CN105126909A - Application of immobilized palladium catalyst in synthesis of methyl 4-phenylethynyl-3-nitrobenzoate - Google Patents
Application of immobilized palladium catalyst in synthesis of methyl 4-phenylethynyl-3-nitrobenzoate Download PDFInfo
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Abstract
The invention provides an application of an immobilized palladium catalyst in synthesis of methyl 4-phenylethynyl-3-nitrobenzoate. The immobilized palladium catalyst refers to a palladium (II) imprinted polymer of which a macromolecular side chain contains a tertiary amine group, a quaternary ammonium cation and salicylaldoximate palladium (II). The catalyst is applied in a cascade reaction among methyl 4-chloro-3-nitrobenzoate, potassium iodide or sodium iodide, and phenylacetylene to synthesize the methyl 4-phenylethynyl-3-nitrobenzoate. The immobilized palladium catalyst is simple in synthesis technology, is stable in catalytic activity, is easy to regenerate, is high in yield of a cascade reaction product, is simple in separation between raw materials and products, and is low in unit consumption of raw materials.
Description
Technical field
The present invention relates to a kind of application of immobilized palladium catalyst, particularly palladium (II) ion imprinted polymer is as the application of immobilized palladium catalyst in the synthesis of 4-phenylacetylene base-3-nitrobenzene methyl, belongs to functional high polymer material field.
Ni Danibu (English name nintedanib), trade name is Ofev, have another name called BIBF1120, it is the oral Mutiple Targets inhibitors of kinases of one of German Boehringer Ingelheim company initiative, it is the unique specific medicament being used for the treatment of idiopathic pulmonary fibrosis (IPF) at present, in October, 2014 is examined fast by U.S. food and Drug Administration (FDA), is preferentially examined, set up the status of Orphan drug, from then on finish idiopathic pulmonary fibrosis without medicine can epoch.The said firm WO2002081445 discloses the synthetic route of Ni Danibu:
Apply this conventional method and obtain Ni Danibu, first must obtain 2-indolone-6-methyl formate.So numerous scholar and research institution give and very big concern for the synthesis of 2-indolone-6-methyl formate and process optimization, mainly contain: CN102267934, US8304541, US2005324037, CN102531996 etc.These in disclosed document listed initiation material be: the chloro-3-nitrobenzene methyl of methyl-m-nitrobenzoate, 4-methyl-3-nitro methyl benzoate or 4-, synthesis step is all more than 9 steps, mostly because side reaction is many, or there is isomers phenomenon because of product, the total recovery of Ni Danibu is all very low.So the synthetic technology of Ni Danibu and method are badly in need of improving.
Based on this, the present inventor is in conjunction with traditional chemical synthesis and modern synthetic technology, design studies following Ni Danibu succinct synthetic route, still with the chloro-3-nitrobenzene methyl of 4-for initiation material, obtain Ni Danibu through phenylacetylene reaction, nitro-reduction reaction, isocyanation esterification reaction, ring-closure reaction and aminating reaction.In the succinct synthetic route of described Ni Danibu, do not have product isomer phenomenon, each step products yield is high, and separation method is easy, is easy to industrialization.
Professional knows, and the phenylacetylene of the chloro-3-nitrobenzene methyl of 4-is combined to 4-phenylacetylene base-3-nitrobenzene methyl and belongs to the reaction of typical structure C-C key.Realize the phenylacetyleneization reaction of the chloro-3-nitrobenzene methyl of described 4-, can have been come by the nucleophilic substitution of phenylacetylene salt and the chloro-3-nitrobenzene methyl of 4-.But in recent years, such as iodo aromatic hydrocarbon as the representative of active halogenated aryl hydrocarbon, at PdCl
2with under the classical catalyst system and catalyzing effect of CuI composition, Sonogashira coupling reaction is carried out with phenylacetylene, aryl phenylacetylene product can be obtained by high yield, so 4-iodo-3-nitrobenzene methyl can be used as active halogenated aryl hydrocarbon, Sonogashira coupling reaction is carried out, convenient obtained 4-phenylacetylene base 3-nitrobenzene methyl with phenylacetylene.But the poor stability of the iodo-3-nitrobenzene methyl of 4-, merchandise resources is rare, and price is noble.The present inventor tests that find can chloro-3-nitrobenzene methyl be under CuI catalytic action by cheap 4-, and in aprotic polar solvent, the nucleophilic substitution with KI or sodium iodide, is easy to the iodo-3-nitrobenzene methyl of obtained 4-; Therefore, based on mechanism and the feature of described nucleophilic substitution and described Sonogashira coupling reaction, two-step reaction can be coexisted in one pot and complete, adopt cascade reaction technology, obtain 4-phenylacetylene base-3-nitrobenzene methyl by the chloro-3-nitrobenzene methyl of 4-, described cascade reaction can be expressed by following formula:
And the service efficiency of expensive palladium catalyst is one of key reducing further synthesis 4-phenylacetylene base-3-nitrobenzene methyl cost of material so far.Therefore, in the succinct synthetic route of described Ni Danibu, the service efficiency improving palladium catalyst is the centre point that the present invention pays close attention to.
Professional knows, early application PdCl
2classical catalyst system and catalyzing with CuI composition, all will use various baroque part to improve the catalytic activity of catalyst system, and reaction all needs higher catalytic amount (1-5%).For many parts, its chemical constitution is complicated, and preparation condition is harsh, easily runs off, is difficult to recovery and re-uses after reaction.Therefore the palladium catalyst studying support type also becomes the focus of concern already.The carrier of common load type palladium catalyst is divided into inorganic matter and organic matter two kinds.Common inorganic matter carrier has active carbon, molecular sieve, natural clay mineral, metal oxide, magnalium hydrotalcite etc.The carrier of organic matter supported palladium type catalyst belongs to and comparatively common are the large molecule of machine, is divided into natural polymer and synthetic polymer two class.
Inorganic matter is the supported palladium composition catalyst of carrier, belongs to palladium " complex is open " load, and described " complex is open " refers to Pd (0) or Pd (II) complex is deposited on mineral surfaces in a free form.Be subject to organic reaction fuel factor, stir concussion, desorption between catalyst and carrier and absorption, solvent the Chemical Physics Processing such as dissolution affect, Pd (0) or Pd (II) complex all very easily depart from carrier, Pd (0) or Pd (II) complex very easily run off in solvent and product, or form palladium bunch (also have and be called palladium black), cause the catalytic activity of inorganic matter load type palladium composition catalyst to decline fast.Whether people notice that Pd (0) or Pd (II) complex slip into inorganic matter carrier deep internal in addition, and be beyond expression its catalytic activity, may also be one of palladium catalyst deactivation causes.
By chemical bond, part is bonded on carrier (described carrier comprises silica gel, inorganic organic framework polymer, organic macromolecule), then by complexation reaction thereafter, by immobilized on carrier for Pd (0) or Pd (II).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.Described " complex semi open model " load type palladium catalyst refers to the chelation being bonded in part on carrier and Pd (0) or Pd (II) self assembling type, by Pd (0) or Pd (II) " card " on carrier.Disclosed described " complex semi open model " load type palladium catalyst is various, and such as silica gel bonded bisoxazoline, bidentate phosphine, polyamines, polyether or schiff bases are the palladium complex of cheland and ring palladium compound etc.The high praise that mode is various, ligand structure is changeful, easy times of coordination synthetic technology is subject to people especially on, cheland bonded support of a great variety with bonding cheland of the organic macromolecule of bonding cheland, so this type of " complex semi open model " load type palladium catalyst is the focus of people's research and development now.
But owing to being subject to the impact of factors in Sonogashira course of reaction; " card " of the part to Pd (0) or Pd (II) of " complex semi open model " load type palladium catalyst is easily opened; the coordination protective effect of Pd (0) or Pd (II) was lost efficacy; palladium departs from ligand protection and is tending towards forming palladium black; or palladium runs off in solvent and product, catalysis efficiency declines eventually.But described part is without any loss.So it has been observed that the catalysis efficiency stability of described " complex semi open model " load type palladium catalyst has improve many than above-mentioned " complex is open " load type palladium catalyst.
Porphyrin has the Conjugate macrocycle part of armaticity, high stable complex is formed with the coordination closed and many metal ions, so also there is multidigit scholar to report Sonogashira reaction or the Heck catalytic reaction activity of porphyrin palladium complex, and polymer fixes the application in porphyrin palladium complex coupling reaction, and not only catalysis efficiency is high, selective height, recycle more than 20 catalyst to run off hardly, catalytic activity reduction of speed is slow, such as Tetra.Let.2007,48,6688-6691; 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; Nearest Liu understands the Heck reaction result that the people such as continent disclose chloromethylation micropore polystyrene spheres bonding meta tetrahydroxy phenyl porphyrin palladium chtalyst iodobenzene and ethyl acrylate, 100 DEG C, catalyst amount is 0.1% mole, N
2protective reaction 4 hours, the yield recycling the ethyl phenylacrylate of 6 times, all more than 94%, does not have palladium leakage to occur.Angew.Chem.Int.Ed.2001,40 (18), 3469-3471 report polystyrene parcel palladium complex Heck catalytic reaction activity medium, the achievement that catalyst does not run off.The Heck catalytic reaction activity that Ind.Eng.Chem.Res.2014,53,8339-834 also report cellulose encapsulation palladium complex is higher, the achievement that catalyst does not run off.Described polystyrene bonding porphyrin palladium complex, or polystyrene or cellulose encapsulation palladium complex, we are referred to as " complex is closed " load type palladium catalyst.Described " complex is closed " load type palladium catalyst refers to Pd (0) or Pd (II) and cyclic ligand, by embedded bonding pattern or parcel mode " delineation " on carrier, be hardly subject to reaction environment factor impact and depart from carrier.Especially the load type palladium catalyst of polystyrene bonding porphyrin palladium complex; the closure coordination of porphyrin and bonding action are strong to the coordination protective effect of Pd (0) or Pd (II), and what the molecule participating in coupling reaction did not need to penetrate " encapsulation palladium complex " yet wraps up in clothing barrier.
Professional knows, and ion coordination imprinted polymer has identity, high selectivity and strong compatibility for target metal ions, and its mechanical stability is high, and Coordination Space structure is fixed, and coordination is directed, and coordination is by force selective, and coordination is quick and reversible.The present inventor once disclosed: a kind of water-solubility function monomer agent preparation method (CN201310141108.8) containing quaternary ammonium salt and schiff bases complex, a kind of coordination imprinted polymer and preparation method thereof (CN201310113527.0), the solid phase trace dibit extractant of copper (II) and preparation method thereof (20141056563768.X), crosslinkable containing quaternary ammonium cation and schiff base of salicylaldehyde conjunction copper (II) monomer (CN201410563769.4).Accordingly, palladium (II) ion imprinted polymer is converted in coupling reaction by the present inventor, as " complex is closed " immobilized palladium catalyst of synthesis 4-phenylacetylene base 3-nitrobenzene methyl, there is synthetic technology easy, catalytic activity is stablized, and can regenerate, thus form the application of the immobilized palladium catalyst of the present invention in synthesis 4-phenylacetylene base-3-nitrobenzene methyl.
Summary of the invention
The object of this invention is to provide the application of immobilized palladium catalyst in synthesis 4-phenylacetylene base-3-nitrobenzene methyl.Described immobilized palladium catalyst refers to palladium (II) ion imprinted polymer, described palladium (II) ion imprinted polymer refers on macromolecule side chain and closes palladium (II) ion imprinted polymer containing tertiary amine groups, quaternary ammonium cation and salicylaldoxime, is applied to the synthesis of 4-phenylacetylene base-3-nitrobenzene methyl as immobilized palladium catalyst.
It is with general formula (A) function monomer, general formula (B) function monomer and crosslinking agent for raw material that described macromolecule side chain closes palladium (II) ion imprinted polymer containing tertiary amine groups, quaternary ammonium cation and salicylaldoxime, is obtained by polymerization process.Concrete preparation manipulation: in four-hole bottle, add organic solvent, function monomer (A), function monomer (B), crosslinking agent, initator and pore-foaming agent, open and stir, after stirring, fill nitrogen deoxygenation 30 minutes, be warming up to 60 ~ 65 DEG C, polymerisation carries out 2 hours, improve temperature to 90 ~ 95 DEG C, after polymerisation carries out 2 hours again, cooling, by precipitate particle shape resin in polymeric reaction product system impouring methyl alcohol, filter, use acetone successively, saturated aqueous sodium carbonate and deionized water washing, after drying, obtained palladium (II) ion imprinted polymer hollow resin particles, as immobilized palladium catalyst.
Wherein said organic solvent is selected from chlorobenzene, methyl phenyl ethers anisole, 1-METHYLPYRROLIDONE, N, N-dimethylacetylamide, N, N-diethyl acetamide, N, N-Valpromide, N, N-dibutyl acetamide, N, one or more in the benzinum of N-dimethyl benzamide, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, normal octane or boiling range=90 ~ 120 DEG C, the consumption of described organic solvent is 2 ~ 10 times of general formula (A), general formula (B) and crosslinking agent quality summation;
Described general formula (A) function monomer and general formula (B) function monomer structure are expressed as:
R in wherein said general formula (A) and general formula (B) is selected from C
1~ C
18one in alkyl, X-is selected from Cl
-, Br
-, SO
4 2-, NO
3 -, CH
3cOO-or p-CH
3c
6h
4sO
4 -in one or more;
Described crosslinking agent is selected from divinylbenzene, triallyl isocyanurate, N, N-methylene-bisacrylamide, N, N-methylenebismethacrylamide, N-methyl-N, N-diallyl ammonium chloride, N-benzyl-N, one or more in N-diallyl ammonium chloride or N, N-diallyl ammonium chloride.
Described general formula (A): general formula (B): the consumption mass ratio of crosslinking agent is 20 ~ 80: 20 ~ 80: 20 ~ 80.
Described initator is selected from azodiisobutyronitrile or benzoyl peroxide; The consumption of described initator is 0.5 ~ 5% of the consumption quality summation of general formula (A), general formula (B) and crosslinking agent;
Professional knows, described palladium (II) is if ion imprinted polymer presents hollow sphere state, the specific area of palladium (II) ion imprinted polymer can be significantly improved, fully show the catalytic capability of palladium (II) ion imprinted polymer.So the appropriate technology preparing described palladium (II) ion imprinted polymer is suspension polymerisation or polymerisation in solution, and add pore-foaming agent.Described pore-foaming agent is selected from magnesium sulfate, magnesium chloride, sodium sulphate, sodium chloride, calcium carbonate, toluene, chlorobenzene, methyl phenyl ethers anisole, 1-METHYLPYRROLIDONE, N, N-dimethylacetylamide, N, N-diethyl acetamide, N, N-Valpromide, N, N-dibutyl acetamide, N, N-dimethyl benzamide, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, one or more in normal octane or boiling range=90 ~ 120 DEG C benzinum, the consumption of described pore-foaming agent is general formula (A), general formula (B) and crosslinking agent quality summation 1 ~ 10 times.
The embody rule operation of immobilized palladium catalyst in synthesis 4-phenylacetylene base-3-nitrobenzene methyl: chloro-for 4-3-nitrobenzene methyl, KI or sodium iodide, cuprous iodide and solvent are added in reactor, fill nitrogen deoxygenation after 30 minutes, control reaction temperature to 30 ~ 130 DEG C, stirring reaction is after 0.5 ~ 2.5 hour, add alkali, phenylacetylene and immobilized palladium catalyst, continue stirring reaction 6 ~ 12 hours, after TLC detection reaction terminates, reduce product system temperature to room temperature; Filter obtain respectively solid insoluble 1. with filtrate 1.; Described insoluble matter is 1. mainly containing cuprous iodide and immobilized palladium catalyst, and through saturated sodium bicarbonate aqueous solution and absolute ethanol washing, dry Posterior circle uses; Thereafter temperature control 60 ~ 70 DEG C, 1. carries out negative pressure to described filtrate and revolves steaming recycling design; Gained revolves and boils off the residue deionized water dissolving after desolventizing, filter obtain insoluble matter 2. with filtrate 2.; 2. gained filtrate reclaim KI, potassium chloride or sodium iodide, sodium chloride respectively; Use absolute ethyl alcohol 2. to carry out recrystallization to described insoluble matter to purify, obtained 4-phenylacetylene base-3-nitrobenzene methyl;
Wherein said solvent selects toluene, chlorobenzene, oxolane, 1,4-dioxane, glycol dimethyl ether, 1-METHYLPYRROLIDONE, N, dinethylformamide, N, one in N-dimethylacetylamide, hexamethyl phosphoramide or methyl-sulfoxide, the consumption of described solvent is 2 ~ 5 times of 4-chloro-3-nitrobenzene methyl consumption quality;
Described alkali selects the one in sodium carbonate, potash, cesium carbonate, triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), tri-n-butylamine, DMAP, methyl piperidine or Isosorbide-5-Nitrae-lupetazin;
The mole dosage ratio of described 4-chloro-3-nitrobenzene methyl, KI or sodium iodide, cuprous iodide, alkali, phenylacetylene, immobilized palladium catalyst 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, drop into 45 grams of N, N-dimethylacetylamide, function monomer (a-1) 7 grams (function monomer (a-1) is shown in shown in formula), function monomer (b-1) 25 grams (function monomer (b-1) is shown in shown in formula), divinylbenzene 18 grams, azodiisobutyronitrile 0.46 gram, after unlatching stirs, fill nitrogen deoxygenation 30 minutes, be warming up to 60 ~ 65 DEG C, after polymerisation carries out 2 hours, improve polymerization temperature to 90 ~ 95 DEG C, after polymerisation carries out 2 hours again, cooling, add 23 grams, magnesium sulfate, solid in precipitate particle in impouring methyl alcohol after stirring, filter, use acetone successively, saturated aqueous sodium carbonate and deionized water washing, after drying, obtained khaki 47.5 grams of palladiums (II) ion imprinted polymer hollow resin particles (1), as immobilized palladium catalyst (1).In elementary analysis shows hollow resin particles (1), palladium content is 22.31mg/g (0.2105mmol/g).
Embodiment 2 prepares immobilized palladium catalyst (2)
According to embodiment 1 method and operating procedure, be 36 grams by divinylbenzene 18 grams of changes, obtained khaki 64.3 grams of palladiums (II) ion imprinted polymer hollow resin particles (2), as immobilized palladium catalyst (2).In elementary analysis shows hollow resin particles (2), palladium content is 16.51mg/g (0.1535mmol/g).
The synthesis of embodiment 34-phenylacetylene base-3-nitrobenzene methyl
By chloro-for 0.01mol4-3-nitrobenzene methyl, 0.012mol KI, 0.003mol cuprous iodide and 60 milliliter 1,4-dioxane adds in 100 milliliters of reaction bulbs, fill nitrogen deoxygenation after 30 minutes, raise reaction temperature to 80 ~ 85 DEG C, stirring reaction after 2 hours, then adds 0.03mol triethylamine, 0.01mol phenylacetylene and 0.5 gram of immobilized palladium catalyst (1), continues stirring reaction 8 hours, after TLC detection reaction terminates, reduce product system temperature to room temperature; Filter obtain respectively solid insoluble 1. with filtrate 1.; 1. insoluble matter comprises immobilized palladium catalyst (1), triethylamine hydrochloride and some iodized salts, and through saturated sodium bicarbonate aqueous solution and absolute ethanol washing, dry Posterior circle uses; 1. negative pressure is carried out to filtrate and revolves steaming recovery Isosorbide-5-Nitrae-dioxane and some triethylamines; Revolve and boil off the residue deionized water dissolving after desolventizing, filter obtain insoluble matter 2. with filtrate 2.; Filtrate 2. in containing KI and potassium chloride; Use absolute ethyl alcohol 2. to carry out recrystallization to described insoluble matter to purify, obtained 4-phenylacetylene base-3-nitrobenzene methyl, calculated yield of weighing;
The immobilized palladium catalyst (1) reclaimed is utilized to repeat above-mentioned operation 6 times; And adopt identical pulp furnish condition, investigate the catalytic performance of immobilized palladium catalyst (2), contrast the catalytic stability energy of immobilized palladium catalyst (1) and immobilized palladium catalyst (2), the results are shown in Table 1.
The catalytic performance of the immobilized palladium catalyst of table 1 (1) and immobilized palladium catalyst (2)
Claims (2)
1. the application of immobilized palladium catalyst in the synthesis of 4-phenylacetylene base-3-nitrobenzene methyl, is characterized in that described immobilized palladium catalyst refers to palladium (II) ion imprinted polymer;
Embody rule adds in reactor by chloro-for 4-3-nitrobenzene methyl, KI or sodium iodide, cuprous iodide and solvent, fill nitrogen deoxygenation after 30 minutes, control reaction temperature to 30 ~ 130 DEG C, stirring reaction is after 0.5 ~ 2.5 hour, add alkali, phenylacetylene and immobilized palladium catalyst, continue stirring reaction 6 ~ 12 hours, after TLC detection reaction terminates, reduce product system temperature to room temperature; Filter obtain respectively solid insoluble 1. with filtrate 1.; Described insoluble matter is 1. containing cuprous iodide and immobilized palladium catalyst, and through saturated sodium bicarbonate aqueous solution and absolute ethanol washing, dry Posterior circle uses; Temperature control 60 ~ 70 DEG C, 1. carries out negative pressure to described filtrate and revolves steaming recycling design; Revolve and boil off the residue deionized water dissolving after desolventizing, filter obtain insoluble matter 2. with filtrate 2.; 2. gained filtrate reclaim KI, potassium chloride or sodium iodide, sodium chloride respectively; Use absolute ethyl alcohol 2. to carry out recrystallization to described insoluble matter to purify, obtained 4-phenylacetylene base-3-nitrobenzene methyl;
Wherein said solvent selects toluene, chlorobenzene, oxolane, 1,4-dioxane, glycol dimethyl ether, 1-METHYLPYRROLIDONE, N, dinethylformamide, N, one in N-dimethylacetylamide, hexamethyl phosphoramide or methyl-sulfoxide, the consumption of described solvent is 2 ~ 5 times of 4-chloro-3-nitrobenzene methyl consumption quality;
Described alkali selects the one in sodium carbonate, potash, cesium carbonate, triethylamine, diisopropyl ethyl amine, tripropyl amine (TPA), tri-n-butylamine, DMAP, methyl piperidine or Isosorbide-5-Nitrae-lupetazin;
The mole dosage ratio of described 4-chloro-3-nitrobenzene methyl, KI or sodium iodide, cuprous iodide, alkali, phenylacetylene, immobilized palladium catalyst is 1: 0.2 ~ 0.5: 0.01 ~ 0.05: 2 ~ 5: 1 ~ 1.5: 0.01 ~ 0.05.
2. according to the application of immobilized palladium catalyst according to claim 1 in synthesis 4-phenylacetylene base-3-nitrobenzene methyl, it is characterized in that described palladium (II) ion imprinted polymer refers on macromolecule side chain and close palladium (II) ion imprinted polymer containing tertiary amine groups, quaternary ammonium cation and salicylaldoxime, described palladium (II) ion imprinted polymer is with general formula (A) function monomer, general formula (B) function monomer and crosslinking agent for raw material, is obtained by polymerization process;
The concrete preparation manipulation of described palladium (II) ion imprinted polymer is in four-hole bottle, add organic solvent, function monomer (A), function monomer (B), crosslinking agent, initator and pore-foaming agent, open and stir, after stirring, fill nitrogen deoxygenation 30 minutes, be warming up to 60 ~ 65 DEG C, polymerisation carries out 2 hours; Improve temperature to 90 ~ 95 DEG C, after polymerisation carries out 2 hours again, cooling, by precipitate particle shape resin in polymeric reaction product system impouring methyl alcohol, filter, successively with the washing of acetone, saturated aqueous sodium carbonate and deionized water, after drying, obtained hollow particle shape palladium (II) ion imprinted polymer;
Wherein said organic solvent is selected from chlorobenzene, methyl phenyl ethers anisole, 1-METHYLPYRROLIDONE, N, accelerine, N, N-dimethylacetylamide, N, N-diethyl acetamide, N, N-Valpromide, N, N-dibutyl acetamide, N, one or more in the benzinum of N-dimethyl benzamide, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, normal octane or boiling range=90 ~ 120 DEG C, the consumption of described organic solvent is 2 ~ 10 times of general formula (A), general formula (B) and crosslinking agent quality summation;
Described general formula (A) function monomer and general formula (B) function monomer structure are represented by general formula (A) and general formula (B) respectively:
R in wherein said general formula (A) and general formula (B) is selected from C
1~ C
18one in alkyl, X
-be selected from Cl
-, Br
-, 8O
4 2-, NO
3 -, CH
3cOO
-or p-CH
3c
6h
4sO
4 -in one or more;
Described crosslinking agent is selected from divinylbenzene, triallyl isocyanurate, N, N-methylene-bisacrylamide, N, N-methylenebismethacrylamide, N-methyl-N, N-diallyl ammonium chloride, N-benzyl-N, one or more in N-diallyl ammonium chloride or N, N-diallyl ammonium chloride;
Described general formula (A): general formula (B): the consumption mass ratio of crosslinking agent is 20 ~ 80: 20 ~ 80: 20 ~ 80;
Described initator is selected from azodiisobutyronitrile or benzoyl peroxide; The consumption of described initator is 0.5 ~ 5% of the consumption quality summation of general formula (A), general formula (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, 1-METHYLPYRROLIDONE, N, N-dimethylacetylamide, N, N-diethyl acetamide, N, N-Valpromide, N, N-dibutyl acetamide, N, N-dimethyl benzamide, acetophenone, cyclohexanone, n-hexyl alcohol, laruyl alcohol, hexahydrotoluene, one or more in normal octane or boiling range=90 ~ 120 DEG C benzinum, the consumption of described pore-foaming agent is general formula (A), general formula (B) and crosslinking agent quality summation 1 ~ 10 times.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391557A (en) * | 1999-10-13 | 2003-01-15 | 贝林格尔英格海姆法玛公司 | 6-position substituted indoline, production and use thereof as medicament |
| WO2004013099A1 (en) * | 2002-07-24 | 2004-02-12 | 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-monoethanesulphonate and the use thereof as a pharmaceutical composition |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391557A (en) * | 1999-10-13 | 2003-01-15 | 贝林格尔英格海姆法玛公司 | 6-position substituted indoline, production and use thereof as medicament |
| WO2004013099A1 (en) * | 2002-07-24 | 2004-02-12 | 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-monoethanesulphonate and the use thereof as a pharmaceutical composition |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
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