CN106046047B - The method for preparing phosphorylation serine phosphonic acids analogies - Google Patents
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Abstract
The present invention relates to the methods for preparing phosphorylation serine phosphonic acids analogies, specifically, the method includes：(1) compound shown in formula 1 carries out reduction reaction, to obtain compound shown in formula 2；(2) compound shown in the formula 2 is made to carry out bromination reaction, to obtain compound shown in formula 3；(3) compound shown in the formula 3 is made to be contacted with compound shown in formula 4, to obtain compound shown in formula 5；(4) make compound Deprotection shown in the formula 5, to obtain compound shown in formula (I), wherein R is hydrogen, benzyl, adjacent nitro benzyl, cumarin or allyl, R1For benzyl, adjacent nitro benzyl, cumarin or allyl.Raw material used by this method is cheap, is easy to get, and reaction route step is less, and the total recovery of whole route can prepare the phosphorylation serine phosphonic acids analogies of high yield high quality 20% or more.
Description
Technical field
The invention belongs to biochemistries to synthesize field, and in particular, to prepare the side of phosphorylation serine phosphonic acids analogies
Method and its application.
Background technology
The phosphorylation of protein is a kind of very important posttranslational modification, it with cell metabolism, signal transduction, immune know
Other and Apoptosis etc. has close relationship, and enzyme related with phosphorylation is also often as the targeting target of drug molecule.So
And the research (especially experiment in vivo) of phosphorylated protein is often relatively difficult, the main reason is that phosphorylated protein is difficult to obtain
And it is easy in cell hydrolyzed.It is natural with the development of recombination and expression techniques and Solid-phase synthesis peptides technology, and such as
It is connected chemically the emergence of the new technologies such as (NCL), expression albumen connection (EPL), obtaining phosphorylated protein is becoming more next
It is more convenient；And the problem of being easy hydrolysis for phosphorylated protein, forefathers also develop a series of analogies and replace natural phosphoric acid
Group, and effect most preferably simulates the phosphonic acids compounds of phosphoric acid ester bond with phosphorus carbon key in these analogies.Phosphonic acids analogies
With similar with phosphate structure height, and can be protein bound excellent with phosphohydrolase etc. in the case of not hydrolyzed
Gesture；By the site for being integrated into phosphorylation in albumen, so that it may to find new egg by way of combination outside aleuroplast
In vain-protein-interacting, or the stability and space distribution situation of albumen in the cell are observed by way of microinjection, from
And obtain the result that some other phosphorylated protein analogies are difficult to.Currently, replacing phosphorylation amino with phosphonic acids analogies
The phosphorylated polypeptide or albumen analogies of acid mainly carry out chemical synthesis by polypeptide solid-state reaction method, and flexibility is high and side chain
The Fmoc strategies of protecting group good compatibility are then the mainstream strategies of existing polypeptide solid-state reaction method.
However, the method for preparing phosphate mimetic at present still has much room for improvement.
Invention content
The present invention is directed to solve at least some of the technical problems in related technologies.
According to the first aspect of the invention, the present invention provides a kind of sides preparing phosphorylation serine phosphonic acids analogies
Method, including：
(1) compound shown in formula 1 carries out reduction reaction, to obtain compound shown in formula 2；
(2) compound shown in the formula 2 is made to carry out halogenation, to obtain compound shown in formula 3；
(3) compound shown in the formula 3 is made to be contacted with compound shown in formula 4, to obtain compound shown in formula 5；
(4) make compound Deprotection shown in the formula 5, to obtain compound shown in formula (I),
Wherein, R is hydrogen, benzyl, adjacent nitro benzyl, cumarin or allyl, R1For benzyl, adjacent nitro benzyl, cumarin
Or the orthogonal protecting group such as allyl,
This method is mainly natural amino acid N- tertbutyloxycarbonyls-acid tert-butyl (Boc-Asp- by protecting
OtBu) by reduction, bromo, phosphite ester substitution and deprotection, to obtain phosphorylation serine phosphonic acids analogies, this method
Used raw material is cheap, is easy to get, and reaction route step is less, and the total recovery of whole route can be prepared and be obtained 20% or more
Obtain the phosphorylation serine phosphonic acids analogies of high yield high quality.The phosphorylation serine phosphonic acids mould prepared using this method
Quasi- object can obtain polypeptide or protein containing phosphorylation serine phosphonic acids analogies, Ke Yi by polypeptide solid-state reaction method
The behavior of phosphorylation serine and will not be by phosphoric acid hydrolysis enzyme hydrolysis, in phosphoric acid in mimic peptide or albumen well into the cell
It is of great significance in terms of changing protein research and inhibitor exploitation.
According to some embodiments of the present invention, step (1) includes：
(1-1) in ethyl acetate there are dicyclohexylcarbodiimide in the case of, make compound shown in the formula 1 with
N-hydroxysuccinimide contacts, to obtain the n-hydroxysuccinimide Acibenzolar of compound shown in formula 1；
(1-2) makes the n-hydroxysuccinimide Acibenzolar and boron of compound shown in the formula 1 in Isosorbide-5-Nitrae-dioxane
Sodium hydride contacts, to obtain compound shown in the formula 2.In the n-hydroxysuccinimide Acibenzolar of compound shown in formula 1
Mesosome is used directly for sodium borohydride reduction without isolating and purifying.
According to a particular embodiment of the invention, step (1) includes：By compound and n-hydroxysuccinimide shown in formula 1
(NHS) it is dissolved in ethyl acetate, and dicyclohexylcarbodiimide (DCC) is added, is stirred to react obtains 1 shownization of formula overnight at room temperature
The NHS Acibenzolars for closing object, are filtered to remove insoluble matter and concentrate filtrate, residue is dissolved in Isosorbide-5-Nitrae-dioxane and hydroboration is added
Sodium, ice bath are simultaneously added dropwise after a small amount of water initiation reaction and continue room temperature reaction 2 hours, reaction are quenched with saturated ammonium chloride solution, concentration
It is extracted with ethyl acetate after removing dioxane, organic phase uses water and saturated common salt water washing after merging, concentrate and be used in combination after dry
Pillar layer separation obtains compound shown in formula 2.
According to a particular embodiment of the invention, the Acibenzolar reduction process reaction time should be according to TLC thin layer colors in step (1)
The result of spectrum monitoring adjusts accordingly, when using the mixed solution of ethyl acetate and hexamethylene as solvent, chemical combination shown in formula 2
The Rf values of object are about 0.7, wherein the volume ratio of ethyl acetate and hexamethylene is 1 in ethyl acetate and hexamethylene mixed solution:1.
According to a particular embodiment of the invention, in step (1) solvent used by pillar layer separation be ethyl acetate and
The volume ratio of ethyl acetate and hexamethylene is 1 in the mixed solution of hexamethylene, wherein ethyl acetate and cyclohexane solution:3.
According to some embodiments of the present invention, in step (2), the halogenation is iodination reaction or bromination reaction.
According to some embodiments of the present invention, bromination reaction is carried out using Appel reactions in step (2), it is possible thereby into
Improve yield to one step.
According to some embodiments of the present invention, step (2) includes：
In methylene chloride, in the case of there are triphenylphosphine, keep compound shown in the formula 2 sub- with N- bromos succinyl
Amine contacts, to obtain compound shown in the formula 3.
According to a particular embodiment of the invention, step (2) includes：Compound shown in the formula 2 is dissolved in dichloromethane, is added
Enter N-bromosuccinimide (NBS) and be dispersed with stirring uniformly, is added dropwise the two of triphenylphosphine into said mixture on ice bath
Chloromethanes solution continues room temperature reaction 2 hours after adding.Reaction is quenched with water, separate organic phase and extracts water with dichloromethane
Phase, extracting solution use water and saturated common salt water washing, pillar layer separation are concentrated and used after dry after merging with organic phase, obtain described in
Compound shown in formula 2.
According to a particular embodiment of the invention, using the dichloromethane after Non-aqueous processing in step (2).Thus, it is possible to carry
In high yield.
According to a particular embodiment of the invention, in step (2) reaction time should according to TLC thin-layer chromatographys monitor result into
The corresponding adjustment of row, when using the mixed solution of ethyl acetate and hexamethylene as solvent, the Rf values of compound shown in formula 3 are about
0.6, wherein the volume ratio of ethyl acetate and hexamethylene is 1 in the mixed solution of ethyl acetate and hexamethylene:4.
According to a particular embodiment of the invention, in step (2) solvent used by pillar layer separation be ethyl acetate and
The mixed solution of hexamethylene, wherein the volume ratio of ethyl acetate and hexamethylene is in the mixed solution of ethyl acetate and hexamethylene
1:7。
According to some embodiments of the present invention, step (3) includes：Under inert gas conditions, in acetonitrile solution, exist
In the case of DBU, compound shown in the formula 3 is made to be contacted with compound shown in the formula 4, to obtain 5 institute of the formula
Show compound.Wherein, it should be noted that 11 carbon -7- alkene of DBU 1,8- diazabicylo.
According to a particular embodiment of the invention, step (3) includes：Under inert gas protection, to dibenzyl phosphite
Compound shown in formula 3 is added in anhydrous acetonitrile, then the agitation and dropping DBU on ice bath, continues room temperature reaction 8 hours.Instead
After answering, impurity is washed away with hexamethylene, acetonitrile mutually concentrates and with pillar layer separation, obtains 2- (t-butoxycarbonyl amino) -4-
(dibenzyl phosphonic acid base) tert-butyl acetate ((Boc-Pma (Bn)2-OtBu)。
According to a particular embodiment of the invention, reaction needs to carry out under conditions of anhydrous and oxygen-free in step (3).As a result,
Yield can be improved.
According to a particular embodiment of the invention, in step (3) reaction time should according to TLC thin-layer chromatographys monitor result into
The corresponding adjustment of row, when using ethyl acetate and hexamethylene mixed solution as solvent, 2- (t-butoxycarbonyl amino) -4- (two
Benzylphosphonic acid base) tert-butyl acetate ((Boc-Pma (Bn)2- OtBu) Rf values be about 0.5, wherein ethyl acetate and hexamethylene
The volume ratio of ethyl acetate and hexamethylene is 1 in mixed solution:1.
According to a particular embodiment of the invention, step (3) if in using phosphorous acid two (o-nitro benzyl alcohol) ester replace phosphorous
Sour dibenzyl ester obtains 2- (t-butoxycarbonyl amino) -4- (two adjacent nitro benzylphosphonic acid bases) tert-butyl acetate, and reacts with after
It should be protected from light in processing procedure.
According to a particular embodiment of the invention, the solvent that pillar layer separation uses in step (3) is ethyl acetate and ring
The mixed solution of hexane, wherein the volume ratio of ethyl acetate and hexamethylene is 1 in the mixed solution of ethyl acetate and hexamethylene:
2。
According to some embodiments of the present invention, step (4) includes：Make compound shown in the formula 5 in trifluoroacetic acid-water-
It is reacted in triethylsilane mixed system, to obtain compound shown in the formula (I).
As a result, according to a particular embodiment of the invention, the present invention proposes following synthetic route, can be used for described in preparation
Compound shown in formula (I),
According to some embodiments of the present invention, R is benzyl, after step (3) and before step (4), is further wrapped
It includes：Debenzylation processing is carried out to compound shown in the formula 5.
According to a particular embodiment of the invention, to the tertiary fourth of 2- (t-butoxycarbonyl amino) -4- (dibenzyl phosphonic acid base) butyric acid
Ester (Boc-Pma (Bn)2- OtBu) ethyl acetate solution in a small amount of 5% palladium carbon catalyst is added, gone out with inert gas replacement
Then air in system displaces inert gas with hydrogen, room temperature reaction is overnight.Filtration of catalyst after reaction,
Then all solvents are removed on a rotary evaporator.Residue trifluoroacetic acid-water-triethylsilane mixed system dissolves, after
Continuous room temperature reaction 2 hours.After reaction, all solvents, residue water and Isosorbide-5-Nitrae-dioxy six are removed on a rotary evaporator
Ring mixed system dissolves, and sodium bicarbonate is added and adjusts pH to alkalescent, and fluorenes methoxy carbonyl acyl succinimide (Fmoc- is added
OSu it) and reacts at room temperature 24 hours.Remove dioxane, remaining water phase ethyl acetate on a rotary evaporator after reaction
After washing plus dilute hydrochloric acid is acidified, then is extracted with ethyl acetate.Extracting solution (not including cleaning solution) uses water and saturated common salt after merging
Water washing removes all solvents after dry, obtains final product 2- (fluorenylmethyloxycarbonyl amino) -4- phosphonic acids on a rotary evaporator
Butyric acid (Fmoc-Pma).
Wherein, it should be noted that in the present invention, " compound shown in Formula X " may be used interchangeably, X with " compound X "
It is the integer of 1-5.
According to a further aspect of the invention, the present invention proposes a kind of phosphorylation serine phosphonic acids analogies, is formula
(I) compound shown in,
Wherein, R is the orthogonal protecting groups such as benzyl, adjacent nitro benzyl, cumarin or allyl.Thus, it is possible to utilize flexibility
Fmoc strategy polypeptide solid-state reaction methods high, with Side chain protective group good compatibility, are simulated using the phosphorylation serine phosphonic acids
Object replaces phosphorylated amino acid synthesis phosphorylated polypeptide or albumen analogies；In addition, by adding adjacent nitro benzyl on phosphonic acid base
The orthogonal protecting group such as base and allyl can relatively easily realize the selectivity deprotection on phosphonic acid base, be utilized to reach
Different condition regulates and controls the active purpose of phosphorylated protein analogies.
According to a further aspect of the invention, the present invention proposes the phosphorylation silk prepared using method noted earlier
Aminophosphonic acid analogies or phosphorylation serine phosphonic acids analogies noted earlier are preparing phosphorylated polypeptide and/or albumen analogies
In purposes.The synthesis of Fmoc solid phase synthesis techniques can be utilized to obtain phosphorylated polypeptide and/or albumen analogies.
According to a particular embodiment of the invention, the present invention proposes following synthetic route, can be by amido protecting group
Fmoc or Alloc are introduced into compound shown in formula (I), and phosphorylated polypeptide and/or albumen analogies are obtained to synthesize
Specific implementation mode
The embodiment of the present invention is described below in detail, the embodiments described below is exemplary, it is intended to for explaining this
Invention, and be not considered as limiting the invention.
Embodiment
Embodiment 1
The synthesis of the N- tertbutyloxycarbonyls-homoserine tert-butyl ester (Boc-HoSer-OtBu, compound 2)
Be added in 100mL round-bottomed flasks 2.89g N- tertbutyloxycarbonyls-acid tert-butyl (Boc-Asp-OtBu,
Compound 1) and 1.29g n-hydroxysuccinimides, 50mL ethyl acetate is added and makes it dissolve, is then added under stiring
2.26g dicyclohexylcarbodiimides continue to be stirred to react overnight at room temperature.It is filtered to remove insoluble matter and revolves on a rotary evaporator
Go out ethyl acetate, residue is dissolved in 50mL Isosorbide-5-Nitraes-dioxane and 0.76g sodium borohydrides are added under stiring, and mixture is in ice
3mL water is slowly added dropwise after being cooled to 0 DEG C in bath, then removes ice bath and continues to react 2 hours at room temperature.10mL is added and is saturated chlorine
Change ammonium salt solution to stir 10 minutes, after removing dioxane on a rotary evaporator, remaining water phase is divided 4 times with 100mL ethyl acetate
Extraction；Extracting solution is respectively washed twice after merging with 20mL water and 20mL saturated salt solutions, anhydrous magnesium sulfate drying, in Rotary Evaporators
On be spin-dried for, then with 1:3 ethyl acetate/hexamethylene is that solvent carries out pillar layer separation, obtains 2.00g N- tertbutyloxycarbonyls-
The homoserine tert-butyl ester (Boc-HoSer-OtBu, compound 2), yield about 72%.
Embodiment 2
The synthesis of 2- (the t-butoxycarbonyl amino) -4- bromobutyric acids tert-butyl ester (Boc-Abu (Br)-OtBu, compound 3)
Be added in 50mL round-bottomed flasks 1.95g N- tertbutyloxycarbonyls-homoserine tert-butyl ester (Boc-HoSer-OtBu,
Compound 2) and 1.60g N-bromosuccinimides, 15mL anhydrous methylene chlorides are added and are uniformly mixed, 0 is cooled on ice bath
DEG C, and the solution that 2.38g triphenylphosphines are dissolved in 10mL anhydrous methylene chlorides is slowly added dropwise with constant pressure funnel under stiring, greatly
About 20min is added；Then ice bath is removed, continues to react 2 hours at room temperature.10mL water is added after reaction, separates organic
Phase, 3 extractions of 75mL dichloromethane point of remaining water phase；Organic phase and extracting solution merge, and 20mL water and 20mL is used in combination to be saturated food
Brine is respectively washed twice, and anhydrous magnesium sulfate drying is spin-dried for, on a rotary evaporator then with 1:7 ethyl acetate/hexamethylene is expansion
Agent carries out pillar layer separation, obtains 1.71g 2- (the t-butoxycarbonyl amino) -4- bromobutyric acids tert-butyl ester (Boc-Abu (Br) -
OtBu, compound 3), yield about 70%.
Embodiment 3
2- (t-butoxycarbonyl amino) -4- (dibenzyl phosphonic acid base) tert-butyl acetate (Boc-Pma (Bn)2- OtBu) conjunction
At
1.69g 2- (the t-butoxycarbonyl amino) -4- bromobutyric acid tert-butyl esters (Boc-Abu is added in 100mL three-necked bottles
(Br)-OtBu, compound 3), it is exchanged for several times to remove air in bottle with argon gas, 1.50g dibenzyl phosphites is then added and are dissolved in
The solution of 10mL anhydrous acetonitriles, is uniformly mixed.Reaction system is cooled to 0 degree on ice bath, is delayed 1mL DBU with syringe
Slowly it is added drop-wise in bottle.It adds recession and removes ice bath, and continue to react 8 hours at room temperature.After reaction, the acetonitrile of mixture is molten
Liquid is washed 3 times with 10mL hexamethylenes, is spin-dried on a rotary evaporator, then with 1:2 ethyl acetate/hexamethylene carries out for solvent
Pillar layer separation obtains 1.68g 2- (t-butoxycarbonyl amino) -4- (dibenzyl phosphonic acid base) tert-butyl acetate (Boc-Pma
(Bn)2- OtBu), yield about 65%.
Embodiment 4
The synthesis of 2- (fluorenylmethyloxycarbonyl amino) -4- phosphonic acids butyric acid (Fmoc-Pma)
In 50mL three-necked bottles, the tertiary fourth of 520mg 2- (t-butoxycarbonyl amino) -4- (dibenzyl phosphonic acid base) butyric acid is added
Ester (Boc-Pma (Bn)2- OtBu) and a small amount of 5% palladium carbon catalyst, 10mL ethyl acetate is then added and is uniformly mixed.Use argon
Gas displaces the air in system, then displaces argon gas with hydrogen, is stirred to react at room temperature overnight.It crosses and filters out after reaction
Catalyst is removed, then removes all solvents on a rotary evaporator.Residue is mixed with 10mL trifluoroacetic acids-water-triethylsilane
Close solution (95:2.5:2.5) it dissolves, continues room temperature reaction 2 hours.After reaction, it removes on a rotary evaporator all molten
Agent, residue 10mL water and 10mL Isosorbide-5-Nitraes-dioxane mixed system dissolving, are used in combination sodium bicarbonate to adjust pH to 8~9, add
Enter 350mg fluorenes methoxy carbonyl acyl succinimides (Fmoc-OSu) and reacts at room temperature 24 hours.After reaction in Rotary Evaporators
Upper back-out dioxane, remaining water phase adds dilute hydrochloric acid to be acidified to pH after being washed twice with 10mL ethyl acetate be 2~3, it is seen that is had
White solid is precipitated；4 extractions of 100mL ethyl acetate point are used again；Extracting solution uses 20mL water and 20mL saturated salt solutions after merging
It respectively washes twice, anhydrous magnesium sulfate drying is spin-dried for, obtains 313mg 2- (fluorenylmethyloxycarbonyl amino) -4- phosphines on a rotary evaporator
Sour butyric acid (Fmoc-Pma), yield about 77%.
Embodiment 5
The synthesis of 2- (t-butoxycarbonyl amino) -4- (two adjacent nitro benzylphosphonic acid bases) tert-butyl acetate
Wherein, R is adjacent nitro benzyl.
1.05g 2- (the t-butoxycarbonyl amino) -4- bromobutyric acid tert-butyl esters (Boc-Abu is added in 50mL three-necked bottles
(Br)-OtBu, compound 3) and 1.58g phosphorous acid two (adjacent nitro benzyl) ester, it is exchanged for several times to remove air in bottle with argon gas,
The dissolving of 10mL anhydrous acetonitriles is added, and is uniformly mixed.Reaction system is cooled to 0 degree on ice bath, with syringe by 0.5mL
DBU is slowly dropped in bottle.It adds recession and removes ice bath, and continue to react 8 hours at room temperature.After reaction, mixture
Acetonitrile solution is washed 3 times with 10mL hexamethylenes, is spin-dried on a rotary evaporator, then with 1:2 ethyl acetate/hexamethylene is expansion
Agent carries out pillar layer separation, obtains 0.67g 2- (t-butoxycarbonyl amino) -4- (two adjacent nitro benzylphosphonic acid bases) tertiary fourth of butyric acid
Ester (Boc-Pma (R)2- OtBu), yield about 37%.
Embodiment 6
The synthesis of 2- (fluorenylmethyloxycarbonyl amino) -4- (two adjacent nitro benzylphosphonic acids) butyric acid
Wherein, R is adjacent nitro benzyl.
In 25mL three-necked bottles, 300mg 2- (t-butoxycarbonyl amino) -4- (two adjacent nitro benzylphosphonic acid bases) fourth is added
Then 5mL trifluoroacetic acids-dichloromethane-water-triethylsilane mixed solution (50 is added in tert-butyl acrylate:45:2.5:2.5) it stirs
It mixes uniformly, reacts 6 hours at room temperature.After reaction, remove all solvents on a rotary evaporator, residue 5mL water and
5mL Isosorbide-5-Nitraes-dioxane mixed system dissolving, are used in combination sodium bicarbonate to adjust pH to 8~9,200mg fluorenes methoxy carbonyl acyl ambers are added
Acid imide (Fmoc-OSu) simultaneously reacts at room temperature 24 hours.Screw out dioxane, remaining water on a rotary evaporator after reaction
It is 2~3 to add dilute hydrochloric acid to be acidified to pH after mutually being washed twice with 5mL ethyl acetate, it is seen that has white solid precipitation；60mL second is used again
4 extractions of acetoacetic ester point；Extracting solution is respectively washed twice after merging with 15mL water and 15mL saturated salt solutions, anhydrous magnesium sulfate drying,
It is spin-dried on a rotary evaporator, obtains 152mg 2- (fluorenylmethyloxycarbonyl amino) -4- (two adjacent nitro benzylphosphonic acids) butyric acid, yield
About 46%.
In addition, term " first ", " second " are used for description purposes only, it is not understood to indicate or imply relative importance
Or implicitly indicate the quantity of indicated technical characteristic.Define " first " as a result, the feature of " second " can be expressed or
Implicitly include at least one this feature.In the description of the present invention, the meaning of " plurality " is at least two, such as two, three
It is a etc., unless otherwise specifically defined.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example
Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not
It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office
It can be combined in any suitable manner in one or more embodiments or example.In addition, without conflicting with each other, the skill of this field
Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples
It closes and combines.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changes, replacing and modification.
Claims (1)
1. a kind of method preparing phosphorylation serine phosphonic acids analogies, which is characterized in that including：
(1) compound shown in formula 1 carries out reduction reaction, to obtain compound shown in formula 2；
(2) compound shown in the formula 2 is made to carry out halogenation, to obtain compound shown in formula 3；
(3) compound shown in the formula 3 is made to be contacted with compound shown in formula 4, to obtain compound shown in formula 5；
(4) make compound Deprotection shown in the formula 5, to obtain compound shown in formula (I),
Wherein, R is benzyl, adjacent nitro benzyl, R1For benzyl, adjacent nitro benzyl,
Step (1) includes：
(1-1) in ethyl acetate there are dicyclohexylcarbodiimide in the case of, make compound shown in the formula 1 and N- hydroxyls
Base succinimide contacts, to obtain the n-hydroxysuccinimide Acibenzolar of compound shown in formula 1；
(1-2) makes the n-hydroxysuccinimide Acibenzolar and hydroboration of compound shown in the formula 1 in Isosorbide-5-Nitrae-dioxane
Sodium contacts, to obtain compound shown in the formula 2,
In step (2), the halogenation is bromination reaction,
In step (2), is reacted using Appel and carries out bromination reaction,
Step (2) includes：
In methylene chloride, in the case of there are triphenylphosphine, compound shown in the formula 2 is made to be connect with N-bromosuccinimide
It touches, to obtain compound shown in the formula 3,
Step (3) includes：
Under inert gas conditions, in acetonitrile solution there are DBU in the case of, make compound shown in the formula 3 and the formula
Compound shown in 4 is contacted, to obtain compound shown in the formula 5,
Step (4) includes：
Compound shown in the formula 5 is set to be reacted in trifluoroacetic acid-water-triethylsilane mixed system, to obtain
Compound shown in formula (I) is stated,
R is benzyl, after step (3) and before step (4), is further comprised：
Debenzylation processing is carried out to compound shown in the formula 5.
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