CN101560170A - Method for preparing 5-(bromoacetyl) salicylamide - Google Patents
Method for preparing 5-(bromoacetyl) salicylamide Download PDFInfo
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- CN101560170A CN101560170A CNA2009103024223A CN200910302422A CN101560170A CN 101560170 A CN101560170 A CN 101560170A CN A2009103024223 A CNA2009103024223 A CN A2009103024223A CN 200910302422 A CN200910302422 A CN 200910302422A CN 101560170 A CN101560170 A CN 101560170A
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Abstract
The invention belongs to the field of medical intermediate and particularly discloses a method for preparing a 5-(bromoacetyl) salicylamide. The 5-(bromoacetyl) salicylamide is obtained by acylation and bromination with the raw materials of salicylamide and acetyl chloride. The invention has the advantages of simple preparation method, easy industrial production, high product yield, high purity, etc.
Description
Technical field
The present invention relates to the medicine intermediate field, specifically relate to a kind of preparation method of 5-acetobrom salicylic amide.
Background technology
5-acetobrom salicylic amide is for making the important intermediate of cardiovascular agent labetalol hydrochloride (Trandate), and it also can be used for other organic synthesis.
Labetalol hydrochloride is the depressor with α, beta receptor retardation, it is first representative medicine of blocking α, beta receptor in the clinical application simultaneously,, hypotensive effect rapid-action because of having is strong, the characteristics of determined curative effect become one of widely used antihypertensive drug of American-European countries, and this medicine comes once coming out just to promote rapidly in countries in the world.This medicine is applicable to various hypertension, and is especially safe and effective to hypertensive crisis, also be applicable to the hypertension of coronary heart disease and with the hypertension of stenocardia or heart failure history, and also be simultaneously the choice drug that the expert is recommended as treatment gestation note blood pressure.The synthesis route of labetalol hydrochloride is more, main 3 kinds of synthetic methods, 1 is arranged) the dibenzylamine method; 2) 1-methyl-3-phenylpropylamine method; 3) ammonolysis process, these three kinds of synthetic methods are starting raw material with 5-acetobrom salicylic amide all, the 1st) the kind synthetic method is lower to the specification of quality of 5-acetobrom salicylic amide, but technology difficulty is big, limited the popularization of technology, the 2nd) and the 3rd) these two kinds of synthetic method ratios are easier to grasp, but its quality to starting raw material 5-acetobrom salicylic amide has the higher requirement of ratio, especially in the 5-acetobrom salicylic amide product that adopts the bromination method preparation 5,5-dibromo ethrisin and 3, the content of these two impurity of 5-dibromo ethrisin have strict restriction.
Along with the continuous increase of the demand of hypertensive medicine, the market requirement of labetalol hydrochloride is also in continuous increase, and therefore, the amount of purchase of 5-acetobrom salicylic amide is also increasing year by year.
The synthetic method of 5-acetobrom salicylic amide mainly contains two:
(1), Fu-Ke reaction method
Be its oldest synthetic method, salicylic amide under the aluminum chloride katalysis with the bromoacetyl chloride generation target product that reacts:
Defectives such as but bromoacetyl chloride character is active, and the quality instability causes the target product reaction yield too low, generally have only about 42%, and this technology exists and easily cause equipment corrosion, and " three wastes " are seriously polluted just are eliminated very soon.
(2), bromination method
Salicylic amide generates the 5-ethrisin with excess acetyl chloride under the aluminum chloride katalysis, get target product with bromine generation bromination reaction again:
This technology has the yield height, pollutes little characteristics, is present the most frequently used technology.But this technology is also deposited and is difficult to difficult points such as separation such as severe reaction conditions, impurity in products.The popularization of labetalol hydrochloride new preparation process has improved the specification of quality of 5-acetyl bromide salicylic amide.At present; the improvement of bromination method is concentrated on 5-acetyl bromide salicylic amide product yield and qualitatively mostly; as Xu Juanjuan etc. in " preparation of 5-acetyl bromide salicylic amide " (referring to fine-chemical intermediate [J]; 2006; 36 (2): 32-33) the synthetic 5-acetyl bromide salicylic amide of the bromination method of reporting in the literary composition; with acetate is that solvent makes 5-ethrisin and bromine generation bromination reaction generate target product, and yield can reach 93.2%.But the present inventor operates according to document record, and this technology of the first can't repeat, and yield can't reach 90%, generally has only 80%; It two is this technology catalyzer useless, and bromine drips more than half, can produce problems such as reaction initiations suddenly, sudden temperature rise, causes reaction to be difficult to control; It three is in this process goal product 5; 5-dibromo ethrisin and 3; the content of these two impurity of 5-dibromo ethrisin can not be lower than 10%; promptly use alcohol to do further refinement treatment; the content of these two impurity is still than higher (generally having about 5%), and this will cause the decline of target product 5-acetyl bromide salicylic amide yield.
Appearance along with the labetalol hydrochloride new preparation process, be above-mentioned mention 2) 1-methyl-3-phenylpropylamine method and 3) ammonolysis process prepares labetalol hydrochloride, these two methods are had higher requirement to 5-acetobrom salicylic amide product purity, content to its impurity has had stricter restriction (to require 5, content≤0.5% of 5-dibromo ethrisin, 3, content≤0.1% of 5-dibromo ethrisin).Above-mentioned technology obviously can't reach the new demand of 5-acetobrom salicylic amide, satisfies the demand in market.
Patent application CN200810155046 discloses a kind of method for preparing ethrisin, refers in particular to use triethyl ammonium-aluminum chloride (C
2H
5)
3NHCL-NALCL
3(N=2.0～2.5) ionic liquid is catalyzer and solvent, catalysis salicylic amide acylations prepares the novel method of ethrisin, specifically be under nitrogen protection when reactant bigcatkin willow acid amides temperature in ionic liquid is raised to 32-46 ℃, it is synthetic to add excess acetyl chloride, but, this method of one only relates to the preparation of 5-acetobrom salicylic amide intermediate ethrisin, its two, this method is different fully with the present patent application intermediates preparation; Wang Bibo etc. at the research of 5-chlorosamide " still synthetic " (referring to using chemical industry [J], 2007,36 (6): the preparation method who discloses the synthetic 5-chlorosamide of an a kind of still 590-592.), it is to be feedstock production 5-chlorosamide with 5-chloro-salicylic acid, sulfur oxychloride, ammonia, mainly solving the traditional technology intermediate need separate purification and just can carry out next step prepared in reaction 5-chlorosamide, one, the structure of the target product of this method exists essence different with the present patent application, its two, the problem difference of solution.
Therefore, providing the preparation method of a kind of high yield, pollution is little, foreign matter content is low 5 acetobrom salicylic amides is needs very.
Summary of the invention
For overcoming the problem that above-mentioned prior art exists; the preparation method who the purpose of this invention is to provide a kind of 5-acetobrom salicylic amide; described method is to be starting raw material with salicylic amide and Acetyl Chloride 98Min., makes target product 5-acetobrom salicylic amide through acylation reaction, bromination reaction.
The objective of the invention is to be implemented by the following technical programs:
A kind of preparation method of 5-acetobrom salicylic amide comprises the steps:
(1) 5-ethrisin preparation
A, salicylic amide and Acetyl Chloride 98Min. 1: 1.0 in molar ratio～1.5 feeds intake, and is solvent with oil of mirbane and chloroparaffin mixture, at AlCl
3Catalysis is reaction down, does centrifugal treating after the reaction product hydrolysis and obtains crude product 1;
B, will make behind the crude product 1 of ammonia solvent suction filtration handle, gained filtrate transfers to pH=3 ± 2 with hydrochloric acid, after the crystallization centrifugal treating of separating out crude product 2;
C, crude product 2 usefulness ethanol are made the 5-ethrisin;
(2) 5-acetobrom salicylic amide preparation
D, 5-ethrisin and bromine 1: 1.0 in molar ratio～1.5 feed intake, with vinyl acetic monomer, triethylamine with contain C
1-4The mixture of lower aliphatic alcohols be solvent, be lower than 60 ℃ of reactions down in temperature, reaction product is done centrifugal treating and is obtained 5-acetobrom salicylic amide.
Adopt oil of mirbane and chloroparaffin mixture solvent in the above-mentioned A step as acylation reaction; its reason is: oil of mirbane can be the dissolving of the intermediate product of reaction; if but solvent all adopts oil of mirbane; when doing centrifugal treating after the reaction product hydrolysis; centrifugal material can be difficult to do centrifugal treating because of containing oil of mirbane; and oil of mirbane can be entrained to the catalyzer aluminum chloride in the reaction product, thereby influences quality product.
In the above-mentioned B step,, reaction mass dissolving back suction filtration must be removed because of there being mechanical impurity in the aluminum chloride raw material unavoidably.Utilize the phenolic hydroxyl group of 5-ethrisin to have acidity, can adopt alkali that it is dissolved, can use sheet alkali (flaky NaOH), but adopt the words of sheet alkali dissolution 5-ethrisin, when doing the acid out processing thereafter, can cause reacting too fast, have inorganic salt and be wrapping in the material, thereby influence product content.And adopt ammonia solvent 5-ethrisin, and when acid out was handled, speed of response was slow, and product content can be than higher; In addition, carry out acid out again behind the employing ammonia solvent 5-ethrisin and handle, be wrapped in the aluminum chloride in the material in the time of can effectively removing hydrolysis.Aluminum chloride content in the 5-ethrisin is few more good more, and this is because aluminum chloride can cause 3 to No. 3 position catalytic brominations when 5-ethrisin bromination, 5-dibromo thing promptly 3, the generation of this impurity of 5-dibromo ethrisin.
In the above-mentioned D step, the solvent that adopts contains triethylamine, can the hydrogen bromide that bromination reaction produces be neutralized, suppress the generation of dibromo thing and many bromides, in addition, triethylamine can dissolve dibromo thing and many bromides, and the content of dibromo thing and many bromides improves product purity in the minimizing target product.
As preferably, according to preparation method of the present invention, wherein, salicylic amide and Acetyl Chloride 98Min. 1: 1.2 in molar ratio～1.3 feed intake in the above-mentioned A step, feed intake to adopt the mode that slowly drips.Feed intake and take the mode that slowly drips, can effectively alleviate the local excessive and too fast situation that causes side reaction to take place of reaction of material.
As preferably, according to preparation method of the present invention, wherein, AlCl in the above-mentioned A step
3Catalysis is temperature≤40 ℃ of reaction down; The temperature of hydrolysis≤70 ℃.Temperature of reaction adopts temperature programming, can effectively control the generation of side reaction, improves product yield.
As preferably, according to preparation method of the present invention, wherein, chloroparaffin is methylene dichloride, ethylene dichloride or tetrachloroethane in the above-mentioned A step.
As preferably, according to preparation method of the present invention, wherein, hydrochloric acid is from the hydrochloric acid regenerant of one of A step salicylic amide and excess acetyl chloride product in the above-mentioned B step.
As preferably,, wherein, add gac before suction filtration is handled in the above-mentioned B step according to preparation method of the present invention.The 5-ethrisin in use can produce oxidation stain, can add the gac processing of decolouring before the suction filtration mechanical impurity for this reason.
As preferably, according to preparation method of the present invention, wherein, with the refining vacuum drying that also comprises of ethanol, vacuum tightness is wanted 〉=0.9kgf/cm in the above-mentioned C step
2
As preferably, according to preparation method of the present invention, wherein, 5 ethrisins and bromine 1: 1.3 in molar ratio～1.5 feed intake in the above-mentioned D step, the mode that bromine adopts slowly and disperses to drip.Disperse to drip bromine, can suppress the generation of dibromo thing and many bromides.
As preferably,, wherein, contain C in the above-mentioned D step according to preparation method of the present invention
1-4Lower alcohol be selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol.
As more preferably,, wherein, contain C in the above-mentioned D step according to preparation method of the present invention
1-4Lower aliphatic alcohols be propyl carbinol.
As preferably,, wherein, apply mechanically after the mother liquor distillation that centrifugal treating obtains in the above-mentioned D step according to preparation method of the present invention.Described mother liquor is because of containing bromo element (hydrogen bromide, bromo alkane), can play katalysis to bromination reaction, and add other catalyzer, can produce the catalytic bromination effect to No. 3 positions of 5-ethrisin as aluminum chloride, Hydrogen bromide, cause 3, the generation of 5-dibromo thing (3,5-dibromo ethrisin); And without catalyzer, in the bromination reaction process, bromine drips the initiation suddenly of more than half afterreactions, temperature of reaction meeting temperature runaway, and dibromo thing and many bromides are many, cause target product off quality.
In addition, the building-up reactions of 5-ethrisin is Fu-Ke reaction, and one of condition of reaction is to guarantee that temperature is low, to prevent temperature runaway, to improve the quality and the yield of product.In addition, there are a large amount of hydrogen chloride gas to emit in the reaction, carry out tail gas absorption work, note personal protection work.
In 5-acetobrom salicylic amide synthetic, mainly be that two requirements are arranged: the purity of products obtained therefrom and yield.Owing in bromination reaction, the generation of many bromides is arranged unavoidably, is mainly 5 in this reaction, 5-dibromo ethrisin and 3,5-dibromo ethrisin.Temperature of reaction, material proportion and choice of Solvent are control 5,5-dibromo ethrisin and 3, the key of 5-dibromo ethrisin content.
After testing, the quality product of the present invention's preparation can reach following standard:
1. 5-ethrisin (5-ASA)
Appearance white is to off-white powder
Content 〉=99.0% (HPLC)
Individual event impurity≤0.5%
Total impurities≤1.0%
222～228 ℃ of fusing points (part is decomposed)
Weight loss on drying≤0.5%
2. 5-acetobrom salicylic amide (5-BrASA)
Appearance white is to off-white powder
Fusing point 200-210 ℃
Main content 〉=95% (HPLC)
5-ethrisin≤4.0%
5,5-dibromo ethrisin≤0.5%
3,5-dibromo ethrisin≤0.1%
Weight loss on drying≤0.5%
Compared with prior art, the present invention has following advantage:
Raw material sources of the present invention are conveniently abundant, cost is low, the production that the preparation method is simple, be convenient to industrially scalable, pollute little, the product yield height, 5-acetobrom salicylic amide has purity height, characteristics that foreign matter content is low, can satisfy the high request of labetalol hydrochloride novel preparation method to raw materials quality well.
Description of drawings
Fig. 1 is a 5-ethrisin preparation technology schematic flow sheet in the embodiment of the invention;
Fig. 2 is a 5-acetobrom salicylic amide preparation technology schematic flow sheet in the embodiment of the invention.
Embodiment
Below in conjunction with embodiment, be described more specifically content of the present invention.Should be appreciated that enforcement of the present invention is not limited to the following examples, all will fall into protection domain of the present invention any pro forma accommodation and/or the change that the present invention made.
In the present invention, if not refer in particular to, all part, per-cents are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is commonly used.
Embodiment 1
(1), 5-ethrisin (5-ASA) preparation
The emptying of acidylate still connects the salt acid-restoring plant, under the condition of normal pressure, throws 1000 kilograms of ethylene dichloride; 200 kilograms in oil of mirbane, freezing temperature control are thrown 500 kilograms of aluminum chlorides less than 10 ℃; slowly drop into 250 kilograms of salicylic amides again, slowly 145 kilograms of dripping acetyl chloride (3 hours, temperature control is less than 10 ℃).Then in 20 ℃ of insulations 6 hours.Put into 100 kilograms of 1200 kg of water and hydrochloric acid in the hydrolysis kettle, the material that top reaction is obtained is slowly put into hydrolysis kettle and is hydrolyzed, and temperature control is less than 60 ℃, and then in 60 ℃ of insulations 2 hours, centrifugal treating got crude product 1.With the centrifugal mother liquor layering that obtains, retortable recovery ethylene dichloride of organic phase and oil of mirbane.Crude product 1 drops into the 1# refining kettle, puts 1000 kg of water, is warmed up to 40 ℃, slowly drips 200 kilograms of ammoniacal liquor and makes material dissolution, adds 5 kilograms of activated carbon, stirs half an hour, suction filtration.To filtrate pH ≈ 3, centrifugal treating gets 5-ASA crude product 2 to filtrate then with the about 250 kilograms of acid outs of the hydrochloric acid that reclaims in the acylation reaction.Again crude product 2 is thrown back the 2# refining kettle, throws 1000 kilograms of ethanol, steam be warming up to 80 ℃ refluxed 1 hour after cold water be cooled to normal temperature.Centrifugal treating gets the 5-ASA elaboration.100 ℃ of vacuum dryings get 304 kilograms of 5-ASA products (yield 93%), and vacuum tightness is greater than 0.9kgf/cm
2The 5-ASA product that present embodiment obtains, outward appearance is a white powder, and after testing, its m.p. is 222～225 ℃, and HPLC content is 99.23%.Enter next step,
(2), 5-acetobrom salicylic amide (5-BrASA) preparation
Under the normal pressure, throw 400 kilograms in mother liquor, 150 kilograms of triethylamines, 200 kilograms of Virahols, 500 kilograms of vinyl acetic monomers, 230 kilograms of 5-ASA products to the bromination still.The cooling temperature control is less than 50 ℃, slowly disperse to drip the mixing liquid of 210 kilograms of bromines and 300 kilograms of Virahols, in 50 ℃ of insulations 10 hours, be cooled to normal temperature then, get 290 kilograms of 5-BrASA products (yield 88%) in 100 ℃ of vacuum dryings after the centrifugal treating, can apply mechanically after the centrifugal mother liquor distillation that obtains.The 5-BrASA product that present embodiment obtains, outward appearance is a white powder, after testing, its m.p. is 205～208 ℃, and HPLC content 5-BrASA is 95.21%, 5, and 5-dibromo ethrisin is 0.35%, 3,5-dibromo ethrisin is 0.04%, and the 5-ethrisin is 4.4%.
Embodiment 2
(1), 5-ethrisin (5-ASA) preparation
The emptying of acidylate still connects the salt acid-restoring plant, under the condition of normal pressure, throws 1200 kilograms of tetrachloroethane; 100 kilograms in oil of mirbane, freezing temperature control are thrown 550 kilograms of aluminum chlorides less than 20 ℃; slowly drop into 250 kilograms of salicylic amides again, slowly 175 kilograms of dripping acetyl chloride (5 hours, temperature control is less than 30 ℃).Then in 30 ℃ of insulations 4 hours.Put into 150 kilograms of 1200 kg of water and hydrochloric acid in the hydrolysis kettle, the material that top reaction is obtained is slowly put into hydrolysis kettle and is hydrolyzed, and temperature control is less than 50 ℃, and then in 50 ℃ of insulations 1 hour, centrifugal treating got crude product 1.With the centrifugal mother liquor layering that obtains, tetrachloroethane and oil of mirbane are reclaimed in the organic phase distillation.Crude product 1 drops into the 1# refining kettle, puts 1000 kg of water, is warmed up to 50 ℃, slowly drips 150 kilograms of ammoniacal liquor and makes material dissolution, adds 5 kilograms of activated carbon, stirs half an hour, suction filtration.To filtrate pH=3, centrifugal treating gets 5-ASA crude product 2 to filtrate then with the about 200 kilograms of acid outs of the hydrochloric acid that reclaims in the acylation reaction.Again crude product 2 is thrown back the 2# refining kettle, throws 1000 kilograms of ethanol, steam be warming up to 80 ℃ refluxed 1 hour after cold water be cooled to normal temperature.Centrifugal treating gets the 5-ASA elaboration.100 ℃ of vacuum dryings get 310 kilograms of 5-ASA products (yield 95%), and vacuum tightness is greater than 0.9kgf/cm
2The 5-ASA product that present embodiment obtains, outward appearance is a white powder, and after testing, its m.p. is 223～227 ℃, and HPLC content is 99.45%.Enter next step,
(2), 5-acetobrom salicylic amide (5-BrASA) preparation
Under the normal pressure, throw 300 kilograms in mother liquor, 200 kilograms of triethylamines, 200 kilograms of propyl carbinols, 500 kilograms of vinyl acetic monomers, 230 kilograms of 5-ASA products to the bromination still.The cooling temperature control is less than 40 ℃, slowly disperse to drip the mixing liquid of 270 kilograms of bromines and 300 kilograms of vinyl acetic monomers, in 40 ℃ of insulations 10 hours, be cooled to normal temperature then, get 302 kilograms of 5-BrASA products (yield 91%) in 100 ℃ of vacuum dryings after the centrifugal treating, can apply mechanically after the centrifugal mother liquor distillation that obtains.The 5-BrASA product that present embodiment obtains, outward appearance is a white powder, after testing, its m.p. is 202～207 ℃, and HPLC content 5-BrASA is 95.68%, 5, and 5-dibromo ethrisin is 0.43%, 3,5-dibromo ethrisin is 0.05%, and the 5-ethrisin is 3.82%.
Embodiment 3
(1), 5-ethrisin (5-ASA) preparation
The emptying of acidylate still connects the salt acid-restoring plant, under the condition of normal pressure, throws 1000 kilograms of methylene dichloride; 600 kilograms in oil of mirbane, freezing temperature control are thrown 600 kilograms of aluminum chlorides less than 30 ℃; slowly drop into 250 kilograms of salicylic amides again, slowly 215 kilograms of dripping acetyl chloride (2 hours, temperature control is less than 30 ℃).Then in 40 ℃ of insulations 3 hours.Put into 110 kilograms of 1200 kg of water and hydrochloric acid in the hydrolysis kettle, the material that top reaction is obtained is slowly put into hydrolysis kettle and is hydrolyzed, and temperature control is less than 40 ℃, and then in 40 ℃ of insulations 1 hour, centrifugal treating got crude product 1.With the centrifugal mother liquor layering that obtains, retortable recovery methylene dichloride of organic phase and oil of mirbane.Crude product 1 drops into the 1# refining kettle, puts 1000 kg of water, is warmed up to 20 ℃, slowly drips 100 kilograms of ammoniacal liquor and makes material dissolution, adds 5 kilograms of activated carbon, stirs half an hour, suction filtration.To filtrate pH=3, centrifugal treating gets 5-ASA crude product 2 to filtrate then with the about 150 kilograms of acid outs of the hydrochloric acid that reclaims in the acylation reaction.Again crude product 2 is thrown back the 2# refining kettle, throws 1000 kilograms of ethanol, steam be warming up to 80 ℃ refluxed 1 hour after cold water be cooled to normal temperature.Centrifugal treating gets the 5-ASA elaboration.100 ℃ of vacuum dryings get 315 kilograms of 5-ASA products (yield 96%), and vacuum tightness is greater than 0.9kgf/cm
2The 5-ASA product that present embodiment obtains, outward appearance is a white powder, and after testing, its m.p. is 223～226 ℃, and HPLC content is 99.65%.Enter next step,
(2), 5-acetobrom salicylic amide (5-BrASA) preparation
Under the normal pressure, throw 500 kilograms in mother liquor, 100 kilograms of triethylamines, 250 kilograms of ethanol, 500 kilograms of vinyl acetic monomers, 230 kilograms of 5-ASA products to the bromination still.Freezing temperature control is less than 30 ℃, slowly disperse to drip the mixing liquid of 310 kilograms of bromines and 300 kilograms of mother liquors, in 30 ℃ of insulations 10 hours, be cooled to normal temperature then, get 296 kilograms of 5-BrASA products (yield 89%) in 100 ℃ of vacuum dryings after the centrifugal treating, can apply mechanically after the centrifugal mother liquor distillation that obtains.The 5-BrASA product that present embodiment obtains, outward appearance is a white powder, after testing, its m.p. is 201～209 ℃, and HPLC content 5-BrASA is 95.92%, 5, and 5-dibromo ethrisin is 0.48%, 3,5-dibromo ethrisin is 0.08%, and the 5-ethrisin is 3.24%.
Embodiment 4
(1), 5-ethrisin (5-ASA) preparation
The emptying of acidylate still connects the salt acid-restoring plant, under the condition of normal pressure, throws 1200 kilograms of tetrachloroethane; 150 kilograms in oil of mirbane, freezing temperature control are thrown 600 kilograms of aluminum chlorides less than 30 ℃; slowly drop into 250 kilograms of salicylic amides again, slowly 186 kilograms of dripping acetyl chloride (1 hour, temperature control is less than 30 ℃).Then in 40 ℃ of insulations 6 hours.Put into 150 kilograms of 1200 kg of water and hydrochloric acid in the hydrolysis kettle, the material that top reaction is obtained is slowly put into hydrolysis kettle and is hydrolyzed, and temperature control is less than 70 ℃, and then in 70 ℃ of insulations 1 hour, centrifugal treating got crude product 1.With the centrifugal mother liquor layering that obtains, retortable recovery tetrachloroethane of organic phase and oil of mirbane.Crude product 1 drops into the 1# refining kettle, puts 1000 kg of water, is warmed up to 70 ℃, slowly drips 200 kilograms of ammoniacal liquor and makes material dissolution, adds 5 kilograms of activated carbon, stirs half an hour, suction filtration.To filtrate pH ≈ 3, centrifugal treating gets 5-ASA crude product 2 to filtrate then with the about 250 kilograms of acid outs of the hydrochloric acid that reclaims in the acylation reaction.Again crude product 2 is thrown back the 2# refining kettle, throws 1000 kilograms of ethanol, steam be warming up to 80 ℃ refluxed 1 hour after cold water be cooled to normal temperature.Centrifugal treating gets the 5-ASA elaboration.100 ℃ of vacuum dryings get 308 kilograms of 5-ASA products (yield 94.4%), and vacuum tightness is greater than 0.9kgf/cm
2The 5-ASA product that present embodiment obtains, outward appearance is a white powder, and after testing, its m.p. is 224～226 ℃, and HPLC content is 99.73%.Enter next step,
(2), 5-acetobrom salicylic amide (5-BrASA) preparation
Under the normal pressure, throw 500 kilograms in mother liquor, 100 kilograms of triethylamines, 150 kilograms of isopropylcarbinols, 500 kilograms of vinyl acetic monomers, 230 kilograms of 5-ASA products to the bromination still.Freezing temperature control is less than 25 ℃, slowly disperse to drip the mixing liquid of 310 kilograms of bromines and 300 kilograms of vinyl acetic monomers, in 25 ℃ of insulations 10 hours, be cooled to normal temperature then, get 296 kilograms of 5-BrASA products (yield 89%) in 100 ℃ of vacuum dryings after the centrifugal treating, can apply mechanically after the centrifugal mother liquor distillation that obtains.The 5-BrASA product that present embodiment obtains, outward appearance is a white powder, after testing, its m.p. is 201～209 ℃, and HPLC content 5-BrASA is 95.94%, 5, and 5-dibromo ethrisin is 0.46%, 3,5-dibromo ethrisin is 0.07%, and the 5-ethrisin is 3.18%.
Comparative example 1
Add 100 milliliters of vinyl acetic monomers in 300 milliliters of there-necked flasks, the cooling temperature control stirs down slowly Dropwise 50 gram bromine less than 20 ℃, drips in 10 minutes.Add 250 milliliters of 5 ethrisins, 50 grams and vinyl acetic monomers in 500 milliliters of four-hole boiling flasks, the water-bath temperature control stirs down about 30 ℃, slowly drips above bromine solutions.About 30 minutes, drip and remove 30 milliliters of bromine solutions, the reaction solution reddish-brown takes off more and more darker, reaction does not start, continue dripping bromine solution, splash into as 50 milliliters of bromine solutions, temperature of reaction raises suddenly, reaction is activated, be controlled at and continue dripping bromine solution about 30 ℃, dropwised in 3 hours, insulation reaction is suction filtration after 12 hours, vacuum-drying gets grey powder 56 grams, its m.p. is 201～207 ℃, and HPLC content 5-BrASA is 75.22%, 5, and 5-dibromo ethrisin is 10.35%, 3,5-dibromo ethrisin is 4.65%, and the 5-ethrisin is 9.56%.
Comparative example 2
Add 100 milliliters of vinyl acetic monomers in 300 milliliters of there-necked flasks, the cooling temperature control stirs down slowly Dropwise 50 gram bromine less than 20 ℃, drips in 10 minutes.In 500 milliliters of four-hole boiling flasks, add 250 milliliters of 5-ethrisin 50 grams and vinyl acetic monomers, add 2 milliliters of Hydrogen bromides again, the water-bath temperature control is about 40 ℃, stir down, slowly drip several above bromine solutions, the reaction solution reddish-brown is slowly taken off, and reaction starts, and continues dripping bromine solution, dropwised in 3 hours, 40 ℃ of insulation reaction suction filtration after 12 hours, vacuum-drying get pale powder 58 grams, and its m.p. is 200～208 ℃, HPLC content 5-BrASA is 81.46%, 5,5-dibromo ethrisin is 8.44%, 3,5-dibromo ethrisin is 5.42%, and the 5-ethrisin is 4.53%.
Comparative example 3
Add 100 milliliters of anhydrous diethyl ethers in 300 milliliters of there-necked flasks, the cooling temperature control stirs down slowly Dropwise 54 gram bromines less than 10 ℃, drips in 10 minutes.In 500 milliliters of four-hole boiling flasks, add 250 milliliters of 5-ethrisin 50 grams and anhydrous diethyl ethers, add aluminum chloride 0.5 gram again, flask connects 30 centimetres of spherical condensation tubes, warming-in-water is about 32 ℃, anhydrous diethyl ether begins to reflux, and stirs down, slowly drips above bromine solutions, there is the reddish-brown cigarette to emerge in the reaction flask, continue dripping bromine solution, dropwised 1 hour postcooling suction filtration of back flow reaction in 2 hours, vacuum-drying gets white powder 55 grams, its m.p. is 197～205 ℃, and HPLC content 5-BrASA is 43.35%, 5,5-dibromo ethrisin is 20.24%, 3,5-dibromo ethrisin is 13.53%, and the 5-ethrisin is 23.37%.
Claims (10)
1. the preparation method of a 5-acetobrom salicylic amide comprises the steps:
(1) 5-ethrisin preparation
A, salicylic amide and Acetyl Chloride 98Min. 1: 1.0 in molar ratio～1.5 feeds intake, and is solvent with oil of mirbane and chloroparaffin mixture, reacts under AlCl3 catalysis, does centrifugal treating after the reaction product hydrolysis and obtains crude product 1;
B, will make behind the crude product 1 of ammonia solvent suction filtration handle, gained filtrate transfers to pH=3 ± 2 with hydrochloric acid, after the crystallization centrifugal treating of separating out crude product 2;
C, crude product 2 usefulness ethanol are made the 5-ethrisin;
(2) 5-acetobrom salicylic amide preparation
D, 5-ethrisin and bromine 1: 1.0 in molar ratio～1.5 feed intake, with vinyl acetic monomer, triethylamine and the mixture that contains the lower aliphatic alcohols of C1-4 is solvent, be lower than 60 ℃ of reactions down in temperature, reaction product is done centrifugal treating and is obtained 5-acetobrom salicylic amide.
2. preparation method as claimed in claim 1 is characterized in that, salicylic amide and Acetyl Chloride 98Min. 1: 1.2 in molar ratio～1.3 feed intake in the described A step, feeds intake to adopt the mode that slowly drips.
3. preparation method as claimed in claim 1 is characterized in that, following temperature≤40 ℃ of reaction of AlCl3 catalysis in the described A step; The temperature of hydrolysis≤70 ℃.
4. preparation method as claimed in claim 1 is characterized in that, chloroparaffin is methylene dichloride, ethylene dichloride or tetrachloroethane in the described A step.
5. preparation method as claimed in claim 1 is characterized in that, hydrochloric acid is from the hydrochloric acid regenerant of one of A step salicylic amide and excess acetyl chloride product in the described B step.
6. preparation method as claimed in claim 1 is characterized in that, adds gac before suction filtration is handled in the described B step.
7. preparation method as claimed in claim 1 is characterized in that, also comprises vacuum drying with ethanol after refining in the described C step, and vacuum tightness is wanted 〉=0.9kgf/cm2.
8. preparation method as claimed in claim 1 is characterized in that, 5-ethrisin and bromine 1: 1.3 in molar ratio～1.5 feed intake in the described D step, the mode that bromine adopts slowly and disperses to drip.
9. preparation method as claimed in claim 1 is characterized in that, the lower aliphatic alcohols that contains C1-4 in the described D step is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol.
10. preparation method as claimed in claim 1 is characterized in that, applies mechanically after the mother liquor distillation that centrifugal treating obtains in the described D step.
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| CN113698316B (en) * | 2021-09-03 | 2022-04-19 | 安徽美致诚药业有限公司 | Preparation method of labetalol hydrochloride |
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