CN106892954B - The preparation process of shellfish cholic acid difficult to understand - Google Patents
The preparation process of shellfish cholic acid difficult to understand 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
This patent application discloses a kind of preparation processes of shellfish cholic acid difficult to understand, including following preparation step: AB-1-AB-2-AB-3-AB-4-AB-5-AB-6-AB-7-AB-8-AB-9-AB-10, it is simple and efficient using the reaction condition in the preparation process of the preparation process, so as to make the quality controllable of shellfish cholic acid final product difficult to understand.
Description
Technical field
The present invention relates to a kind of steroids, and in particular to a kind of preparation process of Austria's shellfish cholic acid.
Background technique
Shellfish cholic acid category farnesoid X receptor agonist difficult to understand inhibits cytochromes 7A1 by activating farnesoid X receptor indirectly
(CYP7A1) gene expression.Since CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, shellfish cholic acid difficult to understand can inhibit cholic acid
Synthesis, for treating primary biliary cirrhosis and non-alcohol fatty liver.
In the patent document of Publication No. WO2006/122977, shellfish cholic acid synthesis technology difficult to understand, but above-mentioned patent text are disclosed
Following problems are still had in synthesis technology disclosed in part:
1, it during preparing Austria shellfish cholic acid intermediate (AB-5), to use and arrive intermediate (AB-4), diisopropylamine, three
Methylchlorosilane, the materials such as tetrahydrofuran, these reagents and solvent, which require thoroughly drying, to be used, and reaction condition compares
Harshness, if reaction uses n-BuLi, reaction must be carried out at -78 DEG C.When carrying out scale up test according to above-mentioned condition, need
It expends considerable time and effort and dries all materials, and since intermediate (AB-4) is an oily object, it more difficult to by it
It dries to complete anhydrous state.It to be used in reaction process and arrive a large amount of n-BuLi, danger coefficient is higher.And reaction also needs
It to be carried out in the case where pilot plant is difficult to reach -78 DEG C.So entire reaction condition is all that comparison is harsh.One in reaction process
More stubborn problem is: since reaction process is first to make diisopropylamine lithium (3 equivalent), trim,ethylchlorosilane is then added
(5 equivalent) adds intermediate (AB-4) (1 equivalent).If finding that intermediate (AB-4) does not turn in monitoring reaction course
Change completely, can not add during the reaction above-mentioned material again.If unreacted intermediate (AB-4) returned again
It receives, repeats above-mentioned reaction condition, take a substantial amount of time again and energy.It finds during the reaction, only intermediate (AB-
4) the quality controllable of shellfish cholic acid final product difficult to understand can just be made by completely consuming.
2, it during preparing Austria shellfish cholic acid intermediate (AB-8), to use and arrive intermediate (AB-7), 3 atmospheric pressure
Hydrogen, the materials such as palladium carbon.Above-mentioned reaction it is higher to pressure requirements, laboratory existence conditions are unable to satisfy using 3 atmospheric pressure
Hydrogen reaction requirement.
3, it during preparing Austria shellfish cholic acid intermediate (AB-9), to use and arrive intermediate (AB-8), water and hydroxide
The materials such as sodium.But above-mentioned reaction can be in two phase reaction, and the AB-8 of (24 hours) also 5% or so is not anti-after long-time is reacted
It should be complete.
In conclusion although method disclosed in above-mentioned patent document can be used in synthesizing shellfish cholic acid difficult to understand, preparation process
Severe reaction conditions, and the quality of shellfish cholic acid final product difficult to understand is difficult to control.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation processes of shellfish cholic acid difficult to understand, using in the preparation process of the preparation process
Reaction condition be simple and efficient, so as to make the quality controllable of shellfish cholic acid final product difficult to understand.
In order to achieve the above objectives, base case of the invention is as follows:
A kind of preparation process of Austria's shellfish cholic acid, including following preparation step: AB-1-AB-2-AB-3-AB-4-AB-
5-AB-6-AB-7-AB-8-AB-9-AB-10, wherein AB-1-AB-2:
AB-2-AB-3:
AB-3-AB-4:
AB-5-AB-6:
AB-6-AB-7:
AB-9-AB-10:
In AB-4-AB-5, include the following steps:
(1) when -15 DEG C, it is molten that trifluoromethanesulfonic acid trimethyl silicane fat drips are entered into the methylene chloride dissolved with AB-4, triethylamine
In liquid and stir；
(2) water stirring is added after completion of the reaction, separated organic phase out is washed, and is done after separating organic layer
It is dry, through filtering, AB-5 crude product is obtained after filtrate is spin-dried for；
(3) n-hexane dissolution AB-5 crude product is used, be filtered, washed and obtains AB-5 after evaporated under reduced pressure, is reacted as follows:
In AB-7-AB-8, include the following steps:
(1) methanol solution dissolved with AB-7, ammonium formate, palladium carbon is heated with stirring to 50 DEG C；
(2) reacting liquid temperature is down to 30 DEG C after the reaction was completed, filters and filtrate is cooled to 0~5 DEG C, hydrochloric acid water is added
Solution adjusts pH=3, and stirring is precipitated and filtered until obtaining solid, and obtains AB-8 in 50 DEG C of decompression dryings, reacts as follows:
In AB-8-AB-9, include the following steps:
(1) it will be dissolved with AB-8, the mixed solution of the second alcohol and water of sodium hydroxide is heated with stirring to reflux, by reaction solution temperature
Degree is down to 0~5 DEG C；
(2) water and aqueous hydrochloric acid solution is added, adjusts pH=3, stirring is precipitated and filtered until obtaining solid, and is subtracted in 50 DEG C
Pressure drying obtains AB-9 crude product；
(3) ethyl alcohol is added into AB-9 crude product and heating is completely dissolved crude product, adds water, keeps the temperature 1 hour at 50 DEG C,
40 DEG C keep the temperature 1 hour, 30 DEG C heat preservation 1 hour after filter, ethyl alcohol is added into filtered solid, is heated to being completely dissolved, add
Entering water, is cooled to room temperature, filtering obtains AB-9, it reacts as follows:
This programme has the advantages that
1, in AB-4-AB-5, entire reaction uses trifluoromethanesulfonic acid trimethyl silicone grease as alkene purified reagent, uses
Triethylamine is as alkali.When adopting said method carrys out synthetic intermediate AB-5, reaction condition is mild, can be carried out at room temperature anti-
It answers.And the reagent used of reaction process and solvent are all needed not move through and are deliberately dried, and operability is all very simple.
2, in AB-7-AB-8, entire reaction use ammonium formate former as hydrogen, and palladium carbon is as catalyst, the behaviour that entirely reacts
The property made is all very simple.And intermediate A B-8 can be used as preparation shellfish cholic acid impurity isomers difficult to understand and use.
3, in AB-8-AB-9, it is the second alcohol and water of 1:1 as solvent that reaction, which uses volume ratio, so that it may be made well anti-
It answers liquid in homogeneous reaction, both can shorten the reaction time in this way, or so two hours can react completion, can reduce significantly
Translocation reaction time and conversion ratio.
Prioritization scheme 1, advanced optimizes base case, in the step 1 of AB-4-AB-5, presses and works as meter, described
The equivalent proportion of AB-4, trifluoromethanesulfonic acid trimethyl silicone grease and triethylamine are 1:1.5:3.Applicants experimentally found that AB-4, three
When fluorine methanesulfonic acid trimethyl silicone grease and triethylamine use above-mentioned equivalent proportion, reacts the yield for obtaining AB-5 and purity is higher.
Prioritization scheme 2, advanced optimizes base case, in the step 1 of AB-7-AB-8, presses and works as meter, described
The equivalent proportion of AB-7, ammonium formate and palladium carbon are 1:10:0.05.Applicants experimentally found that AB-7, ammonium formate and palladium carbon use
When above-mentioned equivalent proportion, the yield and purity for the AB-5 being prepared are higher, and the fast speed reacted.
Prioritization scheme 3, advanced optimizes base case, in the step 1 of AB-4-AB-5, is monitored using TLC method
Reaction adds trifluoromethanesulfonic acid trimethyl silicone grease if AB-4 consumption is not complete, until AB-4 consumption is complete.Applicant passes through reality
It issues after examination and approval now, on the one hand can save raw material, on the other hand can effectively reduce the impurity content in reaction product.
Prioritization scheme 4, in the step 1 of AB-7-AB-8, the temperature of heating is 45-50 DEG C.Applicant sends out in an experiment
It is existing, it reacts within the said temperature range, the time of the AB-8 reacted is short, and high income.
Prioritization scheme 5, in the step 1 of AB-4-AB-5, triethylamine raw material is dry using NaH, and control moisture content is small
In 0.01%.Applicant in experiments it is found that, after above-mentioned steps are handled, the purity of AB-5 can be effectively improved.
Prioritization scheme 6 controls reaction system moisture content less than 0.06% in the step 1 of AB-4-AB-5.Applicant
In experiments it is found that the purity for the AB-5 being prepared is higher when reaction system moisture content is controlled within the above range, and
Reaction speed is also very fast.
Prioritization scheme 7, to advanced optimizing for any one of base case, prioritization scheme 1-6, in AB-1-AB-2, also
Including the purifying to AB-2, comprising the following steps:
(1) AB-2 solid addition tetrahydrofuran to be purified after drying is heated to reflux and is completely dissolved, normal pressure boils off four
Hydrogen furans；
(2) it is added dropwise to n-hexane, solution is then cooled to 0 DEG C, is stirred 60 minutes, the solid being precipitated is filtered；
(3) by filter cake in 50 DEG C of decompression dryings, to get the AB-2 arrived after purification until product is no longer weightless.
Applicants experimentally found that the high income of the method using above-mentioned purifying AB-2.
Prioritization scheme 8, to advanced optimizing for any one of base case, prioritization scheme 1-6, in AB-1-AB-2, also
Including the purifying to AB-2, comprising the following steps:
(1) water is added into AB-2 solid to be purified, stirs and be heated to 100 DEG C of heat preservations 1 hour, is washed with water, it will
Filter cake is in 50 DEG C of decompression dryings, until product is no longer weightless；
(2) solid after drying is added in the solution of ethyl acetate, is heated to reflux；
(3) it is complete to solid to be added dropwise to methanol, normal pressure boils off solvent, and it is then that solution is 0 DEG C cooling, it stirs 60 minutes, it will
The solid filtering being precipitated；
(4) by filter cake in 50 DEG C of decompression dryings, to get the AB-2 arrived after purification until product is no longer weightless.
It is handed over applicants experimentally found that first can be avoided with water mashing using the above method and ester occurs in methanol eddy
It changes, is crystallized when more suitable for crude product impurity.
Specific embodiment
Below by specific embodiment, the present invention is described in further detail:
The preparation process of entire shellfish cholic acid difficult to understand is described in detail by taking embodiment 1 as an example below, other embodiments are only to difference
Place is illustrated, and unaccounted part is same as Example 1.
Embodiment 1:
A kind of preparation process of Austria's shellfish cholic acid, including following preparation step: AB-1-AB-2-AB-3-AB-4-AB-
5-AB-6-AB-7-AB-8-AB-9, wherein the reaction of AB-1-AB-2 is as follows:
Each raw material proportioning of AB-1-AB-2 is as shown in table 1:
Table 1
The preparation process of AB-1-AB-2 is as follows: will be dissolved with the mixing of the 700mL acetone and 400mL water of AB-1 (100g)
Solution is cooled to -10 DEG C, and NBS (59g) and 700mL acetone are heated to 50 DEG C and are completely dissolved, and is then cooled to room temperature, and is then added dropwise
Enter in reaction solution (interior temperature is less than -10 DEG C) stirring 2 hours.Monitoring after the reaction was completed (raw material < 1%), is added dropwise to and is dissolved with
The aqueous solution 100mL of sodium hydrogensulfite (26.4g), normal pressure boil off solvent 700mL, hence it is evident that have solid precipitation, filter while hot, use
200mL water washing, by filter cake in 50 DEG C of decompression dryings (6 hours), until product is no longer weightless (96g).
It further include the purifying to AB-2 in AB-1-AB-2, comprising the following steps:
(1) solid addition tetrahydrofuran (430mL) after drying is heated to reflux and is completely dissolved, normal pressure boils off tetrahydro furan
Mutter (143mL)；
(2) n-hexane (574mL) is added dropwise inwards again, then by 0 DEG C of solution Slow cooling, stirs 60 minutes, will be precipitated
Solid filtering；
(3) by filter cake in 50 DEG C of decompression dryings, until product is no longer weightless to get to after purification AB-2 (75g,
75%), the method high income.
The reaction of AB-2-AB-3 is as follows:
Each raw material proportioning of AB-2-AB-3 is as shown in table 2:
Table 2
The preparation process of AB-2-AB-3 is as follows: will be dissolved with AB-2 (76.2g), the methanol solution of methanesulfonic acid (400mg)
(380mL) is heated with stirring to reflux.After stirring 2 hours, HPLC is monitored after the reaction was completed (raw material < 1%), and methanol is removed under reduced pressure
(50℃).Reacting liquid temperature is down to room temperature, methylene chloride (600mL) and saturated sodium bicarbonate aqueous solution (250mL), water is added
(180mL) is stirred 30 minutes, is layered (being likely to occur emulsion, filtering can obviously get well layering), water layer uses 150mL again
Methylene chloride extraction, merges all organic layers, is washed with saturation NaCl solution (300mL), with anhydrous magnesium sulfate (38g) dry 2
Hour (moisture content is 0.07% after dry).Filtering, filtrate are directly used in the preparation of AB-4 without further purification.
AB-3-AB-4:
Each raw material proportioning of AB-3-AB-4 is as shown in table 3:
Table 3
The preparation process of AB-3-AB-4 is as follows: at 0 DEG C, trim,ethylchlorosilane (63.2g) is slowly dropped into dissolved with AB-3
(78.8g), in methylene chloride (750mL) solution of triethylamine (98.7g, 54.4mmol).It is added dropwise within 20 minutes, stirring 1 is small
When.TLC is monitored after the reaction was completed, and water (700mL) is added toward reaction solution and stirs 10 minutes, and separated organic phase out is made respectively
With saturated sodium-chloride and anhydrous magnesium sulfate (40g) dry about half an hour.The resulting remnants after evaporated under reduced pressure on Rotary Evaporators
Object 92g is added n-hexane (280mL) and heats 50 DEG C to basic dissolution, filters out insoluble matter, filtrate is slow cooling to -25 DEG C, stirs
It mixes 60 minutes, there is good solid to be precipitated, filtering, filter cake is dried under reduced pressure to obtain white solid 63g (purity 94%).
In AB-4-AB-5, include the following steps:
(1) when -15 DEG C, trifluoromethanesulfonic acid trimethyl silicone grease (new to steam) (44.1g) is slowly dropped into dissolved with AB-4
(63.0g), in methylene chloride (600mL) solution of triethylamine (44.0g).It is added dropwise within about 80 minutes that (interior temperature must not exceed -10
DEG C), stir about 1 hour；
(2) TLC monitoring after the reaction was completed, is added water (600mL) and stirs 10 minutes, and separated organic phase out is made respectively
It is washed with saturated sodium-chloride (500mL), separates organic layer, it is 2 hours dry with 35g anhydrous magnesium sulfate.Filter out MaSO4, filtrate
AB-5 crude product 75g is obtained after being spin-dried for；
(3) 250mL n-hexane dissolution AB-5 crude product is used, 35g silica white is put down layer, upper layer adds lower anhydrous magnesium sulfate 35g
It is made into a filter device, filters, is washed in three times with 400mL n-hexane, filtrate obtains after evaporated under reduced pressure on Rotary Evaporators
AB-5 grease 72g is directly used in preparation AB-6, reacts as follows:
Each raw material proportioning of AB-4-AB-5 is as shown in table 4:
Table 4
AB-5-AB-6:
Each raw material proportioning of AB-5-AB-6 is as shown in table 5:
Table 5
The preparation process of AB-5-AB-6 is as follows: dissolved with AB-5 (18.0gl), the new steaming dichloromethane of acetaldehyde (7.2g)
Alkane (180mL) solution is cooled to -78 DEG C under nitrogen protection, and in -78 DEG C, boron trifluoride acetonitrile complex compound (44.6g) is slowly dripped
Enter into solution (heat release is severe when starting to be added dropwise).(interior temperature must not exceed -55 DEG C) is added dropwise within about 40 minutes.It is small to stir 1.5
When after contact plate TLC show raw material react), be warming up to 0 DEG C stirring 1 hour after, monitoring after the reaction was completed (have partially be removed
Protection becomes intermediate A B-3), saturated sodium bicarbonate aqueous solution (250mL) is added and stirs 10 minutes (water layer pH=7-8), by institute
The organic phase isolated washed once with saturated sodium-chloride, and separation organic layer is resulting residual after evaporated under reduced pressure on Rotary Evaporators
Excess (15g) (HPLC shows AB-6:AB-3=97:3) AB-6.
AB-6-AB-7:
Each raw material proportioning of AB-6-AB-7 is as shown in table 6:
Table 6
The preparation process of AB-6-AB-7 is as follows: will be dissolved with the 36mL methanol and 3.35g hydroxide of AB-6 (crude product 18g)
The mixed solution of sodium water (12mL) solution is heated with stirring to 45 DEG C.After stirring 2 hours, TLC is monitored after the reaction was completed by reaction solution
Temperature is down to 10 DEG C, and water 200mL is added, and adjusts pH=3-4 or so with 3N HCl solution, and filtering is washed with water to be neutral, Gu
Body decompression drying (55 DEG C, 8 hours), obtains solid 16g.It is heated to reflux and is completely dissolved with 32mLTHF, n-hexane is added dropwise
(96mL) has obvious solid to be precipitated, and after being stirred at room temperature 0.5 hour, filtering, solid decompression drying obtains 11g.Ethyl alcohol is added dropwise toward solid
(about 38mL) heats Hui Cheng to being completely dissolved, and is added dropwise water (38mL), is slow cooling to 40 DEG C, is stirred overnight.Filtering, solid are used
20mL (50%EA/PE) washing, obtains solid 9g and (is denoted as AB 7-1, purity is about 95%).Ethyl alcohol is added (about in AB7-1 (9g)
36mL) heating Hui Cheng is added dropwise water (36mL) to being completely dissolved, is slow cooling to 30 DEG C, is stirred overnight.Filtering, dries to obtain solid
8g (is denoted as AB 7-2, purity about 97% or more).
AB-7-AB-8: in, include the following steps:
(1) it will be dissolved with AB-7 (50.0g, 120mmol), ammonium formate (75.7g, 1200mmol), the first of palladium carbon (5.0g)
Alcoholic solution (250mL) is heated with stirring to 50 DEG C；
(2) after reacting 2 hours, reacting liquid temperature is down to 30 DEG C after the reaction was completed by HPLC monitoring.By the palladium in reaction solution
After carbon filters out.Filtrate is cooled to 0~5 DEG C, is slowly added to the aqueous hydrochloric acid solution (220mL) of 3mol/L, adjusts pH=3, stirring
Until obtaining good solid precipitating.After the filtering of generated solid, and in 50 DEG C of decompression dryings, until product is no longer weightless
Until, obtain AB-8.(49g, 98%) reacts as follows:
Each raw material proportioning of AB-7-AB-8 is as shown in table 7:
Table 7
In AB-8-AB-9, include the following steps:
(1) AB-8 (50.0g), the 150mL ethyl alcohol of sodium hydroxide (48.0g) and the mixed solution of 300mL water will be dissolved with
It is heated with stirring to reflux (105 DEG C of oil bath temperature).After HPLC monitoring reaction (AB-8 surplus is less than 4%), by reacting liquid temperature
It is down to 0~5 DEG C；
(2) water 1.3L is added, is slowly added to the aqueous hydrochloric acid solution (400mL) of 3mol/L, adjusts pH=3, stirring is until obtain
It is precipitated to good solid.After the filtering of generated solid, with 300mL water washing until water layer is neutrality, and in 50 DEG C
Decompression drying obtains AB-9 crude product 49g until product is no longer weightless；
(3) 200mL ethyl alcohol is added into AB-9 crude product, is heated to 75 DEG C, is completely dissolved.Dropwise addition 300mL water inward, 50
DEG C 1 hour, 40 DEG C 1 hour, 30 DEG C after 1 hour, are filtered to obtain 45g (purity 93.5%).160mL ethyl alcohol, heating is added toward solid
To 75 DEG C, it is completely dissolved.240mL water is added dropwise inward, is slowly cooled to room temperature overnight, filters to obtain 42g (purity 95.7%), reacts
It is as follows:
Each raw material proportioning of AB-8-AB-9 is as shown in table 8:
Table 8
AB-9-AB-10:
Each raw material proportioning of AB-9-AB-10 is as shown in table 9:
Table 9
The preparation process of AB-9-AB-10 is as follows: toward dissolved with AB-9 (42.0g), the 140mL of sodium hydroxide (32.0g)
Sodium borohydride (19.1g) is added in the mixed solution of ethyl alcohol and 280mL water.After reaction response is stablized, reaction solution is heated 40 DEG C
About 15 hours.After HPLC monitors fully reacting.Reacting liquid temperature is down to 0~5 DEG C, water 1.2L, methyl tertiary butyl ether(MTBE) is added
(250mL) is slow added into the aqueous hydrochloric acid solution (430mL) of 3mol/L, adjusts pH=3.Ethyl acetate is then added
(400mL) is stirred 10 minutes.Stratification separates organic phase.Organic phase uses saturated sodium-chloride and anhydrous sodium sulfate dry respectively
It is dry.Rear resulting residue (39g) will be evaporated and be dissolved in methylene chloride (400mL), a large amount of solids are gradually generated after stirring.By institute
The solid filtered out dries until no longer weightless that (about 30g shows that poor purity is 99.3%), to be added toward solid at 50 DEG C
30mL ethyl acetate is heated to 60 DEG C, is completely dissolved.270ml methylene chloride is added dropwise inward, is slowly cooled to room temperature overnight, then
It is cooled to 15 DEG C to stir 2 hours, crosses filter solid and dry at 50 DEG C until obtaining 22g until no longer weightless (shows poor purity
99.8%) to get to shellfish cholic acid difficult to understand.
Embodiment 2:
It is in place of the difference of embodiment 1: further includes the purifying to AB-2, including following step in AB-1-AB-2
It is rapid:
(1) 1L water is added into AB-2 solid to be purified while hot, is stirred and heated to 100 DEG C and keeps the temperature 1 hour, use 200mL
Water washing, by filter cake in 50 DEG C of decompression dryings (6 hours), until product is no longer weightless (96g).
(2) solid after drying is added in the solution of ethyl acetate of 960mL, is heated to reflux
(3) methanol is added dropwise to it to be completely dissolved (about 140mL) to it, it is then that solution is slow that normal pressure boils off solvent 350mL
It is 0 DEG C cooling, it stirs 60 minutes, the solid being precipitated is filtered；
(4) by filter cake in 50 DEG C of decompression dryings, until product is no longer weightless to get to after purification AB-2 (60g,
60%), the method first with water mashing is tied when more suitable for crude product impurity in order to avoid transesterification occurs in methanol eddy
It is brilliant.
By filter cake in 50 DEG C of decompression dryings, to get the AB-2 arrived after purification until product is no longer weightless.
What has been described above is only an embodiment of the present invention, and the common sense such as well known characteristic do not describe excessively herein in scheme.
It should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise, several changes can also be made
Shape and improvement, these also should be considered as protection scope of the present invention, these all will not influence the effect and patent that the present invention is implemented
Practicability.The scope of protection required by this application should be based on the content of the claims, the specific embodiment party in specification
The records such as formula can be used for explaining the content of claim.
Claims (9)
1. the preparation process of shellfish cholic acid difficult to understand, including following preparation step: AB-1-AB-2-AB-3-AB-4-AB-5-AB-
6-AB-7-AB-8-AB-9-AB-10, wherein AB-1-AB-2:
AB-2-AB-3:
AB-3-AB-4:
AB-5-AB-6:
AB-6-AB-7:
AB-9-AB-10:
。
It is characterized in that, including the following steps: in AB-4-AB-5
(1) when -15 DEG C, by trifluoromethanesulfonic acid trimethyl silicane fat drips enter dissolved with AB-4, triethylamine dichloromethane solution in
And it stirs；
(2) water stirring is added after completion of the reaction, separated organic phase out is washed, and is dried after separating organic layer, is passed through
Filtering obtains AB-5 crude product after being spin-dried for filtrate；
(3) n-hexane dissolution AB-5 crude product is used, be filtered, washed and obtains AB-5 after evaporated under reduced pressure, is reacted as follows:
In AB-7-AB-8, include the following steps:
(1) methanol solution dissolved with AB-7, ammonium formate, palladium carbon is stirred and is heated；
(2) reacting liquid temperature is down to 30 DEG C after the reaction was completed, filters and filtrate is cooled to 0~5 DEG C, it is water-soluble that hydrochloric acid is added
Liquid adjusts pH=3, and stirring is precipitated and filtered until obtaining solid, and obtains AB-8 in 50 DEG C of decompression dryings, reacts as follows:
In AB-8-AB-9, include the following steps:
(1) it will be dissolved with AB-8, the mixed solution of the second alcohol and water of sodium hydroxide is heated with stirring to reflux, reacting liquid temperature is dropped
To 0~5 DEG C；
(2) water and aqueous hydrochloric acid solution is added, adjusts pH=3, stirring is precipitated and filtered until obtaining solid, and is dried in 50 DEG C of decompressions
It is dry to obtain AB-9 crude product；
(3) ethyl alcohol is added into AB-9 crude product and heating is completely dissolved crude product, adds water, keeps the temperature 1 hour, 40 DEG C at 50 DEG C
Heat preservation 1 hour, 30 DEG C heat preservation 1 hour after filter, ethyl alcohol is added into filtered solid, is heated to being completely dissolved, addition water,
It is cooled to room temperature, filtering obtains AB-9, it reacts as follows:
2. the preparation process of Austria's shellfish cholic acid according to claim 1, which is characterized in that in the step 1 of AB-4-AB-5,
By meter is worked as, the equivalent proportion of the AB-4, trifluoromethanesulfonic acid trimethyl silicone grease and triethylamine are 1:1.5:3.
3. the preparation process of Austria's shellfish cholic acid according to claim 1, which is characterized in that in the step 1 of AB-7-AB-8,
By meter is worked as, the equivalent proportion of the AB-7, ammonium formate and palladium carbon are 1:10:0.05.
4. the preparation process of Austria's shellfish cholic acid according to claim 1, which is characterized in that in the step 1 of AB-4-AB-5,
It is monitored and is reacted using TLC method, if AB-4 consumption is not complete, add trifluoromethanesulfonic acid trimethyl silicone grease, until AB-4 consumption is complete.
5. the preparation process of Austria's shellfish cholic acid according to claim 1, which is characterized in that in the step 1 of AB-7-AB-8,
The temperature of heating is 45-50 DEG C.
6. the preparation process of Austria's shellfish cholic acid according to claim 1, which is characterized in that in the step 1 of AB-4-AB-5
In, triethylamine raw material is dry using NaH, controls moisture content less than 0.01%.
7. the preparation process of Austria's shellfish cholic acid according to claim 1, which is characterized in that in the step 1 of AB-4-AB-5,
Reaction system moisture content is controlled less than 0.06%.
8. the preparation process of Austria's shellfish cholic acid according to claim 1-7, which is characterized in that in AB-1-AB-2
In, it further include the purifying to AB-2, comprising the following steps:
(1) AB-2 solid addition tetrahydrofuran to be purified after drying is heated to reflux and is completely dissolved, normal pressure boils off tetrahydro furan
It mutters；
(2) it is added dropwise to n-hexane, solution is then cooled to 0 DEG C, is stirred 60 minutes, the solid being precipitated is filtered；
(3) by filter cake in 50 DEG C of decompression dryings, to get the AB-2 arrived after purification until product is no longer weightless.
9. the preparation process of Austria's shellfish cholic acid according to claim 1-7, which is characterized in that in AB-1-AB-2
In, it further include the purifying to AB-2, comprising the following steps:
(1) water is added into AB-2 solid to be purified, stirs and be heated to 100 DEG C of heat preservations 1 hour, is washed with water, by filter cake
In 50 DEG C of decompression dryings, until product is no longer weightless；
(2) solid after drying is added in the solution of ethyl acetate, is heated to reflux；
(3) it is complete to solid to be added dropwise to methanol, normal pressure boils off solvent, and it is then that solution is 0 DEG C cooling, it stirs 60 minutes, will be analysed
Solid filtering out；
(4) by filter cake in 50 DEG C of decompression dryings, to get the AB-2 arrived after purification until product is no longer weightless.
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