CN102731327A - Preparation method of 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde - Google Patents
Preparation method of 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde Download PDFInfo
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- CN102731327A CN102731327A CN2012102300425A CN201210230042A CN102731327A CN 102731327 A CN102731327 A CN 102731327A CN 2012102300425 A CN2012102300425 A CN 2012102300425A CN 201210230042 A CN201210230042 A CN 201210230042A CN 102731327 A CN102731327 A CN 102731327A
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Abstract
The invention discloses a preparation method of 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde. The method uses p-fluorobenzaldehyde or p-chlorobenzaldehyde and diethanol amine as a raw material to react under the action of a catalyst to obtain the 4-[N,N-bis(2-hydroxyethyl)amino]benzaldehyde. The preparation method has the characteristics of simple process, the easily accessible raw materials, moderate reaction conditions, safe operation, environment-friendliness and being liable to industrialize. The HPLC (high performance liquid chromatography) purity of the obtained product is more than 99%.
Description
Technical field
The invention belongs to industrial chemicals intermediate preparation technical field, but particularly relate to a kind of industriallization, the novel preparation method of high purity 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde.
Background technology
4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde is a kind of important pharmaceutical-chemical intermediate, at aspects such as spices, medicine important application is arranged all.This product is light yellow to yellow solid, and fusing point is 55-62 ℃.Domestic less production, main foreign demand amount is bigger.Its present main preparation methods, reaction equation is as follows:
With N, N-dihydroxy ethyl aniline is raw material, obtains intermediate A through hydroxyl protection, obtains intermediate B through the Vilsmeier reaction again, last hydrolysis deprotection, and three steps prepared compound 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde.
Like Synethetic Communications, 2007, vol.37, p921-926, it reports this method, adopts intermediate B to prepare compound I, is Yellow-to-orange oily matter, yield 85% obtains the lower melting point solid, purity after crystallization is spent the night>97%.Dyes and Pigments (2009), 82 (3), 329-335, its report adopt N, N-dihydroxy ethyl aniline be feedstock production to compound I, yield 62%, 60 ℃ of fusing points.CN102249940 adopts aforesaid method equally, obtains yellow oily liquid, no yield and purity report.This its preparation process shortcoming is: technology is unstable, and it is poor to obtain product purity.Reactions step is long, complex operation, and the production cycle is long, and the equipment occupation rate is high, and cost of material is expensive.The POCl3 that need use is a hazardous agents, and process safety is poor, and the wastewater flow rate that the Vilsmeier reaction produces is very big, and environmental pollution is serious.
Summary of the invention
Technical problem to be solved by this invention provides a kind of 4-[N; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde, this method has solved traditional technology in deficiency, be simple and easy to raw material synthetic compound 4-[N; Two (2-hydroxyethyl) amino of N-] phenyl aldehyde; It is short that this method has step, simple to operate, is easy to industrialized advantage.
The present invention solves the problems of the technologies described above the technical scheme that is adopted: the preparation method of a kind of 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde, and reaction formula is:
X=Cl,F
Carry out successively as follows:
Step 1), there are system in formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde and formula (III) compound diethylolamine or have solvent to exist in the system solvent-free, reaction in the presence of catalyzer;
Step 2), treated 4-[N, two (2-hydroxyethyl) amino of the N-] phenyl aldehyde that obtains in said reaction back.
In the said step 1), carry out under the said 100-170 of being reflected at ℃ the temperature of reaction condition, the reaction times is 12 ~ 48 hours.Preferably, carry out under the said 110-130 of being reflected at ℃ the temperature of reaction condition.Reaction temperature is spent low reaction and is not carried out, and the too high meeting of temperature causes product degradation.
In the said step 1), the consumption mol ratio of described raw material formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde and formula (III) compound diethylolamine is 1: 1.6 ~ 4; The excessive purpose of diethylolamine is for raw material is fully reacted completely.
In the said step 1); Said catalyzer is a lewis acid catalyst; It is selected from aluminum chloride, zinc chloride, BFEE and the iron(ic)chloride any one, and the mass ratio of said catalyst levels and raw material formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 0.01-0.1:1.Preferably, the mass ratio of said catalyst levels and raw material formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 0.05:1.The effect of catalyzer is through complexing action, improve the ability of leaving away of halogen, thereby intensified response is active, and reaction is carried out smoothly.Consumption is crossed low effect can be not obvious, and consumption is crossed conference and caused that aftertreatment is loaded down with trivial details, cost increases, and it is p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption 5% o'clock that preparation method of the present invention selects the catalytic amount quality, best results.
In the said step 1), have solvent to exist in the system said, said solvent is selected from high boiling solvents such as toluene, YLENE, chlorobenzene, dichlorobenzene, hexone (MIBK) and propyl carbinol.The consumption of the consumption of said solvent and raw material p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde, mass ratio are 2 ~ 10:1; Preferably, said mass ratio is 2 ~ 5:1.Suitable solvent helps the carrying out that react.
Said step 2) in; Said reacted treatment step is: after reaction finishes, transfer to pH6.5 ~ 7.5 with aqueous acid, then with extraction solvent after extracting 3-4 time under 10-100 ℃ the extraction temperature; After the organic layer drying; Solvent distillation, residue obtains 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde with solvent recrystallization.
As preferably, said step 2) in, after reaction finished, aqueous acid transferred to pH7.Being adjusted to pH7, is the remaining diethylolamine of neutralization.Because of product 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde has certain solvability in water, so need product be extracted up with organic solvent.
As preferably, said step 2) in, preferred 70 ~ 100 ℃ of extraction temperature.Temperature is too low, and product is difficult for being extracted into organic layer.
Said step 2) in, said aqueous acid is diluted hydrochloric acid aqueous solution or aqueous sulfuric acid, said extraction solvent be selected from propyl carbinol, MIBK, toluene, ETHYLE ACETATE and methylene dichloride in any one.Wherein, n-butanol extraction and water have certain mutual solubility, and the extracted products ability is better.
Said step 2) in, the mass ratio of the extraction solvent consumption of said each extraction and raw material p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 0.8 ~ 4:1.
Said step 2) in, said recrystallization solvent is selected from any one in isopropyl acetate, ETHYLE ACETATE, t-butyl methyl ether and the isopropyl ether, and the mass ratio of said recrystallization solvent consumption and raw material p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 2 ~ 4:1.The too big product of recrystallization solvent amount loses easily, influences yield.
The present invention compares with existing Technology, has following advantage:
(1) preparing method's reaction scheme of 4-of the present invention [N, N-two (2-hydroxyethyl) amino] phenyl aldehyde is short, only needs single step reaction, so technology simply is easy to industriallization, and with short production cycle, space-time yield is high.
(2) preparation method of 4-of the present invention [N, N-two (2-hydroxyethyl) amino] phenyl aldehyde is raw materials used is simple and easy to low price.
(3) preparing method's reaction conditions of 4-of the present invention [N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde is gentle, and safe and reliable, cost is low.
(4) preparing method's quality product of 4-of the present invention [N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde is high, and the prepared product HPLC purity that obtains is more than 99.1%; The products obtained therefrom yield is also higher, and yield can reach more than 60%.
Embodiment
In order to understand content of the present invention better, be described further below in conjunction with specific embodiment.Should be understood that these embodiment only are used for the present invention is further specified, and be not used in restriction scope of the present invention.Should be understood that in addition that after having read content of the present invention the technician in this field makes some nonessential change or adjustment to the present invention, still belongs to protection scope of the present invention.
Embodiment 1
In reaction flask, drop into p-Fluorobenzenecarboxaldehyde 160g, diethylolamine 540g, aluminum chloride 8g, heating temperature control to 100 ℃-115 ℃, insulation reaction 24 hours.Aftertreatment is cooled to room temperature, in reaction flask, drips 10% Hydrogen chloride and transfers to about PH7.Reaction solution is added 320g water, extract three times extraction temperature 70-100 ℃ with propyl carbinol 640g+450g+160g respectively.The basic product-free point of some plate water layer merges organic layer, and the underpressure distillation propyl carbinol (75 ℃ of heated water bath, pressure-1.0MPa), condensing temperature-15 ℃ recovery propyl carbinol.After finishing, get oily matter than the about 200kg of thickness.Oily matter is added isopropyl acetate 480g, be heated to 50-60 ℃ dissolve clear after, stir naturally cool to room temperature after, add icy salt solution to 0 ℃ left and right sides crystallization, centrifugal after 1 hour, about 180g article that wet.30 ℃ of forced air dryings obtain the 162kg light yellow solid, yield 60.0%.HPLC purity 99.0%.
Embodiment 2
In reaction kettle, p-Fluorobenzenecarboxaldehyde 250.0g drops into diethylolamine 625.0g, zinc dichloride 25g, and propyl carbinol 500g finishes, and is warming up to backflow.About reflux temperature 105-120 ℃, backflow insulation reaction 24 hours, the feed liquid color becomes wine red.Insulation is finished, the aftertreatment cooling, and below the circulating water cooling to 30 ℃, and temperature control is below 30 ℃, and the dripping hydrochloric acid aqueous solution is transferred PH to 7, stirs repetition measurement behind the 5min.Transfer PH to finish, add water 300ml layering.Water layer extracts respectively three times with propyl carbinol 400g+200g+200g again, stirs 10min at every turn, leaves standstill 10min, 30 ℃ of extraction temperature.Extraction is finished, and merges organic layer,, 70 ℃ of hot water bath temperature controls, evaporated under reduced pressure solvent.Steam and finish, get wine red thickness oily matter.Add ETHYLE ACETATE 1000g again, stir down with hot water bath heat temperature raising to 60 ℃, treat that oily matter dissolves after; Drop into anhydrous magnesium sulfate 12.5g, dry 0.5 hour, suction filtration while hot then; The filtrating nature is cooled to 25 ℃, after icy salt solution is cooled to 5 ℃, continues stirring and crystallizing 1 hour; Filter, get faint yellow wet cake 275.4g.Elder generation's room temperature 20 ℃ of forced air dryings 24 hours, be warming up to again 30 ℃ of air blast dry the 257.0g faint yellow solid, yield 61%, purity 99.3%, single maximum contaminant 0.24%.
Embodiment 3
In reaction kettle, p-Fluorobenzenecarboxaldehyde 250.0g drops into diethylolamine 625.0g, aluminum chloride 25g, and MIBK500g is warming up to after finishing about temperature 100-110 ℃, insulation reaction 24 hours, feed liquid darkens.Insulation is finished, the aftertreatment cooling, and below the circulating water cooling to 30 ℃, and temperature control is below 30 ℃, and the dripping hydrochloric acid aqueous solution is transferred about PH to 7.Transfer PH to finish, add water 300ml layering.Water layer extracts respectively three times with MIBK 400g+200g+200g again, stirs 10min at every turn, leaves standstill 10min, 30 ℃ of extraction temperature.Extraction is finished, and merges organic layer, dry filter, 70 ℃ of filtrating hot water bath temperature controls, evaporated under reduced pressure solvent.Steam and finish, get wine red thickness oily matter.Add t-butyl methyl ether 1000g again, stirring is cooled to 25 ℃ after treating the oily matter dissolving with the hot water bath heat temperature raising down naturally, after icy salt solution is cooled to 5 ℃, continues stirring and crystallizing 1 hour, filters, and gets faint yellow wet cake 280.0g.Elder generation's room temperature 20 ℃ of forced air dryings 24 hours, be warming up to again 30 ℃ of air blast dry the 247.0g faint yellow solid, yield 57.1%, purity 99.1%.
Embodiment 4
In reaction kettle, p-Fluorobenzenecarboxaldehyde 25.0g drops into diethylolamine 84.6g, BFEE 2.5g, and toluene 50g finishes, and is warming up to backflow.About reflux temperature 105-110 ℃, backflow insulation reaction 24 hours.Insulation is finished, the aftertreatment cooling, and below the circulating water cooling to 30 ℃, and temperature control is below 30 ℃, and the dripping hydrochloric acid aqueous solution is transferred PH to 7, stirs repetition measurement behind the 10min.Transfer PH to finish, add water 80ml layering.Water layer extracts respectively three times with toluene 200g+100g+100g again, stirs 10min at every turn, leaves standstill 10min, 100 ℃ of extraction temperature.Extraction is finished, and merges organic layer, dry filter, 60 ℃ of filtrating hot water bath temperature controls, evaporated under reduced pressure solvent.Steam and finish, get wine red thickness oily matter.Add isopropyl ether 75.0g again, stirring is cooled to 25 ℃ after treating the oily matter dissolving with the hot water bath heat temperature raising down naturally, after icy salt solution is cooled to 5 ℃, continues stirring and crystallizing 3 hours, filters, and gets faint yellow wet cake 20.4g.Elder generation's room temperature 20 ℃ of forced air dryings 24 hours, be warming up to again 30 ℃ of air blast dry the 17.0g faint yellow solid, yield 40.8%, purity 99.4%.
Embodiment 5
In reaction flask, drop into 4-chloro-benzaldehyde 160g, diethylolamine 270g, YLENE 320g, aluminum chloride 16g, the about 140 ℃ of insulation reaction of reflux 24 hours.Aftertreatment is cooled to room temperature, in reaction flask, drips 10% Hydrogen chloride and transfers about PH7, and temperature control drips in 30 ℃.Stir the 10min repetition measurement after having transferred pH.Reaction solution is transferred in the extraction flask, and water layer extracts respectively three times with propyl carbinol 640g+450g+160g, about 10 ℃ of extraction temperature room temperatures.Merge organic layer, reclaim waste water.The underpressure distillation propyl carbinol (70 ℃ of heated water bath, pressure-1.0MPa), condensing temperature-15 ℃ recovery propyl carbinol.After finishing, get oily matter than the about 235g of thickness.Oily matter is added ETHYLE ACETATE 640g, be heated to 50-60 ℃ dissolve clear after, stir naturally cool to room temperature after, add icy salt solution to 0 ℃ left and right sides crystallization, centrifugal after 1 hour, about 190g article that wet.30 ℃ of forced air dryings obtain the 83.5g light yellow solid, yield 35.1%.HPLC purity 99.1%.Fusing point: 62.5-63.0 ℃.
As stated, just can realize the present invention preferably.
Claims (10)
1. the preparation method of a 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde, reaction formula is:
X＝Cl,F
Carry out successively as follows:
Step 1), there are system in formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde and formula (III) compound diethylolamine or have solvent to exist in the system solvent-free, reaction in the presence of catalyzer;
Step 2), treated 4-[N, two (2-hydroxyethyl) amino of the N-] phenyl aldehyde that obtains in said reaction back.
2. the preparation method of 4-according to claim 1 [N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde, it is characterized in that: in the said step 1), carry out under the said 100-170 of being reflected at ℃ the temperature of reaction condition, the reaction times is 12 ~ 48 hours.
3. 4-[N according to claim 2; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde; It is characterized in that: in the said step 1), the consumption mol ratio of described raw material formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde and formula (III) compound diethylolamine is 1:1.6 ~ 4.
4. according to claim 2 or 3 described 4-[N; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde is characterized in that: in the said step 1); Said catalyzer is selected from any one in aluminum chloride, zinc chloride, BFEE and the iron(ic)chloride, and the mass ratio of said catalyst levels and raw material formula (II) compound p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 0.01-0.1:1.
5. according to claim 2 or 3 described 4-[N; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde; It is characterized in that: in the said step 1); Have solvent to exist in the system said, said solvent is selected from any one in toluene, YLENE, chlorobenzene, dichlorobenzene, hexone and the propyl carbinol.
6. according to claim 2 or 3 described 4-[N; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde, it is characterized in that: in the said step 1), have solvent to exist in the system said; The consumption of the consumption of said solvent and raw material p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde, mass ratio are 2 ~ 10:1.
7. the preparation method of 4-according to claim 3 [N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde is characterized in that: said step 2); Said reacted treatment step is: after reaction finishes, transfer to pH6.5 ~ 7.5 with aqueous acid, then with extraction solvent after extracting 3-4 time under 10-100 ℃ the extraction temperature; After the organic layer drying; Solvent distillation, residue obtains 4-[N, two (2-hydroxyethyl) amino of N-] phenyl aldehyde with solvent recrystallization.
8. 4-[N according to claim 7; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde; It is characterized in that: said step 2); Said aqueous acid is diluted hydrochloric acid aqueous solution or aqueous sulfuric acid, said extraction solvent be selected from propyl carbinol, MIBK, toluene, ETHYLE ACETATE and methylene dichloride in any one.
9. 4-[N according to claim 7; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde; It is characterized in that: said step 2), the mass ratio of the extraction solvent consumption of said each extraction and raw material p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 0.8 ~ 4:1.
10. 4-[N according to claim 7; Two (2-hydroxyethyl) amino of N-] preparation method of phenyl aldehyde; It is characterized in that: said step 2); Said recrystallization solvent is selected from any one in isopropyl acetate, ETHYLE ACETATE, t-butyl methyl ether and the isopropyl ether, and the mass ratio of said recrystallization solvent consumption and raw material p-Fluorobenzenecarboxaldehyde or 4-chloro-benzaldehyde consumption is 2 ~ 4:1.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4757130A (en) * | 1987-07-01 | 1988-07-12 | Hoechst Celanese Corporaton | Condensation polymers with pendant side chains exhibiting nonlinear optical response |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4757130A (en) * | 1987-07-01 | 1988-07-12 | Hoechst Celanese Corporaton | Condensation polymers with pendant side chains exhibiting nonlinear optical response |
Non-Patent Citations (1)
| Title |
|---|
| 罗军: "微波促进卤素交换氟化反应研究", 《中国优秀博硕士学位论文全文数据库(博士) 工程科技I辑，2003年》 * |
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Application publication date: 20121017 |