CN106892954A - The preparation technology of shellfish cholic acid difficult to understand - Google Patents
The preparation technology of shellfish cholic acid difficult to understand Download PDFInfo
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- CN106892954A CN106892954A CN201710102306.1A CN201710102306A CN106892954A CN 106892954 A CN106892954 A CN 106892954A CN 201710102306 A CN201710102306 A CN 201710102306A CN 106892954 A CN106892954 A CN 106892954A
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- cholic acid
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- 0 CCC[C@@](CC(C)C)C=C(*)C(C)C(CCC1)[C@@](C)C1[C@](C)CC* Chemical compound CCC[C@@](CC(C)C)C=C(*)C(C)C(CCC1)[C@@](C)C1[C@](C)CC* 0.000 description 2
- MEBONNVPKOBPEA-UHFFFAOYSA-N CC1C(C)(C)CCCC1 Chemical compound CC1C(C)(C)CCCC1 MEBONNVPKOBPEA-UHFFFAOYSA-N 0.000 description 1
- KUYUGMAABRGACL-DFALEMJPSA-N CCC(C(CCCC1)[C@@]1(C)C(CC1)CC(CC2)[C@@]1(C)C2[C@H](C)CCC(O)=O)=C=O Chemical compound CCC(C(CCCC1)[C@@]1(C)C(CC1)CC(CC2)[C@@]1(C)C2[C@H](C)CCC(O)=O)=C=O KUYUGMAABRGACL-DFALEMJPSA-N 0.000 description 1
- YDZIGWVXGAPQTQ-GVXQRQBISA-N CC[C@@H](C(CCCC1)[C@@]1(C)C(CC1CC2)C3C2[C@H]1C(O)=O)C3=O Chemical compound CC[C@@H](C(CCCC1)[C@@]1(C)C(CC1CC2)C3C2[C@H]1C(O)=O)C3=O YDZIGWVXGAPQTQ-GVXQRQBISA-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
Abstract
The present patent application discloses a kind of preparation technology of shellfish cholic acid difficult to understand, including following preparation process：9-AB of AB 1-AB, 2-AB, 3-AB, 4-AB, 5-AB, 6-AB, 7-AB, 8-AB 10, it is simply efficient using the reaction condition in the preparation process of the preparation technology, so as to make the quality controllable of shellfish cholic acid end-product difficult to understand.
Description
Technical field
The present invention relates to a kind of steroid, and in particular to a kind of preparation technology of shellfish cholic acid difficult to understand.
Background technology
Shellfish cholic acid difficult to understand belongs to farnesoid X receptor activator, by activating farnesoid X receptor, cytochromes 7A1 is suppressed 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.
In the patent document of Publication No. WO2006/122977, shellfish cholic acid synthesis technique difficult to understand, but above-mentioned patent text are disclosed
Problems with is still present in synthesis technique disclosed in part：
1st, during shellfish cholic acid intermediate (AB-5) difficult to understand is prepared, to use to intermediate (AB-4), diisopropylamine, three
The materials such as methylchlorosilane, tetrahydrofuran, these reagents and solvent are required for the thorough drying could to use, and reaction condition compares
Harshness, such as reaction use n-BuLi, and reaction must be carried out at -78 DEG C.When carrying out scale up test according to above-mentioned condition, it is necessary to
Expend considerable time and effort and dry all of material, and because intermediate (AB-4) is an oily object, it more difficult to by it
Dry to complete anhydrous state.Will be using substantial amounts of n-BuLi be arrived in course of reaction, danger coefficient is higher.And reaction is also needed
To be carried out in the case where pilot plant is difficult to reach -78 DEG C.So whole reaction condition is all that comparing is harsh.One in course of reaction
More stubborn problem is：Because course of reaction is first to make diisopropylamine lithium (3 equivalent), trim,ethylchlorosilane is subsequently added
(5 equivalent), adds intermediate (AB-4) (1 equivalent).If finding that intermediate (AB-4) is no in monitoring reaction course to turn
Change completely, above-mentioned material can not possibly be during the course of the reaction added again.If unreacted intermediate (AB-4) returned again
Receive, repeat above-mentioned reaction condition, take a substantial amount of time again and energy.Find during the course of the reaction, only intermediate (AB-
4) consuming completely can just make the quality controllable of shellfish cholic acid end-product difficult to understand.
2nd, during shellfish cholic acid intermediate (AB-8) difficult to understand is prepared, using to intermediate (AB-7), 3 atmospheric pressure
The materials such as hydrogen, palladium carbon.Above-mentioned reaction it is higher to pressure requirements, laboratory existence conditions cannot be met using 3 atmospheric pressure
Hydrogen reaction requirement.
3rd, during shellfish cholic acid intermediate (AB-9) difficult to understand is prepared, to use to intermediate (AB-8), water and hydroxide
The materials such as sodium.But above-mentioned reaction can be in two phase reaction, and (24 hours) also have 5% or so AB-8 not anti-after long-time is reacted
Should be complete.
In sum, although the method disclosed in above-mentioned patent document can be used in synthesizing shellfish cholic acid difficult to understand, but preparation process
Severe reaction conditions, and the quality of shellfish cholic acid end-product difficult to understand is difficult to control to.
The content of the invention
It is an object of the invention to provide a kind of preparation technology of shellfish cholic acid difficult to understand, using in the preparation process of the preparation technology
Reaction condition it is simply efficient, so as to make the quality controllable of shellfish cholic acid end-product difficult to understand.
To reach above-mentioned purpose, base case of the invention is as follows：
A kind of preparation technology of shellfish cholic acid difficult to understand, including following preparation process：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, comprise the following steps：
(1) when -15 DEG C, by TFMS trimethyl silicane fat drips enter to be dissolved with AB-4, triethylamine dichloromethane it is molten
In liquid and stir；
(2) add water stirring after completion of the reaction, by it is separated go out organic phase washing, and done after separating organic layer
It is dry, through filtering, AB-5 crude products are obtained after filtrate is spin-dried for；
(3) n-hexane dissolution AB-5 crude products are used, AB-5 is obtained after filtering, washing and evaporated under reduced pressure, reacted as follows：
In AB-7-AB-8, comprise the following steps：
(1) AB-7, ammonium formate, the methanol solution of palladium carbon will be dissolved with and is heated with stirring to 50 DEG C；
(2) reacting liquid temperature is down to 30 DEG C after the completion of reacting, is filtered and filtrate is cooled to 0~5 DEG C, add hydrochloric acid water
Solution, adjusts PH=3, stirring until obtaining solids of sedimentation and filtering, and obtains AB-8 in 50 DEG C of decompression dryings, reacts as follows：
In AB-8-AB-9, comprise the following steps：
(1) AB-8 will be dissolved with, the mixed solution of the second alcohol and water of NaOH is heated with stirring to backflow, will react liquid temperature
Degree is down to 0~5 DEG C；
(2) water and aqueous hydrochloric acid solution are added, PH=3, stirring is adjusted until obtaining solids of sedimentation and filtering, and subtract in 50 DEG C
Pressure drying obtains AB-9 crude products；
(3) toward ethanol is added in AB-9 crude products and heating is completely dissolved crude product, water is added, in 50 DEG C of insulations 1 hour,
40 DEG C be incubated 1 hour, 30 DEG C insulation 1 hour after filter, toward filter after solid in add ethanol, be heated to being completely dissolved, plus
Enter water, be cooled to room temperature, filtering obtains AB-9, reacts as follows：
This programme has the following advantages that：
1st, in AB-4-AB-5, whole reaction uses TFMS trimethyl silicone grease as alkene purified reagent, uses
Triethylamine is used as alkali.When adopting said method carrys out synthetic intermediate AB-5, reaction condition is gentle, can be carried out at room temperature anti-
Should.And the reagent used of course of reaction and solvent are all needed not move through and deliberately dried, and operability is all very simple.
2nd, in AB-7-AB-8, whole reaction uses ammonium formate former as hydrogen, and palladium carbon is used as catalyst, the behaviour of whole reaction
The property made is all very simple.And intermediate A B-8 can be used as shellfish cholic acid impurity isomers difficult to understand is prepared.
3rd, in AB-8-AB-9, reaction is 1 using volume ratio:1 second alcohol and water is used as solvent, it is possible to make well anti-
Answer liquid in homogeneous reaction, so both can shorten the reaction time, or so two hours can just react completion, can reduce significantly
Translocation reaction time and conversion ratio.
Prioritization scheme 1, the further optimization to base case, 1 the step of AB-4-AB-5 in, it is described by gauge is worked as
The equivalent proportion of AB-4, TFMS trimethyl silicone grease and triethylamine is 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, the yield and purity that reaction obtains AB-5 are higher.
Prioritization scheme 2, the further optimization to base case, 1 the step of AB-7-AB-8 in, it is described by gauge is worked as
The equivalent proportion of AB-7, ammonium formate and palladium carbon is 1：10：0.05.Applicants experimentally found that, AB-7, ammonium formate and palladium carbon are used
During above-mentioned equivalent proportion, the yield and purity of the AB-5 for preparing are higher, and reaction speed.
Prioritization scheme 3, the further optimization to base case, 1 the step of AB-4-AB-5 in, using TLC methods monitor
Reaction, if AB-4 consumption is not complete, adds TFMS trimethyl silicone grease, until AB-4 consumption is complete.Applicant is by real
Issue after examination and approval now, on the one hand can save raw material, on the other hand can effectively reduce the impurity content in product.
Prioritization scheme 4,1 the step of AB-7-AB-8 in, the temperature of heating is 45-50 DEG C.Applicant sends out in an experiment
It is existing, to be reacted in the range of said temperature, the time of the AB-8 that reaction is obtained is short, and high income.
Prioritization scheme 5,1 the step of AB-4-AB-5 in, triethylamine raw material using NaH dry, control moisture it is small
In 0.01%.Applicant in experiments it is found that, through above-mentioned steps process after, the purity of AB-5 can be effectively improved.
Prioritization scheme 6,1 the step of AB-4-AB-5 in, control reaction system moisture is less than 0.06%.Applicant
In experiments it is found that, reaction system moisture is controlled when within the above range, and the purity of the AB-5 for preparing is higher, and
Reaction speed is also very fast.
Prioritization scheme 7, to base case, the further optimization of prioritization scheme any one of 1-6, in AB-1-AB-2, also
Including the purifying to AB-2, comprise the following steps：
(1) tetrahydrofuran is added to be heated to reflux being completely dissolved AB-2 solids to be purified after drying, normal pressure boils off four
Hydrogen furans；
(2) n-hexane is added dropwise to, solution is then cooled to 0 DEG C, stirred 60 minutes, the solid filtering that will be separated out；
(3) filter cake untill product no longer weightlessness, that is, is obtained into AB-2 after purification in 50 DEG C of decompression dryings.
Applicants experimentally found that, using the high income of the method for above-mentioned purifying AB-2.
Prioritization scheme 8, to base case, the further optimization of prioritization scheme any one of 1-6, in AB-1-AB-2, also
Including the purifying to AB-2, comprise the following steps：
(1) to water is added in AB-2 solids to be purified, stir and be heated to 100 DEG C and be incubated 1 hour, wash with water, will
Filter cake in 50 DEG C of decompression dryings, untill product no longer weightlessness；
(2) solid after drying is added in the solution of ethyl acetate, is heated to reflux；
(3) it is added dropwise to methyl alcohol complete to solid, normal pressure boils off solvent, and solution then is cooled down into 0 DEG C, stirs 60 minutes, will
The solid filtering for being separated out；
(4) filter cake untill product no longer weightlessness, that is, is obtained into AB-2 after purification in 50 DEG C of decompression dryings.
Applicants experimentally found that, being first beaten with water using the above method can avoid ester friendship in methanol eddy
Change, it is adaptable to crystallized when crude product impurity is more.
Specific embodiment
Below by specific embodiment, the present invention is further detailed explanation：
Describe the preparation technology of whole Austria's shellfish cholic acid in detail by taking embodiment 1 as an example below, other embodiment is only to distinguishing it
Place is illustrated, and unaccounted part is same as Example 1.
Embodiment 1：
A kind of preparation technology of shellfish cholic acid difficult to understand, including following preparation process：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：The mixing of the 700mL acetone and 400mL water of AB-1 (100g) will be dissolved with
Solution is cooled to -10 DEG C, and NBS (59g) and 700mL acetone are heated to 50 DEG C and are completely dissolved, and are then cooled to room temperature, is then added dropwise
Enter in reaction solution (interior temperature is less than -10 DEG C) stirring 2 hours.(raw material after the completion of monitoring reaction<1%), it is added dropwise to and is dissolved with
The aqueous solution 100mL of sodium hydrogensulfite (26.4g), normal pressure boils off solvent 700mL, hence it is evident that has solid to separate out, filters while hot, uses
200mL water washings, by filter cake in 50 DEG C of decompression dryings (6 hours), untill product no longer weightlessness (96g).
In AB-1-AB-2, also including the purifying to AB-2, comprise the following steps：
(1) tetrahydrofuran (430mL) is added to be heated to reflux being completely dissolved the solid after drying, normal pressure boils off tetrahydrochysene 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 separated out
Solid filtering；
(3) by filter cake in 50 DEG C of decompression dryings, untill product no longer weightlessness, that is, obtain 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：AB-2 (76.2g), the methanol solution of methanesulfonic acid (400mg) will be dissolved with
(380mL) is heated with stirring to backflow.After stirring 2 hours, (raw material after the completion of HPLC monitoring reactions<1%) methyl alcohol, is removed under reduced pressure
(50℃).Reacting liquid temperature is down to normal temperature, dichloromethane (600mL) and saturated sodium bicarbonate aqueous solution (250mL), water is added
(180mL), stirs 30 minutes, is layered (being likely to occur emulsion, filtering can substantially get well layering), and water layer uses 150mL again
Dichloromethane is extracted, and merges all organic layers, is washed with saturation NaCl solution (300mL), and 2 are dried with anhydrous magnesium sulfate (38g)
Hour (moisture is 0.07% after drying).Filtering, the not purified preparation for being directly used in AB-4 of filtrate.
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 and is dissolved with AB-3
(78.8g), in dichloromethane (750mL) solution of triethylamine (98.7g, 54.4mmol).20 minutes completion of dropping, stirring 1 is small
When.TLC monitoring reaction after the completion of, toward reaction solution add water (700mL) stir 10 minutes, by it is separated go out organic phase make respectively
About half an hour is dried with saturated sodium-chloride and anhydrous magnesium sulfate (40g).In the remnants of gained after evaporated under reduced pressure on Rotary Evaporators
Thing 92g, adds n-hexane (280mL) to heat 50 DEG C to basic dissolving, filters out insoluble matter, and filtrate is slow cooling to -25 DEG C, stirs
Mix 60 minutes, there is good solid to separate out, filtering, filter cake drying under reduced pressure obtains white solid 63g (purity is 94%).
In AB-4-AB-5, comprise the following steps：
(1) when -15 DEG C, TFMS trimethyl silicone grease (new to steam) (44.1g) is slowly dropped into and is dissolved with AB-4
(63.0g), in dichloromethane (600mL) solution of triethylamine (44.0g).(interior temperature must not exceed -10 to about 80 minutes completion of dropping
DEG C), stir about 1 hour；
(2) TLC monitoring reaction after the completion of, add water (600mL) stir 10 minutes, by it is separated go out organic phase make respectively
Washed with saturated sodium-chloride (500mL), separate organic layer, dried 2 hours with 35g anhydrous magnesium sulfates.Filter out MaSO4, filtrate
AB-5 crude products 75g is obtained after being spin-dried for；
(3) 250mL n-hexane dissolution AB-5 crude products are used, 35g silica whites is put down layer, upper strata adds lower anhydrous magnesium sulfate 35g
Make a filter, filter, washed in three times with 400mL n-hexanes, filtrate is in 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：Being 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 in solution (heat release is severe when starting to be added dropwise).About 40 minutes completion of dropping (interior temperature must not exceed -55 DEG C).Stir 1.5 small
Shi Houdian plates TLC display raw material reaction it is complete), be warmed up to 0 DEG C stirring 1 hour after, monitoring reaction after the completion of (have part be removed
Protection turns into intermediate A B-3), add saturated sodium bicarbonate aqueous solution (250mL) to stir 10 minutes (water layer PH=7-8), by institute
The organic phase isolated washed once with saturated sodium-chloride, separate organic layer in after evaporated under reduced pressure on Rotary Evaporators gained it is residual
(HPLC shows AB-6 to excess (15g)：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：The 36mL methyl alcohol and 3.35g hydroxides of AB-6 (crude product 18g) will be dissolved with
The mixed solution of sodium water (12mL) solution is heated with stirring to 45 DEG C.After stirring 2 hours, by reaction solution after the completion of TLC monitoring reactions
Temperature is down to 10 DEG C, adds water 200mL, and PH=3-4 or so is adjusted with 3N HCl solutions, filters, and it is neutrality to wash with water, Gu
Body decompression drying (55 DEG C, 8 hours), obtains solid 16g.It is heated to reflux being completely dissolved with 32mLTHF, n-hexane is added dropwise
(96mL), has obvious solid to separate out, and after being stirred at room temperature 0.5 hour, filtering, solid decompression drying obtains 11g.Ethanol is added dropwise toward solid
(about 38mL) heats Hui Cheng to being completely dissolved, and water (38mL) is added dropwise, and is slow cooling to 40 DEG C, is stirred overnight.Filtering, solid is used
20mL (50%EA/PE) is washed, and is obtained solid 9g and (is designated as AB 7-1, purity is about 95%).AB7-1 (9g) is added into ethanol (about
36mL) heating Hui Cheng is added dropwise water (36mL) to being completely dissolved, and is slow cooling to 30 DEG C, is stirred overnight.Filtering, dries to obtain solid
8g (is designated as AB 7-2, purity about more than 97%).
AB-7—AB-8：In, comprise the following steps：
(1) AB-7 (50.0g, 120mmol), ammonium formate (75.7g, 1200mmol), the first of palladium carbon (5.0g) will be dissolved with
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 completion of HPLC monitoring reactions.By the palladium in reaction solution
After carbon is filtered.Filtrate is cooled to 0~5 DEG C, the aqueous hydrochloric acid solution (220mL) of 3mol/L is slowly added to, PH=3, stirring is adjusted
Until obtaining good solids of sedimentation.After by produced solid filtering, and in 50 DEG C of decompression dryings, until product is no longer weightless
Untill, 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, comprise the following steps：
(1) AB-8 (50.0g), the 150mL ethanol of NaOH (48.0g) and the mixed solution of 300mL water will be dissolved with
It is heated with stirring to backflow (105 DEG C of oil bath temperature).After HPLC monitorings reaction (AB-8 surpluses are less than 4%), by reacting liquid temperature
It is down to 0~5 DEG C；
(2) water 1.3L is added, the aqueous hydrochloric acid solution (400mL) of 3mol/L is slowly added to, PH=3, stirring is adjusted until obtaining
To good solids of sedimentation.After by produced solid filtering, with 300mL water washings to water layer is neutrality, and in 50 DEG C
Decompression drying, untill product no longer weightlessness, obtains AB-9 crude products 49g；
(3) toward addition 200mL ethanol in AB-9 crude products, 75 DEG C are heated to, are completely dissolved.300mL water, 50 DEG C are added dropwise inward
1 hour, 40 DEG C 1 hour, 30 DEG C after 1 hour, are filtered to obtain 45g (purity 93.5%).160mL ethanol is added toward solid, is heated to
75 DEG C, it is completely dissolved.240mL water is added dropwise inward, is slowly cooled to room temperature overnight, filter to obtain 42g (purity 95.7%), reaction is such as
Under：
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：It is past to be dissolved with AB-9 (42.0g), the 140mL of NaOH (32.0g)
The mixed solution of ethanol and 280mL water adds sodium borohydride (19.1g).After question response stable reaction, reaction solution is heated 40 DEG C
About 15 hours.After HPLC monitoring reactions completely.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.It is subsequently added ethyl acetate
(400mL), stirs 10 minutes.Stratification, separates organic phase.Organic phase is dry using saturated sodium-chloride and anhydrous sodium sulfate respectively
It is dry.The residue (39g) of gained is dissolved in dichloromethane (400mL) after being evaporated, and a large amount of solids are gradually produced after stirring.By institute
In drying at 50 DEG C, (about 30g shows poor purity 99.3%), 30mL to be added toward solid to the solid for leaching untill no longer weightlessness
Ethyl acetate, is heated to 60 DEG C, is completely dissolved.270ml dichloromethane is added dropwise inward, is slowly cooled to room temperature overnight, then cool down
Stirred 2 hours to 15 DEG C, cross filter solid and 22g (showing poor purity 99.8%) is obtained untill no longer weightlessness in drying at 50 DEG C, i.e.,
Obtain shellfish cholic acid difficult to understand.
Embodiment 2：
It is with place of the difference of embodiment 1：In AB-1-AB-2, also including the purifying to AB-2, including following step
Suddenly：
(1) while hot to 1L water is added in AB-2 solids to be purified, 100 DEG C are stirred and heated to and are incubated 1 hour, use 200mL
Water washing, by filter cake in 50 DEG C of decompression dryings (6 hours), untill product no longer weightlessness (96g).
(2) solid after drying is added in the solution of ethyl acetate of 960mL, is heated to reflux
(3) methyl alcohol 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
0 DEG C of cooling, stirs 60 minutes, the solid filtering that will be separated out；
(4) by filter cake in 50 DEG C of decompression dryings, untill product no longer weightlessness, that is, obtain after purification AB-2 (60g,
60%) it is in order to avoid there is ester exchange in methanol eddy that, the method is first beaten with water, it is adaptable to tied when crude product impurity is more
It is brilliant.
By filter cake in 50 DEG C of decompression dryings, untill product no longer weightlessness, that is, AB-2 after purification is obtained.
Above-described is only embodiments of the invention, and the general knowledge such as known characteristic does not make excessive description herein in scheme.
It should be pointed out that for a person skilled in the art, without departing from the inventive concept of the premise, some changes can also be made
Shape and improvement, these should also be considered as protection scope of the present invention, these effects and patent for implementing all without the influence present invention
Practicality.This application claims protection domain should be defined by the content of its claim, the specific embodiment party in specification
Formula etc. records the content that can be used for explaining claim.
Claims (9)
1. the preparation technology of shellfish cholic acid difficult to understand, including following preparation process：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：
Characterized in that, in AB-4-AB-5, comprising the following steps：
(1) when -15 DEG C, in entering to be dissolved with the dichloromethane solution of AB-4, triethylamine by TFMS trimethyl silicane fat drips
And stir；
(2) add water stirring after completion of the reaction, by it is separated go out organic phase washing, and be dried after separating organic layer, pass through
Filtering, obtains AB-5 crude products after filtrate is spin-dried for；
(3) n-hexane dissolution AB-5 crude products are used, AB-5 is obtained after filtering, washing and evaporated under reduced pressure, reacted as follows：
In AB-7-AB-8, comprise the following steps：
(1) AB-7, ammonium formate, the methanol solution of palladium carbon will be dissolved with to stir and heat；
(2) reacting liquid temperature is down to 30 DEG C after the completion of reacting, is filtered and filtrate is cooled to 0~5 DEG C, add hydrochloric acid water-soluble
Liquid, adjusts PH=3, stirring until obtaining solids of sedimentation and filtering, and obtains AB-8 in 50 DEG C of decompression dryings, reacts as follows：
In AB-8-AB-9, comprise the following steps：
(1) AB-8 will be dissolved with, the mixed solution of the second alcohol and water of NaOH is heated with stirring to backflow, reacting liquid temperature is dropped
To 0~5 DEG C；
(2) water and aqueous hydrochloric acid solution are added, PH=3, stirring is adjusted until obtaining solids of sedimentation and filtering, and is dried in 50 DEG C of decompressions
It is dry to obtain AB-9 crude products；
(3) toward ethanol is added in AB-9 crude products and heating is completely dissolved crude product, water is added, in 50 DEG C of insulations 1 hour, 40 DEG C
Insulation 1 hour, 30 DEG C insulation 1 hour after filter, toward filtering after solid in add ethanol, be heated to being completely dissolved, addition water,
Room temperature is cooled to, filtering obtains AB-9, reacts as follows：
2. the preparation technology of shellfish cholic acid difficult to understand according to claim 1, it is characterised in that in 1 the step of AB-4-AB-5,
By gauge is worked as, the equivalent proportion of the AB-4, TFMS trimethyl silicone grease and triethylamine is 1：1.5：3.
3. the preparation technology of shellfish cholic acid difficult to understand according to claim 1, it is characterised in that in 1 the step of AB-7-AB-8,
By gauge is worked as, the equivalent proportion of the AB-7, ammonium formate and palladium carbon is 1：10：0.05.
4. the preparation technology of shellfish cholic acid difficult to understand according to claim 1, it is characterised in that in 1 the step of AB-4-AB-5,
Monitored using TLC methods and reacted, if AB-4 consumption is not complete, add TFMS trimethyl silicone grease, until AB-4 consumption is complete.
5. the preparation technology of shellfish cholic acid difficult to understand according to claim 1, it is characterised in that in 1 the step of AB-7-AB-8,
The temperature of heating is 45-50 DEG C.
6. the preparation technology of shellfish cholic acid difficult to understand according to claim 1, it is characterised in that in 1 the step of AB-4-AB-5,
Triethylamine raw material is dried using NaH, and control moisture is less than 0.01%.
7. the preparation technology of shellfish cholic acid difficult to understand according to claim 1, it is characterised in that in 1 the step of AB-4-AB-5,
Control reaction system moisture is less than 0.06%.
8. the preparation technology of the shellfish cholic acid difficult to understand according to claim any one of 1-7, it is characterised in that in AB-1-AB-2
In, also including the purifying to AB-2, comprise the following steps：
(1) tetrahydrofuran is added to be heated to reflux being completely dissolved AB-2 solids to be purified after drying, normal pressure boils off tetrahydrochysene furan
Mutter；
(2) n-hexane is added dropwise to, solution is then cooled to 0 DEG C, stirred 60 minutes, the solid filtering that will be separated out；
(3) filter cake untill product no longer weightlessness, that is, is obtained into AB-2 after purification in 50 DEG C of decompression dryings.
9. the preparation technology of the shellfish cholic acid difficult to understand according to claim any one of 1-7, it is characterised in that in AB-1-AB-2
In, also including the purifying to AB-2, comprise the following steps：
(1) to water is added in AB-2 solids to be purified, stir and be heated to 100 DEG C and be incubated 1 hour, wash with water, by filter cake
In 50 DEG C of decompression dryings, untill product no longer weightlessness；
(2) solid after drying is added in the solution of ethyl acetate, is heated to reflux；
(3) it is added dropwise to methyl alcohol complete to solid, normal pressure boils off solvent, and solution then is cooled down into 0 DEG C, stirs 60 minutes, will be analysed
The solid filtering for going out；
(4) filter cake untill product no longer weightlessness, that is, is obtained into AB-2 after purification in 50 DEG C of decompression dryings.
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| WO2020039449A1 (en) * | 2018-08-24 | 2020-02-27 | Solara Active Pharma Sciences Limited | An improved process for the preparation of obeticholic acid and intermediates used in the process thereof |
| 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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