CN104513177B - A kind of preparation method of 5-(N, N-dibenzyl amino) ethrisin - Google Patents
A kind of preparation method of 5-(N, N-dibenzyl amino) ethrisin Download PDFInfo
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- CN104513177B CN104513177B CN201410760196.4A CN201410760196A CN104513177B CN 104513177 B CN104513177 B CN 104513177B CN 201410760196 A CN201410760196 A CN 201410760196A CN 104513177 B CN104513177 B CN 104513177B
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- salicylamide
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Abstract
nullOne 5 (N of the present invention,N dibenzyl amino) preparation method of ethrisin，Salicylamide and chloracetyl chloride are joined in a container according to mol ratio 1:2.5 ~ 5.5 and reacts，With ionic liquid as solvent，The mol ratio of ionic liquid and salicylamide is 5 10:1，React under 35 55 DEG C of normal pressures，Product 5 chloracetyl salicylamide is obtained by extraction with organic solvent after having reacted，5 prepared chloracetyl salicylamides and dibenzylamine are added in the mixed liquor of water and methanol，The volume ratio of described first alcohol and water is 2 ~ 4:1，50 ~ 70 DEG C of reacting by heating 2 ~ 4 hours，5 chloracetyl salicylamides and dibenzylamine mol ratio be: 1:1.0 ~ 1.2，After having reacted, decompression is distilled off solvent、It is recrystallized to give 5 (N，N dibenzyl amino) ethrisin.Production cost of the present invention is low, and synthesis step is short, yield is high, environmental pollution is little.
Description
Technical field
The invention belongs to organic chemistry filed, particularly relate to a kind of 5-(N, N-dibenzyl amino) ethrisin, tool
It it is a kind of 5-(N, N-dibenzyl amino) ethrisin preparation method for body.
Background technology
5-(N, N-dibenzyl amino) ethrisin is adrenoceptor blocker, labetalol
One of important intermediate in (Labetalol has another name called labetalol) pharmaceutical synthesis.Labetalol is α, beta adrenergic is subject to
Body blocade.Its selective exclusion α receptor, blocks beta receptor the most again simultaneously, and the ratio of α and beta receptor retardation, is 1 during intravenous:
6.9, beta receptor is act as relatively strong, the A-V that can slow down conducts, and can make decreased heart rate while blood pressure lowering, and cardiac output is
Reducing, coronary flow increases.Peripheral vascular resistance persistently reduces, and hemodynamics is optimum change, to lipids in serum, fat egg
Pseudobulbus Bletillae (Rhizoma Bletillae) uric acid concentration has no significant effect.Labetalol is controlling fall in various preoperative preparation, operation, hypertension danger
As etc. the urgent blood pressure lowering ideal medicament of hypertension situation.
5-(N, N-dibenzyl amino) ethrisin is as one of the important intermediate of labetalol medicine, La Beiluo
You are currently mainly by three kinds of methods:
A kind of method is to be obtained 5-ASA (yield 80.0% left side by salicylamide and chloroacetic chloride through Friedel-Crafts reaction
Right), then obtained 5-BrASA (yield 78%) by bromine and 5-ASA reaction, then by dibenzylamine and 5-bromine
Ethrisin synthesis 5-(N, N-dibenzyl amino) ethrisin, then by absolute ether and dry hydrogen chloride gas
5-(N, N-dibenzyl amino) ethrisin hydrochlorate is generated with the reaction of 5-(N, N-dibenzyl amino) ethrisin.
2-hydroxyl-5-(2-(1-phenyl is synthesized again by benzalacetone and 5-(N, N-dibenzyl amino) ethrisin hydrochlorate
Butylene-3-imido grpup) acetyl group) Benzoylamide, finally to 2-hydroxyl-5-(2-(1-phenylbutene-3-imido grpup) acetyl group)
Benzoylamide carries out catalytic hydrogenation and obtains product labetalol.
Second method is to prepare 5-(N, N mono-or two saves ammonia second phthalidyl) from 5-halogen acetic acid salicylic acid first vinegar and two joint amine
The cruel hydrochlorate of salicylic acid first, then obtain 5-(N, N mono-or two saves nitrilo acetic acid base) bigcatkin willow phthalein amine, the latter and 4-phenyl fourth through ammonolysis
The liquor-saturated solution of first of ketone-2 at ambient pressure with platinum oxide and charcoal as catalyst carry out reduce alkylation reaction, obtain corresponding amine,
The ethanol Ji liquid adding hydrogen chloride i.e. becomes the willow amine joint heart calmly.Calculating according to 5 acetyl bromide salicylic acid first vinegar, gross production rate is
22.4%。
The third method is 5-chloracetyl salicylamide and dibenzylamine effect obtains 5-(N, N dibenzyl ammonia acetyl group) water
Poplar acid amide, carries out reduction hydrocarbonylation the most again and makes labetalol.Gross production rate is 31.2%.
As the main synthesis material of labetalol (labetalol), need a large amount of production.Therefore reduction production cost, carry
High reaction yield, reduces the response time, the top-priority problem of Shi Ge enterprise.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of 5-(N, N-dibenzyl amino) acetyl water
Poplar amide preparation method, described this 5-(N, N-dibenzyl amino) ethrisin preparation method solves prior art
In preparation method cost high, the technical problem that yield is low.
The preparation method of one 5-of the present invention (N, N-dibenzyl amino) ethrisin, comprises the steps:
(1) mol ratio 1:2.5 ~ 5.5 of salicylamide and chloracetyl chloride, salicylamide and chloracetyl chloride are weighed, by bigcatkin willow
Amide and chloracetyl chloride join in a container and react, with ionic liquid as solvent, ionic liquid and salicylamide
Mol ratio be 5-10:1, under 35-55 DEG C of normal pressure react, product 5-chloracetyl is obtained by extraction with organic solvent after having reacted
Salicylamide,
(2) 5-chloracetyl salicylamide previous step reaction prepared and dibenzylamine add in the mixed liquor of water and methanol,
The volume ratio of described first alcohol and water is 2 ~ 4:1,50 ~ 70 DEG C of reacting by heating 2 ~ 4 hours, 5-chloracetyl salicylamide and dibenzylamine
Mol ratio be 1:1.0 ~ 1.2, after having reacted, decompression is distilled off solvent, is recrystallized to give 5-(N, N-dibenzyl amino) second
Acyl salicylamide.
The equation of above-mentioned reaction is described below:
Concrete, above-mentioned ionic liquid (N,N-Diethylethanamine hydrochloride-aluminum chloride) i.e. makees again Friedel-Crafts reaction for urging as solvent
Agent.
Further, described ionic liquid is N,N-Diethylethanamine hydrochloride-aluminum chloride.
Further, described organic solvent is ethyl acetate.
Further, after ionic liquid first set reaction, the ionic liquid that recycling obtains repeats this reaction needs and adds
Aluminum chloride, the amount of the aluminum chloride added calculates in molar ratio, aluminum chloride: salicylamide is 0.8-1.5:1.
Further, calculate in molar ratio, the triethylamine hydrochlorate in ionic liquid: aluminum chloride is 1:1.5 ~ 5.0.
Further, it is 45 DEG C that described anti-temperature controls preferable temperature.
Due to the fact that and have employed chloracetyl chloride and ionic liquid, 5-chloracetyl salicylamide can be directly synthesized.Tradition
Method typically need to be generated 5-ASA by salicylamide and excess acetyl chloride, then generates 5-halogen second with halogen such as bromine reaction
Acyl salicylamide.The present invention eliminates a reactions steps than the latter, improves productivity, reduces reaction cost.The additionally present invention
Ionic liquid used can reclaim to be recycled, then secondary response, only need to add the aluminum chloride of certain equivalent, and the present invention has
There is production cost low, the feature that synthesis step is short, yield is high, environmental pollution is little.
Can recycle after intermediate ion liquid reactions of the present invention is complete, as long as the ionic liquid after recovery adds 0.8-again
The aluminum chloride of 1.5 equivalents, still can use after reclaiming 5-6 time, and script three-step reaction is now reduced to two steps, carries
High reaction yield, yield reaches more than 90%.5-ASA and bromine reaction are obtained 5-acetyl bromide salicyloyl by original technique
Amine, this operational pollution is big, bigger to human injury.This step of upper chloracetyl chloride, is substantially reduced people as solvent without Nitrobenzol
Body injury and the pollution to environment.
The present invention compares with prior art, and its technological progress is significant.The present invention improves production labetalol (willow amine
The benzyl heart is fixed) reaction yield, decrease reactions steps, reduce production cost with this, reduce the response time, make that there is more preferable city
Field competition profit, also reduces the burden of patient simultaneously.
Detailed description of the invention
Below by specific embodiment, the present invention is expanded on further, but is not limiting as the present invention.
Raw material used in the present invention, reagent are commercially available AR/CP level.
Embodiment 1
A kind of 5-simple, efficient (N, N-dibenzyl amino) ethrisin preparation method, i.e. with salicylamide, chlorine
Chloroacetic chloride is raw material, and ionic liquid (N,N-Diethylethanamine hydrochloride-aluminum chloride), as solvent and catalyst, reacts at 45 DEG C, obtains
5-chloracetyl salicylamide, the 5-chloracetyl salicylamide obtained and dibenzylamine reaction obtain 5-(N, N-dibenzyl amino) acetyl
Salicylamide, specifically comprises the following steps that
Salicylamide (10g, 0.073mol), ionic liquid (N,N-Diethylethanamine hydrochloride-aluminum chloride) is added in there-necked flask
50g, to be mixed uniformly after, drip chloracetyl chloride (20.43g, 0.18mol) under room temperature, drip rear oil bath and control reaction temperature
Being 45 DEG C of reactions, reaction 2-3h, TCL monitor reaction, after having reacted, are extracted with ethyl acetate 3-4 time, are spin-dried for the second after extraction
Ethyl acetate layer obtains white solid 5-chloracetyl salicylamide 11.14g, and yield is 93%.
Addition 5-chloracetyl salicylamide (18.424g, 0.0679mol) in there-necked flask, dibenzylamine (14.725g,
0.0747mol), water and methyl alcohol mixed liquor (water 15ml, methanol 50ml), oil bath temperature control 60 DEG C reaction, boil off molten after having reacted
Agent obtains 5-(N, N-dibenzyl amino) ethrisin head product 18.87g, with twice of the mixed liquor recrystallization of first alcohol and water
After product 23.907g, productivity 94.1%.
Embodiment 2
A kind of 5-simple, efficient (N, N-dibenzyl amino) ethrisin preparation method, i.e. with salicylamide, chlorine
Chloroacetic chloride is raw material, and 1,2-dichloroethanes, as solvent and aluminum trichloride catalyst, reacts at 45 DEG C, obtains 5-chloracetyl water
Poplar amide, then the 5-chloracetyl salicylamide obtained and dibenzylamine reaction are obtained 5-(N, N-dibenzyl amino) acetyl salicylic acyl
Amine, specifically comprises the following steps that
In there-necked flask, add salicylamide (10g, 0.073mol), 1,2-dichloroethanes 50g, to be mixed uniformly after,
Add contained aluminum chloride in aluminum chloride 35g(and 50g ionic liquid identical in quality), then under room temperature, drip chloracetyl chloride
(20.43g, 0.18mol), drip rear oil bath controlling reaction temperature is 45 DEG C of reactions, and reaction 2-3h, TCL monitor reaction, reaction
After completing, it is extracted with ethyl acetate 3-4 time, is spin-dried for the ethyl acetate layer after extraction and obtains white solid 5-chloracetyl salicylamide
8.39g, yield is 70%.
Addition 5-chloracetyl salicylamide (8.39g, 0.039mol) in there-necked flask, dibenzylamine (8.48,0.043mol),
Water and methyl alcohol mixed liquor (water 15ml, methanol 50ml), oil bath temperature control 60 DEG C reaction, boil off solvent and obtain head product after having reacted
10.21g, with after twice of the mixed liquor recrystallization of first alcohol and water product 10.11g productivity 69.3%.
Friedel-Crafts reaction in this experiment is with 1, and 2-dichloroethanes is as solvent, and the consumption of 1,2-dichloroethanes is salicylamide
5 times of quality, extend the response time after reaction certain time and increase tri-chlorination aluminum amount all can not increase raising productivity, and this reaction is received
Rate less than with ionic liquid as the reaction of solvent, therefore with ionic liquid carry out reacting not only simple and also efficiently.
Embodiment 3
A kind of 5-simple, efficient (N, N-dibenzyl amino) ethrisin preparation method, i.e. with salicylamide, chlorine
Chloroacetic chloride is raw material, Nitrobenzol) as solvent and aluminum chloride as catalyst, react at 45 DEG C, obtain 5-chloracetyl water
Poplar amide, then the 5-chloracetyl salicylamide obtained and dibenzylamine reaction are obtained 5-(N, N-dibenzyl amino) acetyl salicylic acyl
Amine, specifically comprises the following steps that
In there-necked flask, add salicylamide (10g, 0.073mol), Nitrobenzol 50g, to be mixed uniformly after, add three
In aluminum chloride 35g(and 50g ionic liquid, contained aluminum chloride is identical in quality), then drip under room temperature chloracetyl chloride (20.43g,
0.18mol), drip rear oil bath controlling reaction temperature is 45 DEG C of reactions, and reaction 2-3h, TCL monitor reaction, after having reacted,
It is extracted with ethyl acetate 3-4 time, is spin-dried for the ethyl acetate layer after extraction and obtains white solid 5-chloracetyl salicylamide 9.34g,
Yield is 78%.
Addition 5-chloracetyl salicylamide (9.34g, 0.044mol) in there-necked flask, dibenzylamine (9.54,0.048mol),
Water and methyl alcohol mixed liquor (water 15ml, methanol 50ml), oil bath temperature control 60 DEG C reaction, boil off solvent and obtain head product after having reacted
12.35g, with after twice of the mixed liquor recrystallization of first alcohol and water product 15.47g, this step productivity 94.0%.
Friedel-Crafts reaction Nitrobenzol in this experiment is as solvent, and the consumption of Nitrobenzol is 5 times of salicylamide quality, instead
Should extend the response time after certain time and increase tri-chlorination aluminum amount all can not increase raising productivity, this reaction yield is less than using ion
Liquid as the reaction of solvent, therefore with ionic liquid carry out reacting not only simple and also efficiently.
Embodiment 4
Different temperatures is on reaction impact
A kind of 5-simple, efficient (N, N-dibenzyl amino) ethrisin preparation method, i.e. with salicylamide, chlorine
Chloroacetic chloride is raw material, and ionic liquid (N,N-Diethylethanamine hydrochloride-aluminum chloride), as solvent and catalyst, reacts at 45 DEG C, obtains
5-chloracetyl salicylamide, then the 5-chloracetyl salicylamide obtained and dibenzylamine reaction are obtained 5-(N, N-dibenzyl amino)
Ethrisin, specifically comprises the following steps that
Salicylamide (10g, 0.073mol), ionic liquid (N,N-Diethylethanamine hydrochloride-tri-chlorination is added in 5 there-necked flasks
Aluminum) 50g, to be mixed uniformly after, drip chloracetyl chloride (20.43g, 0.18mol) under room temperature, drip rear oil bath and control reaction temperature
Degree is respectively 35 DEG C, 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, and reaction 2-3h, TCL monitor reaction, after having reacted, extract by ethyl acetate
Take 3-4 time, be spin-dried for the ethyl acetate layer after extraction and obtain white solid 5-chloracetyl salicylamide 10.9g, 11.14g, 11.5g,
11.51g, 11.51g yield is 91%, 93%, 96%, 92.1%, 92.1%.
5 there-necked flasks are separately added into and walk 5-chloracetyl salicylamide (14.059g, the 0.066mol obtained；
14.464g, 0.0679mol；26.229g, 0.0701mol；14.315g, 0.0672mol；14.315g, 0.0672mol), dibenzyl
Amine (14.311,0.0726mol；14.725g, 0.0747mol；15.198g, 0.0771mol；14.567g, 0.0739mol；
14.567g, 0.0739mol), water and methyl alcohol mixed liquor (water 15ml, methanol 50ml), oil bath temperature control 60 DEG C reaction, reaction completes
After boil off solvent and obtain head product 23.301g, 24.110g, 25.005g, 23.998g, 24.011g, with the mixing of first alcohol and water
After twice of liquid recrystallization product 23.262g, 23.932g, 24.681g, 23.660g, 23.685g productivity 94.2%, 94.2%,
94.1%、94.1%、94.2%。
It can be seen that the one of present invention 5-simple, efficient (N, N-dibenzyl amino) second from the above and in table
The optimal reactive temperature of acyl salicylamide preparation method is 45 DEG C.
Embodiment 5
The amount of different chloracetyl chlorides is on reaction impact
A kind of 5-simple, efficient (N, N-dibenzyl amino) ethrisin preparation method, i.e. with salicylamide, chlorine
Chloroacetic chloride is raw material, and ionic liquid (N,N-Diethylethanamine hydrochloride-aluminum chloride), as solvent and catalyst, reacts at 45 DEG C, obtains
5-chloracetyl salicylamide, then the 5-chloracetyl salicylamide obtained and dibenzylamine reaction are obtained 5-(N, N-dibenzyl amino)
Ethrisin, specifically comprises the following steps that
Salicylamide (10g, 0.073mol), ionic liquid (N,N-Diethylethanamine hydrochloride-tri-chlorination is added in four there-necked flasks
Aluminum) 50g, to be mixed uniformly after, drip under room temperature the amount of chloracetyl chloride be respectively (20.43g, 0.18mol), (26.15g,
0.23mol), (32.69g, 0.29mol), (36.94g, 0.33mol) drip rear oil bath to control reaction temperature to be 45 DEG C, reaction
2-3h, TCL monitor reaction, after having reacted, are extracted with ethyl acetate 3-4 time, are spin-dried for the ethyl acetate layer after extraction and obtain white
Color solid 5-chloracetyl salicylamide 14.15g, 14.51g, 15.084g, 15.099g, 15.099g yield is 91%, 93.3%,
97%、97.1%、97.1%。
5 there-necked flasks are separately added into and walk 5-chloracetyl salicylamide (14.15g, the 0.066mol obtained；
14.51g, 0.0681mol；15.084g, 0.0708mol；15.099g, 0.0709；15.099,0.0709mol), dibenzylamine
(14.31g, 0.0726mol；14.764g, 0.0749mol；15.356g, 0.0779mol；15.375g, 0.0780mol；
15.375g, 0.0780mol), water and methyl alcohol mixed liquor (water 15ml, methanol 50ml), oil bath temperature control 60 DEG C reaction, reaction completes
After boil off solvent obtain head product 23.258,24.078,24997g, 25.110g, 25.112, with the mixed liquor weight of first alcohol and water
After crystallizing twice product 23.238g, 24.028g, 24.954g, 24.963g, 24.989g productivity 94.1%, 94.3%, 94.2%,
94.1%、94.2%。
It can be seen that the one of present invention 5-simple, efficient (N, N-dibenzyl amino) second from the above and in table
Used by acyl salicylamide preparation method, salicylamide and the amount of chloracetyl chloride, calculate, salicylamide: chloracetyl chloride is excellent in molar ratio
Electing 1:4 as, the volume production rate being further added by chloracetyl chloride increases limited.
Embodiment 6
In different ionic liquid, the amount of contained aluminum chloride is on reaction impact
A kind of 5-simple, efficient (N, N-dibenzyl amino) ethrisin preparation method, i.e. with salicylamide, chlorine
Chloroacetic chloride is raw material, and ionic liquid (N,N-Diethylethanamine hydrochloride-aluminum chloride), as solvent and catalyst, reacts at 45 DEG C, obtains
5-chloracetyl salicylamide, then the 5-chloracetyl salicylamide obtained and dibenzylamine reaction are obtained 5-(N, N-dibenzyl amino)
Ethrisin, specifically comprises the following steps that
Salicylamide (10g, 0.073mol), ionic liquid (N,N-Diethylethanamine hydrochloride-tri-chlorination is added in 5 there-necked flasks
Aluminum) 50g, aluminum chloride and the amount of triethylamine hydrochloride in ionic liquid, ratio calculates and is respectively as follows: 1.5,2,2.5,3:1,
To be mixed uniformly after, drip chloracetyl chloride under room temperature, (20.43g, 0.18mol) drip rear oil bath to control reaction temperature is 45
DEG C, reaction 2-3h, TCL monitor reaction, after having reacted, are extracted with ethyl acetate 3-4 time, are spin-dried for the ethyl acetate layer after extraction
Obtaining white solid 5-chloracetyl salicylamide 12.938g, 13.389g, 14.788g, 14.773g, 14.788g yield is
83.2%、86.1%、95.1%、95.0%、95.1%。
5 there-necked flasks are separately added into and walk 5-chloracetyl salicylamide (12.938g, the 0.061mol obtained；
13.389g, 0.063mol；14.788g, 0.0694mol；14.773g, 0.0694mol；14.788g, 0.0694mol), dibenzyl
Amine (13.227g, 0.0671mol；13.660g, 0.0693mol；15.048g, 0.0763mol；15.048g, 0.0763mol；
15.048g, 0.0763mol), water and methyl alcohol mixed liquor (water 15ml, methanol 50ml), oil bath temperature control 60 DEG C reaction, reaction completes
After boil off solvent and obtain head product 21.511g, 22.236g, 24.494g, 24.495g, 24.496g, with the mixing of first alcohol and water
After twice of liquid recrystallization product 21.477g, 22.205g, 24.461g, 24.435g, 24.461g productivity 94.1%, 94.2%,
94.2%、94.1%、94.2%。
From the above and table is it can be seen that the one of present invention 5-simple, efficient (N, N-dibenzyl amino) acetyl
In ionic liquid used by salicylamide preparation method, aluminum chloride and the amount of triethylamine hydrochloride, calculate, trichlorine in molar ratio
Change aluminum: triethylamine hydrochloride 2.5:1 is optimum.
In sum, the preparation method of a kind of 5-chloracetyl salicylamide of the present invention, owing to reactions steps shortens, locate afterwards
Reason operation simplifies, and reaction dissolvent achieves recycling, reduces production cost, and productivity has obtained bigger raising, and yield reaches
To more than 90%.
Foregoing is only the basic explanation under present inventive concept, and according to technical scheme make any etc.
Effect conversion, all should belong to protection scope of the present invention.
Claims (3)
1. the preparation method of 5-(N, N-dibenzyl amino) ethrisin, it is characterised in that comprise the steps:
(1) mol ratio 1:4.0 of salicylamide and chloracetyl chloride, salicylamide and chloracetyl chloride is weighed, by salicylamide and chlorine
Chloroacetic chloride joins in a container and reacts, with ionic liquid as the mol ratio of solvent, ionic liquid and salicylamide
For 5-10:1, react under 45 DEG C of normal pressures, after having reacted, product 5-chloracetyl salicylamide, institute are obtained by extraction with organic solvent
The ionic liquid stated is N,N-Diethylethanamine hydrochloride-aluminum chloride；Calculate in molar ratio, the triethylamine hydrochlorate in ionic liquid: three
Aluminum chloride is 1:4.0；
(2) 5-chloracetyl salicylamide previous step reaction prepared and dibenzylamine add in the mixed liquor of water and methanol, described
The volume ratio of first alcohol and water be 2 ~ 4:1,50 ~ 70 DEG C of reacting by heating 2 ~ 4 hours, rubbing of 5-chloracetyl salicylamide and dibenzylamine
Your ratio is 1:1.0 ~ 1.2, and after having reacted, decompression is distilled off solvent, is recrystallized to give 5-(N, N-dibenzyl amino) acetyl water
Poplar amide.
The preparation method of 5-the most according to claim 1 (N, N-dibenzyl amino) ethrisin, it is characterised in that:
Described organic solvent is ethyl acetate.
3. the preparation method of a kind of 5-(N, N-dibenzyl amino) ethrisin, it is characterised in that:
After ionic liquid first set reaction, the ionic liquid that recycling obtains repeats this reaction to be needed to add aluminum chloride, three added
The amount of aluminum chloride calculates in molar ratio, aluminum chloride: salicylamide is 0.8-1.5:1.
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