CN106046095B - Synthetic method of 6-ethylchenodeoxycholic acid - Google Patents
Synthetic method of 6-ethylchenodeoxycholic acid Download PDFInfo
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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 discloses a synthetic method of 6-ethylchenodeoxycholic acid. The synthetic method comprises steps as follows: chenodeoxycholic acid and an oxidizing agent are subjected to an oxidizing reaction and an esterification reaction, and a compound with a structure represented as a formula III is prepared; hydroxyl and carbonyl on rings of the compound with the structure represented as the formula III are protected with tert-butyldimethylsilyl chloride, and a compound with a structure represented as a formula IV is obtained; the compound with the structure represented as the formula IV and paraldehydeare are subjected to an electrophilic addition reaction and then are subjected to deprotection, and a compound with a structure represented as a formula V is obtained; the compound with the structure represented as the formula V is subjected to catalytic hydrogenation and is subjected to reduction and hydrolysis finally, and the compound 6-ethylchenodeoxycholic acid with a structure represented as a formula VI is obtained. The method is simple and convenient to operate, adopts mild conditions, has higher yield and is suitable for being popularized to industrial production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field and in particular to a kind of Austria shellfish cholic acid (6- ethyl chenodeoxycholic acid) synthesis work
Skill.
Background technology
Liver cirrhosis is clinical common chronic progressive external hepatopathy, is that for a long time or repeated action is formed one or more cause of disease
Diffusivity hepatic lesion.Non-alcohol fatty liver is the new challenge in contemporary medical science field, non-alcoholic fatty liver at no distant date
Disease will be continuously increased to the harm of human health.Shellfish cholic acid difficult to understand belongs to farnesoid X receptor agonist, is subject to by activating farnesol X
Body, the gene expression of suppression cytochrome 7A1 (CYP7A1) indirectly.Because CYP7A1 is the biosynthetic rate-limiting enzyme of cholic acid, because
This shellfish cholic acid difficult to understand can promote cholic acid to synthesize, for treating primary biliary cirrhosiss and non-alcohol fatty liver.
At present, shellfish cholic acid difficult to understand is still in clinical trial, fail large scale investment production application it is known that method in use
The highly basic such as LDA prepare intermediate, this kind of method expensive starting materials and the strict anhydrous and oxygen-free low temperature environment of needs;Make in subsequent step
With this nucleopilic reagent of acetaldehyde, low boiling point, easily it is polymerized, complex operation, is unfavorable for industrialized production.
Content of the invention
The invention aims to solution severe reaction conditions, yield is not high, the problems such as synthetic route is immature, provides
A kind of synthetic method of Austria shellfish cholic acid, this method is easy and simple to handle, mild condition, and yield is higher, is suitable for extending to industrial metaplasia
Produce.
The purpose of the present invention can be reached by following measures:
A kind of synthetic method of Austria shellfish cholic acid, it comprises the steps:
(1) chenodeoxycholic acid and oxidant carry out oxidation reaction and obtain compound (II), then carry out esterification formula
III compound 3 α-carboxyl -7 ketone -5 β cholestane -24- acid methyl ester;
(2) with tert-butyl chloro-silicane, protection is carried out to the hydroxyl on formula III compound ring and carbonyl and obtain formula IV
Compound;
(3) formula IV compound and paraldehydum carry out electrophilic addition reaction, then obtain after deprotection Formula V compound 3 α-
Hydroxyl -6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester;
(4) Formula V compound carries out catalytic hydrogenation, finally carries out reduction and hydrolysis obtain Formula IV compound Austria shellfish gallbladder
Acid;
Hereinafter each step of the present invention is elaborated.
Step (1), chenodeoxycholic acid and oxidant carry out oxidation reaction and obtain compound (II), then carry out esterification system
Standby formula III compound 3 α-carboxyl -7 ketone -5 β cholestane -24- acid methyl ester;
In the oxidation reaction, how optionally to aoxidize the hydroxyl on 7 allows the hydroxyl of 3 not react being simultaneously
Relatively more crucial problem in compound (II) synthesis, therefore in oxidation reaction from specific oxidant, be chosen in particular from NBS,
One or more of PCC, chromic acid, experiment finds permissible when being oxidant using NBS (N-bromosuccinimide)
Reach optimal oxidation effectiveness.
The temperature of this oxidation reaction is 20~30 DEG C, and the solvent of oxidation reaction is acetone water mixed solvent.
Esterification compound of formula H and methanol carry out esterification, add sulphuric acid, reaction temperature 55~65 in reaction
℃.Make the alcohol in esterification using methanol in experimental verification, this reaction, compare compared with other alcohol, such as ethanol, more readily soluble
Solution, in addition methanol boiling point is also lower, is easier to remove during post processing.
In the reaction, chenodeoxycholic acid and the mol ratio of oxidant are 1:1~2, preferably 1:1.5.
Step (2), carries out protection with tert-butyl chloro-silicane to the hydroxyl on formula III compound ring and carbonyl and obtains
Formula IV compound;
In the reaction that hydroxyl and carbonyl are protected, using tert-butyl chloro-silicane, it reacts bar to the present invention
Part is gentle, and yield is high, sloughs simplicity.But tert-butyl chloro-silicane is met water and can be generated hydrogen chloride, therefore will ensure to react
The drying of container when carrying out, in addition this blocking group excessively easily slough, if therefore reaction condition control not good; could be serious
Impact yield.
Using lithium diisopropylamine (LDA) typically can be used during tert-butyl chloro-silicane as pulling out hydrogen, form carbon
The alkali of anion, but during using LDA, must assure that anhydrous and oxygen-free environment, and must carry out at -78 DEG C to ensure the peace reacted
Entirely carry out, operating difficultiess, high cost.The method using being added without LDA for the present invention, is controlled so that in room by suitable condition
React under the conditions of temperature and also obtained the higher compound of yield (IV).
In the reaction of this step, formula III compound and tert-butyl chloro-silicane and imidazoles are in the effect of acid binding agent
Under reacted, reaction temperature be 20~30 DEG C, reaction dissolvent be oxolane.Described acid binding agent can using pyridine, triethylamine,
Triethanolamine, N, accelerine, N,N-dimethylformamide etc.;But it was found that, suitable acid binding agent and its use
Amount is also to improve the key factor of reaction yield;The present invention through experimental verification when using triethylamine as acid binding agent and
The mole of acid binding agent is 1.6~2.5 with the amount ratio with compound III:When 1, or more preferably adopt 2:When 1, Ke Yida
To optimal reaction effect.
In the reaction, formula III compound and the mol ratio of tert-butyl chloro-silicane are 1:1.5~3.5, preferably 1:
2~3, most preferably 1:2.2.
Step (3), formula IV compound and paraldehydum carry out electrophilic addition reaction, then obtain Formula V chemical combination after deprotection
Thing 3 Alpha-hydroxy -6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester,
Formula IV compound carries out electrophilic addition reaction, after reaction with paraldehydum and boron trifluoride diethyl etherate at -35~0 DEG C
Add tetrabutyl ammonium fluoride to carry out deprotection reaction at 0~30 DEG C, obtain Formula V compound.
In electrophilic addition reaction, it is used paraldehydum to add reaction as aldehyde precursors, paraldehydum is stable, and it is strong
Under acid condition, depolymerization is acetaldehyde, and in this reaction, boron trifluoride diethyl etherate is strong Lewis acid, can make to generate acetaldehyde in reaction, from
And avoid acetaldehyde and preserve difficult, the not high problem of purity.The synthesis of compound (V) is key one step preparing shellfish cholic acid difficult to understand,
The carbon of the positively charged on 6 carbanion attack acetaldehyde, allows the oxygen on acetaldehyde remove the group of attack positively charged in reaction, thus de-
Remove a molecular water, generate double bond, so needing Lewis acid to participate in reaction provide positive charged group.Therefore select suitable Lewis acid
Particularly significant to the yield improving compound (V).
Lewis acid used in this reaction is selected from aluminum chloride, iron chloride or boron trifluoride diethyl etherate, but experiment finds,
When Lewis acid is done using boron trifluoride diethyl etherate, higher yield can be obtained.Based on the characteristic of boron trifluoride diethyl etherate, concrete
It is ensured that carrying out in anhydrous condition during use.
The solvent of this electrophilic addition reaction can be selected for dichloromethane.
In this step, formula IV compound and the mol ratio of paraldehydum, boron trifluoride diethyl etherate and tetrabutyl ammonium fluoride are
1:4~6:3~5:0.5~2.
Step (4), Formula V compound carries out catalytic hydrogenation, finally carries out reduction and hydrolysis obtain Formula IV compound Austria
Shellfish cholic acid,
Formula V compound carries out hydrogenation reaction under palladium carbon catalysis, and reaction temperature is 20~30 DEG C, and reaction dissolvent can be selected for ice
Acetic acid;Carry out reduction reaction in 20~30 DEG C in the presence of reducing agent after hydrogenation reaction, be eventually adding sodium hydroxide in 90~
Be hydrolyzed at 110 DEG C reaction, obtains shellfish cholic acid difficult to understand.
Formula V compound, after the step completing catalytic hydrogenation, needs 7 carbonyls optionally to be reduced, therefore
Select suitable go back original reagent very crucial, reducing agent can be real using sodium borohydride, potassium borohydride, stannous chloride or lithium aluminium hydride reduction
Issue after examination and approval existing, higher reduction effect can be reached when reducing agent is using sodium borohydride.Formula V compound and the mol ratio of reducing agent
For 1:5~8, experiment finds that when mol ratio be 1:Optimal yield can be reached when 6.
, with chenodeoxycholic acid as raw material, oxidized, esterification, electrophilic addition, catalytic hydrogenation, reductive hydrolysis 5 step are anti-for the present invention
6- ethyl chenodeoxycholic acid (shellfish cholic acid difficult to understand) should be obtained, total recovery reaches 40%.Its structure warp1HNMR, MS analysis and testing technology is true
Recognize.The method has following characteristics:
(1) dangerous substances such as LDA are not used, reaction condition is gentle, improves the low temperature environment in document, and in addition to hydrogenation
All can carry out at ambient pressure, easy and simple to handle, equipment requirements are low, suitable laboratory is prepared and industrialized production;
(2) use paraldehydum as aldehyde precursors, solve the problem that acetaldehyde purity is not high, is difficult to preserve;
(3) often step product isolate and purify easier, single step yield is all higher with gross production rate;
(4) reaction needed raw material all can be by industrialized production, cheap easy acquisition.
Specific embodiment
With reference to embodiments the present invention is described further, but protection scope of the present invention be not limited to following each
Embodiment.
Reagent and instrument
Chenodeoxycholic acid (98%, Hubei Yuancheng Saichuang Technology Co., Ltd.);Tert-butyl chloro-silicane, imidazoles, four
Butyl ammonium fluoride, paraldehydum (GC, Shanghai Aladdin biochemical technology limited company);N-bromosuccinimide, tetrahydrochysene
Furan, triethylamine (AR, Chengdu Ke Long chemical reagent factory);Boron trifluoride diethyl etherate (CP, Chengdu Ke Long chemical reagent factory);Boron
Sodium hydride, sulphuric acid, hydrochloric acid, 10% (mass fraction) palladium carbon, remaining reagent is AR.
X-5 micro melting point apparatus (temperature control type) (Nanjing Jia Meilun scientific instrument company limited), not calibrated.Bruker
Avance III (500MHz) nuclear magnetic resonance chemical analyser (German Burker company);Finnigan TSQ Quantum ultra AM
Mass spectrograph (Finnigan company of the U.S.).
Embodiment 1, the synthesis of 13 Alpha-hydroxy -7- ketone -5 β-cholanic acid -24- methyl ester (III)
Take 2g (5.1mmol) chenodeoxycholic acid (I), 1.3g (7.3mmol) N-bromosuccinimide is justified in 100mL single port
In the flask of bottom, add 48mL acetone-water (3:1, volume ratio), stirring reaction 4h under room temperature, finish through TLC detection reaction.To burning
Add 10mL 20% (mass fraction) sodium sulfite in bottle, be evaporated acetone, then use 5mL hydrochloric acid solution (5%) to be acidified, treat
Solid filters after separating out, and filtering residue is washed to neutrality, is dried, with re-dry after dehydrated alcohol recrystallization, obtains white solid 1.84g.
Take gained white solid in 150mL single necked round bottom flask, add 60mL methanol, be heated to 60 DEG C, Deca 1mL
98% concentrated sulphuric acid, return stirring reacts 12h, finishes through TLC detection reaction, adds 2g sodium bicarbonate, after bubble-free generates, mistake
Filter excess bicarbonate, filtrate revolving is removed most of methanol, remaining liq is extracted with ethyl acetate, and is evaporated acetic acid second
Ester, obtains white solid 1.66g and is compound (III), yield 91%.1H NMR(CDCl3,500MHz)δ:0.65 (3H, s,
18-CH3), 0.80 (3H, s, 19-CH3), 0.95 (3H, s, 21-CH3), 3.57 (1H, m, 3-CH) 3.65 (3H, s ,-CO2CH3).
In the oxidation reaction of this example, be respectively adopted NBS, PCC, chromic acid, DMSO/ oxalyl chloride, potassium permanganate be oxygen
Agent, the consumption of oxidant is 1.5 times of the amount of compound (I) material, and other conditions are identical with this example, investigates different oxidations
The impact to product for the agent, the results are shown in Table 1.
Table 1
Embodiment 2,3 α, the synthesis of 7- bis- (tert-butyl group dimethylsilyloxy) -6- alkene -5 β-cholanic acid -24- methyl ester (IV)
Take 5g (12.4mmol) compound (III) in 150mL single necked round bottom flask, add the oxolane that 25mL is dried
And dissolve, take 4.1g (27.3mmol) tert-butyl chloro-silicane and 2g (29.8mmol) imidazoles to be added slowly to be stirred continuously
Solution in, take 10mL triethylamine to be slowly added into this solution after 0.5h, under room temperature after all adding stir 4h, through TLC detection
Reaction finishes.Add 25mL saturated solution of sodium bicarbonate in solution, be back to after room temperature after solution temperature, be extracted with ethyl acetate
Organic faciess, after saturated brine washing, anhydrous sodium sulfate drying, revolving obtains brown oil solid 6.63g and is compound (IV),
Yield 84%.1H NMR(CDCl3,500MHz)δ:0~0.2 (12H, m, 3,7-OSi (t-Bu) Me2), 0.66 (3H, s, 18-
CH3), 0.70 (3H, s, 19-CH3), 0.92 (3H, s, 21-CH3), 3.50 (1H, m, 3-CH) 3.68 (3H, s ,-CO2CH3),4.70
(1H, dd, 6-CH).
In this example reaction, it is respectively adopted pyridine, triethylamine, DMA, triethanolamine, N, N- dimethyl methyl
Amide is acid binding agent, and the consumption of acid binding agent is 2 times of the amount of compound (III) material, and other conditions are identical with this example reaction,
Investigate the different impacts to product for the acid binding agent, the results are shown in Table 2.
Table 2
In this example reaction, the mole dosage ratio of adjustment triethylamine and formula III compound, other conditions are reacted with this example
Identical, it is shown in Table 3 to the impact producing.
Table 3
In this example reaction, the mole dosage ratio of adjustment tert-butyl chloro-silicane and formula III compound, other
Part is identical with this example reaction, and it is shown in Table 4 to the impact producing.
Table 4
Embodiment 3, the synthesis of 3 Alpha-hydroxy -6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester (V)
Take 12.7g (23.2mmol) compound (IV) and dichloromethane (20mL) in 150mL single necked round bottom flask, cooling
To -30 DEG C, add 1.7mL (0.121mol) paraldehydum to be stirred continuously, in stirring, be slowly added dropwise 2.2mL (0.09mol) trifluoro
Change borate ether, after stirring lower reaction 1h, 0 DEG C can be warming up to.Then add dichloromethane 20mL in solution, be stirred overnight, warp
TLC detection reaction finishes, and adds 6.5g (25mmol) tetrabutyl ammonium fluoride in solution, adds 50mL after stirring 1h in solution
Stand after saturated solution of sodium bicarbonate, extract organic faciess with dichloromethane, saturated brine washs, anhydrous sodium sulfate drying, decompression
Distillation, with rapid column chromatography (petroleum ether:Ethyl acetate=7:3, v/v) separately obtaining white solid 6.7g is compound
(V), yield 67%.1H NMR(CDCl3,500MHz)δ:0.64 (3H, s, 18-CH3), 0.91 (3H, s, 19-CH3), 0.99
(3H, s, 21-CH3), 1.71 (3H, d, 2 '-CH3), 2.77 (1H, dd, 8-CH), 3.65 (3H, s ,-CO2CH3) 6.21 (1H, dd,
1’-CH).
In this example, it is respectively adopted aluminum chloride, iron chloride, zinc chloride and boron trifluoride diethyl etherate as Lewis acid, its consumption
It is 4 times of formula IV compound mole, other conditions keep constant, test its impact to compound V yield, the results are shown in Table
5.
Table 5
Embodiment 4, the synthesis of 6- ethyl chenodeoxycholic acid (VI)
Take 3.0g (6.97mmol) compound (V) in 500mL autoclave, throw after adding the dissolving of 150mL glacial acetic acid
Enter 0.5g palladium carbon, after extracting the air in container out, be passed through hydrogen exchange 2 times, more logical hydrogen is to 2atm, stirring is lower to react 12h.Instead
Palladium carbon should be filtered to remove after stopping, solution is concentrated, mixed liquor is dissolved in water and the mixture of ethyl acetate, uses unsaturated carbonate
Hydrogen sodium solution washs, and aqueous phase is extracted with ethyl acetate, saturated brine washing after two organic faciess mixing, and anhydrous sodium sulfate drying subtracts
Pressure distillation.
Product is dissolved in 50mL methanol, adds 1.5g sodium borohydride, under room temperature, stir 2h, add acetic acid stopped reaction,
After ethyl acetate extraction product, washing, it is dried, vacuum distillation concentrates, rapid column chromatography (petroleum ether:Ethyl acetate=1:1, v/
V) separate and obtain viscous brown shape solid 2.53g.
Products therefrom is dissolved in 20mL methanol, adds 0.5g sodium hydroxide and 5mL water, be stirred at reflux reaction 5h, will be molten
After liquid concentrates, it is slowly added into 5% hydrochloric acid acidifying, filter after solid separates out, filter cake is washed with water to neutrality, after being dried, use second
Acetoacetic ester recrystallization, obtains white solid 2.45g, yield 83%.M.p.108~110 DEG C;1H NMR(CDCl3,500MHz)δ:
0.56 (3H, s, 18-CH3), 0.72 (3H, t, 6-CH2CH3), 2.20 (2H, m, 23-CH2), 3.11 (1H, m, 7-CH) 3.44
(1H, m, 3-CH).MS,m/z:420.6.
Reduction reaction is respectively adopted the sodium borohydride of 6 times of Formula V compound moles, potassium borohydride, lithium aluminium hydride reduction and
Stannous chloride is reducing agent, and other conditions are prepared the reaction of Formula IV compound using the same method of this example, divide to Formula IV
The yield of compound is as shown in table 6.
Table 6
Sodium borohydride is adopted to be reducing agent in reduction reaction, the mol ratio of adjustment sodium borohydride and Formula V compound respectively,
Other conditions are prepared the reaction of Formula IV compound using the same method of this example, divide the yield such as table 7 to Formula IV compound
Shown.
Table 7
Claims (12)
1. a kind of synthetic method of Austria shellfish cholic acid is it is characterised in that it comprises the steps:
(1) chenodeoxycholic acid and oxidant carry out oxidation reaction and obtain compound (II), then carry out esterification and prepare formula III
Compound 3 α-carboxyl -7 ketone -5 β cholestane -24- acid methyl ester;
(2) formula III compound and tert-butyl chloro-silicane and imidazoles in the presence of acid binding agent triethylamine to formula III chemical combination
Hydroxyl on thing ring and carbonyl carry out protection and obtain formula IV compound;
(3) formula IV compound and paraldehydum carry out electrophilic addition reaction, then obtain after deprotection Formula V compound 3 Alpha-hydroxy-
6- ethylidene -7- ketone -5 β-cholanic acid -24- methyl ester;
(4) Formula V compound carries out catalytic hydrogenation, finally carries out reduction and hydrolysis obtain Formula IV compound Austria shellfish cholic acid;
2. method according to claim 1 is it is characterised in that in step (1), described oxidant be selected from NBS, PCC, three
One or more of chromium oxide;The temperature of oxidation reaction is 20~30 DEG C.
3. method according to claim 2 is it is characterised in that in step (1), described oxidant is selected from NBS.
4. method according to claim 1 is it is characterised in that in step (1), chenodeoxycholic acid and oxidant mole
Than for 1:1~2.
5. method according to claim 4 is it is characterised in that in step (1), chenodeoxycholic acid and oxidant mole
Than for 1:1.5.
6. method according to claim 1 is it is characterised in that in step (1), esterification compound of formula H and first
Alcohol carries out esterification, adds sulphuric acid in reaction, and reaction temperature is 55~65 DEG C.
7. method according to claim 1 is it is characterised in that in step (2), acid binding agent and compound III mole with
Amount ratio is 1.6~2.5:1;Formula III compound is 1 with the mol ratio of tert-butyl chloro-silicane:1.5~3.5.
8. method according to claim 7 is it is characterised in that in step (2), acid binding agent and compound III mole with
Amount ratio is 2:1;Formula III compound is 1 with the mol ratio of tert-butyl chloro-silicane:2~3.
9. method according to claim 1 is it is characterised in that in step (3), formula IV compound and paraldehydum and three
Fluorination borate ether carries out electrophilic addition reaction at -35~0 DEG C, adds tetrabutyl ammonium fluoride to carry out at 0~30 DEG C after reaction
Deprotection reaction, obtains Formula V compound.
10. method according to claim 1 is it is characterised in that in step (4), Formula V compound enters under palladium carbon catalysis
Row hydrogenation reaction, carries out reduction reaction after hydrogenation reaction in the presence of reducing agent, is eventually adding sodium hydroxide and is hydrolyzed instead
Should, obtain shellfish cholic acid difficult to understand.
11. methods according to claim 10 are it is characterised in that in step (4), hydrogenation reaction temperature is 20~30 DEG C;
Reducing agent is selected from sodium borohydride, potassium borohydride, stannous chloride or lithium aluminium hydride reduction, and reduction reaction temperature is 20~30 DEG C, Formula V chemical combination
Thing is 1 with the mol ratio of reducing agent:5~8;Hydrolysising reacting temperature is 90~110 DEG C.
12. methods according to claim 11 are it is characterised in that in step (4), hydrogenation reaction temperature is 20~30 DEG C;
Reducing agent is selected from sodium borohydride, and Formula V compound is 1 with the mol ratio of reducing agent:6.
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