CN106397522A - 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester - Google Patents
3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester Download PDFInfo
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- 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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Abstract
The invention belongs to the technical field of medicines, relates to a method of preparing obeticholic acid through adopting 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester as an intermediate, and particularly relates to the 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester that is a chemical compound, a method of preparing the compound, and a use of the compound for preparation of the obeticholic acid. The invention also relates to a method of preparing the obeticholic acid. The method of preparing the obeticholic acid includes (1) preparing the 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester and (2) preparing the obeticholic acid through adopting the 3,7-di(t-butyldimethylsiloxy)-6-ene-5beta-cholan-24-oic acid methyl ester as the intermediate.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to compound 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5
β-cholane -24- acid methyl esters, prepares the method for described compound and described compound is used for preparing the purposes of shellfish cholic acid difficult to understand.This
Bright further relate to a kind of method preparing shellfish cholic acid difficult to understand, the method comprising the steps of：Step (1)：The preparation 3,7- bis- (tert-butyl group
Dimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters；With step (2)：With 3,7- bis- (t-Butyldimethylsilyl oxygen
Base) -6- alkene -5 β-cholane -24- acid methyl esters is intermediate, preparation shellfish cholic acid difficult to understand.
Background technology
Farnesoid X receptor (FXR) belongs to the family member of the transcription factor nuclear receptor of ligand activation, its native ligand bag
Include primary bile acid chenodesoxycholic acid, secondary bile acid lithocholic acid and deoxycholic acid etc..FXR is bile sensor, and its effect includes
Coordinate with other nuclear receptors, participate in bile acid biosynthesis and the important steps such as cholesterol metabolic.
Shellfish cholic acid (Obeticholic acid, OCA) difficult to understand, that is, 6 α-ethyl chenodeoxycholic acid (6 α-
Ethylchenodeoxycholic acid, 6-ECDCA), call INT-747 or DSP-1747, be a kind of artificial synthesized FXR
Part.Clinical research shows, shellfish cholic acid difficult to understand is to Primary Hepatic fibrillatable, alcoholic fatty liver, the acid diarrhoea of bile and portal vein
Multiple disease related to liver such as high pressure has good therapeutic action, the treatment of these indications is being carried out the II phase and
The clinical research of III phase.U.S. FDA accelerates on May 27th, 2016 to have approved shellfish cholic acid joint urso (UDCA) difficult to understand
For the adult patient of the primary biliary cholangitis (PBC) insufficient with treatment UDCA response, or as single therapy
It is not resistant to the adult patient of UDCA.Additionally, shellfish cholic acid difficult to understand also has, to metabolic diseases such as diabetes, the therapeutic action that can expect,
Currently carry out preclinical study.
The synthesis technique of the shellfish cholic acid difficult to understand of document report mainly has following three kinds：
1. patent US20090062526 and Steroids (Vol77,2012, pp1335) report Austria as follows
The synthesis technique (literature procedures route 1) of shellfish cholic acid：
Literature procedures route 1
The feature of literature procedures route 1 is as follows：
(1) 3 hydroxyls of 3 Alpha-hydroxy -7- ketone group -5 β-cholane -24- acid (compound 1) are protected with oxinane, obtain
To 3 α-tetrahydro-pyran oxy -7- ketone group -5 β-cholane -24- acid (compound 2).
(2) by compound 2 in hexamethyl silicon substrate phosphamide (HMPA), in lithium diisopropylamine (LDA) and butyl lithium
In the presence of, react with iodoethane, introduce ethyl at 6, then slough THP trtrahydropyranyl with para-methylbenzenepyridinsulfonate sulfonate (PPTS)
Protection, obtains 3 Alpha-hydroxy -6 β-ethyl -7- ketone group -5 β-cholane -24- acid (compound 3), finally with sodium borohydride by compound
3 ketone group is reduced to hydroxyl, obtains target compound Austria's shellfish cholic acid (compound 4).
2. patent WO2006122977A and its patent families provide the synthesis technique (literary composition of shellfish cholic acid difficult to understand as follows
Offer process route 2)：
Literature procedures route 2
The feature of literature procedures route 2 is as follows：
(1) step 1：By 3 Alpha-hydroxy -7- ketone group -5 β-cholane -24- acid (compound 1), it is converted into 3 Alpha-hydroxy -7- ketone
Base -5 β-cholane -24- acid methyl esters (compound 5)；
(2) step 2：Compound 5, in toluene, in the presence of triethyl amine, is reacted with trim,ethylchlorosilane, obtain 3 α-
(trimethyl silicon substrate epoxide) -7- ketone group -5 β-cholane -24- acid methyl esters (compound 6)；
(3) step 3：Compound 6, in the presence of lithium diisopropylamine (LDA), is reacted with trim,ethylchlorosilane, obtains
3 α, 7- bis- (trimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters (compound 7)；
(4) step 4：In dichloromethane, in the presence of boron trifluoride, there is condensation reaction with acetaldehyde, so in compound 7
After hydrolyze, obtain 3 Alpha-hydroxy -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters (compound 8)；
(5) step 5：Compound 8 is hydrolyzed, obtains 3 Alpha-hydroxy -6- ethylidene -7- ketone group -5 β-cholane -24- acid
(compound 9)；
(6) step 6：Compound 9 is carried out catalytic hydrogen reduction, and isomerization in the basic conditions, obtain 3 Alpha-hydroxies -6
α-ethyl -7- ketone group -5 β-cholane -24- acid (compound 3)；
(7) step 7：With sodium borohydride, the ketone group of compound 3 is reduced, obtain shellfish cholic acid difficult to understand (compound 4).
3. patent WO2013192097 and its patent families report the synthesis work providing shellfish cholic acid difficult to understand as follows
Skill (literature procedures route 3)：
Literature procedures route 3
Literature procedures route 3, on the basis of literature procedures route 2, the step 2 of literature procedures route 2 and step 3 is closed
And, i.e. in oxolane, directly by 3 Alpha-hydroxy -7- ketone group -5 β-cholane -24- acid methyl esters under conditions of LDA presence, with
Trim,ethylchlorosilane reacts, and obtains 3 α, 7- bis- (trimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters.
Although the above-mentioned three document process routes of comprehensive analysis are it is found that literature procedures route 1 route is shorter, this
One route also has obvious shortcoming, bad including (1) end-product purity, needs column chromatography for separation, is not suitable for industrialized production；
The yield of (2) the 3rd steps is very low, and only 12-13% is so that total recovery only has 3.5%；(3) solvent hexamethyl used in synthesizing
Phosphamide (HMPA) has carcinogenicity.Therefore, literature procedures route 1 is not suitable for producing in a large number.
Literature procedures route 2 and literature procedures route 3 are all by 3 α, 7- bis- (trimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -
As key intermediate, there is problems with both approaches to 24- acid methyl esters：(1) 3 α, 7- bis- (trimethyl silicon substrate epoxide) -6-
Alkene -5 β-cholane -24- acid methyl esters (compound 7) contains two trimethyl silicane ether groups, and trimethylsilyl ethers group property is unstable
Fixed, acid or alkali all compare sensitive so that 3 α, the sour methyl esters of 7- bis- (trimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- is rear
Single silicon ether products, the yield of impact end-product and purity may be hydrolyzed in processing procedure；(2) in preparation 3 α, 7- bis- (front three
Base silicon substrate epoxide) during -6- alkene -5 β-cholane -24- acid methyl esters, need using LDA (tetrahydrofuran solution), this reagent valency
Lattice expensive and it is necessary to sealing preserve in anhydrous conditions, increased storage and the difficulty of transport, and need no when using
Operate under water condition, be not convenient to use.
Content of the invention
In the present invention, if represent same compound, the name of compound and chemical structural formula are not inconsistent, with chemistry knot
Structure formula or chemical equation are defined.
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The implication that personnel are generally understood that.And, laboratory operation step involved herein is in corresponding field and widely uses
Conventional steps.Meanwhile, for a better understanding of the present invention, definition and the explanation of relational language are provided below.
As used in this article, term " shellfish cholic acid difficult to understand " refer to 6 α-ethyl chenodeoxycholic acid (i.e. 3 α, 7 alpha-dihydroxy -6 α -
Ethyl -5 β-cholane -24- acid), it has following structure：
As used in this article, compound 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid
Methyl esters and 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is respectively provided with as formula (1) and formula
Structure shown in (1 ').
As used in this article, term " organic base " refers in alkaline organic compound, such as organic amine, organic amine
Alkali metal salt, the alkali metal salt of alcohol and alkali alkyl compound.
As used in this article, term " organic amine " refers to the organic compound containing amino, including but not limited to fat
Amine (such as ethylenediamine, triethylamine, diisopropylethylamine, diisopropylamine), aliphatic cyclic amine (for example 1,8- diazabicylo 11 carbon-
7- alkene (DBU)) and aromatic amine (such as aniline, diphenylamines).
As used in this article, term " alkali metal " includes lithium, sodium, potassium, rubidium, caesium, francium.
As used in this article, term " room temperature " refers to 25 ± 5 DEG C.
" about " of the present invention should be readily appreciated by one skilled in the art, and will have with the context of part used by it
A certain degree of change.If according to the context of term application, to those skilled in the art, it uses not is clear
, then " about " mean no more than positive and negative the 10% of described special value or scope.
In order to overcome problem present in existing Austria shellfish cholic acid synthesis technique, the present inventor passes through in-depth study and creation
The work of property, there is provided the method preparing shellfish cholic acid difficult to understand below, methods described is with 3 α, 7- bis- (t-Butyldimethylsilyl oxygen
Base) -6- alkene -5 β-cholane -24- acid methyl esters is intermediate.The present invention can avoid in existing method, due to 3 α, 7- bis- (front three
Base silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters property unstable, and to subsequent operation, product purity and yield band
The adverse effect come.On the other hand, present invention also offers one kind prepares 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6-
The method of alkene -5 β-cholane -24- acid methyl esters, methods described avoid using expensive and be not easy to store, transport and operation
LDA (tetrahydrofuran solution), reduces production cost, and makes simple to operation.Technical scheme is as follows：
In one aspect, the invention provides compound 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-courage
Alkane -24- acid methyl esters, it has the structure as shown in formula (1).
In a preferred embodiment, described 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -
24- acid methyl esters is 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters, and it has as formula
Structure shown in (1 ').
In one aspect, the invention provides a kind of prepare compound 3,7- bis- (t-Butyldimethylsilyl epoxide) -6-
The method of alkene -5 β-cholane -24- acid methyl esters, it comprises the following steps：Under conditions of organic base and salt compounded of iodine exist, make 3- hydroxyl
Base -7- ketone group -5 β-cholane -24- acid methyl esters is reacted with tert-butyl chloro-silicane, obtains 3,7- bis- (tert-butyldimethyl silyl
Base epoxide) -6- alkene -5 β-cholane -24- acid methyl esters.
In a preferred embodiment, the method comprising the steps of：The condition existing in organic base and salt compounded of iodine
Under, so that 3 Alpha-hydroxy -7- ketone group -5 β-cholane -24- acid methyl esters is reacted with tert-butyl chloro-silicane, obtain 3 α, 7- bis- (uncle
Butyldimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters.
In a preferred embodiment, described organic base is organic amine；It is highly preferred that described organic amine is selected from three second
Amine, diisopropylethylamine and 1,8- diazabicylo 11 carbon -7- alkene；It is particularly preferred that described organic amine is triethylamine.
In a preferred embodiment, described salt compounded of iodine is selected from alkali-metal salt compounded of iodine and tetrabutylammonium iodide；More preferably
Ground, described alkali-metal salt compounded of iodine is selected from sodium iodide, KI and lithium iodide；It is particularly preferred that described salt compounded of iodine is sodium iodide.
In a preferred embodiment, 3- hydroxyl -7- ketone group -5 β-cholane -24- acid methyl esters：Tert-butyldimethylsilyl chloride
Silane：Salt compounded of iodine：Rate of charge (the mol of organic base:mol:mol:Mol it is) 1:3～6:3～6:4～8, such as 1:3～5:4～6:4
～8,1:3～5:6～8:4～8,1:5～6:4～6:4～6,1:5～6:6～8:4～6,1:3～6:4～6:4～6 or 1:3
～6:3～4:6～8, such as 1:3:5:4、1:6:6:4、1:5:6:8、1:5:3:8 or 1:5:5:6.
In a preferred embodiment, the temperature of described reaction is 20 DEG C～60 DEG C, more preferably 40 DEG C～60 DEG C.
In a preferred embodiment, described reaction is carried out in solvent (such as aprotic solvent), described solvent
Selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE)), halogen
For one or more of alkane (such as dichloromethane or chloroform), acetonitrile, N,N-dimethylformamide and acetone.
In a preferred embodiment, described solvent is the mixed solvent being made up of aromatic hydrocarbon and acetonitrile.
In a preferred embodiment, described aromatic hydrocarbon is toluene.
In a preferred embodiment, described aromatic hydrocarbon and the volume ratio of acetonitrile are 1:3～3:1, such as 1:3～1:
2、1:3～1:1、1:1～2:1 or 1:1～3:1, such as 1:3、1:2、1:1、2:1 or 3:1.
In a preferred embodiment, the quality of 3- hydroxyl -7- ketone group -5 β-cholane -24- acid methyl esters and solvent:Body
Amass than (g:ML it is) 1:5～1:15, such as 1:5～1:7、1:7～1:12、1:5～1:10 or 1:10～1:15, such as 1:5、1:
7、1:10、1:12 or 1:15.
In a preferred embodiment, described reaction carries out 3～6 hours.
In a preferred embodiment, methods described also includes：To 3,7- bis- (t-Butyldimethylsilyl epoxide)-
6- alkene -5 β-cholane -24- acid methyl esters is separated and/or is purified.
In a preferred embodiment, described separation and/or purify one or more of comprises the following steps：
(1) reacted mixture is extracted, separate organic layer；
(2) using water or saturated aqueous common salt, organic layer is washed；
(3) using anhydrous sulfate (such as anhydrous sodium sulfate), organic layer is dried；
(4) vacuum distillation is carried out to dried organic layer, isolate 3,7- bis- (t-Butyldimethylsilyl epoxide) -6-
Alkene -5 β-cholane -24- acid methyl esters；With
(5) utilize silica gel column chromatography to 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid first
Ester is purified.
In one aspect, the invention provides compound 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-courage
Alkane -24- acid methyl esters is used for preparing the purposes of shellfish cholic acid difficult to understand.
In one aspect, the invention provides a kind of method preparing shellfish cholic acid difficult to understand, the method comprising the steps of：
Step (1)：Preparation 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters；With
Step (2)：It is middle with 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters
Body, preparation shellfish cholic acid difficult to understand.
In a preferred embodiment, by the preparation 3 of any one as described above, 7- bis- (tert-butyldimethyl silyl
Base epoxide) method of -6- alkene -5 β-cholane -24- acid methyl esters carries out step (1).
In a preferred embodiment, described 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -
24- acid methyl esters is 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters.
In a preferred embodiment, step (2) is further comprising the steps：
Step (2-1)：3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is converted into
3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters；
Step (2-2)：3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters is converted into 3- hydroxyl -6- Asia
Ethyl -7- ketone group -5 β-cholane -24- acid；
Step (2-3)：3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid is converted into 3- hydroxyl -6 α-ethyl -
7- ketone group -5 β-cholane -24- acid；With
Step (2-4)：3- hydroxyl -6 α-ethyl -7- ketone group -5 β-cholane -24- acid is converted into shellfish cholic acid difficult to understand.
In a preferred embodiment, step (2-1) includes：In the presence of boron trifluoride, make 3,7- bis- (tertiary fourth
Base dimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters reacted with acetaldehyde, obtains 3- hydroxyl -6- ethylidene -7- ketone
Base -5 β-cholane -24- acid methyl esters.
In a preferred embodiment, in described step (2-1), 3,7- bis- (t-Butyldimethylsilyl epoxides)-
6- alkene -5 β-cholane -24- acid methyl esters：Boron trifluoride：Rate of charge (the mol of acetaldehyde:mol:Mol it is) 1:2～3:1.5～2.5, example
As 1:2～2.5:1.5～2,1:2.5～3:2～2.5,1:2～3:1.5～2 or 1:2.5～3:1.5～2.5；Such as 1:2:
1.5、1:2.5:2、1:3:1.5、1:2:2.5、1:3:2.5 or 1:2.5:2.5
In a preferred embodiment, the reaction of described step (2-1) is entered in solvent (such as aprotic solvent)
OK, described solvent is selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl- tert
Butyl ether), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, one of N,N-dimethylformamide and acetone
Or it is multiple.
In a preferred embodiment, described solvent is selected from dichloromethane and acetonitrile.
In a preferred embodiment, in described step (2-1), the temperature of described reaction is -20 DEG C～-70 DEG C,
Such as -20 DEG C～-30 DEG C, -30 DEG C～-40 DEG C, -30 DEG C～-50 DEG C, -40 DEG C～-60 DEG C, -60 DEG C～-65 DEG C or -60 DEG C
～-70 DEG C；More preferably -60 DEG C～-65 DEG C.
In a preferred embodiment, described step (2-1) also includes reacted mixture is post-processed.
In a preferred embodiment, described post processing one or more of comprises the following steps：
(1) reacted mixture is mixed with alkaline aqueous solution；
(2) reacted mixture is extracted, separate organic layer；
(3) using water or saturated aqueous common salt, organic layer is washed；
(4) using anhydrous sulfate (such as anhydrous sodium sulfate), organic layer is dried；
(5) dried organic layer is concentrated.
In a preferred embodiment, described step (2-2) includes：In the presence of alkali compounds, make 3- hydroxyl
Base -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters hydrolysis, obtain 3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -
24- acid.
In a preferred embodiment, the alkali compounds in described step (2-2) is selected from NaOH, hydroxide
Potassium, ammonia, sodium carbonate and sodium acid carbonate；Preferably NaOH.
In a preferred embodiment, in described step (2-2), alkali compounds：3- hydroxyl -6- ethylidene -7-
Rate of charge (the mol of ketone group -5 β-cholane -24- acid methyl esters:Mol) it is more than 1:1.
In a preferred embodiment, the reaction in described step (2-2) is carried out under room temperature or heating condition.
In a preferred embodiment, described step (2-2) includes：By 3- hydroxyl -6- ethylidene -7- ketone group -5 β -
Cholane -24- acid methyl esters solvent dissolves, and mixes with the aqueous solution of alkali compounds；Described solvent is can be miscible with water
Solvent (such as methyl alcohol, ethanol, acetone, oxolane, acetonitrile；Preferably methyl alcohol).
In a preferred embodiment, described step (2-2) also includes reacted mixture is post-processed.
In a preferred embodiment, described post processing one or more of comprises the following steps：
(1) using acid compound (such as phosphoric acid), excessive alkali compounds is neutralized；
(2) reacted mixture is extracted, separate organic layer；
(3) using water or saturated aqueous common salt, organic layer is washed；
(4) using anhydrous sulfate (such as anhydrous sodium sulfate), organic layer is dried；
(5) dried organic layer is concentrated.
In a preferred embodiment, described step (2-3) includes：The condition existing in catalyst (such as palladium carbon)
Under, hydro-reduction is carried out to 3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid, and isomerization in the basic conditions, obtain
To 3- hydroxyl -6 α-ethyl -7- ketone group -5 β-cholane -24- acid.
In a preferred embodiment, described step (2-4) includes：To 3- hydroxyl -6 α-ethyl -7- ketone group -5 β -
Cholane -24- acid carries out reduction reaction, obtains shellfish cholic acid difficult to understand.
In one aspect, the invention provides shellfish cholic acid difficult to understand, it is obtained by the method for any one as described above.
Beneficial effect
The side preparing 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters of the present invention
Method, it is to avoid using expensive and be difficult to store, transport and the LDA using, needed for it also avoid being reacted with LDA
The cryogenic conditions (- 20 DEG C～-40 DEG C) wanted, can make production cost be reduced, so that the operation of reaction is simplified.
The method of the preparation shellfish cholic acid difficult to understand of the present invention, with 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-courage
One or more of alkane -24- acid methyl esters is intermediate, have the effect that：
The property of (1) 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is more stable,
It is less likely to occur in last handling process to hydrolyze；
(2) avoid using LDA that is expensive and being difficult storage, transport and use, it also avoid being carried out with LDA
Cryogenic conditions (- 20 DEG C～-40 DEG C) required for reaction, can make production cost be reduced, make the operation of reaction obtain letter
Change；
(3) avoid the hexamethyl phosphoramide (HMPA) using carcinogenicity, reduce the harm to operator's health, reduce
Environmental pollution.
Specific embodiment
Below in conjunction with drawings and Examples, embodiment of the present invention is described in detail, but people in the art
Member will be understood that, drawings below and embodiment are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Accompanying drawing and
Unreceipted actual conditions person in embodiment, the condition according to normal condition or manufacturer's suggestion is carried out.Agents useful for same or instrument are not
Dated production firm person, be can by city available from conventional products.Anhydrous solvent used is commercially available.
Brief description
3 α that Fig. 1 obtains for embodiment 1,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid first
The nucleus magnetic hydrogen spectrum of ester.
3 α that Fig. 2 obtains for embodiment 1,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid first
The ESI-MS spectrogram of ester.
Embodiment 1 according to the step shown in route 1, prepares 3 α, and 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β -
Cholane -24- acid methyl esters.
Route 1
Preparation process：3 Alpha-hydroxy -7- ketone group -5 β-cholane -24- acid methyl esters (136.5g, 337.4mmol) is added to reaction
In container, described reaction vessel is mounted with mechanical stirring device and the condenser pipe being furnished with drying tube.Use anhydrous acetonitrile
(682mL) with dry toluene (682ml), 3 Alpha-hydroxy -7- ketone group -5 β-cholane -24- acid methyl esters is dissolved, sequentially add anhydrous
NaI (252g, 1.68mol) and triethylamine (281mL, 2.012mol), the solution in reaction vessel is changed into suspension.Add by several times
Tert-butyl chloro-silicane (253.18g, 1.68mol), adds for about 15 minutes.The temperature of reaction system is risen to 40 DEG C, stirs
Mix 1 hour, then heat to 50 DEG C of reaction 3-6 hours.Reactant mixture is cooled to room temperature, filters off insoluble matter, carefully add to
In mixture of ice and water (1360mL), it is sufficiently stirred for, after being layered, separate toluene organic layer；Water layer is washed with 682mL toluene.Close
And organic layer, with pure water (1540mL × 3 time), then wash 1000mL with saturated brine and wash 1 time, use Na2SO4It is dried.Dry
Solution after dry outside temperature less than vacuum distillation under conditions of 50 DEG C, evaporation solvent obtains grease, as 3 α, 7- bis- (tertiary fourth
Base dimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters crude product (yield close to 100%), can be directly used for subsequently anti-
Should.
Take a small amount of sample, through the silica gel column chromatography separating purification (mixed solvent (oil using petroleum ether and ethyl acetate
Ether:The volume ratio of ethyl acetate is 100:5) elute, obtain 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-courage
Alkane -24- acid methyl esters sterling, for characterizing.
The sign of product：Fig. 1 is 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters
Nucleus magnetic hydrogen spectrum.Nuclear magnetic data：1H-NMR(CDCl3,400MHz)δ,0.06(s,3H),0.08(s,3H),0.64(s,3H),
0.77(s,3H),0.81(s,9H),0.87(s,9H),0.80-2.51(m,28H),2.19(m,1H),2.30(m,1H),3.47
(m, 1H), 3.61 (s, 3H), 4.66 (d, J=4.48Hz, 1H).
Fig. 2 is 3 α, the ESI-MS spectrum of 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters
Figure.Mass spectrometric data：ESI-MS (m/e, %):633(MH+,100),655(MNa+).
Embodiment 2 according to the step shown in route 2, by 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-courage
Alkane -24- acid methyl esters, preparation 3 Alpha-hydroxy -6- ethylidene -7- ketone group -5 β-cholane -24- acid.
Route 2
Step 1：3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters and acetaldehyde condensation,
Prepare 3 Alpha-hydroxy -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters.
(1) by 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters crude product (according to
100% yield conversion, 337.4mmol) grease, with 500mL anhydrous THF dissolving, below 50 DEG C, vacuum distillation removes THF,
Repeat this step, until the moisture in THF controls (being recorded with KF titration) within 0.5%.Raffinate is in dichloromethane
(224mL) in, dissolving, is cooled to -60 DEG C～-65 DEG C in advance, adds acetaldehyde (38.1ml, 676mmol), under the conditions of -60 DEG C～0 DEG C
Preserve.
(2)N2Under protection, by dichloromethane (787ml) and boron trifluoride (20wt% acetonitrile solution, 357mL,
843.5mmol) in independent reactor, it is cooled to -60 DEG C～-65 DEG C.At this temperature, add (1) in containing 3 α, 7- bis-
(t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters and the solution of acetaldehyde.Reactant mixture is at -60 DEG C
Stir about 2 hours at～-65 DEG C, are gradually heating to 23 DEG C～28 DEG C, are stirred for about 3 hours.By reactant liquor be cooled to 2 DEG C～
10 DEG C, add in the NaOH aqueous solution of precooling, after strong agitation 10min, separate organic layer, water layer is washed with dichloromethane
(150mL × 2 time).Organic layer merges, and uses 200mL water washing, then is washed with 200mL sodium chloride solution, obtains 3 α-hydroxyl after concentration
Base -6- ethylidene -7- ketone group -5 β-cholane -24- acid first crude product, are directly used in subsequent reactions.
Step 2：With 3 Alpha-hydroxy -6- ethylidene -7- ketone groups-cholane -24- acid methyl esters, preparation 3 Alpha-hydroxy -6- ethylidene -
7- ketone group-cholane -24- acid.
3 Alpha-hydroxy -6- ethylidene -7- ketone groups-cholane -24- acid methyl esters (crude product, about 337mmol) is added in single port bottle,
At 50 DEG C, by residual solvent evaporated in vacuo, Liquid Residue is dissolved in methyl alcohol (200mL), is cooled to room temperature, and addition contains
The aqueous solution 60mL of 23.4gNaOH, is warming up to 50 DEG C, reacts 2 hours.Reactant liquor is diluted with water (580mL), adds toluene
(194mL), after, being sufficiently stirred for, separate water layer.Water layer is transferred in another container, adds ethyl acetate (600mL).Strongly stir
Mix lower 85% phosphoric acid solution (volume before dilution is 43mL) instilling after diluting, after being sufficiently stirred for, separate organic layer.Water layer is used
Ethyl acetate washs (100mL × 2 time).Merge organic layer, washed with NaCl saturated solution, Na2SO4It is dried, filters, concentrate, directly
To evaporant, moisture is less than 1%, or reaches constant boiling point, continues to be concentrated into most of solvent steaming.To residue
Add ethyl acetate (350ml～450mL) in thing, after heating a period of time, be cooled to 20～25 DEG C under stirring, put into refrigerator cold
Hide (0-4 DEG C overnight), suction filtration, washed (50mL × 2 time) with cold ethyl acetate, after air-drying, obtain product 56g, yield 40%.
The nuclear magnetic data of 3 Alpha-hydroxy -6- ethylidene -7- ketone group -5 β-cholane -24- acid is as follows, with document
WO2013192097 report is consistent.1H-NMR(CDCl3, 400MHz), δ, 0.63 (3H, s), 0.92 (3H, d, J=6.0Hz),
0.99 (3H, 10s), 1.04-1.50 (13H, m), 1.61-2.01 (7H, m), 1.67 (3H, d, J=7.2Hz), 2.21-2.28
(2H, m), 2.35-2.41 (2H, m), 2.56 (1H, dd, J=12.8,4.0Hz), 3.58-3.69 (1H, m), 6.16 (lH, q, J
=7.2Hz).
With reference to the method for WO2013192097, under conditions of palladium carbon exists, to 3 Alpha-hydroxy -6- ethylidene -7- ketone groups -5
β-cholane -24- acid carries out hydro-reduction, and isomerization in the basic conditions, obtain 3 Alpha-hydroxy -6 α-ethyl -7- ketone group -5 β -
Cholane -24- acid.Reduction reaction is carried out to 3 Alpha-hydroxy -6 α-ethyl -7- ketone group -5 β-cholane -24- acid, obtains shellfish cholic acid difficult to understand, receive
Rate is 80%, and purity is 99%.
Although the specific embodiment of the present invention has obtained detailed description, it will be appreciated by those skilled in the art that：Root
According to disclosed all teachings, details can be carried out with various modifications and changes, and these change the guarantor all in the present invention
Within the scope of shield.The four corner of the present invention is given by claims and its any equivalent.
Claims (9)
1. compound 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters, it has as formula (1)
Shown structure；
Preferably, described 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is 3 α, 7- bis-
(t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters, it has the structure as shown in formula (1 ')；
2. the method for the compound of preparation claim 1, the method comprising the steps of：The bar existing in organic base and salt compounded of iodine
Under part, so that 3- hydroxyl -7- ketone group -5 β-cholane -24- acid methyl esters is reacted with tert-butyl chloro-silicane, obtain 3,7- bis- (uncle
Butyldimethyl silicon substrate epoxide) -6- alkene -5 β-cholane -24- acid methyl esters；
Preferably, the method comprising the steps of：Under conditions of organic base and salt compounded of iodine exist, make 3 Alpha-hydroxy -7- ketone groups -5
β-cholane -24- acid methyl esters is reacted with tert-butyl chloro-silicane, obtains 3 α, 7- bis- (t-Butyldimethylsilyl epoxide) -6-
Alkene -5 β-cholane -24- acid methyl esters；
Preferably, described organic base is organic amine；It is highly preferred that described organic amine is selected from triethylamine, diisopropylethylamine and 1,
8- diazabicylo 11 carbon -7- alkene；It is particularly preferred that described organic amine is triethylamine；
Preferably, described salt compounded of iodine is selected from alkali-metal salt compounded of iodine and tetrabutylammonium iodide；It is highly preferred that described alkali-metal salt compounded of iodine choosing
From sodium iodide, KI and lithium iodide；It is particularly preferred that described salt compounded of iodine is sodium iodide；
Preferably, 3- hydroxyl -7- ketone group -5 β-cholane -24- acid methyl esters：Tert-butyl chloro-silicane：Salt compounded of iodine：The throwing of organic base
Material is than (mol:mol:mol:Mol it is) 1:3～6:3～6:4～8；
Preferably, the temperature of described reaction is 20 DEG C～60 DEG C, more preferably 40 DEG C～60 DEG C；
Preferably, described reaction is carried out in solvent (such as aprotic solvent), and described solvent is selected from aromatic hydrocarbon (such as toluene)；
Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE)), halogenated alkane (for example dichloromethane or
Chloroform), acetonitrile, one or more of N,N-dimethylformamide and acetone；
Preferably, described solvent is the mixed solvent being made up of aromatic hydrocarbon and acetonitrile；
Preferably, described aromatic hydrocarbon is toluene；
Preferably, described aromatic hydrocarbon and the volume ratio of acetonitrile are 1:3～3:1；
Preferably, the quality of 3- hydroxyl -7- ketone group -5 β-cholane -24- acid methyl esters and solvent:Volume ratio (g:ML it is) 1:5～1:
15；
Preferably, described reaction carries out 3～6 hours；
Preferably, methods described also includes：To 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid first
Ester is separated and/or is purified；
Preferably, described separation and/or purify one or more of comprises the following steps：
(1) reacted mixture is extracted, separate organic layer；
(2) using water or saturated aqueous common salt, organic layer is washed；
(3) using anhydrous sulfate (such as anhydrous sodium sulfate), organic layer is dried；
(4) vacuum distillation is carried out to dried organic layer, isolate 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5
β-cholane -24- acid methyl esters；With
(5) utilize silica gel column chromatography that 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is entered
Row purifies.
3. the compound of claim 1 is used for preparing the purposes of shellfish cholic acid difficult to understand.
4. a kind of method preparing shellfish cholic acid difficult to understand, the method comprising the steps of：
Step (1)：Preparation 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters；With
Step (2)：With 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters for intermediate, system
Standby Austria shellfish cholic acid；
Preferably, step (1) is carried out by the method for claim 2；
Preferably, described 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is 3 α, 7- bis-
(t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters.
5. the method for claim 4, described step (2) is further comprising the steps：
Step (2-1)：3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters is converted into 3- hydroxyl
Base -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters；
Step (2-2)：3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters is converted into 3- hydroxyl -6- Asia second
Base -7- ketone group -5 β-cholane -24- acid；
Step (2-3)：3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid is converted into 3- hydroxyl -6 α-ethyl -7- ketone
Base -5 β-cholane -24- acid；With
Step (2-4)：3- hydroxyl -6 α-ethyl -7- ketone group -5 β-cholane -24- acid is converted into shellfish cholic acid difficult to understand.
6. the method for claim 5, described step (2-1) includes：In the presence of boron trifluoride, make 3, the 7- bis- (tert-butyl group two
Methylsilyl epoxide) -6- alkene -5 β-cholane -24- acid methyl esters reacted with acetaldehyde, obtain 3- hydroxyl -6- ethylidene -7- ketone group -5 β -
Cholane -24- acid methyl esters；
Preferably, in described step (2-1), 3,7- bis- (t-Butyldimethylsilyl epoxide) -6- alkene -5 β-cholane -24- acid first
Ester：Boron trifluoride：Rate of charge (the mol of acetaldehyde:mol:Mol it is) 1:2～3:1.5～2.5；
Preferably, the reaction of described step (2-1) is carried out in solvent (such as aprotic solvent), and described solvent is selected from aromatic hydrocarbon
(such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE)), halogenated alkane are (for example
Dichloromethane or chloroform), acetonitrile, one or more of N,N-dimethylformamide and acetone；
Preferably, described solvent is selected from dichloromethane and acetonitrile；
Preferably, in described step (2-1), the temperature of described reaction is -20 DEG C～-70 DEG C；More preferably -60 DEG C～-65 DEG C；
Preferably, described step (2-1) also includes reacted mixture is post-processed；
Preferably, described post processing one or more of comprises the following steps：
(1) reacted mixture is mixed with alkaline aqueous solution；
(2) reacted mixture is extracted, separate organic layer；
(3) using water or saturated aqueous common salt, organic layer is washed；
(4) using anhydrous sulfate (such as anhydrous sodium sulfate), organic layer is dried；With
(5) dried organic layer is concentrated.
7. the method for claim 5 or 6, described step (2-2) includes：In the presence of alkali compounds, make 3- hydroxyl -6- sub-
Ethyl -7- ketone group -5 β-cholane -24- acid methyl esters hydrolysis, obtain 3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid；
Preferably, the alkali compounds in described step (2-2) is selected from NaOH, potassium hydroxide, ammonia, sodium carbonate and bicarbonate
Sodium；Preferably NaOH；
Preferably, in described step (2-2), alkali compounds：3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid first
Rate of charge (the mol of ester:Mol) it is more than 1:1；
Preferably, the reaction in described step (2-2) is carried out under room temperature or heating condition；
Preferably, described step (2-2) includes：By 3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid methyl esters solvent
Dissolving, and mix with the aqueous solution of alkali compounds；Described solvent be can be miscible with water solvent (for example methyl alcohol, ethanol, third
Ketone, oxolane, acetonitrile；Preferably methyl alcohol)；
Preferably, described step (2-2) also includes reacted mixture is post-processed；
Preferably, described post processing one or more of comprises the following steps：
(1) using acid compound (such as phosphoric acid), excessive alkali compounds is neutralized；
(2) reacted mixture is extracted, separate organic layer；
(3) using water or saturated aqueous common salt, organic layer is washed；
(4) using anhydrous sulfate (such as anhydrous sodium sulfate), organic layer is dried；
(5) dried organic layer is concentrated.
8. the method for any one of claim 5-7, described step (2-3) includes：The condition existing in catalyst (such as palladium carbon)
Under, hydro-reduction is carried out to 3- hydroxyl -6- ethylidene -7- ketone group -5 β-cholane -24- acid, and isomerization in the basic conditions, obtain
To 3- hydroxyl -6 α-ethyl -7- ketone group -5 β-cholane -24- acid.
9. the method for any one of claim 5-8, described step (2-4) includes：To 3- hydroxyl -6 α-ethyl -7- ketone group -5 β-courage
Alkane -24- acid carries out reduction reaction, obtains shellfish cholic acid difficult to understand.
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| 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 |
| US10131688B2 (en) | 2014-11-19 | 2018-11-20 | NZP UK Limited | 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators |
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| US10597423B2 (en) | 2014-11-19 | 2020-03-24 | NZP UK Limited | 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal FXR modulators |
| US10968250B2 (en) | 2016-05-18 | 2021-04-06 | NZP UK Limited | Intermediates for the synthesis of bile acid derivatives, in particular of obeticholic acid |
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