CN101259439B - Ion-exchange resin fluorizating agent and preparation and application - Google Patents
Ion-exchange resin fluorizating agent and preparation and application Download PDFInfo
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- CN101259439B CN101259439B CN2008100609616A CN200810060961A CN101259439B CN 101259439 B CN101259439 B CN 101259439B CN 2008100609616 A CN2008100609616 A CN 2008100609616A CN 200810060961 A CN200810060961 A CN 200810060961A CN 101259439 B CN101259439 B CN 101259439B
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Abstract
The invention provides an ion exchange resin fluridizer (II), a preparation method thereof and application thereof in catalyzing and synthesizing a fluropyridazine compound. The ion exchange resin fluridizer (II) has the concrete application that: a halogenopyridazine compound serving as raw material and the ion exchange resin fluridizer of formula (II) serving as a catalyst go through a reactionin non-proton polar solvent at 50 to 150 DEG C for 1 to 10 hours; after the reaction is finished, at least one chlorine or bromine atom in the halogenopyridazine compound is replaced by a fluorine atom and the fluropyridazine compound is obtained after separating and purifying the reaction solution; the method has simple preparation technique, high yield rate, easy operation and little pollution to environment, which is a green chemical synthesis technique.
Description
(1) technical field
The present invention relates to a kind of ion-exchange resin fluorizating agent and preparation method thereof, with and application in catalysis synthesizing fluoro pyridazine compound.
(2) background technology
The fluoro pyridazine compound have higher anticonvulsion, suppress platelet aggregation, antiviral, anticancer and desinsection, coordinate plant growth isoreactivity.Many pyridazine compounds are as medicine listing, and the fluoro pyridazine is isomer with fluorouracil, thereby have been subjected to chemist's attention in medical and pesticide research field.
Before the present invention made, the method that fluorine atom is introduced on the pyridazine ring mainly contained fusion method, diazotising method, condensation method and halogen exchange method.Fusion method is that compound carries out under molten condition, generally obtain this moment be polyfluoro for product, poor selectivity, reaction temperature height, product separate difficult.The diazotising method can prepare the comparatively complicated compound of structure, but the report of carrying out this respect research at present is few.Condensation method is to carry out ring-closure reaction by hydro carbons fluoro thing to prepare the fluoro pyridazine compound, also is difficult to apply but be subjected to the synthetic restriction of hydro carbons fluoro thing.Halogen exchange method major part is carried out in aprotic polar solvent, and has obtained good result.
Ion exchange resin is the cancellated macromolecular compound that a class has functional group, and it has insoluble three dimensions mesh skeleton, constitutes by being connected exchangeable ion three parts that have opposite charges on functional group on the skeleton and the functional group.
Ion-exchange resin technique has quite long history, along with developing rapidly of modern chemistry industrial technology, developed the ion exchange resin of many kinds of function admirables, and developed multiple new application process, in many high and new technology industries and scientific research field, be used widely.In recent years domestic and international resin kind of producing reaches hundreds of, the annual production few hundred thousand tonnes of.
In commercial Application, the advantage of ion exchange resin mainly is that disposal ability is big, applied range, and long service life, operating cost is low, and iterative regenerable uses.Therefore, the improvement that utilizes ion exchange resin to carry out traditional handicraft is a kind of Green Chemistry synthetic technology that application prospect is arranged.
(3) summary of the invention
The object of the invention is to provide a kind of ion-exchange resin fluorizating agent and preparation thereof and uses, and with this ion-exchange resin fluorizating agent catalysis synthesizing fluoro pyridazine compound, reaction condition is easily controlled, cost is low, reaction system can be recycled.
The technical solution used in the present invention is:
A kind of ion-exchange resin fluorizating agent, structure is suc as formula shown in (II):
In the formula (II), R is C1～C3 alkyl.
N represents contained number of repeat unit purpose mean value on the polymer macromolecule chain, for weighing the index of polymer molecule size.
A kind of method for preparing described ion-exchange resin fluorizating agent, described method comprises: react with the styrene series anion exchange resin quaternary ammonium base and the HF aqueous solution shown in the formula (V), obtain described ion-exchange resin fluorizating agent;
In the formula (V), R is C1～C3 alkyl.
Described styrene series anion exchange resin quaternary ammonium base can react acquisition with bromoalkane, NaOH, HF successively by the weakly basic styrene type anion exchange resin, perhaps reacts acquisition with NaOH, HF successively by strong-basicity styrene series anion exchange resin.
Concrete, described method is as follows: with the weakly basic styrene type anion exchange resin shown in the formula (IV), use the dimethyl formamide swelling, add capacity RCl, RBr or RI, R is C1～C3 alkyl, 50 ℃ were reacted 1～10 hour, reaction finishes after washing, normal temperature descends and the capacity NaOH aqueous solution carries out exchange reaction, the exchange reaction product water is washed till neutrality, obtains strong-basicity styrene series anion exchange resin and fully reacts down in normal temperature with the capacity HF aqueous solution, after reaction finishes, product water is washed till neutrality, obtains described ion-exchange resin fluorizating agent;
In the said method, described strong basicity and weakly basic styrene type anion exchange resin can adopt commercial commodity, described RCl, RBr, RI, and the HF consumption is advisable (theoretical value is and the resin equimolar amounts) with abundant reaction, also can be excessive.Reaction equation is as follows:
Perhaps, described method is: carry out exchange reaction with strong-basicity styrene series anion exchange resin and the NaOH solution shown in the formula (VI), be washed to neutrality, add the HF aqueous solution again and react, obtain described ion-exchange resin fluorizating agent;
In the formula (VI), R is C1～C3 alkyl, and Y is-Cl ,-Br, and-I, or-OH.
Reaction equation is as follows:
The invention still further relates to the application of described ion-exchange resin fluorizating agent in catalysis synthesizing fluoro pyridazine compound.
Concrete, described being applied as: with formula (III-1) (III-2) or the halo pyridazine compound (III-3) be raw material, with the ion-exchange resin fluorizating agent shown in the formula (II) is catalyst, in aprotic polar solvent, reacted 1～10 hour down in 50～150 ℃, after reaction finished, at least one chlorine or bromine atom was replaced by fluorine in the described halo pyridazine compound, and reactant liquor obtains described fluoro pyridazine compound through separation and purification;
Wherein:
X
1～X
3Independent separately is chlorine or bromine;
n
1＝1，2，3，4；n
2＝1，2，3；n
3＝1，2；
R
1, R
2Independent separately is hydrogen, C1～C6 alkyl, benzyl, phenyl, substituted-phenyl or naphthyl;
Described aprotic polar solvent is one of following: acetonitrile, acetone, butanone, methyl-sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethylacetylamide, hexamethylphosphorictriamide, described aprotic polar solvent quality consumption are 3～10 times of described halo pyridazine compound quality.
Described R
1, R
2Independently be preferably hydrogen, phenyl, benzyl, substituted-phenyl, naphthyl or the tert-butyl group separately, the substituting group of described substituted-phenyl is methyl or trifluoromethyl.
Described ion-exchange resin fluorizating agent consumption is so that the halo pyridazine compound fully reacts be advisable (the theoretical value mole dosage is 1: 1), usually to select excessive so that the halo pyridazine compound fully reacts, the ratio of pyridazine compound of halo described in the present invention and ion-exchange resin fluorizating agent amount of substance is preferably 1: 1～and 3.
Preferably, the reaction temperature of described reaction is 100～110 ℃, 6～8 hours reaction time.
Described isolation and purification method is as follows: after reaction finished, with the reactant liquor cooling, dichloromethane extraction was got organic layer and is concentrated, and column chromatography for separation obtains described fluoro pyridazine compound.
Preferably, described being applied as: with halo pyridazine compound shown in the formula (III-2a) and described ion-exchange resin fluorizating agent is raw material, in aprotic polar solvent, reacted 5～8 hours down in 80～110 ℃, after reaction finishes, the reactant liquor cooling, dichloromethane extraction, concentrated, column chromatography for separation obtains the fluoro pyridazine compound shown in the formula (I-2a); The ratio of described halo pyridazine compound and ion-exchange resin fluorizating agent amount of substance is 1: 1～3; Described aprotic polar solvent is acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO) or butanone, and the quality consumption is 3～10 times of described halo pyridazine compound quality;
Among formula (III-2a), (I-2a):
X
2Be chlorine or bromine; R
2Be hydrogen, C1～C6 alkyl, benzyl, phenyl or naphthyl.
Preferably, described being applied as: with halo pyridazine compound shown in the formula (III-3a) and described ion-exchange resin fluorizating agent is raw material, in aprotic polar solvent, reacted 5～8 hours down in 80～110 ℃, after reaction finishes, the reactant liquor cooling, dichloromethane extraction, concentrated, column chromatography for separation obtains the fluoro pyridazine compound shown in the formula (I-3a); The ratio of described halo pyridazine compound and ion-exchange resin fluorizating agent amount of substance is 1: 1～3; Described aprotic polar solvent is acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO) or butanone, and the quality consumption is 3～10 times of described halo pyridazine compound quality;
Among formula (III-3a), (I-3a):
X
3Be chlorine or bromine; R
3For hydrogen, C1～C6 alkyl, phenyl, 4 '-aminomethyl phenyl or 3 '-trifluoromethyl.
Beneficial effect of the present invention is mainly reflected in: a kind of ion-exchange resin fluorizating agent that can be applicable to catalysis synthesizing fluoro pyridazine compound is provided, with it is catalyst synthesizing fluoro pyridazine compound, preparation technology is simple, yield is high, easy to operate, environmental pollution is little, is a kind of Green Chemistry synthetic technology.
(4) specific embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this.
Embodiment 1: the ion-exchange resin fluorizating agent preparation
Get weakly basic styrene type anion exchange resin (Styrene-DVB D301R, Chemical Plant of Nankai Univ.) 2g,, add 1.2g C with 20mL DMF swelling
2H
5Br, 50 ℃ were reacted 5 hours, and reaction finishes after washing, add 10mL 20% (w/w) the NaOH aqueous solution, carry out exchange reaction under normal temperature, the exchange reaction product water is washed till neutrality, adds 20mL 10% (w/w) the HF aqueous solution again, in normal temperature fully reaction down, after reaction finished, product water was washed till neutrality, obtains ion-exchange resin fluorizating agent, outward appearance is a white solid, and recording fluorine content is 3～4mmol/g.
Embodiment 2: the ion-exchange resin fluorizating agent preparation
Get strong-basicity styrene series anion exchange resin (201 * 4 Styrene-DVB, Chemical Plant of Nankai Univ.) 2g adds 20mL 30% (w/w) the NaOH aqueous solution, carries out exchange reaction under normal temperature, the exchange reaction product water is washed till neutrality, add 30mL 10% (w/w) the HF aqueous solution again, in normal temperature fully reaction down, after reaction finishes, product water is washed till neutrality, obtain ion-exchange resin fluorizating agent, outward appearance is a white solid, and recording fluorine content is 3～4mmol/g.
Synthesizing of embodiment 3:4-chloro-5-fluoro-2-phenyl-3 (2H)-pyridazinone
With 4,5-two chloro-2-phenyl-3 (2H)-pyridazinone 0.24g (1 mM), embodiment 1 resin fluorizating agent 0.42g (2 mM), 10 milliliters of methyl-sulfoxides place 50 milliliters of there-necked flasks, and agitating heating was 100 ℃ of reactions 5 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains white powder solid product 0.16 gram, yield 70%.145～146 ℃ of fusing points.MS(m/z)：224(M
+)。
Synthesizing of embodiment 4:4-bromo-5-fluoro-2-phenyl-3 (2H)-pyridazinone
With 4,5-two bromo-2-phenyl-3 (2H)-pyridazinone 0.33 gram (1 mM), embodiment 1 resin fluorizating agent 0.42g (2 mM), 15 milliliters of dimethyl formamides place 100 milliliters of there-necked flasks, and agitating heating was 80 ℃ of reactions 10 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains white powder solid product 0.2 gram, yield 72%.159～160 ℃ of fusing points.MS(m/z)：268(M
+)。
Synthesizing of embodiment 5:4-bromo-5-fluoro-3 (2H)-pyridazinones
With 4,5-two bromo-3 (2H)-pyridazinone 0.25 gram (1 mM), embodiment 2 resin fluorizating agent 0.8g (3 mM), 10 milliliters of dimethyl formamides place 100 milliliters of there-necked flasks, and agitating heating was 80 ℃ of reactions 10 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains white powder solid product 0.13 gram, yield 79%.212～213 ℃ of fusing points.MS(m/z)：192(M
+)。
Embodiment 6: utilize the recovery resin fluorizating agent to prepare 4-bromo-5-fluoro-3 (2H)-pyridazinones
Resin fluorizating agent utilizes the method regeneration of embodiment 1 after being reclaimed by embodiment 3 again, and other reactant and consumption thereof and step get product 0.19 gram, yield 71% with embodiment 3.
Synthesizing of embodiment 7:4-chloro-5-fluoro-2-benzyl-3 (2H)-pyridazinone
With 4,5-two chloro-2-benzyls-3 (2H)-pyridazinone 0.26 gram (1 mM), embodiment 1 resin fluorizating agent 0.63g (3 mM), 50 milliliters of acetonitriles place 250 milliliters of there-necked flasks, and agitating heating was 80 ℃ of reactions 10 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains white powder solid product 0.22 gram, yield 85%.71～73 ℃ of fusing points.MS(m/z)：238(M
+)。
Embodiment 8:4-chloro-5-fluoro-2-(2 '-naphthyl)-3 (2H)-pyridazinones synthetic
With 4,5-two chloro-2-(2 '-naphthyl)-3 (2H)-pyridazinones 0.29 gram (1 mM), embodiment 2 resin fluorizating agent 0.63g (3 mM), 50 milliliters of hexamethylphosphorictriamides, place 200 milliliters of there-necked flasks, agitating heating was 150 ℃ of reactions 10 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains white powder solid product 0.24 gram, yield 80%.MS(m/z)：274(M
+)。
Synthesizing of the embodiment 9:4-chloro-5-fluoro-2-tert-butyl group-3 (2H)-pyridazinone
With 4, the 5-two chloro-2-tert-butyl groups-3 (2H)-pyridazinone 0.2 gram (1 mM), embodiment 1 resin fluorizating agent 0.22g (1 mM), 10 milliliters of dimethyl sulfones place 100 milliliters of there-necked flasks, and agitating heating was 150 ℃ of reactions 10 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains white powder solid product 0.16 gram, yield 80%.52～54 ℃ of fusing points.MS(m/z)：204(M
+)。
Embodiment 10:4-fluoro-1-(4 '-aminomethyl phenyl)-3,6-pyridazine diketone synthetic
With 4-chloro-1-(4 '-aminomethyl phenyl)-3,6-pyridazine diketone (0.20 gram, 1 mM) and embodiment 2 resin fluorizating agent 0.8g (3 mM), 10 milliliters of butanone place 250 milliliters of there-necked flasks, and agitating heating was reacted 6 hours at 80 ℃.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains the white crystalline solid product of white powder solid product 1.7 gram, yield 83%.260～262 ℃ of fusing points.MS(m/z)：204(M
+)。
Embodiment 11:4-fluoro-1-(3 '-trifluoromethyl)-3,6-pyridazine diketone synthetic
With 4-chloro-1-(3 '-trifluoromethyl)-3,6-pyridazine diketone (0.27 gram, 1 mM) and embodiment 1 resin fluorizating agent 0.63g (3 mM), 10 milliliters of butanone place 250 milliliters of there-necked flasks, and agitating heating was reacted 6 hours at 80 ℃.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains the white crystalline solid product of white powder solid product 1.96 gram, yield 76%.261～263 ℃ of fusing points.MS(m/z)：258(M
+)。
Embodiment 12:5-chloro-3,4,6-trifluoro pyridazine synthetic
With 3,4,5,6-tetrachloro pyridazine (0.22 gram, 1 mM) and embodiment 1 resin fluorizating agent 0.63g (3 mM), 20 milliliters of butanone place 250 milliliters of there-necked flasks, and agitating heating was 80 ℃ of reactions 6 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains the white crystalline solid product of white powder solid product 1.2 gram, yield 70%.154～155 ℃ of fusing points.MS(m/z)：168(M
+)。
Embodiment 13:3,6-difluoro pyridazine synthetic
With 3,6-2 chlorine pyridazine (0.15 gram, 1 mM) and embodiment 1 resin fluorizating agent 0.63g (3 mM), 20 milliliters of acetonitriles place 100 milliliters of there-necked flasks, and agitating heating was 80 ℃ of reactions 6 hours.Reaction adds water after finishing, cooling, and reactant liquor dichloromethane extraction product concentrates, and uses silica G F
254Chromatographic column (ethyl acetate: benzinum=1: 1, v/v) separation and purification obtains the white crystalline solid product of white powder solid product 1.2 gram, yield 70%.53～54 ℃ of fusing points.MS(m/z)：116(M
+)。
Claims (10)
1. ion-exchange resin fluorizating agent, structure is suc as formula shown in (II):
In the formula (II), R is C1～C3 alkyl.
2. one kind prepares the method for ion-exchange resin fluorizating agent according to claim 1, and described method comprises: react with the styrene series anion exchange resin quaternary ammonium base and the HF aqueous solution shown in the formula (V), obtain described ion-exchange resin fluorizating agent;
In the formula (V), R is C1～C3 alkyl.
3. method as claimed in claim 2, it is characterized in that described method is as follows: with the weakly basic styrene type anion exchange resin shown in the formula (IV), use the dimethyl formamide swelling, add capacity RCl, RBr or RI, R is C1～C3 alkyl, 50 ℃ were reacted 1～10 hour, reaction finishes after washing, normal temperature descends and the capacity NaOH aqueous solution carries out exchange reaction, the exchange reaction product water is washed till neutrality, obtains strong-basicity styrene series anion exchange resin and fully reacts down in normal temperature with the capacity HF aqueous solution, after reaction finishes, product water is washed till neutrality, obtains described ion-exchange resin fluorizating agent;
4. method as claimed in claim 2, it is characterized in that described method is as follows: carry out exchange reaction with strong-basicity styrene series anion exchange resin and the NaOH solution shown in the formula (VI), be washed to neutrality, add the HF aqueous solution again and react, obtain described ion-exchange resin fluorizating agent;
In the formula (VI), R is C1～C3 alkyl, and Y is-Cl ,-Br ,-I or-OH.
5. the application of ion-exchange resin fluorizating agent as claimed in claim 1 in catalysis synthesizing fluoro pyridazine compound.
6. application as claimed in claim 5, it is characterized in that described being applied as: with formula (III-1) (III-2) or the halo pyridazine compound (III-3) be raw material, with the ion-exchange resin fluorizating agent shown in the formula (II) is catalyst, in aprotic polar solvent, reacted 1～10 hour down in 50～150 ℃, after reaction finished, at least one chlorine or bromine atom was replaced by fluorine in the described halo pyridazine compound, and reactant liquor obtains described fluoro pyridazine compound through separation and purification;
Wherein:
R is C1～C3 alkyl;
X
1～X
3Independent separately is chlorine or bromine;
n
1＝1，2，3，4；n
2＝1，2，3；n
3＝1，2；
R
1, R
2Independent separately is hydrogen, C1～C6 alkyl, benzyl, phenyl, substituted-phenyl or naphthyl;
Described aprotic polar solvent is one of following: acetonitrile, acetone, butanone, methyl-sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethylacetylamide, hexamethylphosphorictriamide, described aprotic polar solvent quality consumption are 3～10 times of described halo pyridazine compound quality.
7. application as claimed in claim 6, the ratio that it is characterized in that described halo pyridazine compound and ion-exchange resin fluorizating agent amount of substance is 1: 1～3; The reaction temperature of described reaction is 100～110 ℃, 6～8 hours reaction time.
8. application as claimed in claim 6 is characterized in that described isolation and purification method is as follows: after reaction finished, with the reactant liquor cooling, dichloromethane extraction was got organic layer and is concentrated, and column chromatography for separation obtains described fluoro pyridazine compound.
9. application as claimed in claim 5, it is characterized in that described being applied as: with halo pyridazine compound shown in the formula (III-2a) and described ion-exchange resin fluorizating agent is raw material, in aprotic polar solvent, reacted 5～8 hours down in 80～110 ℃, after reaction finishes, the reactant liquor cooling, dichloromethane extraction, concentrated, column chromatography for separation obtains the fluoro pyridazine compound shown in the formula (I-2a); The ratio of described halo pyridazine compound and ion-exchange resin fluorizating agent amount of substance is 1: 1～3; Described aprotic polar solvent is acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO) or butanone, and the quality consumption is 3～10 times of described halo pyridazine compound quality;
Among formula (III-2a), (I-2a): X
2Be chlorine or bromine; R
2Be hydrogen, C1～C6 alkyl, benzyl, phenyl or naphthyl.
10. application as claimed in claim 5, it is characterized in that described being applied as: with halo pyridazine compound shown in the formula (III-3a) and described ion-exchange resin fluorizating agent is raw material, in aprotic polar solvent, reacted 5～8 hours down in 80～110 ℃, after reaction finishes, the reactant liquor cooling, dichloromethane extraction, concentrated, column chromatography for separation obtains the fluoro pyridazine compound shown in the formula (I-3a); The ratio of described halo pyridazine compound and ion-exchange resin fluorizating agent amount of substance is 1: 1～3; Described aprotic polar solvent is acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO) or butanone, and the quality consumption is 3～10 times of described halo pyridazine compound quality;
Among formula (III-3a), (I-3a):
X
3Be chlorine or bromine; R
3For hydrogen, C1～C6 alkyl, phenyl, 4 '-aminomethyl phenyl or 3 '-trifluoromethyl.
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