CN105061304A - Method for preparing isoxazoline compound and intermediate thereof - Google Patents
Method for preparing isoxazoline compound and intermediate thereof Download PDFInfo
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- CN105061304A CN105061304A CN201510306677.2A CN201510306677A CN105061304A CN 105061304 A CN105061304 A CN 105061304A CN 201510306677 A CN201510306677 A CN 201510306677A CN 105061304 A CN105061304 A CN 105061304A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to a method for preparing an isoxazoline compound and an intermediate thereof. The method comprises that an intermediate nitrone solution in an aromatic hydrocarbon solvent and substituted styrene are subjected to a cycloaddition reaction, wherein the nitrone solution preparation method comprises that pyridyl ketone reacts with a hydroxylamine salt in a reaction medium to obtain a nitrone-containing liquid material, the liquid material is subjected to pressure reducing distillation, and the aromatic hydrocarbon solvent is added before or during the pressure reducing distillation process so as to obtain the nitrone solution in the aromatic hydrocarbon solvent after the pressure reducing distillation. With the method of the present invention, the stability and the quality of the obtained pressure reducing distillation are good, the product yield is improved, and the high-purity solid product can be obtained.
Description
Technical field
The present invention relates to the preparation of compound.More particularly, the present invention relates to the method preparing isoxazoline compounds and intermediate thereof.
Background technology
Chinese patent ZL99113093.6 discloses the heterocyclic substituted isoxazoline compounds and preparation method thereof as sterilant, the method comprises reacts the heterocyclic radical ketone such as 3-pyridyl ketone, 5-pyrimidyl ketone and R-NHOH such as N-methyl hydroxylamine hydrochloride to obtained intermediate nitrous ketone (also referred to as nitrone) under sodium acetate exists, then the alkene of this nitrone and replacement is made to occur 1,3-Dipolar Cycloaddition, generate heterocyclic substituted isoxazoline compounds, gained compound is the oily matter comprising isomer A and B.This patent also describes the reaction preparing intermediate nitrone and can carry out in suitable protonic solvent, and described solvent is such as methyl alcohol, ethanol, preferred alcohol; This solvent of removing after reaction, then add methylene dichloride, removed by filtration insolubles, evaporate to dryness filtrate obtains this nitrone, and its state is that solid or distillation terminate remaining liquid oily matter.
Chinese patent ZL200510046262.2 discloses a kind of method preparing fragrant cyclosubstituted isoxazoline compounds, the method directly with nitrone and monosubstituted aryl ethylene for raw material, under the existence of Lewis acid or organic acid catalyzer, described raw material is made to occur 1,3-Dipolar Cycloaddition, obtains the cyclosubstituted isoxazoline compounds of described virtue.
But, still need to be optimized technological process, improve the synthesis yield of compound, to reduce the consumption of raw material, thus meet the needs that commercial scale production can be used as sterilant isoxazoline compounds.
Summary of the invention
An object of the present invention is the synthesis technique that will improve intermediate nitrone, to obtain high-quality nitrone.For this reason, the invention provides a kind of method preparing nitrone solution, the method comprises the following steps:
A) in reaction medium, the hydroxylammonium salt shown in the pyridyl ketone shown in formula I and formula II is reacted, and obtain comprising the liquid material of nitrone shown in formula III, reaction formula is as follows:
Wherein, R
1, R
3be methyl or ethyl independently of one another; And
B) by described liquid material underpressure distillation;
Wherein, before described underpressure distillation or in vacuum distillation process, add aromatic hydrocarbon solvent, thus after described underpressure distillation, obtain the nitrone solution of the nitrone shown in formula III in described aromatic hydrocarbon solvent.
Another object of the present invention to improve the synthesis technique of isoxazoline compounds (i.e. former medicine), to improve the synthesis yield of former medicine.For this reason, the invention provides a kind of method preparing isoxazoline compounds, the method comprise make according to method of the present invention prepare containing the nitrone solution of nitrone in aromatic hydrocarbon solvent shown in formula III and the substituted phenylethylene initial ring addition reaction shown in formula IV, the isoxazoline compounds of shown in production V, reaction formula is as follows:
Wherein, R
1, R
3define the same; R
2be selected from the one in (C1-C3) alkyl, (C1-C3) alkoxyl group, halo (C1-C3) alkyl, halogen, cyano group.
Another object of the present invention to develop the aftertreatment technology of former medicine, to obtain highly purified solid phase prod.For this reason, the invention provides a kind of post-treating method, the method is included in after described cycloaddition reaction terminates, and carries out following post-processing step to the output material of isoxazoline compounds shown in the contained V of gained:
At the temperature of 0 ~ 80 DEG C, in described output material, add water, and by pH regulator to 2 ~ 7, make described isoxazoline compounds be dissolved in aqueous phase;
Isolate described aqueous phase;
At the temperature of-20 ~ 60 DEG C, by pH regulator to 7 ~ 14 of described aqueous phase, solid is separated out, obtains solidliquid mixture; And
Described solidliquid mixture is filtered, obtains solid form isoxazoline compounds.
The present invention also comprises providing and obtains isoxazoline compounds solid thus.The content of this solid Zhong isoxazoline compounds can more than 95wt%.
Present invention optimizes the synthesis technique of intermediate nitrone, owing to the addition of protection solvent (aromatic hydrocarbon solvent) when building-up reactions and/or underpressure distillation, thus make stability and the better quality of intermediate nitrone.The nitrone of gained (comprises nitrone and protection solvent with nitrone solution; or comprise nitrone, protection solvent and other solvents (amount of other solvents is no more than 20wt%, 15wt%, 10wt%, 5wt%, 2.5wt%, 1wt% or less of solution total amount) on a small quantity) form discharging, follow-up former medicine synthesis technique can be directly used in.
The present invention also optimizes former medicine synthesis technique, improves synthesis yield, significantly can reduce preparation cost, thus can meet the needs of commercial scale production.
The former medicine crystallization processes of the present invention's exploitation, can obtain the highly purified solid phase prod content > 95wt% of isoxazoline compounds (in the solid).
Embodiment
In order to make those skilled in the art understand the present invention better, provide more detailed description below with reference to specific embodiments, but the present invention is not limited thereto.
The method preparing nitrone solution of the present invention, comprises the following steps:
A) in reaction medium, the hydroxylammonium salt shown in the pyridyl ketone shown in formula I and formula II is reacted, and obtain comprising the liquid material of nitrone shown in formula III, reaction formula is as follows:
Wherein, R
1, R
3be methyl or ethyl independently of one another; And
B) by described liquid material underpressure distillation;
Wherein, before described underpressure distillation or in vacuum distillation process, add aromatic hydrocarbon solvent, thus after described underpressure distillation, obtain the nitrone solution of the nitrone shown in formula III in described aromatic hydrocarbon solvent.
In this article, " aromatic hydrocarbons " refers to the substituted or unsubstituted aromatics with a phenyl ring.As solvent, in its molecule, carbon atom number is generally no more than 20, such as, for being equal to or less than 18,15,12,10.Unsubstituted aromatic hydrocarbons is such as trimethylbenzene, dimethylbenzene, toluene, ethylbenzene, benzene.The aromatic hydrocarbons replaced is such as the aromatic hydrocarbons that one or more halogen atom replaces, as chlorobenzene, dichlorobenzene.
When preparing nitrone solution, it is liquid and those aromatic hydrocarbon solvents be not substantially distilled out of under the condition of underpressure distillation at normal temperatures and pressures that described aromatic hydrocarbon solvent is selected from usually." be not substantially distilled out of " and refer to that the steam amount of this aromatic hydrocarbon solvent when underpressure distillation is no more than 20wt%, 15wt%, 10wt%, 5wt%, 2.5wt%, 1wt% or lower of its charging capacity.Preferably, described aromatic hydrocarbon solvent is the unsubstituted aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms, such as dimethylbenzene, ethylbenzene, benzene; Or such as, by the aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms that one or more halogen atom replaces, chlorobenzene, dichlorobenzene; Or their arbitrary combination.
Described hydroxylammonium salt can be inorganic acid salt or the acetate of azanol, such as N-methyl hydroxylamine hydrochloride, N-methyl hydroxylamine acetate, N-methyl hydroxylamine phosphoric acid salt, N-methyl hydroxylamine vitriol, N-ethylhydroxyl amine hydrochloride, N-ethylhydroxyl amine acetate, N-ethylhydroxyl amine phosphoric acid salt or N-ethylhydroxyl amine vitriol.
Reaction medium reacts the liquid vehicle of carrying out wherein.In one embodiment, step a) in add aromatic hydrocarbon solvent as described reaction medium.In such embodiments, as required, after step reaction a), step b) underpressure distillation before, or in vacuum distillation process, interpolation aromatic hydrocarbon solvent can also be supplemented.
In another embodiment, step a) in, adopt non-aromatics kind solvent as described reaction medium.Non-aromatics kind solvent refers to the solvent without any aromatic ring structure.Described non-aromatics kind solvent is selected from usually at normal temperatures and pressures for liquid state and substantially by those non-aromatics kind solvents steamed completely under the condition of underpressure distillation." substantially steamed completely " and referred to that the residual quantity of this non-aromatics kind solvent after underpressure distillation is no more than 20wt%, 15wt%, 10wt%, 5wt%, 2.5wt%, 1wt% or lower of its charging capacity.Generally speaking, the boiling point of non-aromatics kind solvent is lower than the boiling point of aromatic hydrocarbon solvent, such as low more than 10,15,20,25 or 30 DEG C.Preferably, described non-aromatics kind solvent is selected from: the saturated alcohol kind solvent with 1 ~ 4 carbon atom, such as methyl alcohol, ethanol; Water; There is naphthenic hydrocarbon or the halo cyclic alkane solvents of 3 ~ 6 carbon atoms; There is the paraffin solvents of 5 ~ 8 carbon atoms; And there is the halogenated alkane solvent of 1 ~ 3 carbon atom.Using non-aromatics kind solvent as in the embodiment of described reaction medium, after step reaction a), step b) underpressure distillation forward direction described in add aromatic hydrocarbon solvent in liquid material, or add aromatic hydrocarbon solvent in vacuum distillation process.
" in vacuum distillation process " is included in any time in this vacuum distillation process or stage.
Step a) in may have some throw outs generate.Therefore, preferably, this step also can be included in the step of carrying out after pyridyl ketone and hydroxylammonium salt are reacted filtering, thus obtains described liquid material.
Preferably, step a) in reaction be carry out under the condition of 6 ~ 10 at pH, such as pH is 6,7,8,9 or 10.
Step a) in reaction can carry out under the existence of following material, described material is selected from: an alkali metal salt with the saturated alcohol of 1 ~ 4 carbon atom, and an alkali metal salt of described saturated alcohol is preferably sodium salt, such as, be sodium methylate, sodium ethylate; Mineral alkali, such as alkali metal hydroxide is as sodium hydroxide or sodium carbonate.These materials can be used to regulating step a) in the pH of reaction system, such as make pH be 6 ~ 10.
Preferably, the temperature of underpressure distillation is 20-80 DEG C (being such as 20,30,40,50,60,70,80 DEG C), and vacuum tightness be 0.05-0.095MPa (be such as 0.05,0.06,0.07,0.08,0.09MPa).
The concentration of described nitrone solution is: relative to 1mol nitrone, the quality of described aromatic hydrocarbon solvent be 100g ~ 2000g (be such as 100,250,500,750,1000,1250,1500,1750,2000g).
The method preparing isoxazoline compounds of the present invention comprise make according to method of the present invention prepare containing the nitrone solution of nitrone in aromatic hydrocarbon solvent shown in formula III and the substituted phenylethylene initial ring addition reaction shown in formula IV, the isoxazoline compounds of shown in production V, reaction formula is as follows:
Wherein, R
1, R
3define the same; R
2be selected from the one in (C1-C3) alkyl, (C1-C3) alkoxyl group, halo (C1-C3) alkyl, halogen, cyano group.
In this article, the statement " (Ca-Cb) " (a, b represent positive integer) before a certain group refers to that this group has a to b carbon atom, and such as, " (C1-C3) " refers to that this group has 1 to 3 carbon atom.
In this article, " halogen " or " halogen " refers to fluorine, chlorine, bromine, atomic iodine.Halo can be single halo or many halos.
Preferably, the method preparing isoxazoline compounds of the present invention can be further comprising the steps: mixed with inert organic solvents and optional stopper by described substituted phenylethylene, forms mixture; And described nitrone solution and optional catalyst drops are added in described mixture, to carry out described cycloaddition reaction.
In this article, " can optionally " represents not essential, determines as required.
Stopper is conventional those in this area, and be such as phenols, general consumption is the 0.05-1% of olefin feed weight.
Catalyzer can adopt those Lewis acids described in ZL200510046262.2 or organic acid catalyst, and general consumption is 0.05-1.0mol/mol nitrone.The full content of this patent is incorporated to herein by reference.
In this article, " inert organic solvents " refers to the organic solvent that can not have an impact to cycloaddition reaction, and it generally plays the effect of dilution, in order to avoid local reaction is irregular.Described inert organic solvents is generally aromatic hydrocarbon solvent, and it can be identical with preparing aromatic hydrocarbon solvent used in nitrone solution, also can be different.Preferably, described inert organic solvents is the unsubstituted aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms, such as trimethylbenzene, dimethylbenzene, toluene, ethylbenzene, benzene; Or such as, by the aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms that one or more halogen atom replaces, chlorobenzene, dichlorobenzene; Or their arbitrary combination.
Usually, described dropwise operation time used can be 1 ~ 10 hour, such as, be 2,4,6,8,10 hours, is preferably 1 ~ 4 hour.
The mol ratio of described nitrone and substituted phenylethylene can in the scope of 1:0.7 ~ 1:5, such as, be 1:1,1:2,1:3,1:4.
The temperature of described cycloaddition reaction can be 70 ~ 150 DEG C, such as 90,100,110,120,130,140 DEG C, is preferably greater than 110 DEG C to being up to 150 DEG C.
The method preparing isoxazoline compounds of the present invention also can be included in after described cycloaddition reaction terminates, and carries out following post-processing step to the output material of isoxazoline compounds shown in the contained V of gained:
At the temperature of 0 ~ 80 DEG C (such as 0,20,40,60,80 DEG C), in described output material, add water, and by pH regulator to 2 ~ 7 (such as 2,5,7), make described isoxazoline compounds be dissolved in aqueous phase;
Isolate described aqueous phase;
At the temperature of-20 ~ 60 DEG C (such as-20,0,20,40,60 DEG C), by pH regulator to 7 ~ 14 (such as 7,9,11,13) of described aqueous phase, solid is separated out, obtains solidliquid mixture; And
Described solidliquid mixture is filtered, obtains solid form isoxazoline compounds.
In this article, " aqueous phase " refers to that main take water as the thing phase of medium, and the amount of water can be greater than 50wt%, 60wt%, 70wt%, 80wt%, 90wt%, 95wt% of medium total amount, or even all medium is water.
Preferably, be adopt mineral acid to realize by pH regulator to 2 ~ 7, described mineral acid generally adds in form of an aqueous solutions, such as, drip.Described mineral acid is such as hydrochloric acid, sulfuric acid, phosphoric acid etc.The time of described dissolving can be 1 ~ 10 hour.The time that described solid is separated out can be 0.5 ~ 5 hour.PH regulator to 7 ~ 14 of described aqueous phase can be carried out under this aqueous phase is the first temperature within the scope of 20 ~ 60 DEG C, then this aqueous phase is incubated at the second temperature than low 20 ~ 60 DEG C of described first temperature, such as, is incubated 0.5 ~ 5 hour.
Can obtain isoxazoline compounds solid according to method of the present invention, the content of described solid Zhong isoxazoline compounds can be greater than 95wt%.
By the following examples exemplary explanation is carried out to the present invention.In this article, unless specifically stated otherwise, otherwise all amounts, concentration, ratio all calculate with weight (wt).
Embodiment
The explanation of HPLC testing method
Adopt high performance liquid chromatograph (the variable UV-detector of Agilent1200 tool), Agilent chromatographic working station, with the microsyringe sample introduction of 50 μ l.Operational condition is as follows:
Chromatographic column: 250mm × 4.6mm (id) stainless steel column, in-built C18 weighting material, particle diameter 5 μm; Moving phase: methyl alcohol: water=80:20; Flow velocity: 0.8mL/min; Wavelength: 236nm; Temperature: room temperature, wherein methyl alcohol is chromatographically pure, and water is redistilled water.
Prepare solvent as follows:
Standardized solution: respectively take former medicine standard specimen E body, Z body 0.020g ~ 0.025g (being accurate to 0.0002g) in 100mL volumetric flask, add 10mL methyl alcohol, ultrasonic cleaner vibrates 5min, to be cooled to after room temperature with methanol dilution to scale, to shake up.
Sample solution: take former medicine sample 0.030g ~ 0.035g (being accurate to 0.0002g) in 100mL volumetric flask, add 10mL methyl alcohol, ultrasonic cleaner vibrates 5min, to be cooled to after room temperature with methanol dilution to scale, to shake up.
Then, under the operating conditions described above, after chromatographic instrument baseline stability, continuous injection number pin mark sample solution, calculate each pin response value, treat that the response value change of adjacent two pins is less than 1.2%, measure according to the order of standard specimen solution, sample solution, sample solution, standard specimen solution.
By peak area in two pin mark sample solution before and after the two pin sample solutions that record and sample, be averaged respectively.Quality product mark X (%), is calculated as follows:
In formula:
A
1the mean value of z/e peak area in-standard specimen solution;
A
2the mean value of peak area in-sample solution;
M
1the quality of-standard specimen z/e, unit is gram (g);
M
2the quality of-sample, unit is gram (g);
The massfraction of P-standard specimen z/e.
The preparation of embodiment 1:C, N-dimethyl-(3-pyridyl) nitrone
In 1L four-hole boiling flask, add 127.5g3-acetylpyridine (1mol), 500ml ethanol and 79.7gN-methyl hydroxylamine phosphoric acid salt (1mol), be warming up to 85 DEG C.
Control temperature is 85 DEG C, drips the aqueous sodium hydroxide solution of 50% content of 80g in reaction system, within about 5 hours, adds.Drip and terminate, back flow reaction 5 hours, is cooled to 10 DEG C, filters, obtains the filtrate containing C, N-dimethyl-(3-pyridyl) nitrone.
In filtrate, add 100ml benzene, then carry out underpressure distillation (vacuum tightness: 0.05MPa), until stop heating when system temperature reaches 80 DEG C, be cooled to 10 DEG C, obtain C, N-dimethyl-(3-pyridyl) nitrone solution, yield 60% (in HPLC result).
The preparation of embodiment 2:C, N-diethyl-(3-pyridyl) nitrone
142.2g3-propionyl pyridine (1mol) is added, 200ml water and 480.4gN-ethylhydroxyl amine hydrochloride (5mol) in 1L four-hole boiling flask.
Under room temperature condition, in reaction system, add 397.5g sodium carbonate solid (3.75mol), within about 3 hours, add.Reinforced end, reacts 20 hours, filters, obtains the filtrate containing C, N-diethyl-(3-pyridyl) nitrone.
In filtrate, add 200ml dimethylbenzene, carry out underpressure distillation (vacuum tightness: 0.095MPa), until stop heating when temperature reaches 60 DEG C, be cooled to 15 DEG C, obtain C, N-diethyl-(3-pyridyl) nitrone solution, yield 71% (in HPLC result).
The preparation of embodiment 3:C, N-dimethyl-(3-pyridyl) nitrone
In 1L four-hole boiling flask, add 127.5g3-acetylpyridine (1mol), 100ml toluene and 48gN-methyl hydroxylamine hydrochloride (0.5mol), be warming up to 115 DEG C.
Control reflux conditions, the content in methyl alcohol dripping 70g in reaction system is the sodium methylate (0.35mol) of 27%, within about 1 hour, adds.Drip and terminate, back flow reaction 1 hour, is cooled to 25 DEG C, filters, obtains the filtrate containing C, N-dimethyl-(3-pyridyl) nitrone.
This filtrate is carried out underpressure distillation (vacuum tightness: 0.085MPa), until stop heating when system temperature reaches 35 DEG C, be cooled to 0 DEG C, obtain C, N-dimethyl-(3-pyridyl) nitrone solution, yield 70% (in HPLC result).
The preparation of embodiment 4:C, N-dimethyl-(3-pyridyl) nitrone
In 1L four-hole boiling flask, add 127.5g3-acetylpyridine (1mol), 800ml ethanol and 124.8gN-methyl hydroxylamine hydrochloride (1.3mol), be warming up to 64 DEG C.
Temperature controlled to be 64 DEG C, the content in ethanol dripping 352.8g in reaction system is the sodium ethylate (1.4mol) of 27%, within about 1 hour, adds.Drip and terminate, back flow reaction 1.5 hours, is cooled to 25 DEG C, filters, obtains the filtrate containing C, N-dimethyl-(3-pyridyl) nitrone.
This filtrate is carried out underpressure distillation (vacuum tightness: 0.09MPa), until stop heating when system temperature reaches 40 DEG C, add 100ml dimethylbenzene, continue underpressure distillation, until stop heating when temperature reaches 65 DEG C, be cooled to 25 DEG C, obtain C, N-diethyl-(3-pyridyl) nitrone solution, yield 95% (in HPLC result).
Embodiment 5:5-(3-p-methoxy-phenyl)-2, the 3-diethyl-3-(preparation of 3-pyridyl) isoxazoline
145.8g3-methoxy styrene (1mol) and 100ml trimethylbenzene is added in 1L four-hole boiling flask, heat up 150 DEG C, above-mentioned 3 are dripped in system) the nitrone solution (0.9mol) prepared, within 1 hour, add, drip and terminate reaction 1 hour.
Reaction terminates, and is cooled to 30 DEG C, adds 100g water in system, and drip hydrochloric acid to pH=2, be incubated 10 hours, layering, lower floor's aqueous phase is product, and upper organic phase is solvent.
Control temperature is 60 DEG C, drips 30% sodium hydroxide, to pH=8 in aqueous phase, be cooled to 30 DEG C and be incubated 3.5 hours, filtering, obtain 5-(3-p-methoxy-phenyl)-2,3-diethyl-3-(3-pyridyl) isoxazoline, yield 70%, content 94%.
Embodiment 6:5-(4-chloro-phenyl-)-2, the 3-dimethyl-3-(preparation of 3-pyridyl) isoxazoline
In 1L four-hole boiling flask, add 145.8g to chloro-styrene (1mol) and 300ml chlorobenzene, heat up 130 DEG C, in system, drip above-mentioned 4) the nitrone solution (1.3mol) prepared, within 3 hours, add, drip and terminate back flow reaction 8 hours.
Reaction terminates, and is cooled to 15 DEG C, adds 200g water in system, and drip hydrochloric acid to pH=3, be incubated 4 hours, layering, lower floor's aqueous phase is product, and upper organic phase is solvent.
Control temperature is 20 DEG C, drips saturated sodium carbonate solution, to pH regulator=10 in aqueous phase, be cooled to 0 DEG C and be incubated 1 hour, filtering, obtain 5-(4-chloro-phenyl-)-2,3-dimethyl-3-(3-pyridyl) isoxazoline, yield 85%, content 95%.
Embodiment 7:5-(4-chloro-phenyl-)-2, the 3-dimethyl-3-(preparation of 3-pyridyl) isoxazoline
In 1L four-hole boiling flask, add 145.8g to chloro-styrene (1mol) and 100ml toluene, heat up 130 DEG C, in system, drip above-mentioned 4) the nitrone solution (0.2mol) prepared, within 5 hours, add, drip and terminate back flow reaction 5 hours.
Reaction terminates, and is cooled to 15 DEG C, adds 100g water in system, and drip hydrochloric acid to pH=7, be incubated 1 hour, layering, lower floor's aqueous phase is product, and upper organic phase is solvent.
Control temperature is 40 DEG C, drips 40% potassium hydroxide, to pH regulator=14 in aqueous phase, be cooled to-20 DEG C and be incubated 5 hours, filtering, obtain 5-(4-chloro-phenyl-)-2,3-dimethyl-3-(3-pyridyl) isoxazoline, yield 87%, content 96%.
Visible, the present invention is when preparing intermediate nitrone, and owing to adding aromatic hydrocarbon solvent as protection solvent, thus can significantly improve yield and the stability of nitrone, be the form of nitrone solution during nitrone discharging, can be directly used in follow-up former medicine synthesis technique.The present invention, by being optimized the feed way, temperature of reaction, proportioning raw materials etc. of the raw materials such as nitrone solution, alkene and changing, improves former medicine yield, thus significantly can reduce preparation cost.After former medicine end of synthesis, present invention employs crystallization processes and carry out aftertreatment, make the proterties of products obtained therefrom become solid from liquid, the solid phase prod of purity > 95wt% can be obtained.Thus, method of the present invention is applicable to commercial scale production more.
Be understandable that, the illustrative embodiments that above embodiment is only used to principle of the present invention is described and adopts, but the present invention is not limited thereto.For one of ordinary skilled in the art, without departing from the spirit and substance in the present invention, can make various variants and modifications, these variants and modifications are also in protection scope of the present invention.
Claims (15)
1. prepare a method for nitrone solution, comprise the following steps:
A) in reaction medium, the hydroxylammonium salt shown in the pyridyl ketone shown in formula I and formula II is reacted, and obtain comprising the liquid material of nitrone shown in formula III, reaction formula is as follows:
Wherein, R
1, R
3be methyl or ethyl independently of one another; And
B) by described liquid material underpressure distillation;
Wherein, before described underpressure distillation or in vacuum distillation process, add aromatic hydrocarbon solvent, thus after described underpressure distillation, obtain the nitrone solution of the nitrone shown in formula III in described aromatic hydrocarbon solvent.
2. method according to claim 1, wherein, described aromatic hydrocarbon solvent is the unsubstituted aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms, such as dimethylbenzene, ethylbenzene, benzene; Or such as, by the aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms that one or more halogen atom replaces, chlorobenzene, dichlorobenzene; Or their arbitrary combination; And/or
Described hydroxylammonium salt is inorganic acid salt or the acetate of azanol, such as N-methyl hydroxylamine hydrochloride, N-methyl hydroxylamine acetate, N-methyl hydroxylamine phosphoric acid salt, N-methyl hydroxylamine vitriol, N-ethylhydroxyl amine hydrochloride, N-ethylhydroxyl amine acetate, N-ethylhydroxyl amine phosphoric acid salt or N-ethylhydroxyl amine vitriol.
3. method according to claim 1 and 2, wherein, step a) is also included in the step of carrying out after described pyridyl ketone and described hydroxylammonium salt are reacted filtering, thus obtains described liquid material.
4. method according to claim 1 and 2, wherein, step a) in add described aromatic hydrocarbon solvent as described reaction medium.
5. method according to claim 1 and 2, wherein, step a) in, adopt non-aromatics kind solvent as described reaction medium, preferably, described non-aromatics kind solvent is selected from: the saturated alcohol kind solvent with 1 ~ 4 carbon atom, such as methyl alcohol, ethanol; Water; There is naphthenic hydrocarbon or the halo cyclic alkane solvents of 3 ~ 6 carbon atoms; There is the paraffin solvents of 5 ~ 8 carbon atoms; And there is the halogenated alkane solvent of 1 ~ 3 carbon atom; And
Wherein, after step reaction a), step b) underpressure distillation forward direction described in add described aromatic hydrocarbon solvent in liquid material, or add described aromatic hydrocarbon solvent in described vacuum distillation process.
6. method according to claim 1 and 2, wherein, step a) in reaction be carry out under the condition of 6 ~ 10 at pH.
7. the method according to claim 1 or 6, wherein, step a) in reaction carry out under the existence of following material, described material is selected from: an alkali metal salt with the saturated alcohol of 1 ~ 4 carbon atom, the an alkali metal salt of described saturated alcohol is preferably sodium salt, such as, be sodium methylate, sodium ethylate; Mineral alkali, such as alkali metal hydroxide is as sodium hydroxide or sodium carbonate.
8. method according to claim 1 and 2, wherein, the temperature of described underpressure distillation is 20-80 DEG C, and vacuum tightness is 0.05-0.095MPa; And/or
The concentration of described nitrone solution is: relative to 1mol nitrone, and the quality of described aromatic hydrocarbon solvent is 100g ~ 2000g.
9. prepare the method for isoxazoline compounds for one kind, comprise make according to method described in any one in claim 1-8 prepare containing the nitrone solution of nitrone in aromatic hydrocarbon solvent shown in formula III and the substituted phenylethylene initial ring addition reaction shown in formula IV, the isoxazoline compounds of shown in production V, reaction formula is as follows:
Wherein, R
1, R
3defined with in claim 1; R
2be selected from the one in (C1-C3) alkyl, (C1-C3) alkoxyl group, halo (C1-C3) alkyl, halogen, cyano group.
10. method according to claim 9, further comprising the steps:
Described substituted phenylethylene is mixed with inert organic solvents and optional stopper, forms mixture; And
Described nitrone solution and optional catalyst drops are added in described mixture, to carry out described cycloaddition reaction.
11. methods according to claim 10, wherein, described dropwise operation time used is 1 ~ 10 hour, is preferably 1 ~ 4 hour; And/or
Described inert organic solvents is the unsubstituted aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms, such as trimethylbenzene, dimethylbenzene, toluene, ethylbenzene, benzene; Or such as, by the aromatic hydrocarbon solvent with 6 ~ 10 carbon atoms that one or more halogen atom replaces, chlorobenzene, dichlorobenzene; Or their arbitrary combination.
12. according to the method in claim 9-11 described in any one, and wherein, the mol ratio of described nitrone and described substituted phenylethylene is in the scope of 1:0.7 ~ 1:5; And/or
The temperature of described cycloaddition reaction being 70 ~ 150 DEG C, being preferably greater than 110 DEG C to being up to 150 DEG C.
13. according to the method in claim 9-11 described in any one, is also included in after described cycloaddition reaction terminates, and carries out following post-processing step to the output material of isoxazoline compounds shown in the contained V of gained:
At the temperature of 0 ~ 80 DEG C, in described output material, add water, and by pH regulator to 2 ~ 7, make described isoxazoline compounds be dissolved in aqueous phase;
Isolate described aqueous phase;
At the temperature of-20 ~ 60 DEG C, by pH regulator to 7 ~ 14 of described aqueous phase, solid is separated out, obtains solidliquid mixture; And
Described solidliquid mixture is filtered, obtains solid form isoxazoline compounds.
PH regulator to 2 ~ 7 wherein, are adopt mineral acid to realize by 14. methods according to claim 13; And/or
The time of described dissolving is 1 ~ 10 hour; And/or
The time that described solid is separated out is 0.5 ~ 5 hour; And/or
Be carry out pH regulator to 7 ~ 14 of described aqueous phase under this aqueous phase is the first temperature within the scope of 20 ~ 60 DEG C, then this aqueous phase be incubated at the second temperature than low 20 ~ 60 DEG C of described first temperature.
15. 1 kinds of isoxazoline compounds solids, it is obtained by the method described in claim 13 or 14, and in described solid, the content of isoxazoline compounds is greater than 95wt%.
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