CN102060731B - Method for preparing 2-acetamido-6-acetylphenol - Google Patents
Method for preparing 2-acetamido-6-acetylphenol Download PDFInfo
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- CN102060731B CN102060731B CN 201010571580 CN201010571580A CN102060731B CN 102060731 B CN102060731 B CN 102060731B CN 201010571580 CN201010571580 CN 201010571580 CN 201010571580 A CN201010571580 A CN 201010571580A CN 102060731 B CN102060731 B CN 102060731B
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Abstract
The invention discloses a method for preparing 2-acetamido-6-acetylphenol. In the method, 2-amino-4-chlorophenol is taken as a main starting material, and the 2-acetamido-6-acetylphenol is prepared through acylation reaction, rearrangement reaction and hydrogenation reaction. The method comprises the following steps: a. acylation reaction: carrying out acylation reaction between the 2-amino-4-chlorophenol and acetyl chloride in a solvent to generate an intermediate I; b. rearrangement reaction: adding the intermediate I, AlCl3 and a cosolvent to a vessel, heating for reacting to generate an intermediate II, and extracting the purified intermediate II; and c. hydrogenation reaction: adding the intermediate II, Pd/C, an acid binding agent and a solvent to the reaction vessel, heating and introducing hydrogen, reacting to obtain the target product, and extracting and purifying the target product. The method has the advantages of wide and available raw material source, short synthetic route, low cost, less pollution and the like, and is applicable to large-scale production.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to the method for a kind of 2-of preparation acetamido-6-ethyl ketone base phenol.
Background technology
Pranlukast (Pranlukast) is that the leukotriene of Japanese ONO Pharmaceutical Co., Ltd. exploitation is closely questioned anti-dose, be a gas official treating asthma, go on the market in Japan in nineteen ninety-five, bronchial asthma is a kind of common disease of respiratory system, frequently-occurring disease, pranlukast is by blocking-up leukotriene receptor and leukotriene C, D4, thereby E4 is in conjunction with bronchial asthma is played therapeutic action, these product compare with the like product of listing, curative effect is better than Ibudilast (Ibudilast), Zafirlukast (Zafirlukast), be characterized in making patient's pulmonary function obviously to improve, can reduce the consumption of reflunomide and bronchodilator, the pranlukast structural formula is:
2-acetamido-6-ethyl ketone base phenol is the original intermediate of pranlukast, is white or off-white color pressed powder, and its structural formula is:
The main synthetic route of existing 2-acetamido-6-ethyl ketone base phenol is: is raw material with para hydroxybenzene phenol, by acetylize, resets, and nitrated, just can obtain the finished product after debrominate and the acidylate, exist route long, the cost height pollutes shortcomings such as big.
Summary of the invention
The object of the present invention is to provide the method for a kind of 2-of preparation acetamido-6-ethyl ketone base phenol.
Purpose of the present invention can be achieved through the following technical solutions:
Be that the synthetic route of the synthetic 2-acetamido of starting raw material-6-ethyl ketone base phenol is with 2-amino-4-chlorophenol:
The above-mentioned method for preparing 2-acetamido-6-ethyl ketone base phenol, it is with 2-amino-4-chlorophenol is that main starting raw material prepares 2-acetamido-6-ethyl ketone base phenol by acylation reaction, rearrangement reaction, hydrogenation reaction:
A, acylation reaction: in solvent, 2-amino-4-chlorophenol and Acetyl Chloride 98Min. generation acylation reaction generate intermediate compound I: acetic acid (2-acetylaminohydroxyphenylarsonic acid 4-chlorine) phenyl ester, temperature of reaction is 60-75 ℃, reaction times 1h-5h, reaction finishes and washs purify intermediates I, need in the reaction process to add acid binding agent, the mol ratio of 2-amino-4-chlorophenol, Acetyl Chloride 98Min. and acid binding agent is 1: 2～5: 1～5, and the mass ratio of 2-amino-4-chlorophenol and solvent is 1: 2.5～6; Described solvent is toluene, benzene, methylene dichloride, chloroform, DMF (dimethyl formamide), DMSO (dimethyl sulfoxide (DMSO)) or ethyl acetate, and described acid binding agent is pyridine, di-n-propylamine, n-Butyl Amine 99 or triethylamine.
B, rearrangement reaction: intermediate compound I, AlCl
3Join the vessel in heating reaction with flux and generate intermediate II: 2-acetamido-4-chloro-6-ethyl ketone base phenol, temperature of reaction is 110-140 ℃, reaction times 1h-4h extracts purify intermediates II, intermediate compound I, AlCl after reaction finishes
3With the mol ratio of flux be: 1: 2～5: 2～5; Described flux is NH
4Cl, NaCl, KCl, MgCl
2Or CaCl
2
C, hydrogenation reaction: intermediate II, Pd/C, acid binding agent and solvent add in the reaction vessel, heating also feeds hydrogen reaction, temperature of reaction is 50-75 ℃, reaction times is 3h-6h, the reaction products therefrom is target product, extracts the purification of target product, and intermediate II and Pd/C weight ratio are 1: 0.05～0.2, the mol ratio of intermediate II and acid binding agent is: 1: 1～3, and the weight ratio of intermediate II and reaction solvent is: 1: 5～10.Described acid binding agent is triethylamine, sodium bicarbonate, yellow soda ash, sodium hydroxide or sodium acetate, and described solvent is ethanol or methyl alcohol.
The above-mentioned method for preparing 2-acetamido-6-ethyl ketone base phenol, it is that the process of extracting purify intermediates II among the step b is: reaction soln cooling and adding recrystallization solvent that reaction is finished keep stirring under the reflux state, after lowering the temperature then and adding water washing, cooling crystallization, filtering drying, the weight ratio of intermediate compound I and recrystallization solvent is: 1: 2～5.Described recrystallization solvent is mixture or the toluene of ethyl acetate and toluene, recrystallization solvent.The weight ratio 0.5～1: 2～3 of ethyl acetate and toluene in the mixture of ethyl acetate and toluene.Product among step a and the step c can adopt ordinary method to extract and purifying.
Beneficial effect of the present invention:
The present invention is the synthetic pranlukast intermediate 2-acetamido of starting raw material-6-ethyl ketone base phenol with 2-amino-4-chlorophenol, obtains product by acidylate, rearrangement and hydrogenation reaction.Preparation method's raw material sources of the present invention are more extensive, and other raw materials all are easy to get, and are fit to scale production.It is short to have synthetic route, and cost is low, pollutes advantages such as little.
Description of drawings
Fig. 1 the present invention prepares the process flow sheet of 2-acetamido-6-ethyl ketone base phenol.
The high-efficient liquid phase chromatogram of Fig. 2 product 2-acetamido-6-ethyl ketone base phenol.
The nucleus magnetic resonance figure of Fig. 3 product 2-acetamido-6-ethyl ketone base phenol.
Embodiment
Embodiment 1
Step 1, preparation intermediate compound I: acetic acid (2-acetylaminohydroxyphenylarsonic acid 4-chlorine) phenyl ester
24.0g 2-amino-4-chlorophenol (0.168mol) and 88.0g ethyl acetate are joined in the 250mL three-necked bottle, slowly drip 15.1g Acetyl Chloride 98Min. (0.420mol) under the water-bath, about 1h drips off.Be warmed up to 70 ℃ then and keep slowly dripping 21.0g triethylamine (0.208mol) behind the back flow reaction 2h, this moment, pH value of solution was neutral, and about 0.5h dropwises follow-up continuation of insurance temperature and stirs 15min.TLC detects raw material point and disappears, and has only point of product.Reaction solution is cooled to 10 ℃ of after-filtration.Filtrate can directly be overlapped as using next time.Filter cake and 120mL water are joined 40 ℃ of stirring 1h after-filtration in the 250L reaction flask, and filter cake washes (5mL*3) with water 3 times, with the product oven dry, gets product 34.2g, yield 90% then.
The acid binding agent triethylamine can add or add together with reaction raw materials in the reaction later stage.
TLC detection method: n-hexane/ethyl acetate=1: 1, raw material Rf ≈ 0.6, product Rf ≈ 0.3
Intermediate compound I (0.079mol) and 32.0g AlCl that the 18.0g step 1 is made
3(0.240mol), 16.0g NH
4Cl (0.252mol) joins in the 250L three-necked bottle, is heated to 130 ℃ of reaction 2.5h, and TLC detects raw material point and disappears.Be cooled to adding 43.0g toluene and 14.0g ethyl acetate about 80 ℃, keep stir about 1h under the slight reflux state.Slowly drip 70mL water after cooling the temperature to 40 ℃ then under the water-bath, about 0.5h drips off, and drips off follow-up continuous being warming up to and keeps about 80 ℃ stirring 0.5h under the slight reflux state.Layering while hot after leaving standstill adds 20mL water after water layer removed again, continues to keep slight backflow 15min.Layering while hot after leaving standstill is cooled to 10 ℃ of crystallizatioies after water layer removed, dry after the filtration product 10.8g, yield 60%.
TLC detection method: n-hexane/ethyl acetate=1: 1, raw material Rf ≈ 0.3, product Rf ≈ 0.5
Point has 3 points behind the plate, and one than product height, Rf ≈ 0.8, and another is lower than product, Rf ≈ 0.3, raw material disappears and is reaction end behind the some plate.
Step 3, preparation target product: 2-acetamido-6-ethyl ketone base phenol
The intermediate II (0.03mol) that the 6.8g step 2 is made, 4.0g anhydrous sodium acetate (0.049mol), 1.0g 5%Pd/C (moisture 67%) and 55.0g ethanol join in the 250mL two-neck bottle, filtered while hot behind 60 ℃ of logical hydrogen reaction 4h, TLC detects raw material point and disappears.Filter cake is washed (2L*3) 3 times with ethanol, adds gac and add the heat decoloring after-filtration in filtrate.With filtrate steam be cooled to 10 ℃ after solvent-free substantially come out again (steaming 80% approximately) after crystallization, after the filtration filter cake and 15mL water joined in the single neck bottle of 100mL and stirs 0.5h down at 40 ℃, filter then, after the oven dry product 4.6g, yield 80%.
The TLC detection method: n-hexane/ethyl acetate=1: 1, raw material Rf ≈ 0.5 has only point of product to be defined as reaction end behind 0.4 plate of product Rf ≈
Analytical procedure
The TLC method of each step is seen the top in detail
The HPLC detection method of product:
HPLC chromatographic column: SHISEIDO UG120 4.6mm*150mm 5um
Moving phase: 0.02M KH2P04: CH3CN: CH30H=5: 5: 1
Wavelength: 260nm
Flow velocity: 1.0ml/min
Column temperature: 25 ℃
Sample size: the 0.005g sample is dissolved in sample introduction 20ul in the 25ml moving phase
Step 1, preparation intermediate compound I: acetic acid (2-acetylaminohydroxyphenylarsonic acid 4-chlorine) phenyl ester
24.0kg 2-amino-4-chlorophenol (0.168kmol), 34.0kg triethylamine (0.336kmol) and 88kg ethyl acetate are joined in the 200L reactor, slowly drip 15.1kg Acetyl Chloride 98Min. (0.420kmol) under the room temperature, be warmed up to 70 ℃ then and keep slight back flow reaction 4h.It is centrifugal after reaction solution is cooled to 10 ℃.Filtrate can directly be overlapped as using next time.Filter cake and 120kg water are joined in the 200L reactor 40 ℃ stir behind the 1h centrifugally, filter cake washes (5L*3) with water 3 times, with the product oven dry, gets product 34.2kg, yield 90% then.
Intermediate compound I (0.079kmol) and 32.0kg AlCl that the 18.0kg step 1 is made
3(0.240kmol), 14.7kg NaCl (0.252kmol) joins in the 200L reactor, is heated to 130 ℃ of reaction 2.5h, is cooled to add 43kg toluene and 14kg ethyl acetate about 80 ℃, keeps stir about 1h under the slight reflux state.Open freezing water after cooling the temperature to 40 ℃ then and begin slowly to drip 70kg water, about 1h drips off, and drips off follow-up continuous being warming up to and keeps about 80 ℃ stirring 1h under the slight reflux state.Layering while hot after leaving standstill adds 20kg moisture again and continues to keep slight backflow 0.5h after water layer removed.Layering while hot after leaving standstill, centrifugal after being cooled to 10 ℃ after after water layer removed the organic layer solvent being steamed 1/3, dry thick product 10.8kg, yield 60%.
Step 3, preparation target product: 2-acetamido-6-ethyl ketone base phenol
The intermediate II (0.03kmol) that the 6.8kg step 2 is made, 4.0kg anhydrous sodium acetate (0.049kmol), 1.02kg5%Pd/C (moisture 68%), join in the 200L reactor with 68L ethanol, filtered while hot behind 60 ℃ of logical hydrogen 4h, filter cake is washed (2L*3) 3 times with ethanol, adds gac and add the heat decoloring after-filtration in filtrate.The filtrate steaming is added 20L water to solvent-free substantially (steaming the 80% approximately) back of coming out again at room temperature stir 1h, be cooled to 10 ℃ of after-filtration, get product 4.6kg, yield 80% after the oven dry.
Claims (7)
1. method for preparing 2-acetamido-6-ethyl ketone base phenol is characterized in that its synthetic route is:
Be that main starting raw material prepares 2-acetamido-6-ethyl ketone base phenol by acylation reaction, rearrangement reaction, hydrogenation reaction with 2-amino-4-chlorophenol:
A, acylation reaction: in solvent, 2-amino-4-chlorophenol and Acetyl Chloride 98Min. generation acylation reaction generate intermediate compound I, reaction finishes and washs purify intermediates I, need to add acid binding agent in the reaction process, the mol ratio of 2-amino-4-chlorophenol, Acetyl Chloride 98Min. and acid binding agent is 1:2 ~ 5:1 ~ 5, and the mass ratio of 2-amino-4-chlorophenol and solvent is 1:2.5 ~ 6;
B, rearrangement reaction: intermediate compound I, AlCl
3Join the vessel in heating reaction with flux and generate intermediate II, extract purify intermediates II, intermediate compound I, AlCl after reaction finishes
3With the mol ratio of flux be: 1:2 ~ 5:2 ~ 5;
C, hydrogenation reaction: intermediate II, Pd/C, acid binding agent and solvent add in the reaction vessel, heating also feeds hydrogen reaction, the reaction products therefrom is target product, extract the purification of target product, intermediate II and Pd/C weight ratio are 1:0.05 ~ 0.2, the mol ratio of intermediate II and acid binding agent is: 1:1 ~ 3, and the weight ratio of intermediate II and reaction solvent is: 1:5 ~ 10;
Flux described in the step b is NH
4Cl, NaCl, KCl, MgCl
2Or CaCl
2
2. the method for preparing 2-acetamido-6-ethyl ketone base phenol according to claim 1, the temperature of reaction that it is characterized in that step a is 60-75 ℃, reaction times 1h-5h; The temperature of reaction of step b is 110-140 ℃, reaction times 1h-4h; The temperature of reaction of step c is 50-75 ℃, and the reaction times is 3h-6h.
3. the method for preparing 2-acetamido-6-ethyl ketone base phenol according to claim 1, it is characterized in that the process of extracting purify intermediates II among the step b is: reaction soln cooling and adding recrystallization solvent that reaction is finished keep stirring under the reflux state, after lowering the temperature then and adding water washing, cooling crystallization, filtering drying, the weight ratio of intermediate compound I and recrystallization solvent is: 1:2 ~ 5.
4. the method for preparing 2-acetamido-6-ethyl ketone base phenol according to claim 3 is characterized in that described recrystallization solvent is mixture or the toluene of ethyl acetate and toluene.
5. the method for preparing 2-acetamido-6-ethyl ketone base phenol according to claim 4 is characterized in that weight ratio 0.5 ~ 1:2 ~ 3 of ethyl acetate and toluene in the mixture of described ethyl acetate and toluene.
6. the method for preparing 2-acetamido-6-ethyl ketone base phenol according to claim 1, it is characterized in that the solvent described in the step a is toluene, benzene, methylene dichloride, chloroform, DMF, DMSO or ethyl acetate, described acid binding agent is pyridine, di-n-propylamine, n-Butyl Amine 99 or triethylamine.
7. the method for preparing 2-acetamido-6-ethyl ketone base phenol according to claim 1 is characterized in that the acid binding agent described in the step c is triethylamine, sodium bicarbonate, yellow soda ash, sodium hydroxide or sodium acetate, and described solvent is ethanol or methyl alcohol.
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| CN109824537B (en) * | 2019-04-03 | 2021-12-28 | 重庆医药高等专科学校 | Preparation method of N- (3-acetyl-2-hydroxyphenyl) acetamide |
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