CN103980088A - Method of preparing floralozone intermediate - Google Patents
Method of preparing floralozone intermediate Download PDFInfo
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- CN103980088A CN103980088A CN201410202047.6A CN201410202047A CN103980088A CN 103980088 A CN103980088 A CN 103980088A CN 201410202047 A CN201410202047 A CN 201410202047A CN 103980088 A CN103980088 A CN 103980088A
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Abstract
The invention discloses a method of preparing a floralozone intermediate. Under the action of an aqueous sulfuric acid solution and a quaternary ammonium salt as a phase transfer catalyst, by controlling the reaction temperature, hydrogen chloride gas is continuously fed into a reaction system containing ethylbenzene and paraformaldehyde so as to perform chloromethylation of the ethylbenzene, and ethylbenzyl chloride with a purity higher than 95% and a yield being 85-94% is finally prepared. By adoption the ethylbenzyl chloride as the intermediate, floralozone can be prepared by condensing the intermediate and isobutyraldehyde.
Description
Technical field
The present invention relates to a kind of preparation method of organic intermediate, in particular to the preparation method of Hai Feng Quan " intermediate.
Background technology
The compound of substituted benzene propionic aldehyde series has the lily of the valley, root of Common Pecteilis note, clear fresh air style, name be Hai Feng Quan ", its fragrance is elegant, lasting, for perfume formulation promotes blue or green gas, strengthens blue or green fragrant volatile of fresh flowers, has valuable use value.
Hai Feng Quan " can be raw material by ethyl halogenation benzyl, under the effect of catalyzer, makes with isobutyric aldehyde condensation.As can be seen here, ethyl halogenation benzyl seems particularly important as a kind of organic synthesis intermediate to the synthetic of Hai Feng Quan ".
In the prior art, the synthetic ethyl halogenation benzyl that mostly adopts of Hai Feng Quan " is as initiator, and ethyl halogenation benzyl is taking ethylbenzene, paraformaldehyde as raw material, at catalyzer, especially, under lewis acidic katalysis, carry out the reaction of chloromethylation or bromomethylation and prepare.Ethyl halogenation benzyl is as a kind of important organic synthesis intermediate, all the time just by people institute broad research.As far back as 1898, Grassi and Maselli just found can realize by introduce a chloromethyl on aromatic hydrocarbons the chloromethylation of aromatic hydrocarbons.In nineteen twenty-three, Blanc has found to realize the short-cut method of aromatic hydrocarbons chloromethylation,, under zinc chloride exists, realizes the chloromethylation of aromatic hydrocarbons by the effect of formaldehyde and hydrogen chloride gas.In recent years, aromatic hydrocarbons halomethylation still has many improvement.
Li Hongqi etc. are in " chemistry world " 09 phase in 1988 " phase-transfer catalysis is synthesized Hai Feng Quan " ", employing zinc chloride is catalyzer, in the mixing solutions of ethylbenzene and paraformaldehyde, pass into hydrogen chloride gas, carry out chloromethylation, the target product yield obtaining is 65%.In the literature, zinc chloride can not recycle, and produces the waste water that contains in a large number zinc chloride in last handling process, and very serious to environmental hazard, in addition, yield is lower, catalyzer cost is higher.US Patent No. 201200264981 discloses and adopted Hydrogen bromide, acetic acid is the electrophilic substitution reaction that bromomethylation reagent carries out aromatic hydrocarbons.In this patent, the raw materials cost that not only adopted is higher, and will reclaim bromine in post-reaction treatment process, and operation is loaded down with trivial details, and " three wastes " generation is larger.In 392nd～396 pages of " Chem Cat chem " the 2nd phases in 2010, describe and adopted aluminum chloride, polyoxyethylene glycol etc. to carry out the halomethylation reaction of aromatic hydrocarbons as catalyzer, same catalyzer can not be reused, and cost is higher, wastewater flow rate is larger, is unfavorable for suitability for industrialized production.
Can find out from existing patent and technical literature analysis, in existing ethylbenzene chlorine/bromomethylation technique, have many problems, for example catalyzer and aftertreatment cost are higher, catalyzer can not reclaim or recycle, yield is low, and the waste water that reaction produces is more, is unfavorable for environmental protection.
Summary of the invention
In order to address the above problem, the inventor has carried out research with keen determination, found that: under aqueous sulfuric acid and the effect using quaternary ammonium compound as phase-transfer catalyst, in the situation that controlling temperature of reaction, ethylbenzene is carried out to chloromethylation, can high level and higher yields make ethyl Benzyl Chloride, taking as intermediate, can synthesize final product Hai Feng Quan ", thereby complete the present invention.
One of the object of the invention is to provide a kind of preparation method of Hai Feng Quan " intermediate, and the method comprises the following steps:
(1) in reactor, add ethylbenzene, formaldehyde, aqueous sulfuric acid and quaternary ammonium salt-type phase transfer catalyst, after mixing, stir, wherein, the mol ratio of described ethylbenzene and formaldehyde is 1:1～2, the mass percent concentration of described aqueous sulfuric acid is 30～95%, 0.2～20wt% that the consumption of described quaternary ammonium salt-type phase transfer catalyst is ethylbenzene;
(2) reactor is warmed up to 50～115 DEG C, controlling in temperature of reaction situation, continue to pass into hydrogen chloride gas and carry out chloromethylation, reaction times is 2～20 hours, then stop ventilation, wherein, to make the mol ratio of hydrogenchloride and ethylbenzene be 0.1～1:1 to hydrogen chloride gas air flow hourly;
(3) stop, after ventilation, reactor is cooled to 10～30 DEG C, then carry out separatory, the organic phase after separatory or/and salt water washing is carried out underpressure distillation to the organic phase after washing, obtains target product ethyl Benzyl Chloride with buck.
The ethyl Benzyl Chloride that provides a kind of preparation method above-mentioned according to the present invention to obtain is provided another object of the present invention, wherein, mol ratio 2～the 3.5:1 of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride, the content of 3-ethyl Benzyl Chloride is 1%～2% of ethyl Benzyl Chloride weight.
A further object of the present invention is to provide a kind of preparation method of Hai Feng Quan ", wherein, the method that employing comprises above-mentioned steps (1)～(3) is prepared Hai Feng Quan " intermediate ethyl Benzyl Chloride, then under the effect of catalyzer, this intermediate ethyl Benzyl Chloride carries out condensation with isobutyric aldehyde, makes Hai Feng Quan ".
Embodiment
Below by the present invention is described in detail, the features and advantages of the invention will become more clear, clear and definite along with these explanations.
According to the present invention, a kind of preparation method of Hai Feng Quan " intermediate is provided, this preparation method comprises following 3 steps:
Step 1, in reactor, add ethylbenzene, formaldehyde, aqueous sulfuric acid and quaternary ammonium salt-type phase transfer catalyst, after mixing, stir, wherein, mol ratio 1:1～2 of described ethylbenzene and formaldehyde, the mass percent concentration of described aqueous sulfuric acid is 30～95%, 0.2～20wt% that the consumption of described quaternary ammonium salt-type phase transfer catalyst is ethylbenzene.
According to the present invention, adopt the catalyzer of protonic acid sulfuric acid as the chloromethylation of ethylbenzene, the effectively chloromethylation of catalysis ethylbenzene, sulfuric acid is as a kind of large-tonnage Chemicals, cheap simultaneously, can reduce production costs.
Sulfuric acid uses with aqueous solution form, and the mass percent concentration of aqueous sulfuric acid is 30～95%, and preferably 50～80%, the aqueous sulfuric acid that more preferably functional quality percentage concentration is 75%.The consumption of aqueous sulfuric acid is not particularly limited, can use with convention amount, and be 2～6:1, preferably 3～5:1 but generally make the mass ratio of sulfuric acid and ethylbenzene.Because reaction system of the present invention is the nonhomogeneous system of the aqueous solution and organism ethylbenzene and formaldehyde composition, therefore add quaternary ammonium compound as phase-transfer catalyst, both can accelerate speed of reaction, can improve again reaction yield.
Wherein, 0.2～20wt% that the consumption of phase-transfer catalyst is ethylbenzene, is preferably 0.5～15wt%, more preferably 1～10wt%.If lower than 0.2wt%,, because consumption is few, can not play good phase-transfer catalysis effect, if consumption is greater than 20wt%,, because consumption is too much, by product increases, and causes many chloromethylations of ethylbenzene.
The phase-transfer catalyst that the present invention uses is quaternary ammonium compound, preferably use quaternary alkylammonium halides, the carbonatoms of described alkyl can be identical, also can be different, preferred alkyl carbonatoms is identical, in order to reach better phase transfer catalysis, preferred alkyl carbonatoms is 2～12, more preferably 3～8, most preferably be 4～6, described ammonium halide is preferably ammonium chloride or brometo de amonio.
According to the present invention, preferably use Tetrabutyl amonium bromide or tetrabutylammonium chloride as phase-transfer catalyst.
The formaldehyde that the present invention adopts can be that paraformaldehyde can be also formalin (formalin), preferably uses paraformaldehyde.
Step 2, reactor is warmed up to 50～115 DEG C, controlling in temperature of reaction situation, continues to pass into hydrogen chloride gas, reaction times is 2～20 hours, then stop ventilation, wherein, the mol ratio of hydrogen chloride gas air flow hourly and ethylbenzene is 0.1～1:1.
According to the present invention, by after raw material and catalyst mix, reactor is warmed up to 50～115 DEG C, preferably be warming up to 50～95 DEG C, more preferably temperature is 80～85 DEG C, is then controlling in temperature of reaction situation, and preferably controlling temperature is 50～95 DEG C, more preferably controlling temperature is 80～85 DEG C, passes into hydrogen chloride gas and carries out chloromethylation.
The present invention selects chloromethylation to generate halogenation benzyl, generate halogenation benzyl and do not adopt bromomethylation reagent to carry out bromomethylation reaction, be mainly the loaded down with trivial details operation that will reclaim bromine in last handling process, make whole technological operation simple, be conducive to amplify and promote.
Study discovery through the inventor, if chloromethylation temperature lower than 50 DEG C, because temperature is low, speed of reaction is slow, it is insufficient that reaction is carried out, and affects the yield of final product; If temperature of reaction, higher than 115 DEG C, due to excess Temperature, many chloromethylations easily occurs, the by product of generation increases, and directly causes final product yield to reduce.
According to the present invention, preferably constantly to logical hydrogen chloride gas in reactor, and keep the draft speed of hydrogen chloride gas constant when logical hydrogen chloride gas, it is 0.1～1:1 that intake hourly preferably makes the mol ratio of hydrogenchloride and ethylbenzene.Can have a negative impact to reaction although the air flow of hydrogenchloride is crossed very much not, the mol ratio that makes hydrogenchloride and ethylbenzene when the air flow per hour of hydrogenchloride during higher than 1:1, not only causes waste, and unnecessary side reaction can occur; And the mol ratio that makes hydrogenchloride and ethylbenzene when the air flow per hour of hydrogenchloride is during lower than 0.1:1, can find that speed of response is obviously slack-off.
Therefore,, according to the present invention, it is 0.2～0.5:1, more preferably 0.3:1 that intake hourly preferably makes the mol ratio of hydrogenchloride and ethylbenzene.
According to the present invention, the reaction times of chloromethylation is 2～20 hours, if temperature of reaction, lower than 2 hours, because the reaction times is short, is unfavorable for fully carrying out of reaction, affect the yield of reaction product, if higher than 20 hours, along with the prolongation in reaction times, the by product of generation increases, target product ethyl Benzyl Chloride content declines, and affects the performance of this Hai Feng Quan " intermediate.Preferably the reaction times of chloromethylation is 5～15 hours, more preferably 6～12 hours, be especially preferably 8～10 hours, and then stop ventilation.
Step 3, stop, after ventilation, reactor is cooled to 10～30 DEG C, then carry out separatory, organic phase after separatory or/and salt water washing is carried out underpressure distillation to the organic phase after washing, obtains target product ethyl Benzyl Chloride with buck.
In a preferred embodiment, after reaction finishes, reaction system is cooled to 15～25 DEG C, preferably 18～22 DEG C, then carry out separatory, can carry out at ambient temperature.
According to the present invention, the water optional recycle after separatory is used, if recycled,, without additional purification, directly join in reaction system, and can not affect reaction efficiency, and yield and the content of target product ethyl Benzyl Chloride, be therefore preferred operating method.In addition, water recycles and has also reduced production cost, has greatly reduced the generation of the three wastes, is conducive to environmental protection.
Organic phase after separatory adds the saturated sodium carbonate solution as buck, and/or as the saturated aqueous common salt of salt solution, thereby fully wash, by the organic phase underpressure distillation after washing, when underpressure distillation, pump vacuum degree is-0.07～-0.1Mpa, temperature of reaction kettle is 30～100 DEG C, obtains the cut of ethyl Benzyl Chloride in the time of 70～100 DEG C.
According to the present invention, the yield of the target product ethyl Benzyl Chloride obtaining through above step reaches 85～94%, and for example detects by high performance liquid chromatography, knows in product that ethyl Benzyl Chloride content is up to more than 95%, thereby catalysis is higher, by-products content is few.Comprehensive, prepare in the method for Hai Feng Quan " intermediate in the present invention, under certain temperature of reaction condition, continue to pass into hydrogen chloride gas and formaldehyde, especially paraformaldehyde composition chloromethylation reagent, especially, under certain temperature of reaction condition, keep the draft speed of hydrogen chloride gas constant, make the target product ethyl Benzyl Chloride for preparing reliable and stable.
In above-mentioned preparation method, range of reaction temperature, between 50～115 DEG C, because temperature of reaction is can domain of walker large, is therefore very beneficial for the popularization on producing, and makes production technique simple, and easy handling is repeatable strong.In a preferred embodiment, preferable reaction temperature is 80～85 DEG C, and under this temperature condition, the target product ethyl Benzyl Chloride content obtaining is high, and yield reaches best simultaneously.
Prepare in the method for Hai Feng Quan " intermediate in the present invention, pass into hydrogen chloride gas and especially paraformaldehyde as chloromethylation reagent, with chloromethyl ether or bischlormethyl ether as compared with chloromethylation reagent, toxicity reduces greatly, and storage convenient transportation, simultaneously cheap, significantly reduce production costs.
According to a further aspect of the invention, the ethyl Benzyl Chloride that provides a kind of preparation method above-mentioned according to the present invention to obtain, wherein, mol ratio 2～the 3.5:1 of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride, the content of 3-ethyl Benzyl Chloride is 1%～2% of ethyl Benzyl Chloride weight, in addition, the yield of ethyl Benzyl Chloride reaches 85～94%, and the ethyl Benzyl Chloride content detecting by high performance liquid chromatography reaches more than 95%.
The present invention also aims to provide a kind of preparation method of Hai Feng Quan ", wherein, first adopt the method that comprises above-mentioned steps (1)～(3) to prepare Hai Feng Quan " intermediate ethyl Benzyl Chloride, then under the effect of catalyzer, for example, under the basic catalyst of catalyzed carbon-alkylated reaction exists, ethyl Benzyl Chloride carries out condensation with isobutyric aldehyde, makes Hai Feng Quan ".
Particularly, prepare after intermediate ethyl Benzyl Chloride according to the method for above-mentioned steps (1)～(3), carry out following steps:
(a) in reactor, add ethyl Benzyl Chloride, sodium hydroxide, water, quaternary ammonium salt-type phase transfer catalyst and ethylbenzene, after mixing, stir, wherein, the consumption of described ethylbenzene is 0.2～10 times of ethyl Benzyl Chloride weight, the mol ratio of described sodium hydroxide and ethyl Benzyl Chloride is 1～10:1, and the consumption of described quaternary ammonium salt-type phase transfer catalyst is 0.2～20wt% of ethyl Benzyl Chloride;
(b) reactor is warmed up to 50～130 DEG C, controlling in temperature of reaction situation, drips isobutyric aldehyde, after dropwising, at 70～130 DEG C, stir insulation reaction, wherein, the consumption of isobutyric aldehyde is that to make the mol ratio of isobutyric aldehyde and ethyl Benzyl Chloride be 1～4:1;
(c) after reaction finishes, reactor is cooling, after will reaction system filtering, carry out separatory, the organic phase after separatory is with acid solution or/and water washing, and then to organic phase desolvation, underpressure distillation, obtains target product Hai Feng Quan ".Thus obtained Hai Feng Quan ", yield can reach 70～85%, content reaches more than 94%, and this Hai Feng Quan " is mixture, wherein, 4-ethyl-2, the content of 2-dimethyl benzene propionic aldehyde is 60～80wt%, 2-ethyl-2, and the content of 2-dimethyl benzene propionic aldehyde is 15～35wt%, 3-ethyl-2, the content of 2-dimethyl benzene propionic aldehyde is 0～5wt%.
Beneficial effect of the present invention finds expression in following several respects:
(1) in the present invention, adopt phase-transfer catalyst and the chloromethylation reagent of cheap aqueous sulfuric acid, quaternary ammonium salt, greatly reduced production cost.
(2) the present invention does not adopt bromomethylation reagent to generate halogenation benzyl, has effectively avoided will reclaiming in last handling process the loaded down with trivial details operation of bromine, makes whole technological operation simple, is conducive to amplify and promotes.
(3) in the present invention,, under the effect of aqueous sulfuric acid and quaternary ammonium salt-type phase transfer catalyst, control certain temperature of reaction, greatly reduce the generation of by product, catalysis is high, and the content of the target product obtaining is up to more than 95%, and yield is 85～94%.
(4) in the present invention, temperature of reaction is 50～115 DEG C, between this temperature, all can obtain the target product that content is high, yield is high, and temperature domain of walker is large, is conducive to produce repetitive operation, and production stability is strong.
(5) in the present invention, the reactive behavior that overcome the chloromethylation reagent that hydrogen chloride gas and paraformaldehyde form is low, long reaction time and the not high shortcoming of productive rate, just can obtain the target product of the high yield of high-content within the desirable reaction times.
Embodiment
Further describe by the following examples the present invention.But these embodiment are only exemplary, protection scope of the present invention are not formed to any restriction.
Embodiment 1
The aqueous sulfuric acid and the 57.5g Tetrabutyl amonium bromide that are 50% by 378g ethylbenzene, 214g paraformaldehyde, 3552g mass percent concentration add in reactor, after mixing, stir;
Then reactor is warming up to 50 DEG C, then continues to pass into hydrogen chloride gas and carry out chloromethylation, it is 0.3:1 that air flow hourly makes the mol ratio of hydrogenchloride and ethylbenzene, ventilates and stops ventilating after 12 hours;
Reactor is cooled to 20 DEG C, then separatory at room temperature, water after separatory recycles, organic phase adds saturated sodium carbonate solution and saturated common salt water washing, organic phase after washing is carried out to underpressure distillation, the cut that obtains target product ethyl Benzyl Chloride in the time of 70～100 DEG C, its yield reaches 86%.
Detect through GC, ethyl Benzyl Chloride content is 96.5%, and wherein, the mol ratio of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride is 2:1, and the content of 3-ethyl Benzyl Chloride is 1.3% of ethyl Benzyl Chloride weight.
Embodiment 2
The aqueous sulfuric acid and the 57.5g Tetrabutyl amonium bromide that are 80% by 378g ethylbenzene, 214g paraformaldehyde, 2220g mass percent concentration add in reactor, after mixing, stir;
Then reactor is warming up to 115 DEG C, then continues to pass into hydrogen chloride gas and carry out chloromethylation, it is 0.4:1 that air flow hourly makes the mol ratio of hydrogenchloride and ethylbenzene, ventilates and stops ventilating after 5 hours;
Reactor is cooled to 25 DEG C, then separatory at room temperature, water after separatory recycles, organic phase adds saturated sodium carbonate solution and saturated common salt water washing each twice, organic phase after washing is carried out to underpressure distillation, the cut that obtains target product ethyl Benzyl Chloride in the time of 70～100 DEG C, its yield reaches 92%.
Detect through GC, ethyl Benzyl Chloride content is 96.8%, and wherein, the mol ratio of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride is 2.5:1, and the content of 3-ethyl Benzyl Chloride is 1.5% of ethyl Benzyl Chloride weight.
Embodiment 3
Water after separatory in 378g ethylbenzene, 578g37% formalin, 2220g embodiment 2 is added in reactor, after mixing, stir;
Then reactor is warming up to 85 DEG C, then continue to pass into hydrogen chloride gas and carry out chloromethylation, it is 0.5:1 that air flow hourly makes the mol ratio of hydrogenchloride and ethylbenzene, ventilates and after 8 hours, stops ventilation, and to pass into total amount be 4 times of ethylbenzene molar weight to hydrogenchloride;
Reactor is cooled to 30 DEG C, then separatory at room temperature, wherein, organic phase adds saturated sodium carbonate solution and saturated common salt water washing, organic phase after washing is carried out to underpressure distillation, obtain the cut of target product ethyl Benzyl Chloride in the time of 70～100 DEG C, its yield reaches 93%.
Detect through GC, ethyl Benzyl Chloride content is 96%, and wherein, the mol ratio of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride is 3.5:1, and the content of 3-ethyl Benzyl Chloride is 1.8% of ethyl Benzyl Chloride weight.
Embodiment 4
The aqueous sulfuric acid and the 57.5g tetrabutylammonium chloride that are 75% by 378g ethylbenzene, 535g40% formalin, 2368g mass percent concentration add in reactor, after mixing, stir;
Then reactor is warming up to 65 DEG C, then continues to pass into hydrogen chloride gas and carry out chloromethylation, it is 0.2:1 that air flow hourly makes the mol ratio of hydrogenchloride and ethylbenzene, ventilates and stops ventilating after 15 hours;
Reactor is cooled to 18 DEG C, then carry out separatory, water after separatory recycles, organic phase adds saturated sodium carbonate solution washing 2 times, and add saturated common salt water washing once, organic phase after washing is carried out to underpressure distillation, obtain the cut of target product ethyl Benzyl Chloride in the time of 70～100 DEG C, its yield reaches 91%.
Detect through GC, ethyl Benzyl Chloride content is 97%, and wherein, the mol ratio of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride is 3:1, and the content of 3-ethyl Benzyl Chloride is 2% of ethyl Benzyl Chloride weight.
Embodiment 5
The ethyl Benzyl Chloride obtaining using embodiment 4 is as intermediate 400g, and ethyl Benzyl Chloride content is 97%, and wherein, the mol ratio of 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride is 3:1, and the content of 3-ethyl Benzyl Chloride is 2% of ethyl Benzyl Chloride weight; 199.0g sodium hydroxide, 112.0g water, 8g tetrabutylammonium chloride and 200g ethylbenzene add in reactor, after mixing, stir;
Then reactor is warming up to 72 DEG C, in the situation that controlling temperature of reaction, drips 197.5g isobutyric aldehyde, after dropwising, 72 DEG C of insulations 9 hours;
Reactor is cooled to 26 DEG C, separatory at room temperature after reaction system is filtered, the water after separatory recycles, organic phase adds acetum, water washing, to the organic phase desolvation after washing, carries out rectification under vacuum, obtain the cut of target product Hai Feng Quan ", its yield is 85%.
Detect through gas-chromatography instrument, the content of Hai Feng Quan " is 95.2%, wherein, 4-ethyl-2, the content of 2-dimethyl benzene propionic aldehyde is 65%, 2-ethyl-2, and the content of 2-dimethyl benzene propionic aldehyde is 28%, 3-ethyl-2, and the content of 2-dimethyl benzene propionic aldehyde is 2.2%.
Comparative example
Comparative example 1
Repeat embodiment 1, wherein, temperature of reaction is 45 DEG C, and other conditions are constant, and the yield that finally obtains ethyl Benzyl Chloride is 81%.
Comparative example 2
Repeat embodiment 2, wherein, temperature of reaction is 130 DEG C, and other conditions are constant, and the yield that finally obtains ethyl Benzyl Chloride is 70%.
Comparative example 3
Repeat embodiment 1, wherein, do not add Tetrabutyl amonium bromide, other conditions are constant, and the yield that finally obtains ethyl Benzyl Chloride is 5%.
In conjunction with embodiment and exemplary example, the present invention is had been described in detail above, but these explanations can not be interpreted as limitation of the present invention.It will be appreciated by those skilled in the art that in the situation that not departing from spirit and scope of the invention, can carry out multiple replacement of equal value, modify or improve technical solution of the present invention and embodiment thereof, these all fall within the scope of the present invention.Protection scope of the present invention is as the criterion with claims.
Claims (10)
1. a preparation method for Hai Feng Quan " intermediate, the method comprises the following steps:
(1) in reactor, add ethylbenzene, formaldehyde, aqueous sulfuric acid and quaternary ammonium salt-type phase transfer catalyst, after mixing, stir, wherein, mol ratio 1:1～2 of described ethylbenzene and formaldehyde, the mass percent concentration of described aqueous sulfuric acid is 30～95%, 0.2～20wt% that the consumption of described quaternary ammonium salt-type phase transfer catalyst is ethylbenzene;
(2) reactor is warmed up to 50～115 DEG C, controlling in temperature of reaction situation, continue to pass into hydrogen chloride gas and carry out chloromethylation, reaction times is 2～20 hours, then stop ventilation, wherein, to make the mol ratio of hydrogenchloride and ethylbenzene be 0.1～1:1 to hydrogen chloride gas air flow hourly;
(3) stop, after ventilation, reactor is cooled to 10～30 DEG C, then carry out separatory, the organic phase after separatory or/and salt water washing is carried out underpressure distillation to the organic phase after washing, obtains target product ethyl Benzyl Chloride with buck.
2. according to the preparation method of claim 1, it is characterized in that, in step (1), the mass percent concentration of aqueous sulfuric acid is 50～80%, is preferably 75%.
3. according to the preparation method of claim 1 or 2, it is characterized in that, in step (1), the consumption of phase-transfer catalyst is 0.5～15wt% of ethylbenzene, be preferably 1～10wt%, described phase-transfer catalyst is quaternary alkylammonium halides, the carbonatoms of described alkyl is identical or different, preferred alkyl carbonatoms is identical, described alkyl carbon atoms number is 2～12, more preferably 3～8, most preferably be 4～6, described ammonium halide is preferably ammonium chloride or brometo de amonio, most preferably uses Tetrabutyl amonium bromide or tetrabutylammonium chloride as phase-transfer catalyst.
4. according to the preparation method of claims 1 to 3 any one, it is characterized in that, in step (1), described formaldehyde is paraformaldehyde or formalin, preferably paraformaldehyde.
5. according to the preparation method of claim 1 to 4 any one, it is characterized in that, in step (2), after raw material and catalyst mix, reactor is warmed up to 50～95 DEG C, preferably temperature is 80～85 DEG C, then, controlling in temperature of reaction situation, passes into hydrogen chloride gas and carries out chloromethylation.
6. according to the preparation method of claim 1 to 5 any one, it is characterized in that, in step (2), in reactor, lead to hydrogen chloride gas constantly, and when logical hydrogen chloride gas, keep the draft speed of hydrogen chloride gas constant, it is 0.2～0.5:1 that intake hourly preferably makes the mol ratio of hydrogenchloride and ethylbenzene, is preferably 0.3:1.
7. according to the preparation method of claim 1 to 6 any one, it is characterized in that, in step (2), the reaction times of chloromethylation is 5～15 hours, preferably the reaction times of chloromethylation is 6～12 hours, more preferably 8～10 hours, then stops ventilation.
8. according to the preparation method of claim 1 to 7 any one, it is characterized in that, in step (3), after reaction finishes, reaction system is cooled to 15～25 DEG C, preferably 18～22 DEG C, then carry out separatory, can carry out at ambient temperature, water after separatory recycles, organic phase after separatory adds the saturated sodium carbonate solution as buck, and/or as the saturated aqueous common salt of salt solution, thereby wash, by the organic phase underpressure distillation after washing, the vacuum tightness of controlling water pump when underpressure distillation is-0.07～-0.1Mpa, reactor temperature is 30～100 DEG C.
9. the ethyl Benzyl Chloride obtaining according to the preparation method of claim 1 to 8 any one, is characterized in that, the mol ratio 2～3.5:1 of gained 4-ethyl Benzyl Chloride and 2-ethyl Benzyl Chloride, and the content of 3-ethyl Benzyl Chloride is 1%～2wt% of ethyl Benzyl Chloride.
10. the preparation method of a Hai Feng Quan ", wherein, first adopt the method that comprises above-mentioned steps (1)～(3) to prepare Hai Feng Quan " intermediate ethyl Benzyl Chloride, then under the effect of catalyzer, for example, under the basic catalyst of catalyzed carbon-alkylated reaction exists, ethyl Benzyl Chloride carries out condensation with isobutyric aldehyde, makes Hai Feng Quan ".
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104909982A (en) * | 2015-05-29 | 2015-09-16 | 长沙贝塔医药科技有限公司 | Method for synthesizing benzyl bromide compound directly from isotope labeled benzene rings |
| CN113200815A (en) * | 2021-04-29 | 2021-08-03 | 爱斯特（成都）生物制药股份有限公司 | Method for continuous flow synthesis of m-trifluoromethyl benzyl chloride |
| CN115108883A (en) * | 2021-03-17 | 2022-09-27 | 山东泰和水处理科技股份有限公司 | Preparation method of benzyl chloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104909982A (en) * | 2015-05-29 | 2015-09-16 | 长沙贝塔医药科技有限公司 | Method for synthesizing benzyl bromide compound directly from isotope labeled benzene rings |
| CN115108883A (en) * | 2021-03-17 | 2022-09-27 | 山东泰和水处理科技股份有限公司 | Preparation method of benzyl chloride |
| CN113200815A (en) * | 2021-04-29 | 2021-08-03 | 爱斯特（成都）生物制药股份有限公司 | Method for continuous flow synthesis of m-trifluoromethyl benzyl chloride |
| CN113200815B (en) * | 2021-04-29 | 2023-09-29 | 爱斯特（成都）生物制药股份有限公司 | Method for synthesizing m-trifluoromethyl benzyl chloride through continuous flow |
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