CN105126909B - Application of the immobilized palladium catalyst in the synthesis of the nitrobenzene methyl of 4 phenylacetylene base 3 - Google Patents
Application of the immobilized palladium catalyst in the synthesis of the nitrobenzene methyl of 4 phenylacetylene base 3 Download PDFInfo
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Abstract
The present invention provides a kind of application of immobilized palladium catalyst in the synthesis of the nitrobenzene methyl of 4 phenylacetylene base 3.The immobilized palladium catalyst refers to palladium (II) imprinted polymer, palladium (II) imprinted polymer refers to containing tertiary amine groups on macromolecule side chain, quaternary ammonium cation and salicylaldoxime close palladium (II) imprinted polymer, applied to the catalysis nitrobenzene methyl of 4 chlorine 3, cascade reaction between KI or sodium iodide and phenylacetylene, synthesize the nitrobenzene methyl of 4 phenylacetylene base 3, the immobilized palladium catalyst has synthetic technology easy, catalytic activity is stable, it is easy to regenerate, cascade reaction product yield high, simplicity is separated between raw material and product, the characteristics of raw material consumption is low.
Description
Technical field
The present invention relates to a kind of application of immobilized palladium catalyst, and more particularly to palladium (II) ion imprinted polymer is as immobilized
Application of the palladium catalyst in the synthesis of 4- phenylacetylene base -3- nitrobenzene methyls, belongs to functional high polymer material field.
Nintedanib (English name nintedanib), trade name Ofev, also known as BIBF1120, it is German Bo Linge
A kind of oral Mutiple Targets kinase inhibitor of Yin Gehan companies initiative, is currently used for treatment idiopathic pulmonary fibrosis (IPF)
Unique specific medicament, in October, 2014 by U.S.'s food and Drug Administration (FDA) quickly examination ＆ approval, preferential examination ＆ approval, establish
The status of Orphan drug, from this finishes idiopathic pulmonary fibrosis without the medicine available epoch.The said firm WO2002081445
Disclose the synthetic route of Nintedanib：
Nintedanib is made using this conventional method, it is necessary to 2- indolone -6- methyl formates are first made.So numerous scholars
Very big concern has been given with synthesis of the research institution for 2- indolone -6- methyl formates and process optimization, has mainly been had：
CN102267934, US8304541, US2005324037, CN102531996 etc..These are listed in disclosed document
Initiation material is：Methyl-m-nitrobenzoate, 4- methyl-3-nitros methyl benzoate or the chloro- 3- nitrobenzene methyls of 4-, close
Into step all more than 9 steps, mostly because side reaction is more, or because product has isomers phenomenon, the total recovery of Nintedanib is all non-
It is often low.So the synthetic technology and method of Nintedanib need to improve.
Based on this, the present inventor combines traditional chemical synthesis and modern synthetic technology, the following Nintedanib of design studies
Succinct synthetic route, still using the chloro- 3- nitrobenzene methyls of 4- as initiation material, reduced by phenylacetylene reaction, nitro
Nintedanib is made in reaction, isocyanation esterification reaction, ring-closure reaction and aminating reaction.In the succinct synthetic route of the Nintedanib
In, there is no product isomer phenomenon, each step products high income, separation method is easy, is easy to industrialize.
Professional is known, and the phenylacetylene of the chloro- 3- nitrobenzene methyls of 4- is combined to 4- phenylacetylene base -3- nitrobenzoyls
Sour methyl esters belongs to typical structure C-C keys reaction.The phenylacetyleneization reaction of the chloro- 3- nitrobenzene methyls of the 4- is realized, can
Completed with nucleophilic substitution by phenylacetylene salt and the chloro- 3- nitrobenzene methyls of 4-.But in recent years, such as iodo
Representative of the aromatic hydrocarbons as active halogenated aryl hydrocarbon, in PdCl2Under the classical catalyst system and catalyzing effect of CuI compositions, carried out with phenylacetylene
Sonogashira coupling reactions, aryl phenylacetylene product can be obtained in high yield, so the iodo- 3- nitrobenzene methyls of 4- can
As active halogenated aryl hydrocarbon, Sonogashira coupling reactions, convenient obtained 4- phenylacetylene base 3- nitrobenzoyls are carried out with phenylacetylene
Sour methyl esters.But the stability of the iodo- 3- nitrobenzene methyls of 4- is poor, merchandise resources is rare, and price is noble.The present inventor tests
It was found that can by the cheap chloro- 3- nitrobenzene methyls of 4- under CuI catalytic action, in aprotic polar solvent, with
The nucleophilic substitution of KI or sodium iodide, it is easy to that the iodo- 3- nitrobenzene methyls of 4- are made；Therefore, based on the nucleophilic
Substitution reaction and the mechanism and feature of the Sonogashira coupling reactions, two-step reaction can be completed with one pot, used
Cascade reaction technology, 4- phenylacetylene base -3- nitrobenzene methyls, the series connection are made by the chloro- 3- nitrobenzene methyls of 4-
Reaction can be expressed by following formula：
So far, the service efficiency of expensive palladium catalyst is that further reduce synthesizes 4- phenylacetylene base -3- nitrobenzene
One of key of methyl formate cost of material.Therefore, in the succinct synthetic route of the Nintedanib, making for palladium catalyst is improved
It is the centre point that the present invention is paid close attention to efficiency.
Professional is known, early application PdCl2With the classical catalyst system and catalyzing of CuI compositions, will be answered using various structures
Miscellaneous part improves the catalytic activity of catalyst system, and reaction is required for higher catalytic amount (1-5%).For many
For part, its chemical constitution is complicated, and preparation condition is harsh, is easily lost in, is difficult to recovery after reaction and reuses.Therefore study negative
The palladium catalyst of load type also turns into focus of attention already.The carrier of common load type palladium catalyst is divided into inorganic matter and organic matter
Two kinds.The active charcoal of common inorganic matter carrier, molecular sieve, natural clay mineral, metal oxide, magnalium hydrotalcite etc..Have
The carrier of machine thing supported palladium type catalyst belongs to relatively conventional organic macromolecule, is divided into natural polymer and synthetic polymer two
Class.
Inorganic matter is the load palladium complex catalyst of carrier, belongs to palladium " complex is open " the load, " complex
It is open " refer to that Pd (0) or Pd (II) complex are deposited on mineral surfaces in a free form.By organic reaction thermal effect
Should, stirring concussion, the desorption between catalyst and carrier and absorption, the Chemical Physics Processing such as dissolution of solvent influence, Pd
(0) or Pd (II) complex all easily departs from carrier, and Pd (0) or Pd (II) complex are easily lost in solvent and product, or
Palladium cluster (also having referred to as palladium black) is formed, causes the catalytic activity rapid decrease of inorganic matter load type palladium composition catalyst.In addition
Whether people notice that Pd (0) or Pd (II) complex slip into inorganic matter carrier deep internal, and be beyond expression its catalytic activity, can
It can be also one of palladium catalyst deactivation cause.
By chemical bond by part be bonded to carrier (carrier include silica gel, inorganic organic framework polymer, You Ji great
Molecule) on, it is then by complexation reaction thereafter, Pd (0) or Pd (II) is immobilized on carrier.According to different ligands and Pd (0)
Or Pd (II) coordination mode, " complex semi open model " and " complex is closed " load type palladium catalyst can be divided into again.Institute
State " complex semi open model " load type palladium catalyst and refer to being bonded in part on carrier and Pd (0) or Pd (II) self assembly
The chelation of formula, by Pd (0) or Pd (II) " card " on carrier.Disclosed described " complex semi open model " support type
Palladium catalyst is various, such as the palladium that silica gel bonded bisoxazoline, bidentate phosphine, polyamines, polyether or schiff bases are cheland
Complex and ring palladium compound etc..The organic macromolecule for being bonded cheland is even more numerous with bonding cheland species
Mode on more, cheland bonded support is various, ligand structure is changeful, easy times of coordination synthetic technology is by people's
Praise highly, so such " complex semi open model " load type palladium catalyst is the focus of people's research and development now.
But due to being influenceed by factors in Sonogashira courses of reaction, " complex semi open model " load
The part of type palladium catalyst is easily opened to Pd (0) or Pd (II) " card ", and the coordination protective effect to Pd (0) or Pd (II) is lost
Effect, palladium, which departs from ligand protection, to be tended to form palladium black, or palladium is lost in solvent and product, and catalysis efficiency declines eventually.But institute
Stating part does not have any loss.So it has been observed that catalysis of " complex semi open model " load type palladium catalyst
Efficiency stability has improved many than above-mentioned " complex is open " load type palladium catalyst.
Porphyrin has the Conjugate macrocycle part of armaticity, and high stable is formed with the coordination of closing and many metal ions
Complex, so also have Sonogashira reactions or Heck catalytic reactions activity that multidigit scholar reports porphyrin palladium complex, with
And the application that polymer is fixed in porphyrin palladium complex coupling reaction, not only catalysis efficiency is high, and selectivity is high, recycles more than 20
Secondary catalyst is hardly lost in, and catalytic activity reduction of speed is slow, such as Tetra.Let.2007, and 48,6688-6691；
Adv.Synth.Catal.2010,352,2263-2274；Mater.Res.Bull.2010,45 (11), 1648-1653；
Appl.Organometal.Chem.2014,28,337-346；J.Organometal.Chem.2014,759 (1), 46-57；Most
Nearly Liu understands continent et al. and discloses chloromethylation micropore polystyrene spheres bonding middle position tetrahydroxy phenyl porphyrin palladium chtalyst iodobenzene and third
The Heck reaction results of olefin(e) acid ethyl ester, it is 0.1% mole in 100 DEG C, catalyst amount, N2Protection reaction 4 hours, is recycled
The yield of the ethyl phenylacrylate of 6 times occurs all more than 94% without palladium leakage.
Angew.Chem.Int.Ed.2001,40 (18), the Heck reactions that 3469-3471 reports polystyrene parcel palladium complex are urged
Change active medium, the achievement that catalyst is not lost in.Ind.Eng.Chem.Res.2014,53,8339-834 also report cellulose
The Heck catalytic reaction activity of encapsulation palladium complex is higher, the achievement that catalyst is not lost in.The polystyrene bonding
Porphyrin palladium complex, or polystyrene or cellulose encapsulation palladium complex, we term it " complex is closed "
Load type palladium catalyst." complex the is closed " load type palladium catalyst refers to Pd (0) or Pd (II) and cyclic ligand,
" delineation " is hardly influenceed by reaction environment factor on carrier and departs from load by way of embedded bonding pattern or parcel
Body.The especially load type palladium catalyst of polystyrene bonding porphyrin palladium complex, the closure coordination of porphyrin and bonding action
Coordination protective effect to Pd (0) or Pd (II) is strong, and participating in the molecule of coupling reaction, " encapsulation palladium is matched somebody with somebody also without penetrating
Compound " wraps up in clothing barrier.
Professional is known, ion coordination imprinted polymer for target metal ions have identity, high selectivity and
Strong compatibility, its mechanical stability are high, and Coordination Space structure is fixed, and coordination orientation, coordination selectivity is strong, coordination it is quick and
It is reversible.The present inventor once disclosed：A kind of water-solubility function monomer agent preparation method containing quaternary ammonium salt and schiff bases complex
(CN201310141108.8) a kind of, coordination imprinted polymer and preparation method thereof (CN201310113527.0), copper (II)
Solid phase trace dibit extractant and preparation method thereof (20141056563768.X), it is crosslinkable to contain quaternary ammonium cation and bigcatkin willow
Aldehyde Schiff Base copper (II) monomer (CN201410563769.4).Accordingly, the present inventor turns palladium (II) ion imprinted polymer
In coupling reaction, " complex is closed " immobilized palladium chtalyst as synthesis 4- phenylacetylene base 3- nitrobenzene methyls
Agent, have synthetic technology easy, catalytic activity is stable, and can regenerate, and thus form the immobilized palladium catalyst of the present invention and exists
Synthesize the application in 4- phenylacetylene base -3- nitrobenzene methyls.
The content of the invention
It is an object of the invention to provide immobilized palladium catalyst answering in 4- phenylacetylene base -3- nitrobenzene methyls are synthesized
With.The immobilized palladium catalyst refers to palladium (II) ion imprinted polymer, and palladium (II) ion imprinted polymer refers to
Palladium (II) ion imprinted polymer is closed containing tertiary amine groups, quaternary ammonium cation and salicylaldoxime on macromolecule side chain, as immobilized palladium
Catalyst is applied to the synthesis of 4- phenylacetylene base -3- nitrobenzene methyls.
On the macromolecule side chain palladium (II) ion imprinted polymer is closed containing tertiary amine groups, quaternary ammonium cation and salicylaldoxime
It is using formula (A) function monomer, formula (B) function monomer and crosslinking agent as raw material, by made from polymerization process.It is specific to prepare
Operation：In four-hole bottle, organic solvent, function monomer (A), function monomer (B), crosslinking agent, initiator and pore-foaming agent are added, is opened
Stirring is opened, after stirring, nitrogen charging deoxygenation 30 minutes, is warming up to 60~65 DEG C, polymerisation is carried out 2 hours, improves temperature extremely
90~95 DEG C, after polymerisation carries out 2 hours again, cooling, polymeric reaction product system is poured into precipitation graininess tree in methanol
Fat, filtering, is washed with acetone, saturated aqueous sodium carbonate and deionized water successively, after drying, palladium (II) ion blotting is made and gathers
Compound hollow resin particles, as immobilized palladium catalyst.
Wherein described organic solvent is selected from chlorobenzene, methyl phenyl ethers anisole, 1-METHYLPYRROLIDONE, DMA, N,
N- diethyl acetamides, N, N- Valpromides, N, N- dibutyl acetamides, N, N- dimethyl benzamides, acetophenone, ring
One or both of hexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, normal octane or petroleum ether of boiling range=90~120 DEG C with
On, the dosage of the organic solvent is 2~10 times of formula (A), formula (B) and crosslinking agent quality summation；
Formula (A) function monomer and formula (B) the function monomer structure is expressed as：
R in wherein described formula (A) and formula (B) is selected from C1~C18One kind in alkyl, X- are selected from Cl-、Br-、
SO4 2-、NO3 -、CH3COO- or p-CH3C6H4SO4 -One or both of more than；
Described crosslinking agent is selected from divinylbenzene, triallyl isocyanurate, N, N- methylene-bisacrylamides, N, N-
Methylenebismethacrylamide, N- methyl-N, N- diallyl ammonium chloride, N- benzyls-N, N- diallyl ammonium chloride or N,
It is more than one or both of N- diallyl ammonium chlorides.
The formula (A): formula (B): the dosage mass ratio of crosslinking agent is 20~80: 20~80: 20~80.
Described initiator is selected from azodiisobutyronitrile or benzoyl peroxide；The dosage of the initiator be formula (A),
The 0.5~5% of the dosage quality summation of formula (B) and crosslinking agent；
Professional is known, and the palladium (II) can significantly improve if hollow sphere state is presented in ion imprinted polymer
The specific surface area of palladium (II) ion imprinted polymer, fully show the catalytic capability of palladium (II) ion imprinted polymer.So system
The appropriate technology of the standby palladium (II) ion imprinted polymer is suspension polymerisation or polymerisation in solution, and adds pore-foaming agent.Described
Pore-foaming agent be selected from magnesium sulfate, magnesium chloride, sodium sulphate, sodium chloride, calcium carbonate, toluene, chlorobenzene, methyl phenyl ethers anisole, 1-METHYLPYRROLIDONE,
DMA, N, N- diethyl acetamides, N, N- Valpromides, N, N- dibutyl acetamides, N, N- diformazans
Yl-benzamide, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, normal octane or boiling range=90~120 DEG C oil
More than one or both of ether, the dosage of the pore-foaming agent is the 1~10 of formula (A), formula (B) and crosslinking agent quality summation
Times.
Concrete application operation of the immobilized palladium catalyst in 4- phenylacetylene base -3- nitrobenzene methyls are synthesized：4- is chloro-
3- nitrobenzene methyls, KI or sodium iodide, cuprous iodide and solvent are added in reactor, after nitrogen charging deoxygenation 30 minutes,
For controlling reaction temperature to 30~130 DEG C, stirring reaction adds alkali, phenylacetylene and immobilized palladium catalyst after 0.5~2.5 hour, after
Continuous stirring reaction 6~12 hours, after TLC detection reactions terminate, reaction product system temperature is reduced to room temperature；Filtering respectively obtains
Solid insoluble 1. with filtrate 1.；1. the insoluble matter mainly contains cuprous iodide and immobilized palladium catalyst, by unsaturated carbonate
Hydrogen sodium water solution and absolute ethyl alcohol washing, dry Posterior circle and use；Thereafter 60~70 DEG C of temperature control, 1. negative pressure is carried out to the filtrate
Rotate recycling design；2. and filtrate gained revolving removes the residue deionized water dissolving after solvent, is filtrated to get insoluble matter
②；2. KI, potassium chloride or sodium iodide, sodium chloride is separately recovered in gained filtrate；Using absolute ethyl alcohol to the insoluble matter 2.
Recrystallization purification is carried out, 4- phenylacetylene base -3- nitrobenzene methyls are made；
Wherein described solvent is from toluene, chlorobenzene, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, N- methyl pyrroles
One kind in pyrrolidone, DMF, DMA, hexamethyl phosphoramide or dimethyl sulfoxide, it is described
The dosage of solvent is 2~5 times of the chloro- 3- nitrobenzene methyls dosage quality of 4-；
The alkali is from sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), tri-n-butylamine, 4-
One kind in dimethylamino naphthyridine, methyl piperidine or Isosorbide-5-Nitrae-lupetazin；
The 4- chloro- 3- nitrobenzene methyls, KI or sodium iodide, cuprous iodide, alkali, phenylacetylene, immobilized palladium are urged
The mole dosage ratio of agent is 1: 0.2~0.5: 0.01~0.05: 2~5: 1~1.5: 0.01~0.05；
Specific embodiment
Embodiment 1 prepares immobilized palladium catalyst (1)
In four-hole bottle, 45 grams of DMAs of input, 7 grams of function monomer (a-1) (be shown in by function monomer (a-1)
Shown in formula), 25 grams of function monomer (b-1) (function monomer (b-1) is as shown in formula), 18 grams of divinylbenzene, azodiisobutyronitrile
0.46 gram, after unlatching stirs, nitrogen charging deoxygenation 30 minutes, 60~65 DEG C, after polymerisation is carried out 2 hours are warming up to, is improved
Polymerization temperature is to 90~95 DEG C, after polymerisation carries out 2 hours again, cooling, adds 23 grams of magnesium sulfate, first is poured into after stirring
Solid in particle is separated out in alcohol, filtering, is washed successively with acetone, saturated aqueous sodium carbonate and deionized water, after drying, is made
47.5 grams of palladium (II) ion imprinted polymer hollow resin particles (1) of khaki, as immobilized palladium catalyst (1).Through element point
Analysis shows that palladium content is 22.31mg/g (0.2105mmol/g) in hollow resin particles (1).
Embodiment 2 prepares immobilized palladium catalyst (2)
According to the method for embodiment 1 and operating procedure, by divinylbenzene, 18 grams are changed as 36 grams, and 64.3 grams of khaki is made
Palladium (II) ion imprinted polymer hollow resin particles (2), as immobilized palladium catalyst (2).Show hollow tree through elementary analysis
Palladium content is 16.51mg/g (0.1535mmol/g) in fat particle (2).
The synthesis of the 4- phenylacetylene base -3- nitrobenzene methyls of embodiment 3
By the chloro- 3- nitrobenzene methyls of 0.01mol4-, 0.012mol KIs, 0.003mol cuprous iodides and 60 millis
Rise Isosorbide-5-Nitrae-dioxane to add in 100 milliliters of reaction bulbs, after nitrogen charging deoxygenation 30 minutes, rise reaction temperature is stirred to 80~85 DEG C
After mixing reaction 2 hours, 0.03mol triethylamines, 0.01mol phenylacetylenes and 0.5 gram of immobilized palladium catalyst (1) are added, continues to stir
Reaction 8 hours is mixed, after TLC detection reactions terminate, reduces reaction product system temperature to room temperature；It is insoluble that filtering respectively obtains solid
Thing 1. with filtrate 1.；1. insoluble matter includes immobilized palladium catalyst (1), triethylamine hydrochloride and some iodized salts, by saturated carbon
Sour hydrogen sodium water solution and absolute ethyl alcohol washing, dries Posterior circle and uses；Negative pressure revolving recovery Isosorbide-5-Nitrae-dioxy six is 1. carried out to filtrate
Ring and some triethylamines；Revolving remove solvent after residue deionized water dissolving, be filtrated to get insoluble matter 2. with filtrate 2.；
Filtrate 2. in contain KI and potassium chloride；2. recrystallization purification is carried out to the insoluble matter using absolute ethyl alcohol, 4- benzene is made
Acetenyl -3- nitrobenzene methyls, calculated yield of weighing；
Above-mentioned operation is repeated using the immobilized palladium catalyst (1) of recovery 6 times；And use identical raw material proportioning bar
Part, the catalytic performance of immobilized palladium catalyst (2) is investigated, the catalysis for contrasting immobilized palladium catalyst (1) and immobilized palladium catalyst (2) is steady
Qualitative energy, the results are shown in Table 1.
The catalytic performance of the immobilized palladium catalyst (1) of table 1 and immobilized palladium catalyst (2)
Claims (2)
1. application of the immobilized palladium catalyst in the synthesis of 4- phenylacetylene base -3- nitrobenzene methyls, it is characterised in that described solid
Carried palladium catalyst refers to palladium (II) ion imprinted polymer；
Concrete application is that 4- chloro- 3- nitrobenzene methyls, KI or sodium iodide, cuprous iodide and solvent are added into reactor
In, after nitrogen charging deoxygenation 30 minutes, for controlling reaction temperature to 30~130 DEG C, stirring reaction adds alkali, benzene after 0.5~2.5 hour
Acetylene and immobilized palladium catalyst, continue stirring reaction 6~12 hours, after TLC detection reactions terminate, reduce reaction product system temperature
Spend to room temperature；Filtering respectively obtain solid insoluble 1. with filtrate 1.；1. the insoluble matter is urged containing cuprous iodide and immobilized palladium
Agent, washed by saturated sodium bicarbonate aqueous solution and absolute ethyl alcohol, dry Posterior circle and use；60~70 DEG C of temperature control, to described
1. filtrate carries out negative pressure revolving recycling design；Revolving removes the residue deionized water dissolving after solvent, is filtrated to get insoluble
Thing 2. with filtrate 2.；2. KI, potassium chloride or sodium iodide, sodium chloride is separately recovered in gained filtrate；Using absolute ethyl alcohol to institute
State insoluble matter and 2. carry out recrystallization purification, 4- phenylacetylene base -3- nitrobenzene methyls are made；
Wherein described solvent is from toluene, chlorobenzene, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether, N- crassitudes
One kind in ketone, DMF, DMA, hexamethyl phosphoramide or dimethyl sulfoxide, the solvent
Dosage be 2~5 times of the chloro- 3- nitrobenzene methyls dosage quality of 4-；
The alkali is from sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), tri-n-butylamine, 4- diformazans
One kind in aminopyridine, methyl piperidine or Isosorbide-5-Nitrae-lupetazin；
The 4- chloro- 3- nitrobenzene methyls, KI or sodium iodide, cuprous iodide, alkali, phenylacetylene, immobilized palladium catalyst
Mole dosage ratio be 1: 0.2~0.5: 0.01~0.05: 2~5: 1~1.5: 0.01~0.05.
2. according to the answering in the synthesis of 4- phenylacetylene base -3- nitrobenzene methyls of the immobilized palladium catalyst described in claim 1
With, it is characterised in that palladium (II) ion imprinted polymer is referred on macromolecule side chain containing tertiary amine groups, quaternary ammonium cation
Palladium (II) ion imprinted polymer is closed with salicylaldoxime, palladium (II) ion imprinted polymer is with function monomer (A), function
Monomer (B) and crosslinking agent are raw material, by made from polymerization process；
The specific preparation manipulation of palladium (II) ion imprinted polymer is in four-hole bottle, adds organic solvent, function monomer
(A), function monomer (B), crosslinking agent, initiator and pore-foaming agent, stirring is opened, after stirring, nitrogen charging deoxygenation 30 minutes, heating
To 60~65 DEG C, polymerisation is carried out 2 hours；Temperature is improved to 90~95 DEG C, after polymerisation carries out 2 hours again, is cooled down, will
Polymeric reaction product system, which is poured into methanol, separates out particulate resins, filtering, with acetone, saturated aqueous sodium carbonate and goes successively
Ion water washing, after drying, hollow particle shape palladium (II) ion imprinted polymer is made；
Wherein described organic solvent is selected from chlorobenzene, methyl phenyl ethers anisole, 1-METHYLPYRROLIDONE, DMA, N, N- diformazans
Yl acetamide, N, N- diethyl acetamides, N, N- Valpromides, N, N- dibutyl acetamides, N, N- dimethyl phenacyls
In amine, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, normal octane or the petroleum ether of boiling range=90~120 DEG C
One or more, the dosage of the organic solvent are the 2 of function monomer (A), function monomer (B) and crosslinking agent quality summation
~10 times；
The function monomer (A) and function monomer (B) structure are represented by formula (A) and formula (B) respectively：
R in wherein described formula (A) and formula (B) is selected from C1~C18One kind in alkyl, X-Selected from Cl-、Br-、NO3 -Or
CH3COO-One or both of more than；
Described crosslinking agent is selected from divinylbenzene, triallyl isocyanurate, N, N- methylene-bisacrylamides, N, N- methylenes
Base double Methacrylamide, N- methyl-N, N- diallyl ammonium chloride, N- benzyls-N, N- diallyl ammonium chloride or N, N- bis-
It is more than one or both of allyl ammonium chloride；
The function monomer (A)：Function monomer (B)：The dosage mass ratio of crosslinking agent is 20~80: 20~80: 20~80；
Described initiator is selected from azodiisobutyronitrile or benzoyl peroxide；The dosage of the initiator be function monomer (A),
The 0.5~5% of the dosage quality summation of function monomer (B) and crosslinking agent；
Described pore-foaming agent is selected from magnesium sulfate, magnesium chloride, sodium sulphate, sodium chloride, calcium carbonate, toluene, chlorobenzene, methyl phenyl ethers anisole, N- first
Base pyrrolidones, DMA, N, N- diethyl acetamides, N, N- Valpromides, N, N- dibutyl acetyl
Amine, N, N- dimethyl benzamides, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, normal octane or boiling range=90
More than one or both of~120 DEG C of petroleum ethers, the dosage of the pore-foaming agent is function monomer (A), function monomer (B) and handed over
Join 1~10 times of agent quality summation.
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| UA75054C2 (en) * | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Substituted in position 6 indolinones, producing and use thereof as medicament |
| DE10233500A1 (en) * | 2002-07-24 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone monoethanesulfonate and its use as a medicament |
| DK2229359T3 (en) * | 2007-12-03 | 2018-02-05 | Boehringer Ingelheim Int | Process for preparing an indolinone derivative |
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