CN105017322B - The preparation method of diphenyl-imidazole kind anti-cancer drugs object - Google Patents
The preparation method of diphenyl-imidazole kind anti-cancer drugs object Download PDFInfo
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- CN105017322B CN105017322B CN201410158588.3A CN201410158588A CN105017322B CN 105017322 B CN105017322 B CN 105017322B CN 201410158588 A CN201410158588 A CN 201410158588A CN 105017322 B CN105017322 B CN 105017322B
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Abstract
The invention belongs to medicinal chemistry arts, provide the preparation method of 4 (3,5 dimethoxy phenyl) 5 (3 hydroxyl, 4 methoxyphenyl) imidazoles phosphate ester salt, the described method comprises the following steps：1) at a temperature of 30 DEG C to 20 DEG C, under anhydrous condition, in the presence of tetrahydrofuran and N, N diisopropylethylamine, 4 (3,5 dimethoxy phenyl) 5 (3 hydroxyl, 4 methoxyphenyl) imidazoles is made to be reacted with phosphorylating agent；With 2) make step 1）The reactant of acquisition is reacted at salt with base reagent.The preparation method of the present invention is at low cost, and easy to operate, purity and yield are higher, is suitable for commercial scale.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to diphenyl-imidazole kind anti-cancer drugs object 4- (3,5- dimethoxy-benzenes
Base) -5- (3- hydroxyl -4- methoxyphenyls) imidazole phosphate preparation method.
Background technology
4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles disodium phosphate（C118P）It is one
Known compound, has the following structure：
The compound discloses in CN201110422678.5, this document is hereby incorporated by ginseng with entire contents
It examines.CN201110422678.5 reports 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphate
Disodium has tubulin polymerization inhibitory activity.4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphorus
Acid esters disodium is Combretastatin（Combretastatin A4）Derivative is specifically acted on as tumor vessel disrupting agent
Tumor neogenetic blood vessels, influence very little to other histoorgans strong to tumor vascular selectivity can be to avoid conventional cell poison
Some serious adverse reactions of property drug.
Preparation side about 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles disodium phosphate
Method has disclosed in CN201110422678.5, but the C118P yields of this method preparation and purity are relatively low.
Therefore, it is also desirable to develop new 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphoric acid
The preparation method of ester salt, to ensure that raw material and reagent be easy to get, price is relatively low, under the premise of method is simple, and can obtain compared with
High product yield and purity, meets commercial scale.
Invention content
The object of the present invention is to provide 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphoric acid
The preparation method of ester salt.The preparation method of the present invention includes the following steps：
1) at a temperature of -30 DEG C to 20 DEG C, under anhydrous condition, in tetrahydrofuran (THF) and n,N-diisopropylethylamine
(DIEA) in the presence of, 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles is made to be reacted with phosphorylating agent；
2) make step 1）The reactant of acquisition is reacted at salt with base reagent.
It was found by the inventors of the present invention that under low temperature, anhydrous condition, made using tetrahydrofuran and n,N-diisopropylethylamine
For reaction dissolvent and acylation 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphorus is used to prepare with alkali
Acid esters salt enables to reaction speed fast, and the reaction was complete, and product decomposition of little after reaction obtains excellent yield and product purity.
Preferably, in the preparation process in accordance with the present invention, the phosphorylating agent is phosphorus oxychloride or tribromo oxygen phosphorus.
Preferably, in the preparation process in accordance with the present invention, described to be selected from sodium hydroxide, sodium methoxide, carbon at salt base reagent
Sour hydrogen sodium, ammonium hydroxide, potassium methoxide, potassium hydroxide and potassium tert-butoxide, it is highly preferred that described be selected from sodium hydroxide at salt base reagent
And ammonium hydroxide.
Preferably, in the preparation process in accordance with the present invention, 4- (3, the 5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyl groups
Phenyl) imidazoles phosphate ester salt includes its alkali metal salt, alkali salt or amino butanetriol salt.
Preferably, preparation in accordance with the present invention, in step 1), the reaction time through HPLC by monitoring 4- (3,5-
Dimethoxy phenyl) residual quantity less than about 5% (w/w) of -5- (3- hydroxyl -4- methoxyphenyls) imidazoles determines.It is highly preferred that
Preparation in accordance with the present invention, in step 1), the reaction time through HPLC by monitoring 4- (3,5- dimethoxy phenyl) -5-
The residual quantity less than about 1% (w/w) of (3- hydroxyl -4- methoxyphenyls) imidazoles determines.
Preferably, preparation in accordance with the present invention, in step 1), phosphorylating agent and 4- (3,5- dimethoxy phenyl)-
The molar ratio of 5- (3- hydroxyl -4- methoxyphenyls) imidazoles is more than 1.4:1, for example, about 5~1.4:1, it is highly preferred that phosphorylated
The molar ratio of agent and 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles is 2~1.4:1, most preferably
The molar ratio of ground, phosphorylating agent and 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles be 1.6~
1.4:1。
Preferably, preparation in accordance with the present invention, in step 1), tetrahydrofuran and 4- (3,5- dimethoxy phenyl)-
The volume (ml) of 5- (3- hydroxyl -4- methoxyphenyls) imidazoles:Quality (g) ratio is about 5~1:1, it is highly preferred that tetrahydrofuran and
The volume (ml) of 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles:Quality (g) ratio is about 3~1:1,
Most preferably, the volume (ml) of phosphorylating agent and 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles:
Quality (g) ratio is about 1.5~1:1.
Preferably, preparation in accordance with the present invention, in step 1), n,N-diisopropylethylamine and phosphorylating agent rub
Your ratio is about 3~1:1, it is highly preferred that n,N-diisopropylethylamine and the molar ratio of phosphorylating agent are about 2~1:1, most preferably
The molar ratio of ground, n,N-diisopropylethylamine and phosphorylating agent is about 1:1.
Preferably, preparation in accordance with the present invention further comprises 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyls -
4- methoxyphenyls) imidazoles phosphate ester salt recrystallization the step of.It is further preferred that preparation in accordance with the present invention, described
Recrystallization carries out in one or more solvents in water, tetrahydrofuran, methanol, acetone, isopropanol, acetonitrile.
In a preferred embodiment, preparation in accordance with the present invention, 4- (3,5- the dimethoxy phenyl) -5-
(3- hydroxyl -4- methoxyphenyls) imidazoles phosphate ester salt is 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls)
Sodium salt, monoamine butanetriol salt, sylvite, magnesium salts, calcium salt or the ammonia salt of imidazoles phosphate.Preferably, preparation side according to the present invention
Method, 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) the imidazoles phosphate ester salt are 4- (3,5- dimethoxies
Phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt.
It was found by the inventors of the present invention that preparing 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) miaow
In azoles phosphate ester salt, first C118 and phosphorus oxychloride are suspended in tetrahydrofuran, n,N-diisopropylethylamine is then added dropwise, is reacted
More completely.In a preferred embodiment, preparation method of the invention includes the following steps：
A) by 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles, tetrahydrofuran, phosphorus oxychloride
It is added in reactor, maintains the temperature between about -20 DEG C to 10 DEG C, preferably between -10 DEG C to 5 DEG C；
B) at a temperature of about -10 DEG C to 15 DEG C, preferably -5 to 10 DEG C, N is added into the reactor of step a), N- bis- is different
Propylethylamine after the reaction was complete, is washed with water, and filtering obtains filter cake；
C) filter cake of the step b) of taking-up is transferred in pure water, is added into salt base reagent, filtering obtains filtrate；
D) organic solvent crystallization, then crystallization and drying are added into the filtrate of step c).
Preferably, above-mentioned preparation method according to the present invention, phosphorus oxychloride, n,N-diisopropylethylamine and C118 mole
Than being about 1.4~2:1.4~2:1.
Preferably, above-mentioned preparation method according to the present invention is slowly added to n,N-diisopropylethylamine in step b), and
Controlling reaction temperature is at about -5 DEG C to 10 DEG C, and the reaction time through HPLC by monitoring 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyls
Base -4- methoxyphenyls) imidazoles residual quantity less than about 5%, preferably less than about 1% determines, after the reaction was complete, by by reaction solution
It pours into trash ice and stirs simultaneously and fully washed.
Preferably, above-mentioned preparation method according to the present invention is slowly added into salt base reagent and is stirred in step d),
PH9-10 is adjusted, isopropanol/acetone soln is then added and is crystallized.
Preferably, above-mentioned preparation method according to the present invention further comprises 4- (3,5- dimethoxy phenyl) -5- (3-
Hydroxyl -4- methoxyphenyls) imidazoles phosphate ester salt recrystallization the step of.It is further preferred that above-mentioned preparation according to the present invention
Method, the recrystallization carry out in one or more solvents in acetone, isopropanol, tetrahydrofuran, water.More preferably
Ground, it is described recrystallization selected from acetone, isopropanol, isopropanol/acetone, water/acetone solvent in carry out.
It was found by the inventors of the present invention that preparation 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- first according to the present invention
Phenyl) imidazoles phosphate ester salt method, by under low temperature, anhydrous condition, in tetrahydrofuran and N, N- diisopropyl second
In the presence of amine, make 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles and phosphorylating agent such as phosphorus oxychloride
Reaction, then makes the reactant of acquisition be reacted with base reagent at salt with suitable, can obtain the product in high yield with high-purity,
This method is easier simultaneously, and raw materials and reagents reagent is easy to get, and price is relatively low.
Unless otherwise indicated, all technical and scientific terms used herein has and common skill of the art
The normally understood identical meaning of art personnel.
As used herein, 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) the imidazoles phosphate ester salt
Including their crystal form, hydrate, solvate and prodrug.
4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles prepared according to the methods of the invention
Phosphate ester salt has higher yield and purity, disclosure satisfy that plant-scale production and application.
Specific implementation mode
The present invention is further elaborated with reference to embodiment, but the present invention is not limited to these Examples.4-(3,
5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles（C118）Side as disclosed in CN201110422678.5
Prepared by method, other raw materials and reagents are commercially available.
It is prepared by embodiment 14- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt
The selection of middle agents useful for same
The research of 1.1 reaction dissolvents
Test the influence of THF, acetone, dichloromethane and 2- methyltetrahydrofurans as solvent to reaction.Above-mentioned solvent
Each 1ml, C1185g, POCl39.4g, triethylamine 6.2g, reaction temperature are controlled at 0 DEG C or so, and TLC is detected, testing conditions：
Methanol:Ethyl acetate=1:10, C118Rf values 0.5, post-processing approach are to be quenched using trash ice.As a result it is shown in table 1.
Table 1：The selection of reaction dissolvent
| Solvent | Time（h） | Detection is controlled in TLC | TLC product testings |
| THF | 2 | Raw material disappears substantially | It is unchanged |
| Acetone | 8 | Raw material reaction 80% | It is unchanged |
| Dichloromethane | 2 | Raw material disappears substantially | Raw material point is deepened |
| Methyltetrahydrofuran | 8 | Raw material reaction 80% | Raw material point is deepened |
Experimental result shows that process heat release is quenched in post-processing in dichloromethane and 2- methyltetrahydrofuran hydrophobic solvents
Acutely, cause portion of product to decompose, regenerate raw material C118 so that reaction is incomplete, and water-soluble solvent THF reaction rates
It is much better than acetone, therefore selects THF as reaction dissolvent.
The dosage of THF is investigated later, uses C1185g, POCl34.7g, triethylamine 3.1g, about 0 DEG C of temperature,
Reaction time 2h, TLC are detected, testing conditions：Methanol:Ethyl acetate=1:10, C118Rf values 0.5.As a result it is shown in table 2
In.
Table 2：THF dosages
| Solvent dosage（V*） | TLC is detected |
| 10 | C118 residues about 30% |
| 5 | C118 is remaining a small amount of |
| 1.5 | C118 disappears |
| 1 | C118 disappears |
V* indicates the volume (ml) of THF and C118:Quality (g) compares, i.e. the ml numbers of THF used in 1g C118.
Experiment shows that the increase with THF dosages reduces reaction rate instead, and THF usage amounts are fewer to subsequently grasping
Work is more advantageous, therefore selects THF dosages for 1~5V（1g C118 use 1.0~5.0ml THF as reaction dissolvent）, preferably
THF dosages are 1~1.5V.
The research of 1.2 phosphorus esterification reagents
It screens, compared a variety of phosphorus esterification reagents, from a cost perspective, phosphorus oxychloride has been selected to implement as the present invention
The phosphorus esterification reagent of example, but other phosphorus esterification reagents can also be used.Then the dosage of phosphorus oxychloride is studied, is selected
It has taken 1.2mol, 1.4mol, 1.6mol to carry out parallel reaction research, has used C1185g, DIEA and POCl3Equimolar number,
THF7ml, 0 DEG C, time 2h of temperature, TLC testing conditions：Methanol:Ethyl acetate=1:10, C118Rf values 0.5, the results are shown in Table 3.
Table 3：The dosage of phosphorus oxychloride
| Dosage（mol） | TLC is detected |
| 1.2 | C118 residues 20% |
| 1.4 | C118 residues 5% |
| 1.6 | C118 residues 5% |
The experimental results showed that with the increase of phosphorus oxychloride dosage, reaction rate increases, and dosage can react when being 1.4mol
Completely, therefore the dosage of phosphorus oxychloride is chosen as that can be 1.4~1.6mol more than 1.4mol.
The research of 1.3 acylation alkali
Phosphorus acylation reaction needs the addition of alkali that can just be smoothed out, and is studied with alkali reaction, test potassium carbonate,
The influence of triethylamine, pyridine, DIEA as reaction base to reaction, using C1185g, above-mentioned reaction base 1.4mol, THF6ml, temperature
About 0 DEG C of degree, TLC testing conditions：Methanol:Ethyl acetate=1:10, C118Rf values 0.5.It the results are shown in Table 4.
Table 4：The research of acylation alkali
| Alkali | Time（h） | TLC is detected | C118P crude product colors |
| Potassium carbonate | 8 | It cannot the reaction was complete | N/A* |
| Triethylamine | 2 | Response situation is preferable | It is faint yellow |
| Pyridine | 2 | Reaction is very fast | It is faint yellow |
| DIEA | 2 | Reaction is very fast | Off-white color |
N/A* indicates undetermined.
The experimental results showed that for opposite potassium carbonate, triethylamine, pyridine, obtained production most fast using DIEA reaction rates
Product purity is best, chooses DIEA as reaction alkali.
1.4 at salt alkali research
Having studied can be at three kinds of alkali of sodium salt：Sodium hydroxide, sodium methoxide and sodium bicarbonate, the results are shown in Table 5.
Table 5：At the research of salt alkali
| Alkali | As a result |
| Sodium hydroxide | It is complete at salt, gained crude product pH value 9-10 |
| Sodium methoxide | It is very fast at salt, gained crude product pH value 11-12 |
| Sodium bicarbonate | Incomplete at salt, gained crude product is not soluble in water |
The experimental results showed that sodium hydroxide is better than other two kinds of alkali at salt effect
The research of 1.5 recrystallisation solvents
There is water solubility at product after salt, water-soluble reverse phase solvent need to be added, product is precipitated, it is real according to the solubility of product
It tests, has studied a series of solvents：Isopropanol, acetone, methanol, ethyl alcohol, acetonitrile, isopropanol/acetone (volume ratio 2:1) crystallization effect
Fruit.Use C118 crude products 5g（Purity 94%）, purified water 10ml is added following each 60~100ml of reverse phase solvent, carries out crystallization.
Table 6：The research of recrystallisation solvent
| Solvent | Crystalline polamer | Yield（%） | HPLC purity（%） |
| Isopropanol | Solid | 91 | 98.71 |
| Acetone | Solid | 88 | 98.56 |
| Methanol | Solid | 23 | N/A |
| Ethyl alcohol | Solution | N/A | N/A |
| Acetonitrile | Grease | N/A | N/A |
| Isopropanol/acetone (volume ratio 2:1) | Solid | 90 | 99.23 |
N/A* indicates undetermined.
From the experimental results, good using isopropanol and acetone as solvent crystallization effect, yield and purity are high, wherein different
Propyl alcohol/acetone (volume ratio 2:1) best.
In conclusion the optimum process condition of final choice is：For THF as reaction dissolvent, usage amount is 1~1.5V；Three
The dosage of chlorethoxyfos is 1.4~1.6mol；For DIEA as reaction alkali, usage amount is 1.4~1.6mol；Sodium hydroxide is into salt
Use alkali；Select isopropanol/acetone (volume ratio 2:1) it is recrystallisation solvent.
The system of embodiment 24- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt
It is standby
In the three neck round bottom flask of 5L, 0.650Kg C118,1500ml THF is added, leads to argon gas protection, stirring cooling
To about -5~0 DEG C.Then start that 0.428Kg phosphorus oxychloride is added dropwise, interior temperature is controlled during being added dropwise at 0 DEG C or so.Drip off trichlorine
After oxygen phosphorus, start that 0.361Kg DIEA/500ml THF solutions are added dropwise, interior temperature control system is at about 0~5 DEG C.After being added dropwise, heating
To about 15 DEG C, continue to be stirred to react for 24 hours.HPLC monitors raw material and is less than 1%, and reaction finishes.Reaction solution is slowly poured into the ice of 5L
In water, filtering, filter cake uses the purifying water washing mashing of 8L three times respectively.Then filter cake is added to the 4N NaOH solutions of 800ml
In, stirring and dissolving adjusts pH value 9-10 with 4N NaOH solutions, consumes the 4N NaOH solutions of 1000ml in total.Solution is filtered,
The isopropanol of 12L, stirring and crystallizing is slowly added dropwise in the reaction kettle of 15L in filtrate.For 24 hours, filtering, crude product is in 40 DEG C of vacuum for growing the grain
Drying is for 24 hours.Dried crude product is dissolved in the purified water of 2 times of volumes.Solution filters, and filtrate is slowly dripped in the reaction kettle of 15L
Add 4L isopropanols/8L acetone, stirring and crystallizing, for 24 hours, filtering, 40 DEG C of vacuum drying of product are for 24 hours for growing the grain.0.49Kg C118P are obtained,
99% or more purity, yield 54.6%.
The system of embodiment 34- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt
It is standby
Tetrahydrofuran 1.2kg is added in the reaction kettle of 5L, opens stirring, mixing speed is 150~200 revs/min, stirring
30min, it is -5 DEG C~-10 DEG C or so to adjust reaction temperature.It is slowly added to phosphorus oxychloride 0.65kg, is paid attention in observing response kettle
Temperature should keep 0 DEG C or less.C1181kg is added portionwise at a temperature of about -5~-10 DEG C, notices that temperature keeps 0 during charging
DEG C or less.Starting that n,N-diisopropylethylamine 0.55kg is added dropwise, reacting liquid temperature is controlled at 0 DEG C~5 DEG C or so during dropwise addition,
It is added dropwise, solution is in yellow suspension, and reaction starts to sample after one hour, and sample point is 1 hour, and 3 hours, 8 hours, 16 is small
When, whether monitoring reaction is complete.Reacting liquid temperature is controlled at 15 DEG C hereinafter, reaction solution is poured into 10L trash ices, stirring is in ice
Swash and insult shape, places 3 hours.It filters, filter cake is off-white powder, and filter cake 4L pure water is beaten twice.Filter cake is transferred out,
Pure water 1L is added, under stirring condition, is slowly added to 2mol/L sodium hydrate aqueous solutions（About 2.5L）, tune pH value is 9.5-9.6, molten
Liquid is entirely molten, and filtering, filtrate is brown, liquor capacity 3.7L.It filters, 12L mixed solutions is slowly added into filtrate（Acetone:
Isopropanol=1:2）, by gained mixed liquor low temperature crystallization 24 hours.It filters, obtains off-white powder, 35 DEG C of vacuum drying obtain
C118P, purity about 95%~97%.
The essence of embodiment 44- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt
System
Purified water 2kg is added in 5L reaction kettles, stirring is opened, mixing speed is 150~200 revs/min.Above-mentioned reality is added
Apply the C118P crude product 1kg of the preparation of example 2 and 3, stirring filters, filtrate is brown color to complete molten.It is mixed that 12L is slowly added into filtrate
Close solution（Acetone:Isopropanol=1:2）, by gained mixed liquor low temperature crystallization 24 hours.It filters, obtains off-white powder, 35 DEG C of vacuum
It is dry, purity 98.5%.Drying sample is crushed, crosses 80 mesh sieve, obtains off-white powder 0.90kg, yield 90%.
The essence of embodiment 54- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt
System
2L purified waters and 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) miaow are added in a kettle
Azoles organic phosphate disodium salt 0.9kg, opens stirring, and mixing speed is 150~200 revs/min.Solution is light brown, is filtered, toward filtrate
Middle dropwise addition 6L acetone, finishes at a low price, stand at low temperature crystallization 24 hours, filters, and 35 ± 2 DEG C are dried in vacuo 24 hours, obtain off-white color
Powder 0.83k g, yield 92.2%.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.The interest field of the present invention is not limited to
It is described in detail made by above, and claims should be belonged to.
Claims (14)
- The preparation method of 1.4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphate ester salt, the side Method includes the following steps：1) at a temperature of -30 DEG C to 20 DEG C, under anhydrous condition, in the presence of tetrahydrofuran and n,N-diisopropylethylamine, make 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles is reacted with phosphorylating agent；2) reactant that step 1) obtains is made to be reacted with base reagent at salt.
- 2. preparation method according to claim 1, wherein the phosphorylating agent is phosphorus oxychloride or tribromo oxygen phosphorus.
- 3. preparation method according to claim 1, wherein described is selected from sodium hydroxide, sodium methoxide, carbonic acid at salt base reagent Hydrogen sodium, ammonium hydroxide, potassium methoxide, potassium hydroxide and potassium tert-butoxide.
- 4. preparation method according to claim 1, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxybenzenes Base) imidazoles phosphate ester salt be 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles phosphate sodium salt, Amino butanetriol salt, sylvite, magnesium salts, calcium salt or ammonia salt.
- 5. preparation method according to claim 4, wherein the 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- methoxybenzenes Base) imidazoles phosphate ester salt be 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles organic phosphate disodium salt.
- 6. according to the preparation method of any one of claim 1-5, wherein the phosphorylating agent and 4- (3,5- dimethoxy phenyl)- The molar ratio of 5- (3- hydroxyl -4- methoxyphenyls) imidazoles is 5~1.4:1, n,N-diisopropylethylamine and phosphorylating agent rub You are than being 2~1:1.
- 7. according to the preparation method of any one of claim 1-5, the described method comprises the following steps：A) 4- (3,5- dimethoxy phenyls) -5- (3- hydroxyl -4- methoxyphenyls) imidazoles, tetrahydrofuran, phosphorus oxychloride are added In reactor, maintain the temperature between -20 DEG C to 10 DEG C；B) at a temperature of -10 DEG C to 15 DEG C, n,N-diisopropylethylamine is added into the reactor of step a), the reaction was complete Afterwards, it is washed with water, filters, obtain filter cake；C) filter cake of the step b) of taking-up is transferred in pure water, is added into salt base reagent, filtering obtains filtrate；D) organic solvent crystallization, then crystallization and drying are added into the filtrate of step c).
- 8. preparation method according to claim 7, wherein maintained the temperature in step a) between -10 DEG C to 5 DEG C.
- 9. preparation method according to claim 7, wherein be slowly added to n,N-diisopropylethylamine in step b), and control Reaction temperature is at -5 DEG C to 10 DEG C, and the reaction time through HPLC by monitoring 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- first Phenyl) imidazoles less residue in 5% determine, after the reaction was complete, by the way that reaction solution is poured into trash ice and is stirred simultaneously Fully washed.
- 10. preparation method according to claim 9, wherein be slowly added into salt base reagent in step c) and stir, adjust Then pH 9-10 are added acetone-isopropanol solution and are crystallized.
- 11. according to the preparation method of any one of claim 1-5, further comprise 4- (3,5- dimethoxy phenyl) -5- (3- Hydroxyl -4- methoxyphenyls) imidazoles phosphate ester salt recrystallization the step of, it is described recrystallization selected from acetone, isopropanol, tetrahydrochysene furan It mutters, carried out in one or more solvents in water.
- 12. preparation method according to claim 6 further comprises 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- first Phenyl) imidazoles phosphate ester salt recrystallization the step of, it is described recrystallization in acetone, isopropanol, tetrahydrofuran, water It is carried out in one or more solvents.
- 13. preparation method according to claim 7 further comprises 4- (3,5- dimethoxy phenyl) -5- (3- hydroxyl -4- first Phenyl) imidazoles phosphate ester salt recrystallization the step of, it is described recrystallization in acetone, isopropanol, tetrahydrofuran, water It is carried out in one or more solvents.
- 14. according to the preparation method of any one of claim 8-10, further comprise 4- (3,5- dimethoxy phenyl) -5- The step of (3- hydroxyl -4- methoxyphenyls) imidazoles phosphate ester salt recrystallizes, the recrystallization is selected from acetone, isopropanol, four It is carried out in one or more solvents in hydrogen furans, water.
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Citations (4)
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|---|---|---|---|---|
| CN101486730A (en) * | 2009-02-19 | 2009-07-22 | 郑仙锋 | Creatine phosphate sodium compound and method for synthesizing the same |
| CN102863388A (en) * | 2011-07-05 | 2013-01-09 | 南京圣和药业有限公司 | Tumor targeted drug Combretastatin A4 derivatives |
| CN102942586A (en) * | 2012-11-23 | 2013-02-27 | 张家港顺昌化工有限公司 | Preparation method of 2-ethyl methacrylate benzyl phosphate |
| CN103351403A (en) * | 2013-07-24 | 2013-10-16 | 华东师范大学 | Synthetic method of phosphatidylserine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486730A (en) * | 2009-02-19 | 2009-07-22 | 郑仙锋 | Creatine phosphate sodium compound and method for synthesizing the same |
| CN102863388A (en) * | 2011-07-05 | 2013-01-09 | 南京圣和药业有限公司 | Tumor targeted drug Combretastatin A4 derivatives |
| CN102942586A (en) * | 2012-11-23 | 2013-02-27 | 张家港顺昌化工有限公司 | Preparation method of 2-ethyl methacrylate benzyl phosphate |
| CN103351403A (en) * | 2013-07-24 | 2013-10-16 | 华东师范大学 | Synthetic method of phosphatidylserine |
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