CN106256833A - The method preparing 3,7 2 (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester - Google Patents

The method preparing 3,7 2 (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester Download PDF

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CN106256833A
CN106256833A CN201610431872.2A CN201610431872A CN106256833A CN 106256833 A CN106256833 A CN 106256833A CN 201610431872 A CN201610431872 A CN 201610431872A CN 106256833 A CN106256833 A CN 106256833A
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cholane
methyl ester
acid methyl
silica
trimethyl
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CN106256833B (en
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李松
李行舟
钟武
郑志兵
肖军海
周辛波
谢云德
王晓奎
谢菲
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

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Abstract

The invention belongs to pharmaceutical technology field, relate to one and prepare 3, the method of 7 two (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester, preferably, described 3,7 two (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester is 3 α, 7 two (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester.3 prepared by the method for the present invention, 7 two (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester, particularly 3 α, 7 two (the silica-based epoxide of trimethyl) 6 alkene 5 β cholane 24 acid methyl ester, can be used for the preparation of shellfish cholic acid difficult to understand.

Description

Prepare 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester Method
Technical field
The invention belongs to pharmaceutical technology field, relate to one and prepare 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder The method of alkane-24-acid methyl ester, it is preferable that described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.The 3,7-bis-(three prepared by the method for the present invention Methylsilyl epoxide)-6-alkene-5 β-cholane-24-acid methyl ester, particularly 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladders Alkane-24-acid methyl ester, can be used for the preparation of 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 chenodeoxy cholic acid, secondary bile acid lithocholic acid and deoxycholic acid etc..FXR is bile sensor, and its effect includes Coordinate with other nuclear receptor, participate in the important steps such as bile acid biosynthesis and cholesterol metabolism.
Shellfish cholic acid (Obeticholic acid, OCA) difficult to understand, i.e. 6 α-ethyl chenodeoxycholic acid (6 α- Ethylchenodeoxycholic acid, 6-ECDCA), call INT-747 or DSP-1747, be the FXR of a kind of synthetic Part.Clinical research shows, shellfish cholic acid difficult to understand is to Primary Hepatic fibrosis, alcoholic fatty liver, bile acidity diarrhoea and portal vein The multiple disease relevant to liver such as high pressure has good therapeutical effect, the treatment of these indications is being carried out the II phase and The clinical research of III phase.U.S. FDA accelerated to have approved shellfish cholic acid associating ursodesoxycholic acid (UDCA) difficult to understand on May 27th, 2016 For suffering from the adult patient of the insufficient primary biliary cholangitis (PBC) for the treatment of 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 the therapeutical effect that can expect to metabolic diseases such as diabetes, 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-carbonyl-5 β-cholane-24-acid (compound 1) are protected with Pentamethylene oxide., To 3 α-tetrahydro-pyran oxy-7-carbonyl-5 β-cholane-24-acid (compound 2).
(2) by compound 2 in the silica-based phosphamide of hexamethyl (HMPA), at 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-carbonyl-5 β-cholane-24-acid (compound 3), finally with sodium borohydride by compound The carbonyl reduction of 3 is hydroxyl, obtains target compound Austria shellfish cholic acid (compound 4).
2. patent WO2006122977A and patent families thereof 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-carbonyl-5 β-cholane-24-acid (compound 1), be converted into 3 Alpha-hydroxy-7-carbonyls Base-5 β-cholane-24-acid methyl ester (compound 5)；
(2) step 2: compound 5 is in toluene, in the presence of triethyl amine, reacts with trim,ethylchlorosilane, obtain 3 α- (the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester (compound 6)；
(3) step 3: compound 6, in the presence of lithium diisopropylamine (LDA), reacts with trim,ethylchlorosilane, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester (compound 7)；
(4) step 4: compound 7 is in dichloromethane, in the presence of boron trifluoride, and acetaldehyde generation condensation reaction, so Rear hydrolysis, obtains 3 Alpha-hydroxy-6-vinyl-7-ketone group-5 β-cholane-24-acid methyl ester (compound 8)；
(5) step 5: be hydrolyzed by compound 8, obtains 3 Alpha-hydroxy-6-vinyl-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, obtains 3 Alpha-hydroxies-6 α-ethyl-7-ketone group-5 β-cholane-24-acid (compound 3)；
(7) step 7: with sodium borohydride by the carbonyl reduction of compound 3, obtains shellfish cholic acid (compound 4) difficult to understand.
3. patent WO2013192097 and patent families thereof report the synthesis work providing shellfish cholic acid difficult to understand as follows Skill (literature procedures route 3):
Literature procedures route 3
Step 2 and the step 3 of literature procedures route 2, on the basis of literature procedures route 2, are closed by literature procedures route 3 And, i.e. in oxolane, directly by 3 Alpha-hydroxy-7-carbonyl-5 β-cholane-24-acid methyl ester under conditions of LDA exists, with Trim,ethylchlorosilane reacts, and obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
Above-mentioned three the document process routes of comprehensive analysis, it is found that although literature procedures route 1 route is shorter, but 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 the lowest, only 12-13% so that total recovery only has 3.5%；(3) the solvent hexamethyl used in synthesis Phosphamide (HMPA) has carcinogenecity.Therefore, literature procedures route 1 is not suitable for producing in a large number.
Literature procedures route 2 and literature procedures route 3 all by 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester is as key intermediate.In literature procedures route 3, except the concrete technology condition of literature procedures route 2 is done Outside optimizing, significant change is step 2 and the step 3 of literature procedures route 2 to be merged.This change decreases reaction Step, but it is the increase in the consumption of LDA (tetrahydrofuran solution), and the price of this reagent is costly and it is necessary to anhydrous Under the conditions of seal preserve, therefore be not easy to storage, transport and use, and, the consumption of trim,ethylchlorosilane is consequently increased.
In literature procedures route 2, prepare 3 α, 7-bis-(trimethyl from 3 Alpha-hydroxy-7-carbonyl-5 β-cholane-24-acid methyl ester Silica-based epoxide) process of-6-alkene-5 β-cholane-24-acid methyl ester is divided into two steps (step 2 and step 3), reduces the use of LDA Amount, advantageously reduces reaction cost.But, owing to needing to use triethylamine in the reaction of step 2, and triethylamine is after the reaction Need to be removed by extraction, water can be introduced in reaction system, accordingly, it would be desirable to after reaction system is carried out anhydrous process, Just can carry out step 3, so adding operational difficulty and cost.
Summary of the invention
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology The implication that personnel are generally understood that.Further, involved herein laboratory operation step is widely used in being corresponding field Conventional steps.Meanwhile, in order to be more fully understood that the present invention, provide below definition and the explanation of relational language.
As used in this article, term " difficult to understand shellfish cholic acid " refer to 6 α-ethyl chenodeoxycholic acid (i.e. 3 α, 7 alpha-dihydroxy-6 α- Ethyl-5 β-cholane-24-acid), it has a structure that
As used in this article, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester, 3-(the silica-based epoxide of trimethyl)-7- Ketone group-5 β-cholane-24-acid methyl ester and 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester are respectively provided with Structure as shown in structural formula (1), (2) and (3):
As used in this article, 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester, 3 α-(the silica-based epoxide of trimethyl)- 7-ketone group-5 β-cholane-24-acid methyl ester and 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester are respectively There is the structure as shown in structural formula (1 '), (2 ') and (3 '):
As used in this article, term " organic base " refers to the organic compound in alkalescence, 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, includes but not limited to fat Amine (such as ethylenediamine, triethylamine, diisopropylethylamine, diisopropylamine), aliphatic cyclic amine (such as 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 " alkali metal salt of organic amine " refers to the salt that organic amine is formed with alkali metal, such as Lithium diisopropylamine (LDA).
As used in this article, term " silicon etherifying reagent " refers to containing alkyl silicon structure, can hydroxyl or ketone group be become For the reagent of alkyl silyl epoxide (R-Si-O), such as trim,ethylchlorosilane, bromotrimethylsilane, N, double (trimethylsilyl) second of O- Amide.
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 is had by the context with part used by it A certain degree of change.If according to the context of term application, to those skilled in the art, its use is not 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 shellfish cholic acid synthesis technique difficult to understand, the present inventor passes through in-depth study and creation Property work, it is provided that following methods, it can be used for preparing 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester, can serve as synthesizing 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder of the key intermediate of shellfish cholic acid difficult to understand especially Alkane-24-acid methyl ester.Compared with prior art, the cost of the method for the present invention is relatively low, and simple to operation.The present invention's Technical scheme is as follows:
1. prepare 3 for one kind, the method for 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described side Method comprises the following steps: under conditions of organic amine exists, make 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and/or 3- (the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester reacts with silicon etherifying reagent, obtains 3,7-bis-(trimethyl silicane Base epoxide)-6-alkene-5 β-cholane-24-acid methyl ester, and, described reaction does not use lithium diisopropylamine.
In a preferred embodiment, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In a preferred embodiment, said method comprising the steps of: under conditions of organic amine exists, make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and/or 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid Methyl ester reacts with silicon etherifying reagent, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In a preferred embodiment, described organic amine is selected from triethylamine, diisopropylethylamine and 1,8-diaza Bicyclo-11 carbon-7-alkene.
In a preferred embodiment, described silicon etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane.
In a preferred embodiment, described reaction is carried out in solvent (such as aprotic solvent)；Preferably, institute State solvent selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl tertbutyl Ether), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, one or many in N,N-dimethylformamide and acetone Kind.
In a preferred embodiment, described reaction carries out 3～6 hours.
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 method also includes: to 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester carries out separating and/or purification.
In a preferred embodiment, one or more during described separation and/or purification comprise the following steps:
(1) reacted mixture is extracted, separate organic layer；
(2) use water or saturated aqueous common salt that organic layer is washed；
(3) utilize anhydrous sulfate (such as anhydrous sodium sulfate) that organic layer is dried；
(4) dried organic layer is carried out decompression distillation, isolates 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β- Cholane-24-acid methyl ester；With
(5) utilize silica gel column chromatography that 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is carried out Purification.
2. the method for scheme 1, it includes step (a): under conditions of organic amine exists, make 3-hydroxyl-7-ketone group-5 β- Cholane-24-acid methyl ester reacts with silicon etherifying reagent, obtains 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester, described silicon etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane.
In a preferred embodiment, described 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester be 3 Alpha-hydroxies- 7-ketone group-5 β-cholane-24-acid methyl ester, and described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid first Ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester: silicon etherifying reagent: have The rate of charge (mol:mol:mol) of machine amine is 1:3～6:4～8, such as 1:3～5:4～6,1:3～5:6～8,1:5～6:4～ 6 or 1:5～6:6～8, such as 1:3:4,1:6:4,1:5:6,1:5:8 or 1:6:6.
In a preferred embodiment, the temperature of described reaction is 20 DEG C～60 DEG C, such as 20 DEG C～30 DEG C, 30 DEG C ～40 DEG C, 30 DEG C～50 DEG C or 40 DEG C～60 DEG C；More preferably 40 DEG C～60 DEG C；
In a preferred embodiment, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the quality of solvent: body Long-pending is 1:5～1:15 than (g:mL), 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.
3. the method for scheme 2, wherein, described silicon etherifying reagent is bromotrimethylsilane.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, described reaction is with acetonitrile as solvent.
In an especially preferred embodiment, said method comprising the steps of:
Step (a): under conditions of triethylamine exists, make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and front three Bromide silane reaction, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 Alpha-hydroxies- 7-ketone group-5 β-cholane-24-acid methyl ester: bromotrimethylsilane: the rate of charge (mol:mol:mol) of triethylamine be 1:3～6:4～ 8；The temperature of described reaction is 40 DEG C～60 DEG C；Described reaction with acetonitrile as solvent, and 3 Alpha-hydroxy-7-ketone group-5 β-cholane- 24-acid methyl ester is 1:5～1:15 with the mass volume ratio (g:mL) of acetonitrile；Described reaction carries out 3～6 hours.
4. the method for scheme 2, wherein, described silicon etherifying reagent is trim,ethylchlorosilane, and, described reaction is at organic amine Carry out under conditions of existing with iodine salt.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, described iodine salt is selected from alkali-metal iodine salt and tetrabutylammonium iodide；More preferably Ground, described alkali-metal iodine salt is selected from sodium iodide, potassium iodide and lithium iodide；It is particularly preferred that described iodine salt is sodium iodide.
In a preferred embodiment, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester: trim,ethylchlorosilane: Iodine salt: the rate of charge (mol:mol:mol:mol) of organic amine be 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, described reaction is carried out in a solvent, and described solvent is aromatic hydrocarbon and acetonitrile group The mixed solvent become.
In a preferred embodiment, described aromatic hydrocarbon is toluene.
In a preferred embodiment, in described mixed solvent, the volume ratio of aromatic hydrocarbon and acetonitrile is 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 an especially preferred embodiment, said method comprising the steps of:
Step (a): under conditions of triethylamine and sodium iodide exist, make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid first Ester reacts with trim,ethylchlorosilane, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester: trim,ethylchlorosilane: iodine salt: the rate of charge of organic amine (mol:mol: Mol:mol) it is 1:3～6:3～6:4～8；The temperature of described reaction is 40 DEG C～60 DEG C；Described reaction is in toluene and acetonitrile group Carrying out in the mixed solvent become, wherein toluene is 1:3～3:1 with the volume ratio of acetonitrile；3 Alpha-hydroxy-7-ketone group-5 β-cholane- 24-acid methyl ester and the quality of mixed solvent: volume ratio (g:mL) is 1:5～1:15；Described reaction carries out 3～6 hours.
In scheme 2-4, it is understood that there may be following situation: under the same reaction conditions, 3-hydroxyl-7-ketone group-5 β-gallbladder Hydroxyl in alkane-24-acid methyl ester is converted into alkyl silyl epoxide quickly than ketone group, thus generates 3-(the silica-based oxygen of trimethyl Base)-7-ketone group-5 β-cholane-24-acid methyl ester；Afterwards, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester In ketone group be converted into the silica-based epoxide of trimethyl, obtain 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester.Therefore, in the reaction system of step (a), it is understood that there may be 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and 3-(three Methylsilyl epoxide)-7-ketone group-5 β-cholane-24-acid methyl ester；Also likely to be present 3-hydroxyl-7-ketone group-5 β-cholane-24-acid Methyl ester, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and 3,7-bis-(the silica-based epoxide of trimethyl)-6- Alkene-5 β-cholane-24-acid methyl ester.
5. the method for scheme 1, it comprises the following steps:
Step (a '): make 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and double (trimethylsilyl) acetamide of N, O-anti- Should, obtain 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (b '): in the presence of organic amine, make 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester Reacting with silicon etherifying reagent, obtain 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described silicon is etherified Reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane.
In a preferred embodiment, said method comprising the steps of:
Step (a ') make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and double (trimethylsilyl) acetamide of N, O-anti- Should, obtain 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (b '): in the presence of organic amine, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid first Ester reacts with silicon etherifying reagent, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described silicon Etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, described step (a ') in, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester The rate of charge (mol:mol) of (trimethylsilyl) acetamides double with N, O-is 1:1.2～2, such as 1:1.2～1.5,1:1.5～1.8 Or 1:1.8～2；Such as 1:1.2,1:1.5,1:1.8 or 1:2.
In a preferred embodiment, described step (b ') in, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-gallbladder Alkane-24-acid methyl ester: silicon etherifying reagent: the rate of charge (mol:mol:mol) of organic amine is 1:2～5:3～6；Such as 1:2～ 2.5:3～6,1:2.5～5:3～6,1:2～5:3～5,1:2～3:3～6 or 1:2.5～5:3～5, such as 1:2:3,1:2: 6,1:5:3,1:5:6,1:2.5:5 or 1:2.5:3.
In a preferred embodiment, step (a ') in, the temperature of reaction is 10 DEG C～35 DEG C, such as 10 DEG C～15 DEG C, 20 DEG C～30 DEG C, 15 DEG C～25 DEG C or 25 DEG C～35 DEG C.
In a preferred embodiment, step (b ') in, the temperature of reaction is 20 DEG C～60 DEG C, such as 20 DEG C～30 DEG C, 30 DEG C～40 DEG C, 30 DEG C～50 DEG C or 40 DEG C～60 DEG C；More preferably 40 DEG C～60 DEG C.
In a preferred embodiment, in step (a '), reaction carries out 10～15 hours, such as 10～12 hours, 12～13 hours or 13～15 hours, such as 10 hours, 11 hours, 12 hours, 13 hours, 14 hours or 15 hours.
In a preferred embodiment, step (b ') in, reaction is carried out 3～6 hours, such as 3～4 hours, 4～5 Hour or 5～6 hours, such as 3 hours, 4 hours, 5 hours or 6 hours.
In a preferred embodiment, the reaction of described step (a ') 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 in N,N-dimethylformamide and acetone Or it is multiple；Preferably, described solvent is acetonitrile.
In a preferred embodiment, described step (a ') in, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester Quality with solvent: volume ratio (g:mL) 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 step (b ') in, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-gallbladder The quality of alkane-24-acid methyl ester and solvent: volume ratio (g:mL) 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 an especially preferred embodiment, said method comprising the steps of:
Step (a ') make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and double (trimethylsilyl) acetamide of N, O-anti- Should, obtain 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；Wherein, 3 Alpha-hydroxy-7-ketone group-5 β-gallbladder The rate of charge (mol:mol) of alkane-24-acid methyl ester and double (trimethylsilyl) acetamide of N, O-is 1:1.2～2；Described reaction is with second Nitrile is solvent, and the quality of 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and acetonitrile: volume ratio (g:mL) be 1:5～ 1:15；Described reaction carries out 10～15 hours at 10 DEG C～35 DEG C；
Step (b '): in the presence of organic amine, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid first Ester reacts with silicon etherifying reagent, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described silicon Etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane；Wherein, 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-gallbladder Alkane-24-acid methyl ester: silicon etherifying reagent: the rate of charge (mol:mol:mol) of organic amine is 1:2～5:3～6；Described reaction is 40 DEG C～60 DEG C at carry out 3～6 hours.
In a preferred embodiment, between step (a ') and step (b '), described method also includes step (c '): remove unreacted N, double (trimethylsilyl) acetamide of O-.
In a preferred embodiment, it is double (trimethylsilyl) that the method using decompression distillation removes unreacted N, O- Acetamide.
In a preferred embodiment, described decompression distillation is entered under conditions of vacuum is 5mmHg～10mmHg OK, such as 5mmHg～6mmHg, 6mmHg～8mmHg, 8mmHg～10mmHg, 5mmHg～7mmHg, 7mmHg～9mmHg or 9mmHg～10mmHg.
In a preferred embodiment, the temperature of described decompression distillation is 50 DEG C～70 DEG C (temperature outward), such as 50 DEG C ～55 DEG C, 55 DEG C～60 DEG C, 60 DEG C～65 DEG C or 65 DEG C～70 DEG C.Described outer temperature refer to decompression distillation use add thermal medium The temperature of (such as water-bath or oil bath).
6. the method for scheme 5, wherein, step (b ') in, described silicon etherifying reagent is bromotrimethylsilane.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, step (b ') in, described reaction is with acetonitrile as solvent.
In an especially preferred embodiment, step (b ') is: under conditions of triethylamine exists, make 3 α-(front three The silica-based epoxide of base)-7-ketone group-5 β-cholane-24-acid methyl ester reacts with bromotrimethylsilane, obtains 3 α, and (trimethyl is silica-based for 7-bis- Epoxide)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid first Ester: bromotrimethylsilane: the rate of charge (mol:mol:mol) of triethylamine is 1:2～5:3～6；Described reaction is molten with acetonitrile Agent, and the quality of 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and acetonitrile: volume ratio (g:mL) For 1:5～1:15；Described reaction carries out 3～6 hours at 40 DEG C～60 DEG C.
7. the method for scheme 5, wherein, step (b ') in, described silicon etherifying reagent is trim,ethylchlorosilane, and, described React and carry out under conditions of organic amine and iodine salt exist.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, described iodine salt is selected from alkali-metal iodine salt and tetrabutylammonium iodide；More preferably Ground, described alkali-metal iodine salt is selected from sodium iodide, potassium iodide and lithium iodide；It is particularly preferred that described iodine salt is sodium iodide.
In a preferred embodiment, step (b ') in, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester: trim,ethylchlorosilane: iodine salt: the rate of charge (mol:mol:mol:mol) of organic amine be 1:2～5:2～5:3～ 6；Such as 1:2～2.5:2～5:3～6,1:2.5～5:2～5:3～6,1:2.5～5:2～2.5:3～5,1:2～3:2.5～ 5:3～6 or 1:2.5～5:2.5～5:3～5, such as 1:2:2:3,1:2:2:6,1:3:2:3,1:5:3:5,1:2:2.5:3,1: 2.5:2:6 or 1:2.5:2.5:3.
In a preferred embodiment, step (b ') in, described reaction is carried out in a solvent, and described solvent is by virtue The mixed solvent that fragrant hydrocarbon forms with acetonitrile.
In a preferred embodiment, described aromatic hydrocarbon is toluene.
In a preferred embodiment, described aromatic hydrocarbon is 1:3～3:1 with the volume ratio of acetonitrile, 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 an especially preferred embodiment, step (b ') is: under conditions of triethylamine and sodium iodide exist, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester reacts with trim,ethylchlorosilane, obtains 3 α, 7-bis-(three Methylsilyl epoxide)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester: trim,ethylchlorosilane: sodium iodide: the rate of charge (mol:mol:mol:mol) of triethylamine is 1:2～5:2～5:3 ～6；Described reaction is carried out in the mixed solvent that toluene and acetonitrile form, and wherein toluene is 1:3～3 with the volume ratio of acetonitrile: 1, and the quality of 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and described mixed solvent: volume ratio (g:mL) it is 1:5～1:15；Described reaction carries out 3～6 hours at 40 DEG C～60 DEG C.
In the method for such scheme 1～7, it is to avoid use is expensive and is difficult to store, transport and use LDA, it also avoid and carry out reacting required cryogenic conditions (-20 DEG C～-40 DEG C) with LDA, production cost can be made to be dropped Low, make the operation of reaction be simplified.Compared with prior art, the method in operational version 1～7 prepares 3,7-bis-(trimethyl Silica-based epoxide)-6-alkene-5 β-cholane-24-acid methyl ester, particularly 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester, can, operation relatively low at production cost easier under conditions of, reach with prior art the most even Higher productivity.3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β prepared by the method in scheme 1～7-cholane-24-acid Methyl ester, can separate through simple and/or after purification step (such as extract, be dried and concentrate), be directly used in next step Reaction, such as the preparation of shellfish cholic acid difficult to understand.
On the other hand, present invention also offers techniques below scheme:
8. prepare 3 for one kind, the method for 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described side Method comprises the following steps:
Step (i): make 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and double (trimethylsilyl) acetamide of N, O-anti- Answer, and described step (i) does not use triethylamine；
Step (ii): use the method for decompression distillation to remove double (trimethylsilyl) acetamide of unreacted N, O-, obtain 3- (the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (iii): organic base exist under conditions of, make 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester reacts with silicon etherifying reagent, obtains 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In a preferred embodiment, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In a preferred embodiment, described method includes:
Step (i): make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and double (trimethylsilyl) acetamide of N, O-anti- Should；
Step (ii): use the method for decompression distillation to remove double (trimethylsilyl) acetamide of unreacted N, O-, obtain 3 α- (the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (iii): organic base exist under conditions of, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester reacts with silicon etherifying reagent, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In a preferred embodiment, described organic base selected from organic amine (such as triethylamine, diisopropylethylamine and 1,8-diazabicylo 11 carbon-7-alkene) and the lithium salts (such as lithium diisopropylamine) of organic amine.
In a preferred embodiment, described silicon etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane.
In a preferred embodiment, described decompression distillation is entered under conditions of vacuum is 5mmHg～10mmHg OK, such as 5mmHg～6mmHg, 6mmHg～8mmHg, 8mmHg～10mmHg, 5mmHg～7mmHg, 7mmHg～9mmHg or 9mmHg～10mmHg.
In a preferred embodiment, the temperature of described decompression distillation is 50 DEG C～70 DEG C (temperature outward), such as 50 DEG C ～55 DEG C, 55 DEG C～60 DEG C, 60 DEG C～65 DEG C or 65 DEG C～70 DEG C.Described outer temperature refer to decompression distillation use add thermal medium The temperature of (such as water-bath or oil bath).
In a preferred embodiment, after step (iii), described method also includes: to 3,7-bis-(trimethyl Silica-based epoxide)-6-alkene-5 β-cholane-24-acid methyl ester carries out separating and/or purification.
In a preferred embodiment, one or more during described separation and/or purification comprise the following steps:
(1) reacted mixture is extracted, separate organic layer；
(2) use water or saturated aqueous common salt that organic layer is washed；
(3) utilize anhydrous sulfate (such as anhydrous sodium sulfate) that organic layer is dried；
(4) dried organic layer is carried out decompression distillation, isolates 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β- Cholane-24-acid methyl ester；With
(5) utilize silica gel column chromatography that 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is carried out Purification.
9. the method for scheme 8, in step (i), 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the double (front three of N, O- Silica-based) rate of charge (mol:mol) of acetamide is 1:1.2～2, such as 1:1.2～1.5,1:1.5～1.8 or 1:1.8～2；Example Such as 1:1.2,1:1.5,1:1.6,1:1.8 or 1:2.
In a preferred embodiment, in step (i), the temperature of reaction is 10 DEG C～35 DEG C, such as 10 DEG C～15 DEG C, 20 DEG C～30 DEG C, 15 DEG C～25 DEG C or 25 DEG C～35 DEG C.
In a preferred embodiment, the reaction in step (i) carries out 10～15 hours, such as 10～12 hours, 12～13 hours or 13～15 hours, such as 10 hours, 11 hours, 12 hours, 13 hours, 14 hours or 15 hours.
In a preferred embodiment, in step (i), reaction is carried out in solvent (such as aprotic solvent)；Excellent Selection of land, described solvent is selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl Tertbutyl ether), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, in N,N-dimethylformamide and acetone one Plant or multiple.
In a preferred embodiment, described solvent is acetonitrile.
In a preferred embodiment, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the quality of solvent: body Long-pending is 1:5～1:15 than (g:mL), 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 an especially preferred embodiment, described step (i) is: make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24- Acid methyl ester and N, O-double (trimethylsilyl) acetamide reaction；Wherein, 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and N, The rate of charge (mol:mol) of double (trimethylsilyl) acetamide of O-is 1:1.2～2, and described reaction is carried out in acetonitrile.And 3 α- Hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the quality of acetonitrile: volume ratio (g:mL) is 1:5～1:15；Described reaction exists 10～15 hours are carried out under conditions of 10 DEG C～35 DEG C.
10. the method for scheme 8, in step (iii), described organic base is the lithium salts of organic amine, such as diisopropylaminoethyl Lithium.
In a preferred embodiment, described silicon etherifying reagent is trim,ethylchlorosilane.
In a preferred embodiment, in step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester: silicon etherifying reagent: the rate of charge (mol:mol:mol) of organic base is 1:2～3:2.5～3.5, such as 1:2～ 2.5:2.5～3.5,1:2.5～3:2.5～3.5,1:2～3:2.5～3,1:2～3:3～3.5,1:2～2.5:2.5～3 or 1:2.5～3:3～3.5, such as 1:2:2.5,1:2.5:3.5,1:2.5:2,1:3:3 or 1:2.5:3.
In a preferred embodiment, in step (iii), described reaction is carried out at-20 DEG C～-40 DEG C, such as- 20 DEG C～-30 DEG C ,-25 DEG C～-30 DEG C ,-25 DEG C～-35 DEG C or-30 DEG C～-40 DEG C.
In a preferred embodiment, the reaction in step (iii) carries out 2～10 hours, such as 2～4 hours, 3 ～6 hours, 5～8 hours or 8～10 hours, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 little Time or 10 hours.
In a preferred embodiment, in step (iii), described reaction is entered in solvent (such as aprotic solvent) OK；Preferably, described solvent is selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran Or methyl tertiary butyl ether(MTBE)), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, N,N-dimethylformamide and acetone In one or more.
It is highly preferred that described solvent is oxolane.
In a preferred embodiment, in step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester and the quality of solvent: volume ratio (g:mL) 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.
Preferably, described solvent is before the reaction through Non-aqueous processing.
In an especially preferred embodiment, described step (iii) is: the condition existed at lithium diisopropylamine Under, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester react with trim,ethylchlorosilane, obtain 3 α, 7- Two (the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β- Cholane-24-acid methyl ester: trim,ethylchlorosilane: the rate of charge (mol:mol:mol) of lithium diisopropylamine be 1:2～3:2.5～ 3.5；Described reaction is with oxolane as solvent, and 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester Quality with oxolane: volume ratio (g:mL) is 1:5～1:15；It is little that described reaction carries out 2～10 at-20 DEG C～-40 DEG C Time.
The method of 11. schemes 8, in step (iii), described organic base is organic amine.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, in described step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β- Cholane-24-acid methyl ester: silicon etherifying reagent: the rate of charge (mol:mol:mol) of organic amine is 1:2～5:3～6；Such as 1:2～ 2.5:3～6,1:2.5～5:3～6,1:2～5:3～5,1:2～3:3～6,1:2.5～5:3～5, such as 1:2.5:3.
In a preferred embodiment, in described step (iii), reaction temperature is 20 DEG C～60 DEG C, such as 20 DEG C ～30 DEG C, 30 DEG C～40 DEG C, 30 DEG C～50 DEG C or 40 DEG C～60 DEG C；More preferably 40 DEG C～60 DEG C.
In a preferred embodiment, the reaction in step step (iii) is carried out 3～6 hours, and such as 3～4 is little Time, 4～5 hours or 5～6 hours, such as 3 hours, 4 hours, 5 hours or 6 hours.
In a preferred embodiment, in step (iii), described reaction is entered in solvent (such as aprotic solvent) OK.
In a preferred embodiment, described solvent is selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, Dioxane, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE)), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, N, Dinethylformamide and acetone.
Preferably, in step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and solvent Quality: volume ratio (g:mL) 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.
The method of 12. schemes 11, in step (iii), described silicon etherifying reagent is bromotrimethylsilane.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, in step (iii), described reaction thinks that acetonitrile is solvent.
In an especially preferred embodiment, described step (iii) is: triethylamine exist under conditions of, make 3 α- (the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester reacts with bromotrimethylsilane, obtains 3 α, 7-bis-(front three The silica-based epoxide of base)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester: bromotrimethylsilane: the rate of charge (mol:mol:mol) of triethylamine is 1:2～5:3～6；Described reaction is with second Nitrile is solvent, and the quality of 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and acetonitrile: volume ratio (g:mL) it is 1:5～1:15；Described reaction carries out 3～6 hours at 40 DEG C～60 DEG C.
The method of 13. schemes 11, in step (iii), described silicon etherifying reagent is trim,ethylchlorosilane, and, described instead Should carry out under conditions of organic amine and iodine salt exist.
In a preferred embodiment, described organic amine is triethylamine.
In a preferred embodiment, described iodine salt is selected from alkali-metal iodine salt and tetrabutylammonium iodide；More preferably Ground, described alkali-metal iodine salt is selected from sodium iodide, potassium iodide and lithium iodide；It is particularly preferred that described iodine salt is sodium iodide.
In a preferred embodiment, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester: three Methylchlorosilane: iodine salt: the rate of charge (mol:mol:mol:mol) of organic amine is 1:2～5:2～5:3～6；Such as 1:2～ 2.5:2～5:3～6,1:2.5～5:2～5:3～6,1:2.5～5:2～2.5:3～5,1:2～3:2.5～5:3～6 or 1: 2.5～5:2.5～5:3～5, such as 1:2:2:3,1:2:2:6,1:3:2:3,1:5:3:5,1:2:2.5:3,1:2.5:2:6 or 1:2.5:2.5:3.In a preferred embodiment, in step (iii), described reaction is carried out in a solvent, described solvent For 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 is 1:3～3:1 with the volume ratio of acetonitrile, 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 an especially preferred embodiment, described step (iii) is: the condition existed at triethylamine and sodium iodide Under, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester react with trim,ethylchlorosilane, obtain 3 α, 7- Two (the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；Wherein, 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β- Cholane-24-acid methyl ester: trim,ethylchlorosilane: sodium iodide: the rate of charge (mol:mol:mol:mol) of triethylamine is 1:2～5:2 ～5:3～6；Described reaction is carried out in the mixed solvent that toluene and acetonitrile form, and wherein, toluene is 1 with the volume ratio of acetonitrile: 3～3:1, and the quality of 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and described mixed solvent: Volume ratio (g:mL) is 1:5～1:15；Described reaction carries out 3～6 hours at 40 DEG C～60 DEG C.
In the method for such scheme 8～13, step (i) does not use triethylamine, thus avoids after reacting, for Remove triethylamine and need the extracting operation carried out.In step (ii), use the method for decompression distillation can remove the most anti- Double (trimethylsilyl) acetamide of the N answered, O-, it is not necessary to 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane obtained- 24-acid methyl ester carries out anhydrous process, can carry out step (iii).Compared to prior art, the method cost of the present invention is relatively Low, easy and simple to handle, and productivity the most higher with prior art can be reached.Prepared by the method in scheme 8～13 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, can separate and/or purification step through simple Suddenly, after (such as extracting, be dried and concentrate), it is directly used in next step reaction, such as the preparation of shellfish cholic acid difficult to understand.
In one aspect, present invention also offers 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid first Ester, it is obtained by the method for any one of scheme 1-13.
In a preferred embodiment, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester is used for preparing shellfish cholic acid difficult to understand.
In a preferred embodiment, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In one aspect, present invention also offers and comprise 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24- The compositions of acid methyl ester, described compositions is prepared by the method for any one of scheme 1-13.
In a preferred embodiment, described compositions is used for preparing shellfish cholic acid difficult to understand.
In a preferred embodiment, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
In yet another aspect, present invention also offers a kind of method preparing shellfish cholic acid difficult to understand, it comprises the steps of
Step 1: prepare 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder by the method for any one of scheme 1-13 Alkane-24-acid methyl ester；
Step 2: be former with 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester that step 1 obtains Material, preparation shellfish cholic acid difficult to understand.
In a preferred embodiment, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.
Beneficial effect
The preparation 3 of the present invention, the method for 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, have One or more in following beneficial effect:
(1) present method avoids the LDA that use is expensive and is difficult to storage, transports and use, also avoid Carry out reacting required cryogenic conditions (-20 DEG C～-40 DEG C) with LDA, production cost can be made to be reduced, make reaction Operation is simplified；
(2) method of the present invention, being generated 3-by 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester, (trimethyl is silica-based Epoxide)-7-ketone group-5 β-cholane-24-acid methyl ester reaction in, do not use triethylamine, thus avoid after reacting, for Need, to remove triethylamine, the extracting operation carried out, it is not necessary to 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane- 24-acid methyl ester carries out anhydrous process, can carry out next step reaction；
(3) method of the present invention does not use the hexamethyl phosphoramide (HMPA) of carcinogenecity；
(4) compared to prior art, the method cost of the present invention is relatively low, easy and simple to handle, and can reach and existing skill The most higher productivity of art；With
(5) 3 prepared by the method for the present invention, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, Particularly 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, can separate through simple and/or After purification step (such as extract, be dried and concentrate), it is directly used in subsequent reactions, such as the preparation of shellfish cholic acid difficult to understand.
Detailed description of the invention
Below in conjunction with drawings and Examples, embodiment of the present invention are described in detail, but people in the art Member is it will be appreciated 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 advised according to normal condition or manufacturer is carried out.Agents useful for same or instrument are not Indicate production firm person, be can by city available from conventional products.Anhydrous solvent used is commercially available.
Accompanying drawing explanation
Fig. 1 is 3 α that embodiment 1 obtains, the core of 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester Magnetic hydrogen is composed.
Fig. 2 is 3 α that embodiment 1 obtains, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester ESI-MS spectrogram.
Fig. 3 is 3 α that embodiment 2 obtains, the core of 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester Magnetic hydrogen is composed.
Fig. 4 is embodiment 3,3 α that step 1 obtains-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester ESI-MS spectrogram.
Embodiment 1 according to the step shown in route 1, prepare 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester.
Route 1
Preparation process: 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester (136.5g, 337.4mmol) is added to reaction In container, described reaction vessel is mounted with mechanical stirring device and is furnished with the condensing tube of drying tube.Use anhydrous acetonitrile (682mL) with dry toluene (682ml), 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester is dissolved, be sequentially added into anhydrous NaI (252g, 1.68mmol) and triethylamine (281mL, 2.012mol), the solution in reaction vessel becomes suspension.Instill three Methylchlorosilane (213.7mL, 1680mmol), adds for about 15 minutes.The temperature of reaction system is risen to 40 DEG C, stirs 1 hour, Then heat to 50 DEG C react 3-6 hour.Reactant mixture is cooled to room temperature, filters off insoluble matter, carefully add to frozen water mixing In thing (1360mL), it is sufficiently stirred for, after being layered, separates toluene organic layer；Water layer 682mL toluene washs.Merge organic layer, With pure water (1540mL × 3 time), then wash 1 time with saturated brine washing 1000mL, use Na2SO4It is dried.Dried molten Liquid through decompression distillation, evaporation solvent obtain grease, be 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester crude product (productivity close to 100%), can be directly used for subsequent reactions.
Take a small amount of sample, (use the mixed solvent (oil of petroleum ether and ethyl acetate through silica gel column chromatography separating purification Ether: the volume ratio of ethyl acetate is 100:5) eluting, obtain 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24- Acid methyl ester sterling, is used for characterizing.
The sign of product: Fig. 1 is 3 α, the nuclear-magnetism of 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester Hydrogen is composed.Nuclear magnetic data:1H-NMR(DMSO-d6,400MHz)δ,0.06(s,9H),0.13(s,9H),0.64(s,3H),0.79 (s, 3H), 0.80-2.51 (m, 28H), 3.57 (3H), 4.86 (d, J=8Hz, 1H).
Fig. 2 is 3 α, the ESI-MS spectrogram of 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester.Mass spectrum Data: ESI-MS (m/e, %): 549 (M+H+,100),495(32),477(20),388(25)。
Embodiment 2 according to the step shown in route 2, prepare 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester.
Route 2
3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester (136.5g, 337.4mmol) is added in reaction vessel, institute State reaction vessel be furnished with mechanical stirring device and add the condensing tube of drying tube.With anhydrous acetonitrile (682mL) by 3 Alpha-hydroxy-7-ketone Base-5 β-cholane-24-acid methyl ester dissolves, and adds triethylamine (281mL, 2.012mol), and solution becomes suspension.Instill trimethyl Bromo-silicane (213.7mL, 1.687mol), adds for about 15 minutes.The temperature of reaction system is risen to 40 DEG C, stirs 1 hour, then It is warming up to 50 DEG C, reacts 3-6 hour.Reactant mixture being cooled to room temperature, filters, filter cake 682mL toluene washs.By filtrate Carefully add to, in mixture of ice and water (1360mL), be sufficiently stirred for, after being layered, separate toluene organic layer, water layer 682mL toluene Washing, merges organic layer, with pure water (1540mL × 3 time), then washs 1 time with saturated brine washing 1000mL, uses Na2SO4 It is dried.Dried solution in higher vacuum, and outer temperature less than 50 DEG C under conditions of decompression distillation, evaporation solvent obtains oil Shape thing, is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester crude product (productivity close to 100%), can It is directly used in subsequent reactions.
Take a small amount of sample, through silica gel column chromatography separating purification, use the mixed solvent (oil of petroleum ether and ethyl acetate Ether: the volume ratio of ethyl acetate is 100:5) eluting, obtain 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24- Acid methyl ester sterling, is used for characterizing.
The sign of product: Fig. 3 is 3 α, the nuclear-magnetism of 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester Hydrogen is composed.Nuclear magnetic data:1H-NMR(DMSO-d6,400MHz),δ,0.06(s,9H),0.13(s,9H),0.64(s,3H),0.79 (s, 3H), 0.80-2.51 (m, 28H), 3.57 (3H), 4.86 (d, J=8Hz, 1H).
Embodiment 3 according to the step shown in route 3, prepare 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester.
Route 3
Step 1: be that silicon etherifying reagent prepares 3 α-(the silica-based epoxide of trimethyl)-7-with double (trimethylsilyl) acetamide of N, O- Ketone group-5 β-cholane-24-acid methyl ester.
3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester (136.5g, 337.4mmol) is added in reaction vessel, institute State reaction vessel be furnished with mechanical stirring device and add the condensing tube of drying tube.With anhydrous acetonitrile (700mL) by 3 Alpha-hydroxy-7-ketone Base-5 β-cholane-24-acid methyl ester dissolves, and adds double (trimethylsilyl) acetamide (122mL, 506.1mmol) of N, O-, then in room The lower reaction of temperature about 15 hours.Reactant mixture, through decompression distillation, removes solvent and double (trimethylsilyl) acetyl of unreacted N, O- Amine, obtains grease, is 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester crude product, can be directly used for Subsequent reactions.
Take a small amount of sample, through silica gel column chromatography separating purification, use the mixed solvent (oil of petroleum ether and ethyl acetate Ether: the volume ratio of ethyl acetate is 100:5) eluting, obtain 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid Methyl ester sterling, is used for characterizing.
Fig. 4 is the ESI-MS spectrogram of 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester.Spectra count According to: ESI-MS (m/e, %): 499 (M+Na+, 35), 495 (M+NH4+100), 477 (M+H+, 48), 388 (45).
Step 2: 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester is converted into 3 α, 7-bis-(three Methylsilyl epoxide)-6-alkene-5 β-cholane-24-acid methyl ester.
3 α step 1 obtained-(the silica-based epoxide of trimethyl)-7-ketone group-cholane-24-acid methyl ester crude product (is pressed 337.4mmol counts) add in reaction vessel, described reaction vessel is configured with mechanical stirring device and adds the condensing tube of drying tube. With anhydrous acetonitrile (341mL) and dry toluene (341ml) by 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-cholane-24-acid methyl ester Dissolve, be sequentially added into anhydrous Na I (126g, 840.5mmol) and triethylamine (140.4mL, 840.5mmol).Instill trimethyl chlorine Silane (106.8mL, 840mmol), adds for about 15 minutes.The temperature of reaction system is risen to 40 DEG C, stirs 1 hour, then rise Temperature, to 50 DEG C, is reacted 3-6 hour.After completion of the reaction, reactant mixture being cooled to room temperature, filter, filter cake 341ml toluene is washed Wash.Carefully add to filtrate, in mixture of ice and water (816mL), be sufficiently stirred for, after being layered, separate organic layer.Organic layer is with pure Water washing (725mL × 3 time), then wash 1 time with saturated brine 500mL, use Na2SO4It is dried.Higher vacuum and outward temperature Under conditions of 50 DEG C, decompression distillation, evaporation solvent obtains grease, is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6- Alkene-5 β-cholane-24-acid methyl ester crude product (productivity close to 100%).Detect through thin layer chromatography (TLC), obtained product and reality Execute example 1 consistent with the product that embodiment 2 obtains, can be directly used for subsequent reactions.
Embodiment 4 according to the step shown in route 4, prepare 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester.
Route 4
Step 1: be silicon etherifying reagent with double (trimethylsilyl) acetamide of N, O-, prepares 3 α-(the silica-based epoxide of trimethyl)-7- Ketone group-5 β-cholane-24-acid methyl ester.
3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester (136.5g, 337.4mmol) is added in reaction vessel, institute State reaction vessel be configured with mechanical stirring device and add the condensing tube of drying tube.With anhydrous acetonitrile (700mL) dissolve 3 Alpha-hydroxies- 7-ketone group-5 β-cholane-24-acid methyl ester, adds double (trimethylsilyl) acetamide (122mL, 506.1mmol) of N, O-, then in room The lower reaction of temperature about 15 hours.Decompression distillation reaction mixture, removes solvent and double (trimethylsilyl) acetamide of unreacted N, O-, Obtain grease, be that 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester (detects through TLC, with embodiment 2 Product obtained by step 1 is consistent), can be directly used for subsequent reactions.
Step 2: 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester is converted into 3 α, 7-bis-(three Methylsilyl epoxide)-6-alkene-5 β-cholane-24-acid methyl ester.
3 α step 1 obtained-(the silica-based epoxide of trimethyl)-7-ketone group-cholane-24-acid methyl ester crude product (is pressed 337.4mmol counts) add in reaction vessel, described reaction vessel is configured with mechanical stirring device and adds the condensing tube of drying tube. With anhydrous acetonitrile (341mL), 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-cholane-24-acid methyl ester is dissolved, add triethylamine (140.4mL, 840.5mmol), instills bromotrimethylsilane (111mL, 840mmol), within about 15 minutes, adds.By reaction system Temperature rises to 40 DEG C, stirs 1 hour, then heats to 50 DEG C, reacts 3-6 hour.After completion of the reaction, reactant mixture is lowered the temperature To room temperature, filtering, filter cake 341ml toluene washs.Filtrate is carefully added in mixture of ice and water (816mL), and is sufficiently stirred for Making solution be layered, separate organic layer, organic layer is with pure water (725mL × 3 time), then washs 1 time with saturated brine 500mL, Use Na2SO4It is dried.Under conditions of higher vacuum and outer temperature are less than 50 DEG C, decompression distillation, evaporation solvent obtains grease, It is 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester crude product (productivity close to 100%).Examine through TLC Surveying, the product that obtained product obtains with the method for embodiment 1 and embodiment 2 is consistent, can be directly used for subsequent reactions.
Embodiment 5 according to the step shown in route 5, prepare 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane- 24-acid methyl ester.
Route 5
Step 1: be silicon etherifying reagent with double (trimethylsilyl) acetamide of N, O-, prepares 3 α-(the silica-based epoxide of trimethyl)-7- Ketone group-5 β-cholane-24-acid methyl ester.
3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester (136.5g, 337.4mmol) is added in reaction vessel, institute State reaction vessel be configured with mechanical stirring device and add the condensing tube of drying tube.With anhydrous acetonitrile (700mL) by 3 Alpha-hydroxy-7- Ketone group-5 β-cholane-24-acid methyl ester dissolves, and adds double (trimethylsilyl) acetamide (122mL, 506.1mmol) of N, O-, then exists About 15 hours are reacted under room temperature.Decompression distillation reaction mixture, removes solvent and double (trimethylsilyl) acetyl of unreacted N, O- Amine, obtains grease, is that 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester (detects through TLC, with enforcement Product obtained by example 2 step 1 is consistent), can be directly used for subsequent reactions.
Step 2: 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester is converted into 3 α, 7-bis-(three Methylsilyl epoxide)-6-alkene-5 β-cholane-24-acid methyl ester.
(1) 3 α prepared by step 1-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester crude product (337.4mmol), dissolve with 100mL anhydrous tetrahydro furan (THF), N2Under protection, it is cooled to-20 DEG C～-25 DEG C in advance, then, adds Enter trim,ethylchlorosilane (96.6mL, 759.4mmol), preserve at this temperature.
(2)N2Under protection, by the THF solution 506.1mL (concentration is 2M, 1012.2mmol LDA) and THF of LDA (450mL) it is individually added in reactor, is cooled to-20～-25 DEG C.
(3) by 3 α of pre-cooling in (1)-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and trimethyl The THF solution of chlorosilane, under the conditions of-20 DEG C, instills in the LDA solution in (2), keeps temperature not higher than-20 DEG C, and reaction is mixed Close liquid to stir 2 hours.By TLC detection reaction, such as reaction not exclusively, add LDA/ trim,ethylchlorosilane by the ratio of 4/3.Instead After should completing, reactant liquor is added (38.9g, 202.44mmol are dissolved in 60mL frozen water) in the citric acid solution of pre-cooling, 2～8 DEG C Lower addition.Finish, separate organic layer, aqueous layer with ethyl acetate washing (270mL × 2 time).Merge organic layer, wash with 250mL Wash, then wash with 250mL sodium chloride solution, use Na2SO4Being dried, below 50 DEG C, vacuum distilling removes solvent, obtains 3 α, 7-bis- (the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester crude product (productivity close to 100%).Detect through TLC, obtained Product is consistent with the product obtained by embodiment 1 and embodiment 2.Utilize dry toluene (or anhydrous acetonitrile or anhydrous acetic acid second Ester or anhydrous tetrahydro furan) after azeotropic removal of water, can be directly used for subsequent reactions.
Embodiment 6 is according to the step shown in route 6, by 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24- Acid methyl ester, prepares 3 Alpha-hydroxy-6-vinyl-7-ketone group-5 β-cholane-24-acid.
Route 6
Step 1:3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester and acetaldehyde condensation, prepare 3 Alpha-hydroxy-6-vinyl-7-ketone group-5 β-cholane-24-acid methyl ester.
(1) by 3 Alpha-hydroxy-7-ketone groups-cholane-24-acid methyl ester crude product (according to 100% yield conversion, 337.4mmol) oil Shape thing, dissolves with the anhydrous THF of 500mL, and below 50 DEG C, vacuum distilling removes THF, repeats this step, until the moisture in THF Content controls (to record with KF titration) within 0.5%.Raffinate is dissolved in dichloromethane (224mL), is cooled to-60 DEG C in advance ～-65 DEG C, add acetaldehyde (38.1ml, 676mmol), preserve under the conditions of-60 DEG C～0 DEG C.
(2)N2Under protection, by dichloromethane (787ml) and boron trifluoride (20wt% acetonitrile solution, 317mL, 750mmol) In independent reactor, it is cooled to-60 DEG C～-65 DEG C.At this temperature, add in (1) containing 3 Alpha-hydroxy-7-ketone groups-gallbladder Alkane-24-acid methyl ester and the solution of acetaldehyde.Reactant mixture is stir about 2 hours at-60 DEG C～-65 DEG C, are gradually heating to 23 DEG C～28 DEG C, be stirred for about 3 hours.Reactant liquor is cooled to 2 DEG C～10 DEG C, adds to, in the NaOH aqueous solution of pre-cooling, strongly stir After mixing 10min, separating organic layer, water layer dichloromethane washs (150mL × 2 time).Organic layer merges, and washs with 200mL water, Wash with 200mL sodium chloride solution again, obtain 3 Alpha-hydroxy-6-vinyl-7-ketone group-5 β-cholane-24-acid first after concentration thick Product, are directly used in subsequent reactions.
Step 2: with 3 Alpha-hydroxy-6-vinyl-7-ketone groups-cholane-24-acid methyl ester, prepare 3 Alpha-hydroxy-6-vinyls- 7-ketone group-cholane-24-acid.
3 Alpha-hydroxy-6-vinyl-7-ketone groups-cholane-24-acid methyl ester (crude product, about 338mmol) is added in single port bottle, At 50 DEG C, by residual solvent evaporated in vacuo, debris is dissolved in methanol (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 use water (580mL) is diluted, adds toluene (194mL), after being sufficiently stirred for, water layer is separated.Water layer is transferred in another container, adds ethyl acetate (600mL).Strongly stir Mix lower 85% phosphoric acid solution (volume before dilution is 43mL) instilled after diluting, after being sufficiently stirred for, separate organic layer.Water layer is used Ethyl acetate washing (100mL × 2 time).Merge organic layer, wash 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 major part solvent and steams.To residue Adding ethyl acetate (350ml～450mL) in thing, after heating a period of time, stirring borehole cooling, to 20～25 DEG C, puts into refrigerator cold Hide (0-4 DEG C overnight), sucking filtration, wash (50mL × 2 time) with cold ethyl acetate, after air-drying, obtain product.
Use 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-that embodiment 1-embodiment 5 prepares respectively Acid methyl ester, prepares 3 Alpha-hydroxy-6-vinyl-7-ketone group-5 β-cholane-24-acid according to the method described above, product quality 35g～ 75g, yield 25%～53%.
The nuclear magnetic data of 3 Alpha-hydroxy-6-vinyl-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).
Although the detailed description of the invention of the present invention has obtained detailed description, but those skilled in the art will appreciate that root According to disclosed all teachings, details can be carried out various modifications and changes, and these change all the guarantor of the present invention Within the scope of protecting.The four corner of the present invention is given by claims and any equivalent thereof.

Claims (14)

1. prepare 3 for one kind, the method for 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described method bag Include following steps: under conditions of organic amine exists, make 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and/or 3-(front three The silica-based epoxide of base)-7-ketone group-5 β-cholane-24-acid methyl ester reacts with silicon etherifying reagent, obtains 3,7-bis-(the silica-based oxygen of trimethyl Base)-6-alkene-5 β-cholane-24-acid methyl ester, and, described reaction does not use lithium diisopropylamine；
Preferably, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is 3 α, 7-bis-(trimethyl Silica-based epoxide)-6-alkene-5 β-cholane-24-acid methyl ester；
Preferably, said method comprising the steps of: under conditions of organic amine exists, make 3 Alpha-hydroxy-7-ketone group-5 β-gallbladder Alkane-24-acid methyl ester and/or 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester are anti-with silicon etherifying reagent Should, obtain 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；
Preferably, described organic amine is selected from triethylamine, diisopropylethylamine and 1,8-diazabicylo 11 carbon-7-alkene；
Preferably, described silicon etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane；
Preferably, described reaction is carried out in solvent (such as aprotic solvent)；Preferably, described solvent is selected from aromatic hydrocarbon (example Such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE)), halogenated alkane (such as two Chloromethanes or chloroform), acetonitrile, one or more in N,N-dimethylformamide and acetone；
Preferably, described reaction carries out 3～6 hours；
Preferably, the temperature of described reaction is 20 DEG C～60 DEG C, more preferably 40 DEG C～60 DEG C；
Preferably, described method also includes: to 3, and 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is carried out Separate and/or purification；
Preferably, one or more during described separation and/or purification comprise the following steps:
(1) reacted mixture is extracted, separate organic layer；
(2) use water or saturated aqueous common salt that organic layer is washed；
(3) utilize anhydrous sulfate (such as anhydrous sodium sulfate) that organic layer is dried；
(4) dried organic layer is carried out decompression distillation, isolates 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder Alkane-24-acid methyl ester；With
(5) utilize silica gel column chromatography that 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is purified.
2. the method for claim 1, it includes step (a): under conditions of organic amine exists, make 3-hydroxyl-7-ketone group-5 β- Cholane-24-acid methyl ester reacts with silicon etherifying reagent, obtains 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid Methyl ester, described silicon etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane；
Preferably, described 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester is 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid Methyl ester, and described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is 3 α, 7-bis-(trimethyl silicane Base epoxide)-6-alkene-5 β-cholane-24-acid methyl ester；
Preferably, described organic amine is triethylamine；
Preferably, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester: silicon etherifying reagent: the rate of charge of organic amine (mol:mol: Mol) it is 1:3～6:4～8；
Preferably, the temperature of described reaction is 20 DEG C～60 DEG C, more preferably 40 DEG C～60 DEG C；
Preferably, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the quality of solvent: volume ratio (g:mL) is 1:5～1: 15。
3. the method for claim 2, wherein, described silicon etherifying reagent is bromotrimethylsilane；
Preferably, described organic amine is triethylamine；
Preferably, described reaction is with acetonitrile as solvent.
4. the method for claim 2, wherein, described silicon etherifying reagent is trim,ethylchlorosilane, and, described reaction is at organic amine Carry out under conditions of existing with iodine salt；
Preferably, described organic amine is triethylamine；
Preferably, described iodine salt is selected from alkali-metal iodine salt and tetrabutylammonium iodide；It is highly preferred that the choosing of described alkali-metal iodine salt From sodium iodide, potassium iodide and lithium iodide；It is particularly preferred that described iodine salt is sodium iodide；
Preferably, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester: trim,ethylchlorosilane: iodine salt: the rate of charge of organic amine (mol:mol:mol:mol) it is 1:3～6:3～6:4～8；
Preferably, described reaction is carried out in a solvent, and described solvent is the mixed solvent of aromatic hydrocarbon and acetonitrile composition；
Preferably, described aromatic hydrocarbon is toluene；
Preferably, in described mixed solvent, the volume ratio of aromatic hydrocarbon and acetonitrile is 1:3～3:1.
5. the method for claim 1, it comprises the following steps:
Step (a '): make 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and N, O-double (trimethylsilyl) acetamide reaction, To 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (b '): in the presence of organic amine, make 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and silicon Etherifying reagent reacts, and obtains 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described silicon etherifying reagent Selected from trim,ethylchlorosilane and bromotrimethylsilane；
Preferably, said method comprising the steps of:
Step (a ') make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and N, O-double (trimethylsilyl) acetamide reaction, To 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (b '): in the presence of organic amine, make 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester with Silicon etherifying reagent reacts, and obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, and described silicon is etherified Reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane；
Preferably, described organic amine is triethylamine；
Preferably, described step (a ') in, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and double (trimethylsilyl) second of N, O- The rate of charge (mol:mol) of amide is 1:1.2～2；
Preferably, described step (b ') in, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester: silicon is etherified Reagent: the rate of charge (mol:mol:mol) of organic amine is 1:2～5:3～6；
Preferably, step (a ') in, the temperature of reaction is 10 DEG C～35 DEG C；
Preferably, step (b ') in, the temperature of reaction is 20 DEG C～60 DEG C, more preferably 40 DEG C～60 DEG C；
Preferably, step (a ') in, reaction carries out 10～15 hours；
Preferably, step (b ') in, reaction carries out 3～6 hours；
Preferably, the reaction of described step (a ') 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 (such as Dichloromethane or chloroform), acetonitrile, one or more in N,N-dimethylformamide and acetone；Preferably, described solvent For acetonitrile；
Preferably, described step (a ') in, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the quality of solvent: volume ratio (g:mL) it is 1:5～1:15；
Preferably, described step (b ') in, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and solvent Quality: volume ratio (g:mL) is 1:5～1:15；
Preferably, between step (a ') and step (b '), described method also includes step (c '): removing unreacted N, O-is double (trimethylsilyl) acetamide；
Preferably, the method using decompression distillation removes double (trimethylsilyl) acetamide of unreacted N, O-；
Preferably, described decompression distillation is carried out under conditions of vacuum is 5mmHg～10mmHg；
Preferably, the temperature of described decompression distillation is 50 DEG C-70 DEG C (temperature outward).
6. the method for claim 5, wherein, step (b ') in, described silicon etherifying reagent is bromotrimethylsilane；
Preferably, described organic amine is triethylamine；
Preferably, step (b ') in, described reaction is with acetonitrile as solvent.
7. the method for claim 5, wherein, step (b ') in, described silicon etherifying reagent is trim,ethylchlorosilane, and, described React and carry out under conditions of organic amine and iodine salt exist；
Preferably, described organic amine is triethylamine；
Preferably, described iodine salt is selected from alkali-metal iodine salt and tetrabutylammonium iodide；It is highly preferred that the choosing of described alkali-metal iodine salt From sodium iodide, potassium iodide and lithium iodide；It is particularly preferred that described iodine salt is sodium iodide；
Preferably, step (b ') in, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester: trimethylchloro-silicane Alkane: iodine salt: the rate of charge (mol:mol:mol:mol) of organic amine is 1:2～5:2～5:3～6；
Preferably, step (b ') in, described reaction is carried out in a solvent, and described solvent is the mixing being made up of aromatic hydrocarbon and acetonitrile Solvent；
Preferably, described aromatic hydrocarbon is toluene；
Preferably, described aromatic hydrocarbon is 1:3～3:1 with the volume ratio of acetonitrile.
8. prepare 3 for one kind, the method for 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester, described method bag Include following steps:
Step (i): make 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and N, O-double (trimethylsilyl) acetamide reaction, and And described step (i) does not use triethylamine；
Step (ii): use the method for decompression distillation to remove double (trimethylsilyl) acetamide of unreacted N, O-, obtain 3-(front three The silica-based epoxide of base)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (iii): under conditions of organic base exists, makes 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid Methyl ester reacts with silicon etherifying reagent, obtains 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；
Preferably, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is 3 α, 7-bis-(trimethyl Silica-based epoxide)-6-alkene-5 β-cholane-24-acid methyl ester；
Preferably, described method includes:
Step (i): make 3 Alpha-hydroxy-7-ketone group-5 β-cholane-24-acid methyl ester and N, O-double (trimethylsilyl) acetamide reaction；
Step (ii): use the method for decompression distillation to remove double (trimethylsilyl) acetamide of unreacted N, O-, obtain 3 α-(three Methylsilyl epoxide)-7-ketone group-5 β-cholane-24-acid methyl ester；
Step (iii): under conditions of organic base exists, makes 3 α-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid Methyl ester reacts with silicon etherifying reagent, obtains 3 α, 7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester；
Preferably, described organic base is selected from organic amine (such as triethylamine, diisopropylethylamine and 1,8-diazabicylo 11 Carbon-7-alkene) and the lithium salts (such as lithium diisopropylamine) of organic amine；
Preferably, described silicon etherifying reagent is selected from trim,ethylchlorosilane and bromotrimethylsilane；
Preferably, in step (ii), described decompression distillation is carried out under conditions of vacuum is 5mmHg～10mmHg；
Preferably, in step (ii), the temperature of described decompression distillation is 50 DEG C～70 DEG C (temperature outward)；
Preferably, after step (iii), described method also includes: to 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder Alkane-24-acid methyl ester carries out separating and/or purification；
Preferably, one or more during described separation and/or purification comprise the following steps:
(1) reacted mixture is extracted, separate organic layer；
(2) use water or saturated aqueous common salt that organic layer is washed；
(3) utilize anhydrous sulfate (such as anhydrous sodium sulfate) that organic layer is dried；
(4) dried organic layer is carried out decompression distillation, isolates 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder Alkane-24-acid methyl ester；With
(5) utilize silica gel column chromatography that 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is purified.
9. the method for claim 8, in step (i), 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the double (front three of N, O- Silica-based) rate of charge (mol:mol) of acetamide is 1:1.2～2；
Preferably, in step (i), the temperature of reaction is 10 DEG C～35 DEG C；
Preferably, the reaction in step (i) carries out 10～15 hours；
Preferably, in step (i), reaction is carried out in solvent (such as aprotic solvent)；Preferably, described solvent is selected from fragrance Hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE)), halogenated alkane (example Such as dichloromethane or chloroform), acetonitrile, one or more in N,N-dimethylformamide and acetone；
Preferably, described solvent is acetonitrile；
Preferably, 3-hydroxyl-7-ketone group-5 β-cholane-24-acid methyl ester and the quality of solvent: volume ratio (g:mL) is 1:5～1: 15。
10. the method for claim 8, in step (iii), described organic base is the lithium salts of organic amine, such as diisopropylaminoethyl Lithium；
Preferably, described silicon etherifying reagent is trim,ethylchlorosilane；
Preferably, in step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester: silicon etherificate examination Agent: the rate of charge (mol:mol:mol) of organic base is 1:2～3:2.5～3.5；
Preferably, in step (iii), described reaction is carried out at-20 DEG C～-40 DEG C；
Preferably, the reaction in step (iii) carries out 2～10 hours；
Preferably, in step (iii), described reaction is carried out in solvent (such as aprotic solvent)；
Preferably, described solvent is selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran Or methyl tertiary butyl ether(MTBE)), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, N,N-dimethylformamide and acetone In one or more；
It is highly preferred that described solvent is oxolane；
Preferably, in step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and the matter of solvent Amount: volume ratio (g:mL) is 1:5～1:15；
Preferably, described solvent is before the reaction through Non-aqueous processing.
The method of 11. claim 8, in step (iii), described organic base is organic amine；
Preferably, described organic amine is triethylamine；
Preferably, in described step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester: silicon is etherified Reagent: the rate of charge (mol:mol:mol) of organic amine is 1:2～5:3～6；
Preferably, in described step (iii), reaction temperature is 20 DEG C～60 DEG C, more preferably 40 DEG C～60 DEG C；
Preferably, the reaction in step step (iii) carries out 3～6 hours；
Preferably, in step (iii), described reaction is carried out in solvent (such as aprotic solvent)；
Preferably, described solvent is selected from aromatic hydrocarbon (such as toluene)；Ether (such as oxolane, dioxane, methyltetrahydrofuran Or methyl tertiary butyl ether(MTBE)), halogenated alkane (such as dichloromethane or chloroform), acetonitrile, N,N-dimethylformamide and acetone；
Preferably, in step (iii), 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester and the matter of solvent Amount: volume ratio (g:mL) is 1:5～1:15.
The method of 12. claim 11, in step (iii), described silicon etherifying reagent is bromotrimethylsilane；
Preferably, described organic amine is triethylamine；
Preferably, in step (iii), described reaction thinks that acetonitrile is solvent.
The method of 13. claim 11, in step (iii), described silicon etherifying reagent is trim,ethylchlorosilane, and, described instead Should carry out under conditions of organic amine and iodine salt exist；
Preferably, described organic amine is triethylamine；
Preferably, described iodine salt is selected from alkali-metal iodine salt and tetrabutylammonium iodide；It is highly preferred that the choosing of described alkali-metal iodine salt From sodium iodide, potassium iodide and lithium iodide；It is particularly preferred that described iodine salt is sodium iodide；
Preferably, 3-(the silica-based epoxide of trimethyl)-7-ketone group-5 β-cholane-24-acid methyl ester: trim,ethylchlorosilane: iodine salt: organic The rate of charge (mol:mol:mol:mol) of amine is 1:2～5:2～5:3～6；
Preferably, in step (iii), described reaction is carried out in a solvent, and described solvent is by mixing that aromatic hydrocarbon and acetonitrile form Bonding solvent；
Preferably, described aromatic hydrocarbon is toluene；
Preferably, described aromatic hydrocarbon is 1:3～3:1 with the volume ratio of acetonitrile.
14. 1 kinds of methods preparing shellfish cholic acid difficult to understand, it comprises the steps of
Step 1: prepare 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-gallbladder by the method for any one of claim 1-13 Alkane-24-acid methyl ester；
Step 2: 3 obtained with step 1,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is raw material, system Standby shellfish cholic acid difficult to understand；
Preferably, described 3,7-bis-(the silica-based epoxide of trimethyl)-6-alkene-5 β-cholane-24-acid methyl ester is 3 α, 7-bis-(trimethyl Silica-based epoxide)-6-alkene-5 β-cholane-24-acid methyl ester.
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CN108299539A (en) * 2018-03-09 2018-07-20 中山百灵生物技术有限公司 The method for producing 6- ethylidene chenodeoxycholic acids using continuous current micro-reactor
CN110655550A (en) * 2018-06-29 2020-01-07 江苏海悦康医药科技有限公司 (E) Preparation method of (E) -3 alpha-hydroxy-6-ethylene-7-oxo-5 beta-cholestane-24-acid

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CN103772414A (en) * 2013-12-31 2014-05-07 福建省福抗药业股份有限公司 Preparation method for preparing cefatrizine propylene glycolate
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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
CN108299539A (en) * 2018-03-09 2018-07-20 中山百灵生物技术有限公司 The method for producing 6- ethylidene chenodeoxycholic acids using continuous current micro-reactor
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