CN107400154A - One kind prepares 3 α, the method for the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid - Google Patents
One kind prepares 3 α, the method for the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid Download PDFInfo
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- CN107400154A CN107400154A CN201610329642.5A CN201610329642A CN107400154A CN 107400154 A CN107400154 A CN 107400154A CN 201610329642 A CN201610329642 A CN 201610329642A CN 107400154 A CN107400154 A CN 107400154A
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- 0 C[C@](CCC(O*)=O)C(CC1)[C@@](C)(CCC2[C@@](C)(CC[C@](C3)OC4OCCCC4)C3C3=CC)C1C2C3=O Chemical compound C[C@](CCC(O*)=O)C(CC1)[C@@](C)(CCC2[C@@](C)(CC[C@](C3)OC4OCCCC4)C3C3=CC)C1C2C3=O 0.000 description 4
- PMQLAEBMZWRZPJ-UHFFFAOYSA-N C=[O]C1OCCCC1 Chemical compound C=[O]C1OCCCC1 PMQLAEBMZWRZPJ-UHFFFAOYSA-N 0.000 description 1
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Abstract
The invention discloses a kind of new α of preparation 3, the method for the β cholanic acids (Formulas I) of 7 α dihydroxy, 6 α ethyls 5, the preparation process dopant species that are directed to are few, high income, purifying is convenient, simple to operate, is easy to industrialize.The compound is used to treat PBC and non-alcohol fatty liver.
Description
Technical field
The present invention relates to a kind of method of new preparation 3 α, 7 the α-α of bis-hydroxy-6-β of ethyl-5-cholanic acids.
Background technology
3 α, 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid, Chinese name：Shellfish cholic acid (OCA) difficult to understand, its structural formula are as follows：
Shellfish cholic acid category farnesoid X receptor activator difficult to understand, by activating farnesoid X receptor, suppress cytochromes 7A1 indirectly
(CYP7A1) gene expression.Because CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, therefore, shellfish cholic acid difficult to understand can suppress cholic acid
Synthesis, for treating PBC and non-alcohol fatty liver.
Shellfish cholic acid difficult to understand is researched and developed successfully by Intercept drugmakers of the U.S., is first over 20 years research and develop for treating courage
The medicine of juice cholestatic hepatic diseases.Study does not have abundant response to old plant medicine urso or is not resistant to for those
The patient received.
Preparation method about document report is summarized as follows：
(1) patent WO02072598A1 reports following synthetic method：
In the route, (1) whole synthesis step is required for column chromatography to purify each step product, and purifying cost is higher；(2) close
Into in step 2, the hexa-methylene phosphoamide that uses, there is carcinogenicity, and n-BuLi belongs to inflammable and explosive reagent, and need
Want -78 DEG C of reactions, the step yield only 12% or so.Amid all these factors the synthetic route yield is relatively low, and synthesis condition is harsh,
Cost is higher, and security is low, is not suitable for industrialized production.
(2) document J.Med.Chem., 2002,45,3569-3572 report following synthetic method.
Although the route synthesis step is shorter, there is also many weak points：(1) whole synthesis step inventory is very
It is small, and each step product is both needed to column chromatography purifying；(2) the hexa-methylene phosphoamide used in synthesis step three, have carcinogenic
Property；And LDA and n-BuLi belong to inflammable and explosive reagent, and -78 DEG C of reactions are needed, industrial operation difficulty is big, and yield is relatively low.
Amid all these factors the synthetic route yield is relatively low, severe reaction conditions, and dangerous high, industrial operation is difficult, is not easy extensive
Industrialized production.
(3) patent WO2006122977A2 reports following synthetic method
In the synthetic route, using LDA is arrived in (1) synthesis step three, belong to inflammable and explosive reagent, it is dangerous high, and
The step needs -90 DEG C of extremely low reaction temperatures, and industrial operation difficulty is big, and yield is relatively low.Purifying process is difficult；(2) synthesis step
In rapid six, solvent is made with 30% sodium hydroxide, poor to dissolution of raw material degree, reaction is difficult；(3) ester is converted into acid in step 5
- 5 β of Alpha-hydroxy-6- ethylidene-7- ketone of the product 3-sour yield of cholane-24 only about 52%；(4) in step 6, by 3 Alpha-hydroxy -6-
- 5 β of ethylidene-7- ketone groups-cholane acid reaction is converted into the reaction yield of 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone groups-cholanic acid only
There is 62% left side；3-6 β of Alpha-hydroxy-- 5 β of ethyl-7- ketone groups-cholanic acid Conversion of Epimers is 3 α-hydroxyl in right (5) course of reaction
The α of base-6-- 5 β of ethyl-7- ketone groups-cholanic acid is incomplete, 3 hydroxyls and the exposure for a long time of 24 carboxyls in ethyl course of reaction,
Inevitable that 6 more β-ethyl chenodesoxycholic acid and shellfish cholic acid dimer difficult to understand produce, rough shellfish cholic acid purity difficult to understand is not
Height, cause to need increase to be limited the quantity the clarification of the two impurity step in follow-up purge process, product yield also phase
Should be relatively low, purity is not high.
Patent CN201380043964.8 discloses following synthetic method
The synthesis technique substituted for some safer reaction examinations on the basis of WO2006122977A2 process lines
Agent, and replace the purification step in 977 with the way of purification of pure crystallization.Specifically (1) in step 4 to 3 rough Alpha-hydroxies-
The acid of -5 β of 6- ethylidene -7- ketone-cholane -24 is recrystallized using ethanol, and ultimate yield only has about 64% in the step；(2) exist
When preparing final product Austria shellfish cholic acid, by the way that 7- ketone is selectively converted into 7 Alpha-hydroxies to obtain rough shellfish cholic acid difficult to understand, then to thick
Make shellfish cholic acid difficult to understand to be recrystallized, obtain the shellfish cholic acid intermediate difficult to understand of crystallization c-type, further purifying obtains final product Austria shellfish
Cholic acid, this impurity such as 6- β ethyls goose deoxidation and the Ao Bei cholic acid dimers removed by means re-crystallization in course of reaction
Etc. the method for other impurity, acquisition has higher purity compared with the product in 977 methods, but product final yield is also relatively
It is low.In the reaction, the reaction yield for obtaining the intermediate of c-type crystallization only has 77.9%, then the purification of intermediate is obtained finally
The yield of shellfish cholic acid product difficult to understand is about 91%, and final conversion yield only has about 76%, and efficiency of pcr product is not high.
It has to be noted that in preparation technology disclosed in WO2006122977A2 and CN201380043964.8,
Two common issues all be present：(1) ester is converted into product (3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone-cholane-24 of respective acids
Acid) yield is high；(2) due in-6 α of Alpha-hydroxy of intermediate 3-- 5 β of ethyl-7- ketone groups-cholanic acid and 3 obtained by processing reaction
The DL body of the β of Alpha-hydroxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid, it is converted into 3-6 α of Alpha-hydroxy-- 5 β of ethyl-7- ketone groups-cholane
Acid can not be thorough, cause in final product there is be difficult purifying 6- β ethyl chenodesoxycholic acid impurity；(3) in course of reaction,
Because the hydroxyl in structure and carboxyl are exposed always, easily into ester, dimer is generated, causes in final product that there is also this
It is difficult to this dimer impurity removed.Dimer impurity structural formula is as follows：
Because the conversion of DL body in course of reaction is incomplete and the generation of dimer, due to both impurity not
Easily eliminated from product, it is therefore necessary to increase certain purifying process for refining, to control the amount of both impurity.
The content of the invention
In view of various problems existing for the above method, it is necessary to which a kind of low cost of invention, operation is simple, yield is higher is adapted to
The method of industrialized production, the total reaction equation of this method are as follows：
The synthetic route is relatively above-mentioned to be had the following advantages：
(1) because 3 Alpha-hydroxies in structure in course of reaction are protected, final product dimer impurity can be avoided
Produce, substantially increase each step reaction yield；
(2) in step 5, intermediate VI/VII mixture is converted to single intermediate VI high incomes, after conversion
To intermediate VI in be practically free of intermediate VII, for follow-up product purifying provide it is convenient；
(3) yield that ester is converted into respective acids in step 3 is higher than yield of the prior art more than 76%.
(4) that 7- ketone is converted into semifinished product efficiency of pcr product in 7 alpha-hydroxy selective reaction steps is higher, and rough Austria
The purity of shellfish cholic acid is also high, and efficiency of pcr product can reach 91.2%, and purity can reach more than 98%, due to rough shellfish cholic acid difficult to understand
Purity it is high, just more easy subsequently by the further polishing purification of semifinished product.
(5) respectively step reaction yield is high, and isolated each step intermediate is easy to purify, and whole route is easy to industrial metaplasia
Production.
The main of this method comprises the following steps：
(a) in alcohols solvent, under acid catalysed conditions, by 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholanic acid (Formula II
Compound) it is esterified；
To obtain-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups of compound 3-cholane acid esters (formula III compound)；
Wherein, R C1~C6Alkyl.
(b) in a suitable solvent, with 3.4- dihydropyran to 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholanic acid second
Ester (compound III) carries out hydroxyl protection, to obtain corresponding 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholane
Acid esters (formula IV compound)；
Wherein, R is C1~C6 alkyl.
(c) in the basic conditions, by 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid second in alcoholic solvent
Ester compounds IV) it is hydrolyzed, to obtain 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid (Formula V chemical combination
Thing)；
(d) in alcoholic solvent, 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid (compound V) is entered
Row reduction, to obtain 3 α-α of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid (compound VI) and 3 α-oxinane
The DL body of the β of epoxide-6-- 5 β of ethyl-7- ketone groups-cholanic acid (compound VII).
(e) in the metal hydroxides aqueous solution, DL body that heat treatment step (d) is obtained, to obtain 3 α-tetrahydrochysene
- 6 α of pyrans epoxide--5 β of ethyl -7- ketone groups-cholanic acid (compound VI) monomer.
(f) in alcoholic solvent, with 3 α of metal hydride reduction-α of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholane
Sour (compound VI) is to obtain 3 α-α of tetrahydro-pyran oxy-6-- 5 β of the Alpha-hydroxy of ethyl-7-cholanic acid (Formula VIII compound)；
(g) in alcoholic solvent, at room temperature, using under acid condition, by 3 α-Alpha-hydroxy of the α of tetrahydro-pyran oxy-6 ethyls-7-
5 β-cholanic acid (VIII) removings THP is protected to obtain 3 α, the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid (I)；
In some embodiments of the present invention, in step (a), it is characterised in that selected alcohols solvent be methanol, ethanol,
Isopropanol, n-butanol etc., preferably methanol or ethanol.Between 40 DEG C to 80 DEG C of reaction temperature, catalyst is the concentrated sulfuric acid.
In some embodiments of the present invention, in step (b), it is characterised in that selected solvent is dichloromethane, isopropyl
Ether, dioxane, methyl tertiary butyl ether(MTBE), ethyl acetate, acetonitrile or several mixed solvents therein, preferably dichloromethane and first
The mixed solvent of base tertbutyl ether.
In some embodiments of the present invention, in step (c), it is characterised in that the alkali used in described alkalescence condition
For lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.Selected alcoholic solvent is methanol, ethanol, isopropanol, positive fourth
One kind in alcohol, preferably methanol or ethanol.
In some embodiments of the present invention, in step (d), it is characterised in that selected alcoholic solvent is methanol, ethanol, different
One kind in propyl alcohol, n-butanol, preferably methanol or ethanol.Between reaction temperature is 20 to 60 DEG C.Used is reduced to hydrogen
Change hydrogenating reduction, such as reduced with palladium carbon.
In some embodiments of the present invention, in step (e), it is characterised in that be heated between 90~100 DEG C, in institute
The metal hydroxides stated is lithium hydroxide, sodium hydroxide, preferably potassium hydroxide, 1N sodium hydrate aqueous solutions.
In some embodiments of the present invention, in step (f), it is characterised in that selected alcoholic solvent is methanol, ethanol, different
One kind in propyl alcohol, n-butanol, preferably methanol or ethanol, selected metal hydride are sodium borohydride or potassium borohydride.
In some embodiments of the present invention, in step (g), it is characterised in that selected alcoholic solvent is methanol, ethanol, different
One kind in propyl alcohol, n-butanol, preferably methanol or ethanol, mentioned room temperature are 0 to 30 DEG C, selected acid solution hydrochloric acid water
Solution.
Operation is simple for this method, each to walk the product purity height that reaction yield is higher, and cost is relatively low, obtains, and is one
The good method of industrialized production Austria shellfish cholic acid, application prospect are very extensive.
Embodiment
The preparation method of the present invention is described in more detail below with reference to embodiment.However, art technology person
It should be appreciated that following examples are solely for the purpose of illustration, rather than limitation of the invention.Protection scope of the present invention should
It is defined by the appended claims.
Embodiment：
(a) preparation of 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholane acetoacetic ester (compound III)
3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholanic acid (20.0g, 48.0mmol) and ethanol are added into reaction bulb
(200mL), magnetic agitation is uniform, and the concentrated sulfuric acid (20D) is added dropwise at room temperature, after being added dropwise, is heated to flowing back, and reacts 5 hours,
TLC detection reactions are complete.Solvent is evaporated, adds ethyl acetate (200mL) dissolution residual substance, organic phase uses unsaturated carbonate hydrogen successively
Sodium water solution, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying organic phase, evaporate solvent and obtain tan solid
21.1g, yield 98.9%.
1H NMR(400MHz,CDCl3-d3):δ 6.19 (1H, q, J=7.2Hz), 4.12 (2H, q, J=7.2Hz), 3.63-
3.70 (1H, m), 2.58 (1H, dd, J=13.2Hz, 4.4Hz), 2.17-2.43 (4H, m), 1.89-2.03 (4H, m), 1.59-
1.85 (6H, m), 1.06-1.52 (16H, m), 1.01 (3H, s), 0.93 (3H, d, J=6.4Hz), 0.65 (3H, s).
(b) preparation of 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholane acetoacetic ester (compound IV)
Added into reaction bulb 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholane acetoacetic ester (21.0g, 47.2mmol),
P-methyl benzenesulfonic acid monohydrate (1.63g, 9.4mmol), dichloromethane (210mL) and methyl tertiary butyl ether(MTBE) (210mL), magnetic force stirs
Dissolving is mixed, 3.4- dihydropyran (19.9g, 236mmol) is added dropwise at room temperature, after being added dropwise, is reacted at room temperature 5 hours, TLC detections
Reaction is complete.Saturated sodium bicarbonate aqueous solution is added, is shaken up, liquid separation, aqueous phase extracts one again with methyl tertiary butyl ether(MTBE) (200mL)
It is secondary, merge organic phase, washed with saturated aqueous common salt (200mL × 2), anhydrous sodium sulfate drying, filter, evaporate solvent and obtain yellowish-brown
Grease 33.0g, yield ＞ 100%.
1H NMR(400MHz,CDCl3-d3):δ 6.10-6.19 (1H, m), 4.67-4.74 (1H, m), 4.11 (2H, q, J=
7.2Hz),3.82-3.91(1H,m),3.62-3.70(1H,m),3.44-3.57(1H,m),2.52-2.60(1H,m),2.16-
2.42 (4H, m), 1.64-2.02 (12H, m), 1.03-1.58 (19H, m), 0.99 (3H, s), 0.92 (3H, d, J=6.4Hz),
0.63(3H,s)。
(c) preparation of 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid (compound V)
Ethanol (250mL) and 1N sodium hydrate aqueous solutions (125mL), magnetic force are added into the residue obtained by step (b)
Stirring and dissolving, it is heated to 40~60 DEG C and reacts 3 hours, TLC detection reactions is complete, remove heating, reaction solution is cooled to room temperature, adds
Enter water (500mL) and methyl tertiary butyl ether(MTBE) (250mL), liquid separation, aqueous phase is extracted with methyl tertiary butyl ether(MTBE) (250mL × 2) again, aqueous phase
PH=3~4 are adjusted with saturated lemon, ethyl acetate (250mL) is added, shakes up, liquid separation, organic phase saturated aqueous common salt
(250mL) is washed, and organic phase anhydrous sodium sulfate drying, is evaporated solvent and is obtained interior white foam product 18.0g, yield is
76.3%.
1H NMR(400MHz,CDCl3-d3):δ10.50-11.40(1H,brs),6.11-6.20(1H,m),4.70-4.76
(1H,m),3.83-3.96(1H,m),3.62-3.72(1H,m),3.46-3.53(1H,m),2.52-2.61(1H,m),2.36-
2.44(2H,m),2.21-2.30(2H,m),1.66-2.02(12H,m),1.04-1.56(16H,m),0.99(3H,s),0.93
(3H, d, J=6.4Hz), 0.64 (3H, s).
(d) preparation of 3 α-α of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid (compound VI)
By 3 α of compound--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid (18.0g, 35.9mmol), 5%
Palladium carbon (1.8g) and absolute ethyl alcohol (180ml) are added in 500mL three-necked flask, and magnetic agitation is uniform, with nitrogen emptying body
Air in system, it is flushed with hydrogen gas denitrogen gas three times, under hydrogen tire, is heated to 45 DEG C, reacts 5 hours, take a little reaction solution to handle
Afterwards, nuclear-magnetism monitoring reaction end, as a result show that the peak of alkene hydrogen disappears, show that reaction is complete, be cooled to room temperature, filter, evaporate
Solvent obtains interior white foam product.
1N sodium hydrate aqueous solutions (180mL) are added into residue, 90~100 DEG C are heated under magnetic agitation, reaction
8h, room temperature is cooled to, adds deionized water (540mL) and methyl tertiary butyl ether(MTBE) (250mL), shake up, liquid separation, aqueous phase saturation lemon
Lemon aqueous acid adjusts its pH=3~4, adds ethyl acetate extraction (200mL × 2), merges organic phase, with saturated sodium-chloride water
Solution washs (200mL × 2), organic phase anhydrous sodium sulfate drying, evaporates solvent and obtains interior white foam product 14.5g, receives
Rate is 80.2%, and 3 α-β of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid is not detected by the product after conversion.
1H NMR(400MHz,CDCl3-d3):δ4.69-4.73(1H,m),3.85-3.91(1H,m),3.45-3.59(2H,
m),2.63-2.72(1H,m),2.16-2.45(4H,m),1.66-1.98(12H,m),1.06-1.52(19H,m),0.93(3H,
D, J=6.4Hz), 0.79 (3H, t, J=7.6Hz), 0.64 (3H, s).
(e) preparation of 3 α-α of tetrahydro-pyran oxy-6-- 5 β of the Alpha-hydroxy of ethyl-7-cholanic acid (compound VIII)
3 α-α of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid is added in a dry 1L three-necked flask
(14.5g, 28.8mmol) and absolute ethyl alcohol (150mL), magnetic agitation dissolving, ice-water bath are cooled to 0~5 DEG C, boron are added portionwise
Sodium hydride, after addition, ice bath is removed, maintains temperature T=10~20 DEG C to react 0.5~1h, after taking a small amount of reaction solution to handle,
Monitored and reacted by nuclear-magnetism, the results showed that reaction finishes, and adds deionized water (450mL), after stirring, uses saturated lemon
The aqueous solution adjusts PH=3~4.Ethyl acetate extraction (100mL × 2) is added, merges organic phase, is washed with saturated nacl aqueous solution
(100mL × 2), organic phase anhydrous sodium sulfate drying, evaporate solvent and obtain interior white foam product 13.4g, yield is
92.1%.
1H NMR(400MHz,CDCl3-d3):δ4.72-4.75(1H,m),3.85-3.96(1H,m),3.68-3.72(1H,
m),3.40-3.49(2H,m),2.36-2.44(1H,m),2.21-2.29(1H,m),1.15-1.98(31H,m),0.93(3H,
D, J=6.4Hz), 0.89 (3H, t, J=7.2Hz), 0.88 (3H, s), 0.66 (3H, s).
(f) preparation of 3 α, 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid (compound I)
3 α-α of tetrahydro-pyran oxy-6-- 5 β of the Alpha-hydroxy of ethyl-7-courage is added in a dry 500mL three-necked flask
Alkanoic acid (13.4g, 26.6mmol) and absolute ethyl alcohol (150mL), magnetic agitation dissolving, ice-water bath are cooled to 0~5 DEG C, slowly drop
Add 2N hydrochloric acid (80ml), after being added dropwise, remove ice-water bath, react at room temperature 2 hours, TLC detection reactions are complete, add deionization
Water (300mL), PH=9~10 are adjusted with 1N sodium hydrate aqueous solutions, add methyl tertiary butyl ether(MTBE) (200mL), mechanical agitation is equal
Even, liquid separation, aqueous phase is extracted with methyl tertiary butyl ether(MTBE) (200mL) again, liquid separation, and aqueous phase adjusts pH=3 with the saturated lemon aqueous solution
~4, ethyl acetate extraction (150mL × 2) is then added, merges organic phase, (200mL × 2) is washed with saturated nacl aqueous solution,
Organic phase anhydrous sodium sulfate drying, evaporate solvent and obtain final products 3 α, 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid
10.2g, yield 91.1%, shellfish cholic acid semifinished product purity difficult to understand is about 98.5%.
1H NMR(400MHz,CDCl3-d3):δ3.68-3.72(1H,m),3.37-3.45(1H,m),2.36-2.44(1H,
m),2.22-2.30(1H,m),1.74-1.98(7H,m),1.12-1.72(19H,m),0.86-0.94(10H,m),0.66(3H,
s)。
Claims (9)
1. one kind prepares 3 α, the method for the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid (Formulas I),
It is characterized in that comprise the following steps：
(a) in alcohols solvent, under acid catalysed conditions, 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholanic acid (Formula II) is entered
Row esterification；
To obtain-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups of compound 3-cholane acid esters (formula III),
Wherein, R C1~C6Alkyl；
(b) in a suitable solvent, with 3.4- dihydropyran to 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholane acid esters (formula
III hydroxyl protection) is carried out, to obtain 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholane acid esters (formula IV),
Wherein, R is C1~C6 alkyl；
(c) in the basic conditions, by 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholane acid esters (formula in alcoholic solvent
IV) it is hydrolyzed, to obtain 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid (Formula V)；
(d) in alcoholic solvent, 3 α--5 β of tetrahydro-pyran oxy -6- ethylidene -7- ketone groups-cholanic acid (Formula V) is reduced, with
Obtain 3 α-α of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid (Formula IV) and 3 α-β-ethyls-of tetrahydro-pyran oxy-6
The DL body of -5 β of 7- ketone groups-cholanic acid (Formula VII)；
(e) in the metal hydroxides aqueous solution, DL body that heat treatment step (d) is obtained, to obtain 3 α-oxinane
The α of epoxide-6-- 5 β of ethyl-7- ketone groups-cholanic acid (Formula IV) monomer；
(f) in alcoholic solvent, with 3 α of metal hydride reduction-α of tetrahydro-pyran oxy-6-- 5 β of ethyl-7- ketone groups-cholanic acid (formula
VI) to obtain 3 α-α of tetrahydro-pyran oxy-6-- 5 β of the Alpha-hydroxy of ethyl-7-cholanic acid (Formula VIII compound)；
(g) in alcoholic solvent, at room temperature, using under acid condition, by 3 α-α of tetrahydro-pyran oxy-6-β of the Alpha-hydroxy of ethyl-7-5-
Cholanic acid (VIII) removing THP is protected to obtain 3 α, the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic acid (Formulas I)；
2. according to the method for claim 1, it is characterised in that in step (a) selected alcohols solvent be methanol, it is ethanol, different
Propyl alcohol or n-butanol, preferably methanol or ethanol；Reaction temperature is 40 DEG C~80 DEG C, and acid catalysed conditions are the concentrated sulfuric acid.
3. according to the method for claim 1, it is characterised in that selected suitable solvent is that low polarity is organic molten in step (b)
Agent, such as any one in dichloromethane, isopropyl ether, dioxane, methyl tertiary butyl ether(MTBE), ethyl acetate or acetonitrile or its group
Close, preferably the mixed solvent of dichloromethane and methyl tertiary butyl ether(MTBE).
4. according to the method for claim 1, it is characterised in that the alkali used in alkalescence condition described in step (c) is
Lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide；Selected alcoholic solvent is methanol, ethanol, isopropanol or positive fourth
Any one in alcohol, preferably methanol or ethanol.
5. according to the method for claim 1, it is characterised in that selected alcoholic solvent is methanol, ethanol, isopropyl in step (d)
Any one in alcohol or n-butanol, preferably methanol or ethanol；Reaction temperature is 20~60 DEG C；Used is reduced to hydrogenate
Hydrogenating reduction, as palladium carbon reduces.
6. according to the method for claim 1, it is characterised in that heat in step (e) be at 90~100 DEG C, it is described
Metal hydroxides be lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably 1N sodium hydrate aqueous solutions.
7. according to the method for claim 1, it is characterised in that selected alcoholic solvent is methanol, ethanol, isopropyl in step (f)
Any one in alcohol, n-butanol, preferably methanol or ethanol, selected metal hydride are sodium borohydride or potassium borohydride.
8. according to the method for claim 1, it is characterised in that selected alcoholic solvent is methanol, ethanol, isopropyl in step (g)
Any one in alcohol, n-butanol, preferably methanol or ethanol, mentioned room temperature are 0 to 30 DEG C, selected acid solution hydrochloric acid
The aqueous solution.
9. 3 α of the compound-α of tetrahydro-pyran oxy-6-- 5 β of the Alpha-hydroxy of ethyl-7-cholanic acid (Formula VIII)
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| CN107955058A (en) * | 2018-01-08 | 2018-04-24 | 常州制药厂有限公司 | A kind of preparation of the intermediate for being used to prepare shellfish cholic acid difficult to understand, its preparation method and shellfish cholic acid difficult to understand |
| WO2019170521A1 (en) * | 2018-03-07 | 2019-09-12 | Moehs Iberica, S.L. | Synthesis of obeticholic acid and synthesis intermediate |
| WO2020169643A1 (en) | 2019-02-20 | 2020-08-27 | Moehs Iberica, S.L. | DIETHYLAMINE SALT OF 3α-TETRAHYDROPYRANYLOXY-6α-ETHYL-7α-HYDROXY-5ß-CHOLANIC ACID |
| CN114317663A (en) * | 2022-01-19 | 2022-04-12 | 常德云港生物科技有限公司 | Method for synthesizing ursodeoxycholic acid by using baits of pig gall after bilirubin is extracted |
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| CN107955058A (en) * | 2018-01-08 | 2018-04-24 | 常州制药厂有限公司 | A kind of preparation of the intermediate for being used to prepare shellfish cholic acid difficult to understand, its preparation method and shellfish cholic acid difficult to understand |
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