiao Village Committee, Zhenglu Town, Tianning District, Changzhou City, Jiangsu Province Patentee before: JIANGSU JIAERKE PHARMACEUTICALS GROUP CORP., LTD. |