CN106146548A - The preparation of a kind of aryloxy group phosphate ester list sodium salt and application - Google Patents
The preparation of a kind of aryloxy group phosphate ester list sodium salt and application Download PDFInfo
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- CN106146548A CN106146548A CN201510183939.0A CN201510183939A CN106146548A CN 106146548 A CN106146548 A CN 106146548A CN 201510183939 A CN201510183939 A CN 201510183939A CN 106146548 A CN106146548 A CN 106146548A
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Abstract
The invention discloses the preparation method and application of a kind of aryloxy group phosphate ester list sodium salt; its preparation process is in organic solvent; with substituted phenolic compound as raw material; in the presence of phosphorus oxychloride and alkali; phosphinylidyne glycosylation reaction and quaternization is carried out in ice-water bath; add water after having reacted, stir, extract, be dried, concentrating under reduced pressure, obtain the phosphoryl product of phenol；Then dropping NaOH solution is to separate out white precipitate, then cooling, sucking filtration, washing, acetone foam washing, dry, obtains aryloxy group phosphate ester list sodium salt.Further, aryloxy group phosphate ester list sodium salt is used to prepare aryloxy group organic phosphate disodium salt, aryloxy group dihydrogen phosphate and aryloxy group phosphate ester salt.The present invention has the advantage that simple in after-treatment is efficient, yield is high, prepared by applicable scale.
Description
Technical field
The present invention relates to chemical field, particularly to a kind of aryloxy group phosphate ester list sodium salt preparation method and should
With.
Background technology
Phosphation derivatization is medicine to carry out the important of precursor transformation and effective method, this phosphoric acid
The Prodrug formed designs thinking of esterification has become a kind of practical and effective drug design method, and similar changes
Make the application succeeded in multiple medicines, such as, antitumor drug candidate Fosbretabulin, anti-
Deep fungal medicine Fosfluconazole, Newer antiepileptic Fosphenytoin, new antiviral drug
Fosamprenavir Calcium and Novel anesthetic pain relief medicine Fospropofol etc. take the design being similar to.
The common trait of this kind of medicine is to utilize the hydroxyl in parent compound, carries out phosphorylation and forms phosphate ester, enters
Form salt and obtain the higher prodrug of water solublity.
At present, the method preparing aryloxy group phosphate ester salt mainly has following three kinds: (1) uses double (2,2,2-tri-
Chloroethyl) phosphate ester carries out Phosphation, then uses zinc/copper or Iodotrimethylsilane removing alkyloxy side chain to obtain
To aryloxy group dihydrogen phosphate, then forming disodium salt with sodium hydroxide solution, last spent ion exchange resin enters
Row is isolated and purified；But the operating process of this method is relatively complicated, limit its application (US005561122A,
1994；US006743937B2,2004).(2) with dibenzyl phosphite as phosphorylation agent, in three second
Amine/carbon tetrabromide/acetonitrile carries out phosphating reaction, then at bromotrimethylsilane/acetonitrile/methanol sodium/methanol
Or in the presence of dimethylamino naphthyridine or Pd/ carbon/methanol, there is ester hydrolysis, obtain aryloxy group dihydrogen phosphate, then
Obtain, after becoming salt, the aryloxy group organic phosphate disodium salt that water solublity is higher；But the method use multiple costliness
And be unfavorable for the reagent of environment, its application prospect also restrained (Anti-Cancer Drug Design 2000,
15,203-216；Anti-Cancer Drug Design 1998,13,183–191；J.Med.Chem.
2011,54,6014–6027).(3) with dibenzyl phosphoric acid silver as phosphorylation agent, through being condensed to yield phosphoric acid
Three esters, the most hydrogenated reduction, deprotection, then neutralize through sodium carbonate liquor, obtain aryloxy group phosphate ester two
Sodium salt；But the method uses valuable silver salt reagent, and complex steps, it is difficult to realize scale (Chin J
Med Chem 2009,19,161).In a word, these preparation methoies existing exist route complexity, complex operation,
The shortcomings such as required expensive reagents, and during forming water soluble salt (such as disodium salt etc.), may be mingled with
Sodium chloride, sodium hydroxide or other water-solubility impurity are sufficiently close to the physicochemical property of product, it is difficult to purification obtains
Obtain the product that quality is satisfied.Therefore, during preparing water solublity aryloxy group phosphate ester salt, if can obtain
The intermediate having significant difference to physicochemical property with target compound and other impurity, being easily isolated, by non-
Often be conducive to the synthesis of water solublity aryloxy group phosphate ester salt.
Summary of the invention
It is an object of the invention to overcome shortcoming present in prior art, it is provided that a kind of simple to operate, cost
Yield low, high and be easily isolated the preparation method of aryloxy group phosphate ester list sodium salt of purification.
Another object of the present invention is to provide the application of a kind of above-mentioned aryloxy group phosphate ester list sodium salt, to enter one
Step prepares corresponding disodium salt, two hydrogen esters and aryloxy group phosphate ester salt.
The purpose of the present invention is achieved through the following technical solutions:
The preparation method of a kind of aryloxy group phosphate ester list sodium salt, comprises the steps:
(1) it is in organic solvent, former with substituted phenolic compound (structural formula such as formula (1) shown in)
Material, in the presence of phosphorus oxychloride and alkali, carries out phosphinylidyne glycosylation reaction and quaternization in ice-water bath, reaction
Add water after completing, stir, extract, be dried, concentrating under reduced pressure, obtain the phosphoryl product (structure of phenol
As shown in formula (2))；
(2) at a certain temperature, in the phosphoryl product of phenol, dropping NaOH solution is to pH=4～6,
Separate out white precipitate, then cooling, sucking filtration, washing, acetone foam washing, dry, obtain aryloxy group phosphate ester
Single sodium salt (shown in structure such as formula (3)).
Described substituted phenolic compound is to have cis or trans stilbene structure and the phenol containing substituent group
Compounds, shown in structure such as formula (1), wherein R1、R2Can be, but not limited to is single or multiple substituted OCH3、
OH or halogen atom.
Described substituted phenolic compound: phosphorus oxychloride: the amount of the material of alkali is than for 1:(3～5): (1～3),
The most substituted phenolic compound: phosphorus oxychloride: the amount of the material of alkali is than for 1:4:2.
Described organic solvent can be, but not limited to be chloroform, dichloromethane, 1,2-dichloroethanes, preferably have
Machine solvent is dichloromethane.
Described alkali can be, but not limited to be pyridine, triethylamine, DMAP, tripotassium phosphate, preferably alkali
For triethylamine.
In step 1, the response time in ice-water bath is 1～3 hour, and the preferably response time is 2 hours；
Reaction temperature is 0～20 DEG C, and preferable reaction temperature is 10 DEG C.
In step 2, described uniform temperature is 20～40 DEG C, and preferable temperature is 30 DEG C.
In step 2, the concentration of NaOH solution is 0.5M～1.5M, and preferred concentration is 1.0M；The most anti-
The pH answering system is 5.0.
The application of above-mentioned aryloxy group phosphate ester list sodium salt, is for preparing aryloxy group organic phosphate disodium salt, virtue oxygen
Base dihydrogen phosphate or aryloxy group phosphate ester salt；Described aryloxy group phosphate ester salt includes but not limited to aryloxy group phosphorus
Acid esters di-potassium, aryloxy group phosphate ester di-ammonium salts, aryloxy group phosphate ester magnesium salt, aryloxy group calcium phosphate and
Aryloxy group phosphate ester strontium salt.
Use aryloxy group phosphate ester list sodium salt to prepare aryloxy group organic phosphate disodium salt, be in certain reaction temperature
Under, aryloxy group phosphate ester list sodium salt is dissolved in methanol-water, after being cooled to room temperature, dropping sodium hydroxide
Methanol solution, to pH=7～9, has white precipitate to separate out, and then stirs, stands, sucking filtration, then washes with acetone
Wash filter cake, dried recrystallization, obtain aryloxy group organic phosphate disodium salt.
Described reaction temperature is 40～80 DEG C, and preferable reaction temperature is 60 DEG C.
Methanol in described methanol-water: the volume ratio of water is 1:(0.05～0.15), preferred volume ratio is 1:0.1；
The pH of reaction system is preferably 8.
Use aryloxy group phosphate ester list sodium salt to prepare aryloxy group dihydrogen phosphate, be at room temperature, by aryloxy group
Phosphate ester list sodium salt is dispersed in water, and addition mineral acid, to pH=1～3, then extracts with organic solvent, then
Merge organic layer, concentrate, obtain aryloxy group dihydrogen phosphate.
Described mineral acid be 1M hydrochloric acid, 1M sulphuric acid, preferably mineral acid be 1M hydrochloric acid；The pH of reaction system
It is preferably 2.
Described organic solvent be ethyl acetate, toluene, dichloromethane, preferably organic solvent be ethyl acetate.
Use aryloxy group phosphate ester list sodium salt to prepare aryloxy group phosphate ester salt, be to prepare aryloxy group biphosphate
On the basis of ester, at room temperature, in aryloxy group dihydrogen phosphate, the hydroxide containing other cation is added
Or the solution of halogenide, regulation, to pH=7～9, concentrating under reduced pressure, recrystallization, obtains aryloxy group phosphate ester salt.
Other cation described includes but not limited to NH4 +、K+、Ca2+、Mg2+、Sr2+, described solution bag
Include but be not limited to aqueous solution, ethanol solution, methanol solution and alcohol-water, methanol-water mixed solution；Reactant
The pH of system is preferably 8.
The chemical equation that this technology path relates to is as follows:
The present invention compared with prior art has the advantage that and effect:
(1) the aryloxy group phosphate ester list sodium salt that prepared by the present invention is the material that a kind of dissolubility is the lowest, can facilitate
Ground Precipitation realize separating efficiently with other reaction mass or impurity from aqueous phase or organic facies.
(2) the aryloxy group phosphate ester list sodium salt that prepared by the present invention has good purity, can be used for making further
Standby disodium salt, two hydrogen esters or aryloxy group phosphate ester salt, reactions steps is easy, efficient, and good product quality is suitable
Close and amplify application.
Accompanying drawing explanation
The Z-3,4 ' that Fig. 1: embodiment 1 prepares, 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt
Proton nmr spectra (400MHz, DMSO-d6)。
The Z-3,4 ' that Fig. 2: embodiment 1 prepares, 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt
Partial enlarged drawing (400MHz, the DMSO-d of proton nmr spectra6)。
The Z-3,4 ' that Fig. 3: embodiment 1 prepares, 5-trimethoxy styryl-3 '-O-disodic alkaliine
Proton nmr spectra (400MHz, D2O)。
The Z-3,4 ' that Fig. 4: embodiment 1 prepares, 5-trimethoxy styryl-3 '-O-disodic alkaliine
Partial enlarged drawing (400MHz, the D of proton nmr spectra2O)。
The E-3,5-dimethoxy-styryl-4 that Fig. 5: embodiment 7 prepares ' core of-O-disodic alkaliine
Magnetic resonance hydrogen spectrum (400MHz, D2O)。
The E-3,5-dimethoxy-styryl-4 that Fig. 6: embodiment 7 prepares ' core of-O-disodic alkaliine
Partial enlarged drawing (400MHz, the D of magnetic resonance hydrogen spectrum2O)。
The Z-3,4,4 ' that Fig. 7: embodiment 8 prepares, 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate
Proton nmr spectra (400MHz, DMSO-d6)。
The Z-3,4,4 ' that Fig. 8: embodiment 8 prepares, 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate
Partial enlarged drawing (400MHz, the DMSO-d of proton nmr spectra6)。
The proton nmr spectra of the propofol dihydrogen phosphate that Fig. 9: embodiment 10 prepares (400MHz,
DMSO-d6)。
The local of the proton nmr spectra of the propofol dihydrogen phosphate that Figure 10: embodiment 10 prepares is put
Big figure (400MHz, DMSO-d6)。
Detailed description of the invention
Below in conjunction with embodiment, the present invention done further detailed description, but embodiments of the present invention do not limit
In this.
Embodiment 1
(1) in dry 250ml three neck round bottom flask, Z-3 '-hydroxyl-3,4 ', 5-trimethoxy-benzene are added
Ethylene (20mmol, 5.72g), uses 40ml CH2Cl2Dissolve, load onto spherical condensation tube and anhydrous calcium chloride is done
Dry pipe, and thermometer, use 10ml CH2Cl2Molten 7.4ml POCl3(80mmol) constant pressure funnel is poured into
Being slowly added dropwise, dropping process keeps 10 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml CH2Cl2Molten 5.6ml
Et3N (40mmol) loads constant pressure funnel, and 15min dropping is complete, continues stirring 4h, reaction after adding
After, remove drying tube, add 40ml distilled water, continue stirring 30min.Pour reactant liquor into separatory
Funnel, separates CH2Cl2Layer.Water layer CH2Cl2Extract 3 times, merge all CH2Cl2Layer, washes 2
After secondary, it be dried, be spin-dried for, obtain yellow oily phosphate acyl intermediate product.It is slowly added dropwise 1M
NaOH (4g/100ml), limit edged vibrates, and controlling reaction temperature is 30 DEG C, adds to pH=5, has a large amount of white
Color is settled out, and places refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white plates Z-3,4 ', 5-
Trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt 7.37g, yield 95%, purity 99%.1H NMR
(400MHz,DMSO-d6) δ 7.45 (s, 1H), 6.73 (s, 2H), 6.45 (d, J=12.0Hz, 1H),
6.41 (d, J=2.0Hz, 2H), 6.36 (d, J=12.4Hz, 1H), 6.31 (t, J=2.0Hz, 1H),
3.68(s,3H),3.61(s,6H)；FAB-MS m/z 389[M+H]+,411[M+Na]+.As Fig. 1,
Shown in Fig. 2.
(2) Z-3 is taken, 4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt (10mmol, 3.88g), add
Entering 80ml methanol+8ml water, be heated to 60 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down to be dripped
Add the methanol solution (0.8g/20ml) of NaOH, to pH=8, produce white precipitate, continue stirring 2h, quiet
Put, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, washing with acetone 3
Secondary, it is dried to obtain the thick product of white powder.White needles Z-3,4 is obtained through acetone-water recrystallization ', 5-trimethoxy
Styryl-3 '-O-disodic alkaliine 4.06g, yield 99%, purity 99%.1H NMR(400MHz,
D2O) δ 7.23 (s, 1H), 6.72 (d, J=8.4Hz, 1H), 6.64 (d, J=8.4Hz, 1H), 6.52 (d,
J=12.0Hz, 1H), 6.37-6.40 (m, 3H), 6.27 (s, 1H), 3.67 (s, 3H), 3.54 (s, 6H).
As shown in Figure 3, Figure 4.
Embodiment 2
(1) in dry 250ml three neck round bottom flask, Z-3 '-hydroxyl-3,4 ', 5-trimethoxy-benzene are added
Ethylene (20mmol, 5.72g), uses 40ml CHCl3Dissolve, load onto spherical condensation tube and anhydrous calcium chloride is done
Dry pipe, and thermometer, use 10ml CHCl3Molten 7.4ml POCl3(80mmol) constant pressure funnel is poured into
Being slowly added dropwise, dropping process keeps 10 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml CHCl3Molten 3.2ml
Pyridine (40mmol) loads constant pressure funnel, and 15min dropping is complete, continues stirring 4h, reaction after adding
After, remove drying tube, add 40ml distilled water, continue stirring 30min.Pour reactant liquor into separatory
Funnel, separates CHCl3Layer.Water layer CHCl3Extract 3 times, merge all CH2Cl2Layer, washes 2
After secondary, it be dried, be spin-dried for, obtain yellow oily phosphate acyl intermediate product.It is slowly added dropwise 0.5M
NaOH (2g/100ml), limit edged vibrates, and controlling reaction temperature is 20 DEG C, adds to PH=5, has a large amount of white
Color is settled out, and places refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white plates Z-3,4 ', 5-
Trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt 6.98g, yield 90%, purity 99%.
(2) Z-3 is taken, 4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt (10mmol, 3.88g), add
Entering 80ml methanol+4ml water, be heated to 40 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down to be dripped
Add the methanol solution (0.8g/20ml) of NaOH, to pH=8, produce white precipitate, continue stirring 2h, quiet
Put, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, washing with acetone 3
Secondary, it is dried to obtain the thick product of white powder.White needles Z-3,4 is obtained through acetone-water recrystallization ', 5-trimethoxy
Styryl-3 '-O-disodic alkaliine 4.02g, yield 98%, purity 99%.
Embodiment 3
(1) in dry 250ml three neck round bottom flask, Z-3 '-hydroxyl-3,4 ', 5-trimethoxy-benzene are added
Ethylene (20mmol, 5.72g), dissolves with 40ml dichloroethanes, loads onto spherical condensation tube and anhydrous calcium chloride
Drying tube, and thermometer, with 10ml dichloroethanes molten 7.4ml POCl3(80mmol) constant pressure addition is poured into
Funnel is slowly added dropwise, and dropping process keeps 10 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml dichloroethanes
Molten DMAP (40mmol, 4.89g) loads constant pressure funnel, and 15min dropping is complete, adds
The rear stirring 4h that continues, after completion of the reaction, removes drying tube, adds 40ml distilled water, continue stirring 30min.
Pour reactant liquor into separatory funnel, separate CH2Cl2Layer.Water layer CH2Cl2Extract 3 times, merge all
CH2Cl2Layer, after washing 2 times, is dried, is spin-dried for, obtains yellow oily phosphate acyl intermediate product.Slow
Slow dropping 1.5M NaOH (6g/100ml), limit edged vibrates, and controlling reaction temperature is 40 DEG C, adds to PH=5,
There is a large amount of white precipitate to go out, place refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white
Lamellar Z-3,4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt 6.59g, yield 85%.
(2) Z-3 is taken, 4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt (10mmol, 3.88g), add
Entering 80ml methanol+12ml water, be heated to 80 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down
The methanol solution (0.8g/20ml) of dropping NaOH, to pH=8, produces white precipitate, continues stirring 2h,
Stand, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, and acetone is washed
Wash 3 times, be dried to obtain the thick product of white powder.White needles Z-3,4 is obtained through acetone-water recrystallization ', 5-front three
Epoxide styryl-3 '-O-disodic alkaliine 4.01g, yield 97%, purity 99%.
Embodiment 4
(1) in dry 250ml three neck round bottom flask, Z-3 '-hydroxyl-3,4 ', 5-trimethoxy-benzene are added
Ethylene (20mmol, 5.72g), uses 40ml CH2Cl2Dissolve, load onto spherical condensation tube and anhydrous calcium chloride is done
Dry pipe, and thermometer, use 10ml CH2Cl2Molten 7.4ml POCl3(80mmol) constant pressure funnel is poured into
Being slowly added dropwise, dropping process keeps 10 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml CH2Cl2Molten phosphorus
Acid tripotassium (40mmol, 8.49g) loads constant pressure funnel, and 15min dropping is complete, continues stirring after adding
4h, after completion of the reaction, removes drying tube, adds 40ml distilled water, continues stirring 30min.By reactant liquor
Pour separatory funnel into, separate CH2Cl2Layer.Water layer CH2Cl2Extract 3 times, merge all CH2Cl2Layer,
After washing 2 times, it is dried, is spin-dried for, obtains yellow oily phosphate acyl intermediate product.It is slowly added dropwise 1M
NaOH (4g/100ml), limit edged vibrates, and controlling reaction temperature is 30 DEG C, adds to PH=4, has a large amount of white
Color is settled out, and places refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white plates Z-3,4 ', 5-
Trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt 6.75g, yield 87%, purity 99%.
(2) Z-3 is taken, 4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt (10mmol, 3.88g), add
Entering 80ml methanol+8ml water, be heated to 60 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down to be dripped
Add the methanol solution (0.8g/20ml) of NaOH, to pH=7, produce white precipitate, continue stirring 2h, quiet
Put, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, washing with acetone 3
Secondary, it is dried to obtain the thick product of white powder.White needles Z-3,4 is obtained through acetone-water recrystallization ', 5-trimethoxy
Styryl-3 '-O-disodic alkaliine 4.02g, yield 98%, purity 99%.
Embodiment 5
(1) in dry 250ml three neck round bottom flask, Z-3 '-hydroxyl-3,4 ', 5-trimethoxy-benzene are added
Ethylene (20mmol, 5.72g), uses 40ml CH2Cl2Dissolve, load onto spherical condensation tube and anhydrous calcium chloride is done
Dry pipe, and thermometer, use 10ml CH2Cl2Molten 5.6ml POCl3(60mmol) constant pressure funnel is poured into
Being slowly added dropwise, dropping process keeps 0 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml CH2Cl2Molten 2.8ml
Et3N (20mmol) loads constant pressure funnel, and 15min dropping is complete, continues stirring 4h, reaction after adding
After, remove drying tube, add 40ml distilled water, continue stirring 30min.Pour reactant liquor into separatory
Funnel, separates CH2Cl2Layer.Water layer CH2Cl2Extract 3 times, merge all CH2Cl2Layer, washes 2
After secondary, it be dried, be spin-dried for, obtain yellow oily phosphate acyl intermediate product.It is slowly added dropwise 1M
NaOH (4g/100ml), limit edged vibrates, and controlling reaction temperature is 30 DEG C, adds to PH=6, has a large amount of white
Color is settled out, and places refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white plates Z-3,4 ', 5-
Trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt 6.90g, yield 89%, purity 99%.
(2) Z-3 is taken, 4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt (10mmol, 3.88g), add
Entering 80ml methanol+8ml water, be heated to 60 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down to be dripped
Add the methanol solution (0.8g/20ml) of NaOH, to pH=9, produce white precipitate, continue stirring 2h, quiet
Put, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, washing with acetone 3
Secondary, it is dried to obtain the thick product of white powder.White needles Z-3,4 is obtained through acetone-water recrystallization ', 5-trimethoxy
Styryl-3 '-O-disodic alkaliine 4.03g, yield 98%, purity 99%.
Embodiment 6
(1) in dry 250ml three neck round bottom flask, Z-3 '-hydroxyl-3,4 ', 5-trimethoxy-benzene are added
Ethylene (20mmol, 5.72g), uses 40ml CH2Cl2Dissolve, load onto spherical condensation tube and anhydrous calcium chloride is done
Dry pipe, and thermometer, use 10ml CH2Cl2Molten 9.3ml POCl3(100mmol) constant pressure addition leakage is poured into
Bucket is slowly added dropwise, and dropping process keeps 20 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml CH2Cl2Molten
8.4ml Et3N (60mmol) loads constant pressure funnel, and 15min dropping is complete, continues stirring 4h after adding,
After completion of the reaction, remove drying tube, add 40ml distilled water, continue stirring 30min.Reactant liquor is poured into
Separatory funnel, separates CH2Cl2Layer.Water layer CH2Cl2Extract 3 times, merge all CH2Cl2Layer, water
After washing 2 times, it is dried, is spin-dried for, obtains yellow oily phosphate acyl intermediate product.It is slowly added dropwise 1M
NaOH (4g/100ml), limit edged vibrates, and controlling reaction temperature is 30 DEG C, adds to PH=5, has a large amount of white
Color is settled out, and places refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white plates Z-3,4 ', 5-
Trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt 6.82g, yield 88%, purity 99%.
(2) Z-3 is taken, 4 ', 5-trimethoxy styryl-3 '-O-mono phosphoric acid ester sodium salt (10mmol, 3.88g), add
Entering 80ml methanol+8ml water, be heated to 60 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down to be dripped
Add the methanol solution (0.8g/20ml) of NaOH, to pH=8, produce white precipitate, continue stirring 2h, quiet
Put, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, washing with acetone 3
Secondary, it is dried to obtain the thick product of white powder.White needles Z-3,4 is obtained through acetone-water recrystallization ', 5-trimethoxy
Styryl-3 '-O-disodic alkaliine 4.05g, yield 99%, purity 99%.
Embodiment 7
(1) in dry 250ml three neck round bottom flask, E-4 '-hydroxyl-3,5-dimethoxy hexichol are added
Ethylene (Lignum pterocarpi indici, 20mmol, 5.12g), uses 40ml CH2Cl2Dissolve, load onto spherical condensation tube and anhydrous
Calcium chloride tube, and thermometer, use 10ml CH2Cl2Molten 5.6ml POCl3(60mmol) constant voltage is poured into
Dropping funnel is slowly added dropwise, and dropping process keeps 10 DEG C, and 1h drips off.Continue stirring 1h.Use 10ml CH2Cl2
Molten 5.6ml Et3N (40mmol) loads constant pressure funnel, and 15min dropping is complete, continues stirring 4h after adding,
After completion of the reaction, remove drying tube, add 40ml distilled water, continue stirring 30min.Reactant liquor is poured into
Separatory funnel, separates CH2Cl2Layer.Water layer CH2Cl2Extract 3 times, merge all CH2Cl2Layer, water
After washing 2 times, it is dried, is spin-dried for, obtains yellow oily phosphate acyl intermediate product.It is slowly added dropwise 1M
NaOH (4g/100ml), limit edged vibrates, and controlling reaction temperature is 30 DEG C, adds to PH=6, has a large amount of white
Color is settled out, and places refrigerator overnight.Sucking filtration, washes on a small quantity, then acetone foam washing, obtains white plates E-3,5-
Dimethoxy-styryl-4 '-O-phosphate ester list sodium salt 6.30g, yield 88%, purity 99%.
(2) E-3 is taken, 5-dimethoxy-styryl-4 '-O-phosphate ester list sodium salt (10mmol, 3.58g), add
Entering 80ml methanol+8ml water, be heated to 60 DEG C of dissolvings, filter off few insoluble matter, filtrate is stirred at room temperature down to be dripped
Add the methanol solution (0.8g/20ml) of NaOH, to pH=8, produce white precipitate, continue stirring 2h, quiet
Put, sucking filtration.Filtrate adds acetone and separates out again white precipitate, sucking filtration, merges with filter cake before, washing with acetone 3
Secondary, it is dried to obtain the thick product of white powder.White needles E-3,5-dimethoxy benzene is obtained through acetone-water recrystallization
Vinyl-4 '-O-organic phosphate disodium salt 3.76g, yield 99%, purity 99%.1H NMR(400MHz,
D2O) δ 7.39 (d, J=8.4Hz, 2H), 7.03-7.09 (m, 3H), 6.89 (d, J=16.4Hz, 1H),
6.63 (d, J=2.0Hz, 2H), 6.31 (s, 1H), 3.68 (s, 6H)；IR(neat,KBr)-13421,
1594,1508,1459,1427,1297,1155,995,890,586；FAB-MS m/z 381[M+
H]+,403[M+Na]+.Proton nmr spectra is as shown in Figure 5, Figure 6.
The preparation of embodiment 8:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate
In dry 250ml beaker, addition Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-mono phosphoric acid ester sodium
Salt (M418,10mmol, 4.18g), is dispersed in 200ml water, is acidified to pH=2 with 1M hydrochloric acid,
It is extracted with ethyl acetate (30ml × 3), merges organic facies, be spin-dried for, obtain Z-3,4,4 ', 5-tetramethoxy styryl
-3 '-O-dihydrogen phosphate 3.37g, yield 85%.1H NMR(400MHz,DMSO-d6)δ7.50(s,
1H), 6.82-6.89 (m, 2H), 6.55 (s, 2H), 6.44 (d, J=12.0Hz, 1H), 6.34 (d, J=
11.6Hz,1H),3.75(s,3H),3.61(s,3H),3.58(s,6H).Proton nmr spectra such as Fig. 7, figure
Shown in 8.
The preparation of embodiment 9:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate
In dry 250ml beaker, addition Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-mono phosphoric acid ester sodium
Salt (M418,10mmol, 4.18g), is dispersed in 200ml water, is acidified to pH=1 with 1M hydrochloric acid,
Extract (50ml × 3) with dichloromethane, merge organic facies, be spin-dried for, obtain Z-3,4,4 ', 5-tetramethoxy styryl
-3 '-O-dihydrogen phosphate 3.16g, yield 80%, purity 99%.
Embodiment 10: the preparation of propofol dihydrogen phosphate
In dry 250ml beaker, add propofol, phosphate list sodium salt (M280,10mmol, 2.80g),
It is dispersed in 200ml water, is acidified to pH=1 with 1M sulphuric acid, extract (30ml × 3) with toluene, merge
Organic facies, is spin-dried for, and obtains propofol dihydrogen phosphate 2.22g, yield 86%, purity 99%.1H NMR
(400MHz,DMSO-d6) δ 7.11 (m, 3H), 3.53 (m, 2H), 1.14 (d, J=6.8Hz, 12H)；31P NMR(161.9MHz,DMSO-d6)δ-4.17；EI-MS m/z 258[M]+,215[M-C3H7]+,
160[M-H2PO4]+.Proton nmr spectra is as shown in Figure 9, Figure 10.
Embodiment 11: the preparation of propofol dihydrogen phosphate
In dry 250ml beaker, add propofol, phosphate list sodium salt (M280,10mmol, 2.80g),
It is dispersed in 200ml water, is acidified to pH=3 with 1M sulphuric acid, be extracted with ethyl acetate (30ml × 3),
Merge organic facies, be spin-dried for, obtain propofol dihydrogen phosphate 2.08g, yield 81%, purity 99%.
The preparation of embodiment 12:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-di(2-ethylhexyl)phosphate potassium salt
At room temperature, by Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate (M396,
2mmol, 0.79g) it is dissolved in 50ml methanol-water (volume ratio is 1:1), the hydrogen of dropping 5% wherein
Potassium oxide solution, to pH=8, concentrating under reduced pressure, uses water recrystallization, obtains white crystal Z-3, and 4,4 ', 5-tetramethoxy
Styryl-3 '-O-di(2-ethylhexyl)phosphate potassium salt 0.92g, yield 98%, purity 99%.
The preparation of embodiment 13:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-di(2-ethylhexyl)phosphate ammonium salt
At room temperature, by Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate (M396,
2mmol, 0.79g) it is dissolved in 100ml water, the ammonia spirit of dropping 10% is to pH=7, decompression wherein
Concentrate, use water recrystallization, obtain white crystal Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-di(2-ethylhexyl)phosphate ammonium salt
0.79g, yield 92%, purity 98%.
The preparation of embodiment 14:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-phosphoric acid magnesium salt
At room temperature, by Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate (M396,
2mmol, 0.79g) it is dissolved in 50ml alcohol-water (volume ratio is 1:1), drip 20% wherein
Magnesium chloride solution, regulates to pH=8, concentrating under reduced pressure with sodium hydroxide solution, uses water recrystallization, obtain white crystalline substance
Body Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-phosphoric acid magnesium salt 0.80g, yield 95%, purity 99%.
The preparation of embodiment 15:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-synthos
At room temperature, by Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate (M396,
2mmol, 0.79g) it is dissolved in 50ml ethanol, the aqua calcis of dropping 5% is to pH=9 wherein,
Concentrating under reduced pressure, uses water recrystallization, obtains white crystal Z-3, and 4,4 ', 5-tetramethoxy styryl-3 '-O-calcium phosphate
Salt 0.85g, yield 98%, purity 99%.
The preparation of embodiment 16:Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-phosphoric acid strontium salt
At room temperature, by Z-3,4,4 ', 5-tetramethoxy styryl-3 '-O-dihydrogen phosphate (M396,
2mmol, 0.79g) it is dissolved in 50ml methanol, the strontium hydroxide solution of dropping 5% is to pH=9 wherein,
Concentrating under reduced pressure, uses water recrystallization, obtains white crystal Z-3, and 4,4 ', 5-tetramethoxy styryl-3 '-O-strontium phosphate
Salt 0.94g, yield 97%, purity 99%.
Claims (10)
1. the preparation method of an aryloxy group phosphate ester list sodium salt, it is characterised in that comprise the steps:
(1) in organic solvent, with substituted phenolic compound as raw material, in the presence of phosphorus oxychloride and alkali,
In ice-water bath, carry out phosphinylidyne glycosylation reaction and quaternization, after having reacted, add water, stir, extract,
Dry, concentrating under reduced pressure, obtains the phosphoryl product of phenol；
(2) at a certain temperature, in the phosphoryl product of phenol, dropping NaOH solution is to pH=4～6,
Separate out white precipitate, then cooling, sucking filtration, washing, acetone foam washing, dry, obtain aryloxy group phosphate ester
Single sodium salt.
The preparation method of aryloxy group phosphate ester list sodium salt the most according to claim 1, it is characterised in that:
Described substituted phenolic compound is to have cis or trans stilbene structure and the phenol generalization containing substituent group
Compound, shown in structure such as formula (1):
Wherein R1、R2It is single or multiple substituted OCH3, OH or halogen atom.
The preparation method of aryloxy group phosphate ester list sodium salt the most according to claim 1, it is characterised in that:
Described substituted phenolic compound: phosphorus oxychloride: the amount of the material of alkali is than for 1:(3～5): (1～3).
The preparation method of aryloxy group phosphate ester list sodium salt the most according to claim 1, it is characterised in that:
Described organic solvent is chloroform, dichloromethane or 1,2-dichloroethanes.
The preparation method of aryloxy group phosphate ester list sodium salt the most according to claim 1, it is characterised in that:
Described alkali is pyridine, triethylamine, DMAP or tripotassium phosphate.
The preparation method of aryloxy group phosphate ester list sodium salt the most according to claim 1, it is characterised in that:
In step 1, the response time in ice-water bath is 1～3 hour, and reaction temperature is 0～20 DEG C；Step 2
In, described uniform temperature is 20～40 DEG C, and the concentration of NaOH solution is 0.5M～1.5M.
7. an application for the aryloxy group phosphate ester list sodium salt according to any one of claim 1～6, it is special
Levy and be: be to use aryloxy group phosphate ester list sodium salt to prepare aryloxy group organic phosphate disodium salt, aryloxy group di(2-ethylhexyl)phosphate
Hydrogen ester or aryloxy group phosphate ester salt.
Employing aryloxy group phosphate ester list sodium salt the most according to claim 7 prepares aryloxy group disodium phosphate
Salt, it is characterised in that: it is under the reaction temperature of 40～80 DEG C, aryloxy group phosphate ester list sodium salt is dissolved in
In methanol-water, after being cooled to room temperature, the methanol solution of dropping sodium hydroxide, to pH=7～9, has white precipitate
Separate out, then stir, stand, sucking filtration, then use washing with acetone filter cake, dried recrystallization, obtain fragrant oxygen
Base organic phosphate disodium salt.
Employing aryloxy group phosphate ester list sodium salt the most according to claim 7 prepares aryloxy group dihydrogen phosphate,
It is characterized in that: be at room temperature, aryloxy group phosphate ester list sodium salt is dispersed in water, add mineral acid extremely
PH=1～3, then extracts with organic solvent, remerges organic layer, concentrate, obtain aryloxy group biphosphate
Ester.
Employing aryloxy group phosphate ester list sodium salt the most according to claim 7 prepares aryloxy group phosphate ester salt,
It is characterized in that: be at room temperature, aryloxy group phosphate ester list sodium salt is dispersed in water, add mineral acid extremely
PH=1～3, then extracts with organic solvent, remerges organic layer, concentrate, obtain aryloxy group biphosphate
Ester；The most at room temperature, in aryloxy group dihydrogen phosphate add containing other cation hydroxide or
The solution of halogenide, regulation, to pH=7～9, concentrating under reduced pressure, recrystallization, obtains aryloxy group phosphate ester salt.
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| CN109516623A (en) * | 2018-11-16 | 2019-03-26 | 浙江万盛股份有限公司 | A kind of method of comprehensive utilization of tri butylethyl phosphate waste water |
| CN111647016A (en) * | 2020-07-10 | 2020-09-11 | 成都纽瑞特医疗科技股份有限公司 | Process for preparing hydroxy methylene diphosphonates |
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