CN107298694A - The synthetic method and its intermediate of shellfish cholic acid difficult to understand - Google Patents
The synthetic method and its intermediate of shellfish cholic acid difficult to understand Download PDFInfo
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- CN107298694A CN107298694A CN201710385618.8A CN201710385618A CN107298694A CN 107298694 A CN107298694 A CN 107298694A CN 201710385618 A CN201710385618 A CN 201710385618A CN 107298694 A CN107298694 A CN 107298694A
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- 0 CC[C@@](C1)C(CCCC2)[C@@]2(C)C(CC2)C1C(CC1)[C@@]2(C)C1[C@](C)CCC(*)=O Chemical compound CC[C@@](C1)C(CCCC2)[C@@]2(C)C(CC2)C1C(CC1)[C@@]2(C)C1[C@](C)CCC(*)=O 0.000 description 1
- CDXFZTADUACTPI-GYXOBTLJSA-N C[C@H](CCC(O)=O)[C@@H](CCC1C(C(C2)[C@H](CCCC3)C[C@H]3C3)C3=O)[C@@]1(C)[C@H]2O Chemical compound C[C@H](CCC(O)=O)[C@@H](CCC1C(C(C2)[C@H](CCCC3)C[C@H]3C3)C3=O)[C@@]1(C)[C@H]2O CDXFZTADUACTPI-GYXOBTLJSA-N 0.000 description 1
- BKRVKKFGJQEJRD-RSWSSQRXSA-N C[C@H](CCC(OC)=O)[C@@H](CCC1C23)[C@@]1(C)C=CC2[C@@](C)(CCCC1)C1C=C3OS(C)(=O)=O Chemical compound C[C@H](CCC(OC)=O)[C@@H](CCC1C23)[C@@]1(C)C=CC2[C@@](C)(CCCC1)C1C=C3OS(C)(=O)=O BKRVKKFGJQEJRD-RSWSSQRXSA-N 0.000 description 1
Classifications
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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
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- 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
Abstract
The invention discloses a kind of synthetic method of shellfish cholic acid difficult to understand, cholic acid is used for raw material, by 7 α hydroxyls selective oxidations, side chain carboxyl group esterification, the esterification of 3 α hydroxy esterifications, 12 α hydroxymethane sulfonic acids, elimination, 3 ester groups of selective hydrolysis, with trim,ethylchlorosilane reaction generation silicon ether, aldol condensation is carried out with acetaldehyde, reacted again through hydrolysis, catalytic hydrogen reduction ethylene linkage, carbonyl reduction etc., synthesis obtains the shellfish cholic acid difficult to understand.The inventive method uses cheap cholic acid for raw material, and synthetic method novelty, low cost, high income, reaction condition are gentle, and post processing is easy, environment-friendly, is easy to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to the synthetic method and its intermediate of shellfish cholic acid difficult to understand.
Background technology
Shellfish cholic acid (Obeticholic acid) difficult to understand, chemical name 3 α, 7-6 α of alpha-dihydroxy-β of ethyl-5-cholestane-24-
Acid, also known as INT-747 or 6 α-ethyl chenodeoxycholic acid, are researched and developed, its mechanism is mainly logical by Intercept drugmakers of the U.S.
Exciting farnesoid X receptor is crossed, related gene is adjusted, synthesis, secretion, transhipment and the absorption of bile acid is influenceed.Shellfish cholic acid difficult to understand has
Treat the function of the diseases such as PBC (PBC), nonalcoholic fatty liver disease (NASH).Shellfish cholic acid wherein difficult to understand
As the clinical medicine for the treatment of PBC (PBC), ratified to list by FDA in 2016；It is non-as treating
The medicine of alcoholic fatty liver inflammation (NASH), carries out phase iii clinical trial.Count and show in global range, NASH hair
Sick rate is 2-3%.NASH gradually replaces virus hepatitis in recent years, as the topmost hepatopathy of European and American developed countries.Current FDA
Do not ratify any medicine for being used to treat nonalcoholic fatty liver disease also, but it is non-to have authorized shellfish cholic acid treatment difficult to understand
The breakthrough sex therapy of alcohol fatty hepatitis is assert.Shellfish cholic acid difficult to understand is first three phase clinical medicine that NASH welcomes, Townsend road
Prediction shellfish cholic acid difficult to understand will be up to 2,600,000,000 dollars in the year two thousand twenty sale thoroughly.
The crucial synthesis step of shellfish cholic acid difficult to understand mainly has two approach：(1) using chenodeoxycholic acid as raw material, by selectivity
7- hydroxyls are aoxidized, 3- hydroxyls is protected, is alkylated and is esterified, shellfish cholic acid (WO difficult to understand is made in carbonyl reduction and ester hydrolysis, five steps reaction
02072598A).The yield of committed step (alkylation) in route (a) is relatively low, and only 12%, cause total recovery relatively low, be
3%；In this step, document (Steroids, 2012,77,1335-1338) replaces bromoethane using iodoethane, receives this step
Rate brings up to 37%, but total recovery is still relatively low, is 20% (route (b)).In addition, using chenodeoxycholic acid as raw material, cost
It is higher.
(2) it is Benzylation by selective oxidation 7- hydroxyls using chenodeoxycholic acid as raw material, contracted through two step silicon etherificate, aldol
Close, hydrolysis, sodium borohydride reduction, Austria's shellfish cholic acid (J.Med.Chem, 2012,55,84-93) is made in Pd/C catalytic hydrogenations.Or with
KLCA is raw material, through esterification, is etherified through silicon, aldol condensation, hydrolysis, Pd/C catalytic hydrogenations, sodium borohydride reduction, system
Get Ao Bei cholic acid (B of CN 101203526).Total recovery is respectively 32% (route c) and 25% route (d), although total recovery has
Improved, but respectively using chenodeoxycholic acid and KLCA as raw material, cost is all higher.
The content of the invention
The present invention overcomes the drawbacks described above of prior art, and there is provided a kind of chemistry side of synthesis efficiently, easy shellfish cholic acid difficult to understand
Method, uses cheap cholic acid for raw material, synthesis shellfish cholic acid difficult to understand.Synthetic method novelty of the present invention, low cost, high income, environment friend
It is good, it is easy to industrialized production.
Shown in the structure such as formula (I) of shellfish cholic acid difficult to understand：
The synthetic method for the shellfish cholic acid difficult to understand that the present invention is provided, comprises the following steps：
(a) in a solvent, the cholic acid shown in formula (1) is molten and N-bromosuccinimide (NBS) generation selective oxidation is anti-
Should, 7 hydroxyls of selective oxidation obtain formula (2) compound；
(b) in the presence of catalyst, with alcohol esterification occurs for the dissolving of formula (2) compound, obtains formula (3) compound；
(c) in a solvent, with acid anhydrides, alkali esterification occurs for formula (3) compound, obtains formula (4) compound；
(d) in a solvent, formula (4) compound is in the presence of pyridine, and 12 hydroxyls contract with mesyl chloride (MsCl)
Reaction is closed, formula (5) compound is obtained；
(e) in a solvent, elimination reaction occurs for formula (5) compound and potassium acetate, obtains formula (6) compound；
(f) in a solvent, hydrolysis occurs for formula (6) compound and alkali, and the ester group that selective hydrolysis is 3 obtains formula (7)
Compound；
(g) in a solvent, with trim,ethylchlorosilane, highly basic condensation reaction occurs for formula (7) compound, obtains formula (8) silicon ether
Compound；
(h) in a solvent, in the presence of lewis acid, aldol reaction occurs for formula (8) compound and acetaldehyde, obtains
Formula (9) compound；
Formula (9) compound of synthesis, can pass through following three kinds of method synthesising target compounds formula (I) shellfish cholic acid difficult to understand：
Method one：
(i) in a solvent, with alkali hydrolysis occurs for formula (9) compound, obtains formula (10) compound；
(j) in a solvent, in the presence of catalyst, under Hydrogen Vapor Pressure, formula (10) compound is anti-by hydro-reduction
Should, reduction ethylene linkage obtains formula (11) compound；
(k) in a solvent, in the presence of metal hydride, reduction reaction occurs for formula (11) compound, obtains three-dimensional choosing
Selecting property reduzate formula (I) Austria shellfish cholic acid.
Method two：
(l) in a solvent, in the presence of catalyst, formula (9) compound and alkali, metal hydride are obtained through single step reaction
Arrive
Stereoselective reduction product formula (I) Austria shellfish cholic acid.
Method three：
(i) in a solvent, with alkali hydrolysis occurs for formula (9) compound, obtains formula (10) compound；
(m) in a solvent, in the basic conditions, in the presence of metal hydride, it is anti-that reduction occurs for formula (10) compound
Should, obtain Stereoselective reduction product formula (12) compound；
(n) in a solvent, in the presence of catalyst, under Hydrogen Vapor Pressure, formula (12) compound is anti-by hydro-reduction
Should, ethylene linkage is reduced, formula (I) shellfish cholic acid difficult to understand is obtained；
The reaction scheme of the synthetic method is as follows：
Wherein, R1For C1~C20 alkyl；R2For C1~C20 alkyl acyls.
Preferably, the R1Selected from methyl (- CH3), ethyl (- CH2CH3), propyl group (- CH2CH2CH3), butyl (-
CH2CH2CH2CH3)；R2Selected from acetyl group (- COCH3), propiono (- COCH2CH3), bytyry (- COCH2CH2CH3)。
The present invention uses cholic acid for raw material, optimizes Tetrahedron:Change in Asymmetry 11 (2000) 3463-34663
The synthetic method of 3 α of compound (4)-Alpha-hydroxy Methyl cholate of acetoxyl group -7- ketone -12, synthesis compound (4).
In step (a) of the present invention, one kind in acetone, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, water etc. of the solvent or
It is a variety of；Preferably, it is the mixed solvent of acetone and water；It is further preferred that being acetone：Water (volume ratio)=3：1 mixing is molten
Agent.
In step (a) of the present invention, formula (1) compound, the mol ratio of N-bromosuccinimide (NBS) are 1：(1~
5)；Preferably, it is 1：1.6.
In step (a) of the present invention, the temperature of the selective oxidation reaction is 0~40 DEG C；Preferably, it is 25 DEG C of room temperature.
In step (a) of the present invention, the time of the selective oxidation reaction is 1~4h；Preferably, it is 2h.
Step (a) of the present invention is carried out preferably under the conditions of lucifuge.
In an embodiment, the step (a) is specifically carried out in accordance with the following steps：By formula (1) compound cholic acid
It is dissolved in solvent, adds N-bromosuccinimide (NBS), lucifuge reaction.After reaction terminates, sodium hydrogensulfite, revolving are added
Partial solvent is removed, is poured into water, suction filtration, dries, obtains formula (2) compound.
In step (b) of the present invention, the alcohol can be simultaneously as solvent and reaction raw materials, selected from methanol, ethanol, propyl alcohol, fourth
Alcohol etc., it is preferable that be methanol.
In step (b) of the present invention, the one kind or many of the catalyst in the concentrated sulfuric acid, p-methyl benzenesulfonic acid, concentrated hydrochloric acid etc.
Kind；Preferably, it is the concentrated sulfuric acid.
In step (b) of the present invention, formula (2) compound, the mol ratio of catalyst are 1:0.1-1；Preferably, it is 1:1.
In step (b) of the present invention, the temperature of the esterification is 0~70 DEG C；Preferably 70 DEG C.
In step (b) of the present invention, the time of the esterification is 2~4h；Preferably, it is 2h.
In an embodiment, the step (b) is specifically carried out in accordance with the following steps：Formula (2) compound is dissolved in
In alcohols solvent, catalyst, heating response are added.After reaction terminates, revolving removes solvent, adds water, dichloromethane extraction, satisfies
With salt washing, organic phase is concentrated under reduced pressure into dry, obtains formula (3) compound.
In step (c) of the present invention, the acid anhydrides is selected from acetic anhydride, propionic andydride, butyric anhydride etc.；Preferably, it is acetic anhydride.
In step (c) of the present invention, one or more of the solvent in dichloromethane, tetrahydrofuran etc., it is preferable that
For dichloromethane.
In step (c) of the present invention, the catalyst is alkali, the one or more in pyridine, DMAP, triethylamine etc.；
Preferably, it is pyridine and DMAP.
In step (c), the mol ratio of formula (3) compound and acid anhydrides is 1：(1~5)；Preferably, it is 1：1.3.
In step (c), when catalyst selects pyridine and DMAP, formula (3) compound and acid anhydrides, pyridine and DMAP
Mol ratio is 1：(1~5)：(1~5)：(0.1~1)；Preferably, it is 1：1.3：2：0.5.
In step (c) of the present invention, the temperature of the esterification is 0~40 DEG C；Preferably, it is 25 DEG C of room temperature.
In step (c) of the present invention, the time of the esterification is 1~4h；Preferably, it is 2h.
In an embodiment, the step (c) is specifically carried out in accordance with the following steps：Formula (3) compound is dissolved in
In solvent, catalyst, and anhydride reaction are added.After reaction terminates, plus watery hydrochloric acid is washed, and is washed, saturated nacl aqueous solution is washed, organic
Mutually decompression is concentrated to dryness to obtain formula (4) compound.
In step (d) of the present invention, the solvent is aprotic solvent, selected from dichloromethane, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy six
One or more in ring, acetonitrile, toluene, chloroform, acetone, pyridine etc.；Preferably, it is dichloromethane.
In step (d) of the present invention, formula (4) compound and the mol ratio of MsCl, catalyst are：1：(1~10)：(1~
10)；Preferably, it is 1：5：5.
In step (d) of the present invention, the temperature of the condensation reaction is 20~40 DEG C；Preferably, it is 25 DEG C.
In step (d) of the present invention, the time of the condensation reaction is 5~10h；Preferably, it is 8h.
In step (d) of the present invention, the catalyst be organic base, selected from pyridine, triethylamine, diethylamine, ethylenediamine,
One or more in DMAP, triethylene diamine, DIPEA etc..
In an embodiment, the step (d) is specifically carried out in accordance with the following steps：Formula (4) compound is dissolved in
In aprotic solvent, mesyl chloride (MsCl) is added, pyridine reacts at a suitable temperature.After reaction terminates, dilute salt is added
Acid, two-phase laminated flow, saturated nacl aqueous solution is washed, and organic phase is concentrated under reduced pressure into dry, obtains formula (5) compound.
In step (e) of the present invention, the solvent is high boiling solvent, selected from 1-METHYLPYRROLIDONE (NMP), N, N- diformazans
One or more in base formamide (DMF), N, N- dimethyl propylene alkenyl ureas (DMPU), dimethyl sulfoxide (DMSO) (DMSO) etc.；It is preferred that
Ground, is 1-METHYLPYRROLIDONE (NMP).
In step (e) of the present invention, the mol ratio of formula (5) compound and potassium acetate is 1：(1~20)；Preferably, it is
1：(1~10)；It is further preferred that being 1：10.
In step (e) of the present invention, the temperature of the elimination reaction is 100~130 DEG C；Preferably, it is 125 DEG C.
In step (e) of the present invention, the time of the elimination reaction is 5~10h；Preferably, it is 8h；It is further preferred that
For 125 DEG C of reaction 8h.
In an embodiment, the step (e) is specifically carried out in accordance with the following steps：Formula (5) compound is dissolved in
In high boiling solvent, potassium acetate is added, is reacted at a suitable temperature.After reaction terminates, it is poured into water, is extracted with dichloromethane
Take, washing, saturated nacl aqueous solution are washed, organic phase is concentrated under reduced pressure into dry, obtains formula (6) compound.
In step (f) of the present invention, the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate etc.
In one or more；Preferably, it is sodium hydroxide.
In step (f) of the present invention, the one kind or many of the solvent in methanol, ethanol, propyl alcohol, water, tetrahydrofuran etc.
Kind；Preferably, it is methanol.
In step (f) of the present invention, the mol ratio of formula (6) compound and alkali is 1：(1~5)；Preferably, it is 1：1.2.
In step (f) of the present invention, the temperature of the hydrolysis is 20~40 DEG C；Preferably, it is 25 DEG C.
In step (f) of the present invention, the hydrolysis time is 10~100min；Preferably, it is 1h；Further preferably
Ground, is 25 DEG C of reaction 1h.
In an embodiment, the step (f) is specifically carried out in accordance with the following steps：By the dissolving of formula (6) compound
In a suitable solvent, alkali is added, is reacted at a suitable temperature.After reaction terminates, add water and dichloromethane extraction, Ran Houshui
Wash, saturated nacl aqueous solution is washed, organic phase is concentrated under reduced pressure into dry, obtains formula (7) compound.
In step (g) of the present invention, the solvent is ether solvent, one kind in tetrahydrofuran or dioxane etc. or
It is a variety of；Preferably, it is tetrahydrofuran.
In step (g) of the present invention, the highly basic is selected from one kind in diisopropyl ammonia lithium, n-BuLi, tert-butyl lithium etc.
Or it is a variety of；Preferably, it is diisopropyl ammonia lithium.
In step (g) of the present invention, formula (7) compound, trim,ethylchlorosilane, the mol ratio of highly basic are 1:1~10；It is preferred that
Ground, is 1:10.
In step (g) of the present invention, the temperature of the condensation reaction is -78~0 DEG C；Preferably, it is -78~-60 DEG C.
In step (g) of the present invention, the time of the condensation reaction is 0.5~3h；Preferably, it is 2h.
In step (g) of the present invention, preferably first other materials are mixed, highly basic is then added under inert conditions.
In an embodiment, the step (g) is specifically carried out in accordance with the following steps：Formula (7) compound is dissolved in
In ether solvent, less than 0 DEG C is cooled to, trim,ethylchlorosilane is added, resulting solution is instilled in highly basic under inert conditions, is mixed
Hydraulic control system stirring reaction at appropriate temperatures.After reaction terminates, saturated sodium bicarbonate solution is added, is extracted with ethyl acetate, water
Wash, saturated nacl aqueous solution is washed, organic phase is concentrated under reduced pressure into dry, obtains formula (8) compound.
In step (h) of the present invention, the solvent is selected from dichloromethane, dichloroethanes, tetrahydrofuran, acetonitrile, chloroform, first
One or more in benzene, acetone etc.；Preferably, it is dichloromethane.
In step (h) of the present invention, the lewis acid is selected from BFEE, boron trifluoride acetonitrile；Preferably, it is three
It is fluorinated borate ether.
In step (h) of the present invention, it is preferable that formula (8) compound and acetaldehyde are first added in solvent, then under cryogenic
Lewis acid is added, aldol reaction is carried out, obtains formula (9) compound；Wherein, the low temperature is -78~-40 DEG C, preferably
Ground, is -78~-60 DEG C.
In step (h) of the present invention, formula (8) compound, acetaldehyde, lewis acidic mol ratio are 1:1~5:1~10；It is preferred that
Ground, is 1:2:10.
In step (h) of the present invention, the temperature of the aldol reaction is -78~0 DEG C；Preferably, it is -60 DEG C.
In step (h) of the present invention, the time of the aldol reaction is 0.5~3h；Preferably, it is 2h.
In an embodiment, the step (h) is specifically carried out in accordance with the following steps：Formula (8) compound is dissolved in conjunction
In suitable solvent, acetaldehyde is added, inert conditions drop to low temperature, lewis acid solution is added dropwise and carries out aldol reaction, then
Reaction is slowly increased to room temperature by low temperature.After reaction terminates, saturated sodium bicarbonate solution is added, organic phase, washing, saturation chlorine is separated
Change sodium solution to wash, organic phase is concentrated under reduced pressure into dry formula (9) compound.
In step (i) of the present invention, the one kind of the solvent in methanol, ethanol, propyl alcohol, water, tetrahydrofuran, acetone etc.
Or it is a variety of；Preferably, it is methanol.
In step (i) of the present invention, the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate etc.
In one or more；Preferably, it is sodium hydroxide.
In step (i) of the present invention, formula (9) compound, the mol ratio of alkali are 1：(1~5)；Preferably, it is 1：3.
In step (i) of the present invention, the temperature of the hydrolysis is 50~110 DEG C；Preferably, it is 100 DEG C.
In step (i) of the present invention, the time of the hydrolysis is 1~6h；Preferably, it is 3h.
In an embodiment, the step (i) is specifically carried out in accordance with the following steps：Formula (9) compound is dissolved in
In suitable solvent, alkali is added, is reacted at a suitable temperature.After reaction terminates, watery hydrochloric acid is added, organic phase is separated, wash,
Saturated nacl aqueous solution is washed, and organic phase is concentrated under reduced pressure into dry, obtains formula (10) compound.
In step (j) of the present invention, the catalyst is palladium carbon；It is further preferred that be weight percentage 5% palladium carbon.
In step (j) of the present invention, the Hydrogen Vapor Pressure is 0.1~10MPa；Preferably, it is 4MPa.
In step (j) of the present invention, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran
One or more in；Preferably, it is methanol.
In step (j) of the present invention, formula (10) compound, the mass ratio of catalyst are 1：(0.01~0.4)；It is preferred that
Ground, is 1：0.1.
In step (j) of the present invention, the temperature of the hydro-reduction reaction is 50~110 DEG C；Preferably, it is 70 DEG C.
In step (j) of the present invention, the time of the hydro-reduction reaction is 4~24h；Preferably, it is 24h.
In an embodiment, the step (j) is specifically carried out in accordance with the following steps：Add and close in hydrogenation reaction cauldron
Reacted under suitable solvent, catalyst and formula (10) compound, heating condition.After reaction terminates, suction filtration filters out catalyst, and filtrate subtracts
Pressure is concentrated to dryness, and is added 30% sodium hydroxide solution, after 5 hours of backflow, is poured into phosphoric acid, suction filtration obtains formula (11) chemical combination
Thing.
In step (k) of the present invention, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran
One or more in；Preferably, it is water.
In step (k) of the present invention, one or more of the metal hydride in sodium borohydride, potassium borohydride etc.；
Preferably, it is sodium borohydride.
In step (k) of the present invention, formula (11) compound, the mol ratio of metal hydride are 1:5；Preferably, it is 1；1.1.
In step (k) of the present invention, the temperature of the reduction reaction is 50~110 DEG C；Preferably, it is 100 DEG C.
In step (k) of the present invention, the time of the reduction reaction is 1~8h；Preferably, it is 4h.
In an embodiment, the step (k) is specifically carried out in accordance with the following steps：Formula (11) compound is dissolved in
In suitable solvent, add under metal hydride, heating condition and react.After reaction terminates, watery hydrochloric acid, dichloromethane extraction are added
Take, wash, saturated nacl aqueous solution washes, organic phase is concentrated under reduced pressure into dry target compounds of formula (I) shellfish cholic acid difficult to understand.
In step (l) of the present invention, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran
One or more in；Preferably, it is water.
In step (l) of the present invention, the temperature of the reaction is 50~110 DEG C；Preferably, it is 100 DEG C.
In step (l) of the present invention, the time of the reaction is 3-24h；Preferably, it is 24h.
In step (l) of the present invention, the alkaline aqueous solution is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, carbon
One or more in sour sodium etc.；Preferably, it is sodium hydroxide；It is further preferred that being the sodium hydroxide of mass fraction 30%
The aqueous solution.
In step (l) of the present invention, the catalyst is palladium carbon；Preferably, it is palladium carbon (percentage by weight 5%).
In step (l) of the present invention, the Hydrogen Vapor Pressure is 0.1~10MPa, wherein it is preferred that 4MPa.
In step (l) of the present invention, the metal hydride is sodium borohydride, potassium borohydride；Preferably, it is sodium borohydride.
In an embodiment, the step (l) is specifically carried out in accordance with the following steps：Compound (9) is dissolved in alkali
Property the aqueous solution in, add catalyst, metal hydride is reacted under heating condition.After reaction terminates, phosphoric acid, suction filtration, drying are added
Obtain target compounds of formula (I) shellfish cholic acid difficult to understand.
In step (m) of the present invention, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran
One or more in；Preferably, it is water.
In step (m) of the present invention, the pH of the alkalescence condition is 9~14；Preferably, pH is 14.Can be common by adding
Alkali adjusts pH, and the alkali includes but is not limited to NaOH, KOH etc..
In step (m) of the present invention, the metal hydride is selected from sodium borohydride NaBH4, one kind in potassium borohydride etc. or
It is a variety of；Preferably, it is sodium borohydride.
In step (m) of the present invention, formula (10) compound, the mol ratio of metal hydride are 1：(1~5)；Preferably, it is 1：
1.1。
In step (m) of the present invention, the temperature of the reduction reaction is 50~110 DEG C；Preferably, it is 100 DEG C.
In step (m) of the present invention, the time of the reduction reaction is 1~8h；Preferably, it is 4h.
In an embodiment, the step (m) is specifically carried out in accordance with the following steps：Formula (10) compound is dissolved in
In suitable solvent, add under metal hydride, heating condition and react.After reaction terminates, watery hydrochloric acid, dichloromethane extraction are added
Take, wash, saturated nacl aqueous solution washes, organic phase is concentrated under reduced pressure into dry formula (12) compound.
In step (n) of the present invention, the catalyst is palladium carbon；It is further preferred that be weight percentage 5% palladium carbon.
In step (n) of the present invention, the Hydrogen Vapor Pressure is 0.1~10MPa；Preferably, it is 4MPa.
In step (n) of the present invention, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran
One or more in；Preferably, it is methanol.
In step (n) of the present invention, formula (12) compound, the mass ratio of catalyst are 1：(0.01~0.4)；It is preferred that
Ground, is 1：0.1.
In step (n) of the present invention, the temperature of the hydro-reduction reaction is 50~110 DEG C；Preferably, it is 70 DEG C.
In step (n) of the present invention, the time of the hydro-reduction reaction is 4~24h；Preferably, it is 24h.
In an embodiment, the step (n) is specifically carried out in accordance with the following steps：Add and close in hydrogenation reaction cauldron
Reacted under suitable solvent, catalyst and formula (12) compound, heating condition.After reaction terminates, suction filtration filters out catalyst, and filtrate subtracts
Pressure is concentrated to dryness, and is added 30% sodium hydroxide solution, after 5 hours of backflow, is poured into phosphoric acid, suction filtration obtains target compounds of formula
(I) shellfish cholic acid difficult to understand.
The invention also provides a kind of 3 α, 7- bis- (trimethylsiloxy group) -5 β-cholane -6,11- diene -24- acid esters (formulas
8), 3-5 β of Alpha-hydroxy-6- ethylidene-7- carbonyls-cholane-11- alkene-24- acid esters (formula 9), 3 Alpha-hydroxy-6- ethylidene-7- carbonyls
Sour (formula 10) compounds of the β of base-5-cholane-11- alkene-24-, 3 α, 7-5 β of alpha-dihydroxy-6- ethylidene-cholane-11- alkene-24- acid
(formula 12) compound, its structure difference is as follows：
The beneficial effects of the present invention are, the present invention is low by using cholic acid as raw material, synthesizing shellfish cholic acid difficult to understand, cost of material,
Reaction condition is gentle, and post processing is easy, and cost is low, high income (38.5%-40.3%), and the high-quality stabilization of product purity, preferably
In realizing industrialized production.
Embodiment
With reference to specific examples below, the present invention is described in further detail, implements the process, condition, examination of the present invention
Agent, experimental method etc., are the universal knowledege and common knowledge of this area in addition to the following content specially referred to, the present invention
Content is not particularly limited.
Embodiment one
1st, the synthesis of formula (2) compound：Compound (1) cholic acid (9g, 22.0mmol) is dissolved in 200mL acetone/waters (v/
V=3:1) in, lucifuge is slowly added to NBS (5.7g, 31.9mmol), and 25 DEG C of room temperature is reacted 2 hours.TLC detection reactions are complete
Afterwards, add 100mL saturation solution of sodium bisulfite and reaction is quenched, removal of solvent under reduced pressure is poured into stopping when there is white solid
A large amount of white solids are separated out after in 1L water, crystallization is stood, suction filtration drying obtains formula (2) compound (8.5g white solids, yield
95%).It is directly used in next step.
2nd, the synthesis of formula (3-1) compound：Formula (2) compound (8.5g, 20.9mmol) is dissolved in 100mL methanol,
Concentrated sulfuric acid 1mL is added, is heated to reflux 2 hours, methanol is removed under reduced pressure, water 30mL is added, with dichloromethane (30mL × 3) extraction water
Phase.Merge organic phase, washed respectively with water (50mL), saturation NaCl solution (50mL), anhydrous Na2SO4Dry, be concentrated under reduced pressure, obtain
To formula (3-1) compound (8.7g white solids, yield 99%).It is directly used in next step.
3rd, the synthesis of formula (4-1) compound：Formula (3-1) compound (8.7g, 20.9mmol) is dissolved in 80mL dichloromethanes
In alkane, acetic anhydride (2.5mL, 26.78mmol) is added, pyridine (3.3mL, 41.2mmol) and DMAP (125.8mg,
1.03mmol), 25 DEG C of room temperature is reacted 2 hours.After TLC detection reactions completely, removal of solvent under reduced pressure adds 30mL water, uses acetic acid
Ethyl ester extracts (30mL × 3) aqueous phase, merges organic phase, respectively with 2M hydrochloric acid (50mL), water (50mL), saturation NaCl solution
(50mL) is washed, anhydrous Na2SO4Dry, silica gel column chromatography (PE after being concentrated under reduced pressure：EA=3：1) formula (4-1) compound is obtained
(8.6g white solids, yield 90%).1H NMR(400MHz,CDCl3)δ7.35(s,5H),5.15–5.07(m,2H),4.68
(s, 1H), 3.99 (s, 1H), 2.00 (s, 3H), 1.19 (s, 3H), 0.96 (d, J=3.6Hz, 3H), 0.65 (s, 3H)
4th, the synthesis of formula (5-1) compound：Formula (4-1) compound (8.6g, 18.6mmol) is dissolved in 80mL dichloromethanes
In alkane, MsCl (7.3mL, 93mmol) is added dropwise in nitrogen protection successively, and pyridine (7.5mL, 93mmol), 25 DEG C of reactions 8 of room temperature are small
When.After TLC detection reactions completely, removal of solvent under reduced pressure adds 50mL water, (50mL × 3) aqueous phase is extracted with ethyl acetate, and merges
Organic phase, respectively with 2M hydrochloric acid (50mL), water (50mL), saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, decompression
Silica gel column chromatography (PE after concentration：EA=5：1) formula (5-1) compound (9.5g white solids, yield 95%) is obtained.1HNMR
(400MHz,CDCl3)δ5.12(s,1H),4.70–4.62(m,1H),3.66(s,3H),3.06(s,3H),1.99(s,3H),
(s, the 3H) of 1.20 (s, 3H), 0.98 (d, J=6.4Hz, 3H), 0.76
5th, the synthesis of formula (6-1) compound：Formula (5-1) compound (9.5g, 17.6mmol) is dissolved in N- methylpyrroles
In alkanone (80mL), potassium acetate (17.2g, 176mmol) is added, nitrogen protection is heated to 130 DEG C and reacted 8 hours.TLC is detected
After reaction completely, water (150mL) is added, is extracted with ethyl acetate (50mL × 3), merge organic phase, respectively with water (50mL), full
With NaCl solution (50mL) washing, anhydrous Na2SO4Dry, silica gel column chromatography (PE after being concentrated under reduced pressure：EA=10：1) formula (6-1) is obtained
Compound (7.04g white solids, yield 90%).1HNMR(400MHz,CDCl3) δ 6.21 (dd, J=8.4,2.4Hz, 1H),
5.33 (dd, J=8.4,1.2Hz, 1H), 4.74-4.67 (m, 1H), 3.66 (s, 3H), 1.99 (s, 3H), 1.14 (s, 3H),
1.01 (d, J=5.2Hz, 3H), 0.74 (s, 3H)
6th, the synthesis of formula (7-1) compound：7.04g formulas (6-1) compound (15.84mmol) is taken to be dissolved in methanol (48mL)
With the in the mixed solvent of tetrahydrofuran (12mL), sodium hydroxide (950mg, 23.76mmol) is added, is stirred at room temperature 30 minutes.TLC
After detection reaction completely, add watery hydrochloric acid and adjust pH to be 5 or so, removal of solvent under reduced pressure adds water (80mL), is extracted with ethyl acetate
(30mL × 3), merge organic phase, washing, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, concentration, silica gel column layer
Analyse (PE：EA=2：1) purify, formula (7-1) compound (6.1g white solids, yield 95%).1HNMR(400MHz,CDCl3)δ
6.20 (d, J=10.0Hz, 1H), 5.35 (d, J=10.0Hz, 1H), 3.66 (s, 3H), 3.62 (s, 1H), 1.13 (s, 3H),
1.01 (d, J=6.0Hz, 3H), 0.74 (s, 3H)
7th, the synthesis of formula (8-1) compound：LDA (6mL, 1mol/L) is dissolved in anhydrous THF (5mL), -78 are cooled to
DEG C, nitrogen protection after stirring 10 minutes, adds TMSCl (0.63mL, 5mmol), continues after stirring 10 minutes, formula (7-1) is added dropwise
THF (5mL) solution of compound (200mg, 0.5mmol).After reaction 1 hour, triethylamine (0.7mL, 5mmol) is added.Continue
Reaction 1 hour, TLC detection reactions are finished, and are gradually increased to room temperature, add saturated sodium bicarbonate and reaction is quenched.Water (20mL) is added,
It is extracted with ethyl acetate (10mL × 3), merges organic phase, washing, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry,
Concentration, obtains pale yellow oil formula (8-1), direct next step.
8th, the synthesis of formula (9-1) compound：Previous step product formula (8-1) compound is dissolved in anhydrous methylene chloride
In (20mL), acetaldehyde (0.056mL, 1mmol) is added, -60 DEG C are cooled to.After stirring 10 minutes, BFEE is added
(0.63mL, 5mmol).After reaction 2 hours, room temperature is gradually increased to, then at 35 DEG C, is stirred 1 hour.TLC detections have been reacted
Finish, add saturated sodium bicarbonate and reaction is quenched.Water (20mL) is added, is extracted with ethyl acetate (10mL × 3), merges organic phase,
Washing, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, concentration, silica gel column chromatography (DCM：MeOH=40：1) it is pure
Change, obtain formula (9-1) compound (white solid 149mg, 2 step yields 70%).1HNMR(400MHz,CDCl3) δ 6.23 (d, J=
10.0Hz, 1H), 6.16 (d, J=6.8Hz, 1H), 5.41 (d, J=10.4Hz, 1H), 3.66 (s, 3H), 3.65-3.62 (m,
1H), (s, the 3H) of 1.69 (d, J=6.4Hz, 3H), 1.01 (d, J=6.0Hz, 3H), 0.98 (s, 3H), 0.73
9th, the synthesis of formula (10) compound：Formula (9-1) compound (0.25g, 0.58mmol) is dissolved in methanol (15mL)
In, addition sodium hydroxide (70mg, 1.74mmol), water (1mL), 50 DEG C are reacted 3 hours.TLC detection reactions are finished, plus watery hydrochloric acid
PH=5 or so is adjusted, water (20mL) is added, is extracted with dichloromethane (10mL × 3), merges organic phase, washing, saturation NaCl solution
(50mL) is washed, anhydrous Na2SO4Dry, concentration obtains formula (10) compound, direct next step.
10th, the synthesis of formula (11) compound：Formula (10) compound (240mg, 0.58mmol) is dissolved in methanol (20mL)
In, add the palladium carbon (24mg) of percentage by weight 5%, H2(4MPa), 70 DEG C are reacted 24 hours.TLC detection reactions are finished, diatom
Native suction filtration, after concentration, adds NaOH solution (20mL, 30%), after flowing back 5 hours, plus phosphoric acid adjusts pH=5 or so, uses dichloro
Methane extracts (10mL × 3), merges organic phase, washing, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, concentration,
Silica gel column chromatography (DCM：MeOH=20：1) purify, obtain formula (11) compound (white solid 220mg, 2 step yields 90%).1H
NMR(400MHz,CDCl3) δ 3.56-3.51 (m, 1H), 1.25 (s, 3H), 1.22 (s, 3H), 0.93 (d, J=6.4Hz, 3H),
0.80 (t, J=7.4Hz, 3H), 0.65 (s, 3H)
11st, the synthesis of formula (12) compound：Formula (10) compound (200mg, 0.48mmol) is dissolved in containing NaOH
In the water (10mL) of (50%, 0.5mL), it is heated to after 100 DEG C, adds NaBH4The aqueous solution of (20mg, 0.53mmol)
(2.5mL), 100 DEG C are reacted 4 hours.TLC detection reactions are finished, plus watery hydrochloric acid adjusts pH=5 or so, is extracted with dichloromethane
(10mL × 3), merge organic phase, washing, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, concentration, silica gel column layer
Analyse (DCM：MeOH=10：1) purify, obtain formula (12) compound (white solid 186mg, 93%).1H NMR(400MHz,CDCl3)
δ 6.12 (d, J=10.4Hz, 1H), 5.68 (d, J=6.4Hz, 1H), 5.40 (d, J=10.0Hz, 1H), 4.15 (d, J=
10.0Hz, 1H), 3.71-3.62 (m, 1H), 1.62 (d, J=6.8Hz, 3H), 1.02 (d, J=6.0Hz, 3H), 0.75 (d, J=
6.1Hz,3H),0.73(s,3H).
12nd, the synthesis of shellfish cholic acid difficult to understand：By formula (11) compound (100mg, 0.24mmol) be dissolved in containing NaOH (50%,
In water (10mL) 0.2mL), after being heated to reflux, NaBH is added4The aqueous solution (2.5mL) of (10mg, 0.26mmol), reaction 4 is small
When.TLC detection reactions are finished, plus watery hydrochloric acid adjusts pH=5 or so, is extracted with dichloromethane (10mL × 3), merges organic phase, water
Wash, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, concentration, silica gel column chromatography (DCM：MeOH=10：1) purify,
Get Ao Bei cholic acid (white solid 93mg, 93%).1HNMR(400MHz,CDCl3)δ3.70(s,1H),3.42–3.38(m,1H),
(s, the 3H) of 0.94 (d, J=6.0Hz, 3H), 0.91-0.87 (m, 6H), 0.66
13rd, the synthesis of shellfish cholic acid difficult to understand：Formula (9-1) compound (0.25g, 0.58mmol) is dissolved in the water-soluble of sodium hydroxide
In liquid (30%) (10mL), palladium carbon (50mg), NaBH are added4(24mg, 0.64mmol), H2(4MPa), 100 DEG C are reacted 24 hours.
TLC detection reactions are finished, and the acid that phosphorates adjusts pH=5 or so, suction filtration, drying, get Ao Bei cholic acid (white solid 196mg, 80%)1H
NMR(400MHz,CDCl3) δ 3.70 (s, 1H), 3.42-3.38 (m, 1H), 0.94 (d, J=6.0Hz, 3H), 0.91-0.87 (m,
6H),0.66(s,3H).
14th, the synthesis of shellfish cholic acid difficult to understand：Formula (12) compound (200mg, 0.48mmol) is dissolved in methanol (20mL), plus
Enter palladium carbon (20mg), H2(4MPa), 70 DEG C are reacted 24 hours.TLC detection reactions are finished, and suction filtered through kieselguhr after concentration, is added
NaOH solution (20mL, 30%), after flowing back 5 hours, plus phosphoric acid adjusts pH=5 or so, and (10mL × 3) are extracted with dichloromethane,
Merge organic phase, washing, saturation NaCl solution (50mL) washing, anhydrous Na2SO4Dry, concentration, silica gel column chromatography (DCM：MeOH
=20：1) purify, get Ao Bei cholic acid (white solid 192mg, 95%)1H NMR(400MHz,CDCl3)δ3.70(s,1H),
(s, the 3H) of 3.42-3.38 (m, 1H), 0.94 (d, J=6.0Hz, 3H), 0.91-0.87 (m, 6H), 0.66
The present invention protects content not limit to above example.Under the spirit and scope without departing substantially from inventive concept, this area
Technical staff it is conceivable that change and advantage be all included in the present invention, and using appended claims as protection model
Enclose.
Claims (17)
1. the synthetic method of shellfish cholic acid difficult to understand, it is characterised in that the described method comprises the following steps：
(a) in a solvent, the cholic acid shown in formula (1) is molten and selective oxidation reaction, choosing occur for N-bromosuccinimide (NBS)
Selecting property aoxidizes 3 hydroxyls, obtains formula (2) compound；
(b) in the presence of catalyst, with alcohol esterification occurs for the dissolving of formula (2) compound, obtains formula (3) compound；
(c) in a solvent, with acid anhydrides, alkali esterification occurs for formula (3) compound, obtains formula (4) compound；
(d) in a solvent, formula (4) compound is in the presence of pyridine, and it is anti-that with mesyl chloride (MsCl) condensation occurs for 12 hydroxyls
Should, obtain formula (5) compound；
(e) in a solvent, elimination reaction occurs for formula (5) compound and potassium acetate, obtains formula (6) compound；
(f) in a solvent, hydrolysis occurs for formula (6) compound and alkali, and the ester group that selective hydrolysis is 3 obtains formula (7) chemical combination
Thing；
(g) in a solvent, with trim,ethylchlorosilane, highly basic condensation reaction occurs for formula (7) compound, obtains formula (8) compound silicon
Ether；
(h) in a solvent, in the presence of lewis acid, aldol reaction occurs for formula (8) compound and acetaldehyde, obtains formula
(9) compound；
Formula (9) compound of synthesis, can pass through following three kinds of method synthesising target compounds formula (I) shellfish cholic acid difficult to understand：
Method one：
(i) in a solvent, with alkali hydrolysis occurs for formula (9) compound, obtains formula (10) compound；
(j) in a solvent, in the presence of catalyst, under Hydrogen Vapor Pressure, formula (10) compound is reacted by hydro-reduction, also
Former ethylene linkage obtains formula (11) compound；
(k) in a solvent, in the presence of metal hydride, reduction reaction occurs for formula (11) compound, obtains stereoselectivity
Reduzate formula (I) Austria shellfish cholic acid；
Method two：
(l) in a solvent, in the presence of catalyst, formula (9) compound and alkali, metal hydride are stood through single step reaction
Body selective reduction product formula (I) Austria shellfish cholic acid；
Method three：
(i) in a solvent, with alkali hydrolysis occurs for formula (9) compound, obtains formula (10) compound；
(m) in a solvent, in the basic conditions, in the presence of metal hydride, reduction reaction occurs for formula (10) compound, obtains
To formula (12) compound；
(n) in a solvent, in the presence of catalyst, under Hydrogen Vapor Pressure, formula (12) compound is reacted by hydro-reduction, also
Former ethylene linkage, obtains formula (I) shellfish cholic acid difficult to understand；
The reaction scheme of the synthetic method is as follows：
Wherein, R1For C1~C20 alkyl；R2For C1~C20 alkyl acyls.
2. the method as described in claim 1, it is characterised in that in step (a), the solvent is selected from acetone, tetrahydrofuran, 1,
One or more in 4- dioxane, water；And/or, formula (1) compound, mole of N-bromosuccinimide (NBS)
Than for 1：(1~5)；And/or, the temperature of the selective oxidation reaction is 0~40 DEG C；And/or, the selective oxidation reaction
Time be 1~4h.
3. the method as described in claim 1, it is characterised in that in step (b), and/or, the alcohol is selected from methanol, ethanol, third
Alcohol, butanol；One or more of the catalyst in the concentrated sulfuric acid, p-methyl benzenesulfonic acid, concentrated hydrochloric acid；And/or, the formula (2)
Compound, the mol ratio of catalyst are 1:0.1~1；And/or, the temperature of the esterification is 0~70 DEG C.
4. the method as described in claim 1, it is characterised in that in step (c), the acid anhydrides is selected from acetic anhydride, propionic andydride, fourth
Acid anhydrides；One or more of the solvent in dichloromethane, tetrahydrofuran；And/or, the catalyst is alkali, selected from pyrrole
One or more in pyridine, DMAP, triethylamine；And/or, when catalyst selects pyridine and DMAP, formula (3) compound and acid
The mol ratio of acid anhydride, pyridine and DMAP is 1：(1~5)：(1~5)：(0.1~1).
5. the method as described in claim 1, it is characterised in that in step (d), the solvent is aprotic solvent, selected from two
One or more in chloromethanes, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, acetonitrile, toluene, chloroform, acetone, pyridine；And/or, institute
State formula (4) compound and the mol ratio of MsCl, catalyst is：1：(1~10)：(1~10)；And/or, the temperature of the condensation reaction
Spend for 20~40 DEG C；The time of the condensation reaction is 5~10h；And/or, the catalyst is organic base, selected from pyridine, three
One or more in ethamine, diethylamine, ethylenediamine, DMAP, triethylene diamine, DIPEA.
6. the method as described in claim 1, it is characterised in that in step (e), the solvent is high boiling solvent, selected from N-
Methyl pyrrolidone (NMP), DMF (DMF), N, N- dimethyl propylene alkenyl ureas (DMPU), dimethyl sulfoxide (DMSO)
(DMSO) one or more in；And/or, the mol ratio of formula (5) compound and potassium acetate is 1：(1~20)；And/or,
The temperature of the elimination reaction is 100~130 DEG C.
7. the method as described in claim 1, it is characterised in that in step (f), the alkali be selected from sodium hydroxide, potassium hydroxide,
One or more in lithium hydroxide, sodium carbonate, potassium carbonate；And/or, the solvent is selected from methanol, ethanol, propyl alcohol, water, tetrahydrochysene
One or more in furans；And/or, the mol ratio of formula (6) compound and alkali is 1：(1~5)；And/or, the hydrolysis
The temperature of reaction is 20~40 DEG C.
8. the method as described in claim 1, it is characterised in that in step (g), the solvent is ether solvent, selected from tetrahydrochysene
One or more in furans or dioxane；And/or, the highly basic is selected from diisopropyl ammonia lithium, n-BuLi, tert-butyl lithium
In one or more；And/or, formula (7) compound, trim,ethylchlorosilane, the mol ratio of highly basic are 1:1~10；And/or, institute
The temperature for stating condensation reaction is -78~0 DEG C.
9. the method as described in claim 1, it is characterised in that in step (h), the solvent is selected from dichloromethane, two chloroethenes
One or more in alkane, tetrahydrofuran, acetonitrile, chloroform, toluene, acetone；And/or, the lewis acid is selected from boron trifluoride
Ether, boron trifluoride acetonitrile；And/or, formula (8) compound, acetaldehyde, lewis acidic mol ratio are 1:1~5:1~10；It is described
The temperature of aldol reaction is -78~0 DEG C.
10. the method as described in claim 1, it is characterised in that in step (i), the solvent be selected from methanol, ethanol, propyl alcohol,
One or more in water, tetrahydrofuran, acetone；And/or, the alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, carbon
One or more in sour potassium, sodium carbonate；And/or, formula (9) compound, the mol ratio of alkali are 1：(1~5)；The hydrolysis
Temperature be 50~110 DEG C.
11. the method as described in claim 1, it is characterised in that in step (j), the catalyst is palladium carbon；And/or, it is described
Hydrogen Vapor Pressure is 0.1~10MPa；And/or, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrochysene furan
One or more in muttering；And/or, formula (10) compound, the mass ratio of catalyst are 1：(0.01~0.4)；The hydrogen
The temperature for changing reduction reaction is 50~110 DEG C.
12. the method as described in claim 1, it is characterised in that in step (k), the solvent is selected from water, methanol, ethanol, third
One or more in alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran；And/or, the metal hydride is selected from sodium borohydride, boron hydrogen
Change the one or more in potassium；And/or, formula (11) compound, the mol ratio of metal hydride are 1:5；The reduction reaction
Temperature is 50~110 DEG C.
13. the method as described in claim 1, it is characterised in that in step (l), the solvent is selected from water, methanol, ethanol, third
One or more in alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran；And/or, the temperature of the reaction is 50~110 DEG C；With/
Or, the alkaline aqueous solution is the one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate；Institute
Catalyst is stated for palladium carbon；The Hydrogen Vapor Pressure is 0.1~10MPa；The metal hydride is sodium borohydride, potassium borohydride.
14. the method as described in claim 1, it is characterised in that in step (m), the solvent is selected from water, methanol, ethanol, third
One or more in alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran；And/or, the pH of the alkalescence condition is 9~14；And/or,
The metal hydride is selected from one or both of sodium borohydride, potassium borohydride；And/or, formula (10) compound, metal hydride
The mol ratio of thing is 1：(1~5)；The temperature of the reduction reaction is 50~110 DEG C.
15. the method as described in claim 1, it is characterised in that in step (n), the catalyst is palladium carbon；And/or, it is described
Hydrogen Vapor Pressure is 0.1~10MPa；And/or, the solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrochysene furan
One or more in muttering；And/or, formula (12) compound, the mass ratio of catalyst are 1：(0.01~0.4)；The hydrogen
The temperature for changing reduction reaction is 50~110 DEG C.
16. the method as described in claim 1, it is characterised in that step (a) is carried out under the conditions of lucifuge；Step (g) is first by it
He is mixed material, and highly basic is then added under inert conditions.
17. a class compound, it is characterised in that its structure is respectively as shown in formula (8), formula (9), formula (10), formula (12)：
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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 |
| CN107955056A (en) * | 2017-12-06 | 2018-04-24 | 南京法恩化学有限公司 | A kind of synthetic method of Austria's shellfish cholic acid and intermediate |
| CN112898369A (en) * | 2019-12-04 | 2021-06-04 | 博瑞生物医药（苏州）股份有限公司 | Process for the preparation of obeticholic acid |
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