CN108191667A - The preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters - Google Patents
The preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters Download PDFInfo
- Publication number
- CN108191667A CN108191667A CN201810007603.2A CN201810007603A CN108191667A CN 108191667 A CN108191667 A CN 108191667A CN 201810007603 A CN201810007603 A CN 201810007603A CN 108191667 A CN108191667 A CN 108191667A
- Authority
- CN
- China
- Prior art keywords
- nitro
- benzoic acid
- acid methyl
- trifluoromethyl
- methyl esters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Abstract
The invention discloses a kind of preparation methods of 2 nitro, 4 trifluoromethyl benzoic acid methyl ester, belong to technical field of organic synthesis.The technical problems to be solved by the invention are to provide a kind of new method for preparing 2 nitro, 4 trifluoromethyl benzoic acid methyl ester.This method includes：2 nitro, 4 trifluoromethyl benzamide is made in 4 trifluoromethylbenzonitrile of base catalysis or 2 nitro of acid-catalyzed hydrolysis；2 nitro, 4 trifluoromethyl benzamide with methanolic solution is mixed, alcoholysis reaction is carried out, obtains 2 nitro, 4 trifluoromethyl benzoic acid methyl ester.The method of the present invention reaction condition is mild, post processing is simple, can be advantageously implemented industrialized production to obtain 2 nitro of high-purity, 4 trifluoromethyl benzoic acid methyl ester in high yield.
Description
Technical field
The invention belongs to technical field of organic synthesis, are related to a kind of preparation of 2- nitros -4- trifluoromethyl benzoic acid methyl esters
Method.
Background technology
2- nitro -4- trifluoromethyl benzoic acid methyl esters are important medicine and pesticide intermediate, such as nitisinone, isoxazoles
Humulone, TRPV1 receptor antagonists (CN101228131A), CRF receptor antagonists (CN101166729A), Raf kinase
(CN1283180A) etc..
In presently disclosed document, preparing 2- nitro -4- trifluoromethyl benzoic acid methyl esters mainly has following several routes：
First, 2- nitros -4- trifluoromethylbenzoic acid routes：
The route is by preparing intermediate 2- nitro -4- trifluoromethylbenzoic acids, by its direct esterification or first chloride
Resterification obtains 2- nitro -4- trifluoromethyl benzoic acid methyl esters afterwards.The route has following defect：(1) when with 4- trifluoromethylbenzenes
When formic acid prepares 2- nitro -4- trifluoromethylbenzoic acids for raw material, reaction yield is only 48% (CN1886374A)；(2) when with
When 4- trifluoromethylbenzonitriles prepare 2- nitro -4- trifluoromethylbenzoic acids for raw material, acid catalysis or base catalysis may be used.So
And nitrile compounds, when hydrolyzing under acid or alkaline conditions, there are selecting response sex chromosome mosaicisms, i.e., obtain acyl under normal circumstances
The mixture of amine and carboxylic acid, and want improve generation carboxylic acid selectivity, then need higher hydrolysising condition, as high concentration highly basic,
Strong acid or high temperature, improve production cost；Also, using base catalysis (such as NaOH), usually reaction is carried out, is obtained in aqueous solution
Product for 2- nitro -4- trifluoromethylbenzene first metal salts, metal salt is soluble in water, need could to generate after acidification 2- nitros -
4- trifluoromethylbenzoic acids, so as to be precipitated from water.Alkali cannot recycle, and need additional acid, improve environmentally friendly pressure
Power increases production cost.
2nd, 4- trifluoromethyl benzoic acid methyl esters route：
The route is by first preparing intermediate 4- trifluoromethyl benzoic acid methyl esters, then nitrified to obtain 2- nitros -4- three
Methyl fluoride methyl benzoate.However, since nitrification site is there are stronger competition, even if the optimization by multiple parameters, receive
Rate highest only has 69% (study on the synthesis of 2- nitro -4- trifluoromethyl benzoic acid methyl esters, Shandong chemical industry, 2015,44 (19)：18-
19)。
3rd, route is carbonylated：
The route is using -4 trifluoromethyl halogeno-benzene of 2- nitros as raw material, under the action of palladium catalyst, with methanol and an oxygen
Change carbon reaction and 2- nitro -4- trifluoromethyl benzoic acid methyl esters (US6337418) are prepared.However, palladium catalyst is expensive,
And needing high pressure that could obtain in high yield, technique threshold is higher.
Invention content
The technical problems to be solved by the invention, which are to provide, a kind of prepares the new of 2- nitro -4- trifluoromethyl benzoic acid methyl esters
Method, this method is of low cost, mild condition, easy to operate, high income.
There is provided a kind of 2- nitros -4- trifluoromethylbenzenes for technical solution used by the present invention solves above-mentioned technical problem
The preparation method of methyl formate, this method include the following steps：
A, using base catalysis or acid-catalyzed hydrolysis 2- nitro -4- trifluoromethylbenzonitriles, 2- nitro -4- trifluoromethyls are made
Benzamide；
B, 2- nitro -4- trifluoromethyl benzamides obtained by step a with sulfuric acid-methanol solution are mixed, it is anti-carries out alcoholysis
Should, 2- nitro -4- trifluoromethyl benzoic acid methyl esters are made.
Wherein, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, work as use
During base catalysis, the alkali of the base catalysis is selected from inorganic base.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using base catalysis, the molar ratio of the inorganic base and 2- nitro -4- trifluoromethylbenzonitriles is 0.1~4：1.
Preferably, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when adopting
During with base catalysis, the molar ratio of the inorganic base and 2- nitro -4- trifluoromethylbenzonitriles is 1~4：1.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using base catalysis, inorganic base, 2- nitro -4- trifluoromethylbenzonitriles and water are mixed and carry out hydrolysis；The use of the water
It measures as 5~50L/kg2- nitro -4- trifluoromethylbenzonitriles.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using base catalysis, the inorganic base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using base catalysis, the temperature of the hydrolysis is 0 DEG C~65 DEG C.
Preferably, it in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, uses
During base catalysis, when the alkalinity of inorganic base is weaker than potassium hydroxide, the temperature of the hydrolysis is 15 DEG C~60 DEG C.
It is furthermore preferred that in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, adopt
During with base catalysis, when the alkalinity of inorganic base is weaker than potassium hydroxide, the temperature of the hydrolysis is 45 DEG C~55 DEG C.
Further, it in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, adopts
During with base catalysis, when inorganic base is potassium hydroxide, the temperature of the hydrolysis is 55 DEG C~65 DEG C.
More specifically, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, institute
The operation for stating alkali catalyzed hydrolysis 2- nitro -4- trifluoromethylbenzonitriles is：By 2- nitro -4- trifluoromethylbenzonitriles, inorganic base
It is mixed with water and carries out hydrolysis, after the reaction was complete, filtering.
Wherein, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, work as use
During acid catalysis, the acid catalyzed acid is sulfuric acid.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using acid catalysis, a concentration of the 80~98% of the sulfuric acid.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using acid catalysis, the molar ratio of the sulfuric acid and 2- nitro -4- trifluoromethylbenzonitriles is 10~30：1.
Further, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, when
During using acid catalysis, the temperature of the hydrolysis is 90 DEG C~100 DEG C.
More specifically, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step a, institute
The operation for stating acid-catalyzed hydrolysis 2- nitro -4- trifluoromethylbenzonitriles is：2- nitro -4- trifluoromethylbenzonitriles and sulfuric acid are mixed
Reaction is hydrolyzed in conjunction, after completion of the reaction, is extracted, washed, concentrated.
Wherein, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step b, the sulphur
The molar ratio of sulfuric acid and 2- nitro -4- trifluoromethyl benzamides in acid-methanol solution is 3~9：1.
Wherein, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step b, the sulphur
The mass concentration of sulfuric acid in acid-methanol solution is 15~40%.
Wherein, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step b, the alcohol
The temperature of solution reaction is 60 DEG C~80 DEG C.
Wherein, in the preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters described above, in step b, the alcohol
The time of solution reaction for 13~for 24 hours.
The beneficial effects of the invention are as follows：
The method of the present invention makes 2- nitro -4- trifluoromethylbenzonitriles suitable by controlling base catalysis or acid catalysed conditions
At a temperature of highly selective hydrolysis generation 2- nitro -4- trifluoromethyl benzamides, almost free from admixture generate, so as to height
Yield obtains the 2- nitro -4- trifluoromethyl benzamides of high-purity；Then sulfuric acid-methanol solution is added in, adjusts reaction condition,
2- nitro -4- trifluoromethyl benzamide conversion ratios are improved, side reaction is reduced to the greatest extent, makes 2- nitro -4- trifluoromethylbenzenes
Formamide highly selective generation 2- nitro -4- trifluoromethylbenzoic acid first at a suitable temperature；The method of the present invention reacts item
Part is mild, post processing is simple, is advantageously implemented industrialized production.
Specific embodiment
Specifically, a kind of preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters, this method include the following steps：
A, using base catalysis or acid-catalyzed hydrolysis 2- nitro -4- trifluoromethylbenzonitriles, 2- nitro -4- trifluoromethyls are made
Benzamide；
B, 2- nitro -4- trifluoromethyl benzamides obtained by step a with sulfuric acid-methanol solution are mixed, it is anti-carries out alcoholysis
Should, 2- nitro -4- trifluoromethyl benzoic acid methyl esters are made.
In the method for the present invention step a, base catalysis or acid-catalyzed hydrolysis 2- nitro -4- trifluoromethylbenzonitriles can be used, send out
A person of good sense solves the selecting response sex chromosome mosaicism in step a hydrolysis, almost free from admixture is given birth to by a large amount of screenings to reaction condition
Into so as to obtain the 2- nitro -4- trifluoromethyl benzamides of high-purity in high yield.
In step a, when using base catalysis, 2- nitro -4- trifluoromethylbenzonitriles, inorganic base and water are mixed and carry out water
Solution reaction, after the reaction was complete, 2- nitro -4- trifluoromethyl benzamides are made in filtering.Inventor carries out the condition of base catalysis
A large amount of screenings, when the equivalent of inorganic base is 0.1~4eq, hydrolysis effect is preferable.
It is found in addition, inventor tests：In step a, the temperature of base catalysis is major influence factors；At 0 DEG C~65 DEG C
When, a variety of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate may be selected in inorganic base, as long as keeping alkaline environment,
Hydrolysis can carry out；Experiment is found：When the alkalinity of inorganic base is weaker than potassium hydroxide (such as inorganic base for sodium hydroxide,
Sodium carbonate, potassium carbonate etc.), if temperature rises to 60 DEG C or more, although trifluoromethylbenzonitrile can the reaction was complete by 2- nitro -4-,
But 2- nitro -4- trifluoromethyl benzamide yield is less, and by-product is on the high side, in order to accelerate hydrolysis efficiency, when avoiding long
Between reaction by-product is caused to increase, it is preferred that when the alkalinity of inorganic base that base catalysis uses is weaker than potassium hydroxide, the hydrolysis
The temperature of reaction is 15 DEG C~65 DEG C, it is furthermore preferred that the temperature of the hydrolysis is 45 DEG C~55 DEG C；Inventor also found：
When inorganic base is potassium hydroxide, temperature is controlled at 55 DEG C~65 DEG C, then can make raw material nitro -4- trifluoromethylbenzonitriles
The reaction was complete, and obtains 2- nitro -4- trifluoromethyl benzamide products in high yield.
In the method for the present invention step a, during using base catalysis, the methods of HPLC, TLC can be used in the terminal of hydrolysis, supervises
It surveys, it usually can the reaction was complete in 3~10h.
In step a, when using base catalysis, the dosage of the water is 5~50L/kg2- nitro -4- trifluoromethylbenzene first
Nitrile, so as to which in suitable range, reaction system pH controls are conducive to hydrolysis progress.
In step a, when using acid catalysis, 2- nitro -4- trifluoromethylbenzonitriles and sulfuric acid are mixed and are hydrolyzed instead
Should, it after completion of the reaction, extracted, washed, concentrated.Inventor largely screens acid catalyzed condition, and experiment is found：It is dense
Hydrolysis hardly occurs for hydrochloric acid；The sulfuric acid of low concentration, reaction effect are very poor；When a concentration of the 80~98% of sulfuric acid, control
The molar ratio of Sulphuric acid and 2- nitro -4- trifluoromethylbenzonitriles is 10~30：1, reaction effect is preferable.
It is carried out to accelerate acid-catalyzed hydrolysis reaction, the temperature of acid-catalyzed hydrolysis is 90 DEG C~100 DEG C；The terminal of reaction can be adopted
It is monitored with the methods of HPLC, TLC, the reaction was complete usually in 3~10h for reaction.
In the method for the present invention step a, base catalysis and acid catalysis are compared：Base catalyzed reactions condition is more mild, consumption
Can be low, the alkali of base catalysis can recycle that (amide is precipitated, and the liquid phase after filtering is certain density aqueous slkali, can be continued
For base catalysis), it is more environmentally protective compared to acid catalysis；Acid catalysis can make 2- nitro -4- trifluoromethyl benzamides HPLC pure
Degree reaches 99%, and raw material reaction is more complete, does not almost generate by-product, therefore the two respectively has quality, can be according to actual production
Situation flexibly selects.
In the method for the present invention step b, by screening of the inventor to sulfuric acid-methanol solution, experiment is found：Using sulfuric acid
Mass concentration is 15~40% sulfuric acid-methanol solution, and controls the sulfuric acid and 2- nitro -4- trifluoros in sulfuric acid-methanol solution
The molar ratio of methyl benzamide is 3~9：1, raw material 2- nitro -4- trifluoromethyl benzamides can be made to react as far as possible, obtained
In high yield with the 2- nitro -4- trifluoromethyl benzoic acid methyl esters of high-purity.
It is carried out to accelerate alcoholysis reaction, while reduces by-product generation, so as to by simply post-processing with regard to that can obtain
Product, in step b, the temperature of the alcoholysis reaction is 60 DEG C~80 DEG C；The methods of HPLC, TLC can be used in the terminal of reaction
Monitoring, reaction usually 13~it is interior for 24 hours that the reaction was complete.
In the method for the present invention step b, after alcoholysis reaction is complete, it need to be extracted, washed, be concentrated, extraction generally uses two
The organic solvents such as chloromethanes, chloroform, ethyl acetate extraction no less than 3 times, after merging organic phase, organic phase uses saturated carbon again
Sour hydrogen sodium washing is no less than 3 times, and then organic phase is concentrated, and removes organic solvent to get 2- nitro -4- trifluoromethylbenzenes
Methyl formate.
In the method for the present invention, the reaction end of alkali catalyzed hydrolysis, acid-catalyzed hydrolysis or step b in either step a
Middle alcoholysis reaction terminal can be used HPLC (being liquid phase 254nm without particularly pointing out) and be detected, and when raw material, the reaction was complete
When, that is, stop reaction.
The present invention is described in further detail below by test example and embodiment, but is not therefore protected the present invention
Scope limitation is among the embodiment described range.
2- nitros -4- trifluoromethyl benzamide HPLC purity measures to obtain by area normalization method in the present invention.
Test example 1：The conditional filtering of base catalysis catalyzing hydrolysis 2- nitro -4- trifluoromethylbenzonitriles
1st, the screening of alkali type
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 0.74gNaOH are added in into reaction bulb
(0.0184mol, 4eq) and 25mL water, 60 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzonitriles in reaction solution
The reaction was complete, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 39% in reaction solution at this time.
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 1.03g KOH are added in into reaction bulb
(0.0184mol, 4eq) and 25mL water, 60 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzonitriles in reaction solution
The reaction was complete, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 91% in reaction solution at this time.
2nd, the screening of reaction temperature and base amount
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 0.55gNaOH are added in into reaction bulb
(0.0138mol, 3eq) and 25mL water, 80 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzonitriles in reaction solution
The reaction was complete, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 2% in reaction solution at this time.
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 0.28gNaOH are added in into reaction bulb
(0.0069mol, 1.5eq) and 25mL water, 80 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzene first in reaction solution
The reaction was complete for nitrile, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 9% in reaction solution at this time.
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 0.18gNaOH are added in into reaction bulb
(0.0046mol, 1eq) and 25mL water, 45 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzonitriles in reaction solution
The reaction was complete, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 97% in reaction solution at this time.
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 0.37gNaOH are added in into reaction bulb
(0.0092mol, 2eq) and 25mL water, 45 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzonitriles in reaction solution
The reaction was complete, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 98% in reaction solution at this time.
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 0.18gNaOH are added in into reaction bulb
(0.0046mol, 1eq) and 25mL water, 55 DEG C of reactions to HPLC detect raw material 2- nitro -4- trifluoromethylbenzonitriles in reaction solution
The reaction was complete, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 96% in reaction solution at this time.
Summary screening test is understood：When base catalysis temperature is 45~60 DEG C, when the equivalent of alkali is more than 1eq, hydrolysis
Reaction effect is all preferable；When using NaOH as catalyst, reaction effect is preferable at 45~55 DEG C, and at 60 DEG C~80 DEG C
When, significant effect deteriorates；At 60 DEG C, KOH significant effects are better than NaOH.
Test example 2：The conditional filtering of acid catalysis catalyzing hydrolysis 2- nitro -4- trifluoromethylbenzonitriles
1g 2- nitro -4- trifluoromethylbenzonitriles, 5mL 36-38% concentrated hydrochloric acids, back flow reaction are added in into reaction bulb
2- nitro -4- trifluoromethyl benzamide HPLC contents are 0% in 3h, HPLC detection reaction solution, raw material almost unreacted.
1g 2- nitro -4- trifluoromethylbenzonitriles (0.0046mol, 1eq), 5mL 98% are added in into reaction bulb
(9.2g, 0.092mol, 20eq) concentrated sulfuric acid, 100 DEG C of reactions 3h, HPLC detect raw material 2- nitro -4- trifluoromethyls in reaction solutions
The reaction was complete for benzonitrile, and 2- nitros -4- trifluoromethyl benzamide HPLC purity is 99% in reaction solution at this time.
1g 2- nitro -4- trifluoromethylbenzonitriles are added in into reaction bulb, 5mL 80% (16eq) concentrated sulfuric acid, reflux is instead
Answer 3h, the reaction was complete for raw material 2- nitro -4- trifluoromethylbenzonitriles in HPLC detection reaction solutions, at this time 2- nitros in reaction solution -
4- trifluoromethyl benzamide HPLC purity is 99%.
Summary screening test is understood：Acid catalysis, concentrated hydrochloric acid hardly react, preferably sulfuric acid, more preferable mass concentration
For 80~98% sulfuric acid；Base catalysis compares with acid catalysis, respectively there is quality：Acid catalysis can make 2- nitros -4- three in reaction solution
Methyl fluoride benzamide HPLC contents reach 99%, and reaction is more complete；Base catalyzed reactions condition is more mild, and consume energy low, alkali
The alkali of catalysis can be more environmentally protective compared to acid catalysis with recovery.
Test example 3：The screening of methanolic solution
1st, not prewired methanolic solution
10mL methanol is added in reaction bulb, is cooled down under ice bath, 98% concentrated sulfuric acids of 0.75g (9eq), drop is slowly added dropwise
Stirring 5 minutes is added, 0.2g 2- nitro -4- trifluoromethyl benzamides (1eq) is added, is warming up to back flow reaction for 24 hours, it is raw
Into 94%2- nitro -4- trifluoromethyl benzoic acid methyl esters, 6%2- nitro -4- trifluoromethylbenzoic acids.
8mL methanol is added in reaction bulb, is cooled down under ice bath, 98% concentrated sulfuric acids of 0.25g (3eq) are slowly added dropwise, is added dropwise
Complete stirring 5 minutes, adds 0.2g 2- nitro -4- trifluoromethyl benzamides (1eq), is warming up to back flow reaction for 24 hours, generates
27%2- nitro -4- trifluoromethyl benzoic acid methyl esters, remaining is 2- nitro -4- trifluoromethyl benzamides and 2- nitros -4- three
Methyl fluoride benzoic acid.
2nd, prefabricated methanolic solution
Prepare the methanol solution of 15% sulfuric acid of mass fraction：85g methanol solutions are added in into 500mL single port bottles, under ice bath
Cooling, stirring, then the 15g concentrated sulfuric acids (98%) are slowly added dropwise；It is added in into reaction bulb containing 15% methanolic solution 2g
(3.6eq), 0.2g 2- nitro -4- trifluoromethyl benzamides, flow back 13h, HPLC detection generation 75%2- nitro -4- trifluoros
Methyl toluate, remaining 23%2- nitros -4- trifluoromethyl benzamides.
Prepare the methanol solution of 30% sulfuric acid of mass fraction：70g methanol solutions are added in into 500mL single port bottles, under ice bath
Cooling, stirring, then the 30g concentrated sulfuric acids (98%) are slowly added dropwise；It is added in into reaction bulb containing 30% methanolic solution 1g
(3.6eq), 0.2g 2- nitro -4- trifluoromethyl benzamides, flow back 13h, HPLC detection generation 87%2- nitro -4- trifluoros
Methyl toluate, remaining 10%2- nitros -4- trifluoromethyl benzamides.
By above-mentioned screening test it is found that methanolic solution it is prefabricated whether on react without influence, key is sulfuric acid-first
Sulfuric acid concentration in alcoholic solution, when the sulfuric acid concentration in sulfuric acid-methanol solution is relatively low, reaction effect is poor, therefore sulfuric acid-methanol
Sulfuric acid concentration is advisable not less than 15% in solution.
Embodiment 1：2- nitro -4- trifluoromethyl benzoic acid methyl esters are prepared using the method for the present invention
1g 2- nitro -4- trifluoromethylbenzonitriles (0.023mol, 1eq), 0.09g NaOH are added in into reaction bulb
(0.0023mol, 0.1eq) and 30mL water, is warming up to 50 DEG C, reacts to HPLC and detects raw material 2- nitro -4- trifluoros in reaction solution
The reaction was complete for methyl benzonitrile, and reaction was completed, and filtering obtains target product 2- nitro -4- trifluoromethyl benzamides 4.9g, HPLC
Purity 99%, yield 90%；
Prepare the methanol solution of 40% sulfuric acid of mass fraction：60g methanol solutions are added in into 500mL single port bottles, under ice bath
Cooling, stirring, then the 40g concentrated sulfuric acids (98%) are slowly added dropwise；
It is added in into reaction bulb containing 40% methanolic solution 12.4g (5.8eq), 2g 2- nitro -4- trifluoromethylbenzene first
Amide, for 24 hours, HPLC detection product assays are more than 99%, stop reaction, add in 3 × 5mL dichloromethane and wash 3 times, merge for reflux
Organic phase, organic phase are washed 3 times again with saturated sodium bicarbonate, and organic phase is taken to rotate, and obtain 1.9g 2- nitro -4- trifluoromethylbenzenes
Methyl formate, HPLC purity ＞ 99%, yield 90%.
Claims (10)
- The preparation method of 1.2- nitro -4- trifluoromethyl benzoic acid methyl esters, it is characterised in that：Include the following steps：A, using base catalysis or acid-catalyzed hydrolysis 2- nitro -4- trifluoromethylbenzonitriles, 2- nitro -4- trifluoromethylbenzene first is made Amide；B, 2- nitro -4- trifluoromethyl benzamides obtained by step a with sulfuric acid-methanol solution are mixed, carries out alcoholysis reaction, system Obtain 2- nitro -4- trifluoromethyl benzoic acid methyl esters.
- 2. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 1, it is characterised in that：Step In rapid a, the alkali of the base catalysis is inorganic base.
- 3. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 2, it is characterised in that：Institute The molar ratio for stating inorganic base and 2- nitro -4- trifluoromethylbenzonitriles is 0.1~4：1.
- 4. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 3, it is characterised in that：It will Inorganic base, 2- nitro -4- trifluoromethylbenzonitriles and water mixing carry out hydrolysis；The dosage of the water is 5~50L/kg2- Nitro -4- trifluoromethylbenzonitriles.
- 5. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 4, it is characterised in that：Institute The temperature for stating hydrolysis is 0 DEG C~65 DEG C；When the alkalinity of inorganic base is weaker than potassium hydroxide, the temperature of the hydrolysis is excellent It is selected as 15 DEG C~60 DEG C；When inorganic base is potassium hydroxide, the temperature of the hydrolysis is preferably 55 DEG C~65 DEG C.
- 6. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 1, it is characterised in that：Step In rapid a, the acid catalyzed acid is sulfuric acid；A concentration of the 80~98% of the sulfuric acid.
- 7. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 6, it is characterised in that：Institute The molar ratio for stating sulfuric acid and 2- nitro -4- trifluoromethylbenzonitriles is 10~30：1.
- 8. the preparation method of the 2- nitro -4- trifluoromethyl benzoic acid methyl esters described according to claim 6 or 7, it is characterised in that： The temperature of the hydrolysis is 90 DEG C~100 DEG C.
- 9. the preparation method of 2- nitros -4- trifluoromethyl benzoic acid methyl esters according to claim 1, it is characterised in that：Step In rapid b, the molar ratio of sulfuric acid and 2- nitro -4- trifluoromethyl benzamides in the sulfuric acid-methanol solution is 3~9：1；Institute The mass concentration for stating the sulfuric acid in sulfuric acid-methanol solution is 15~40%.
- It is 10. special according to the preparation method of claim 1~9 any one of them 2- nitro -4- trifluoromethyl benzoic acid methyl esters Sign is：In step b, the temperature of the alcoholysis reaction is 60~80 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810007603.2A CN108191667B (en) | 2018-01-04 | 2018-01-04 | Preparation method of 2-nitro-4-trifluoromethyl methyl benzoate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810007603.2A CN108191667B (en) | 2018-01-04 | 2018-01-04 | Preparation method of 2-nitro-4-trifluoromethyl methyl benzoate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108191667A true CN108191667A (en) | 2018-06-22 |
| CN108191667B CN108191667B (en) | 2021-03-26 |
Family
ID=62588262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810007603.2A Active CN108191667B (en) | 2018-01-04 | 2018-01-04 | Preparation method of 2-nitro-4-trifluoromethyl methyl benzoate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108191667B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110143923A (en) * | 2018-07-18 | 2019-08-20 | 四川国为制药有限公司 | A kind of higher pharmaceutical composition of safety |
| CN114634422A (en) * | 2022-03-14 | 2022-06-17 | 河北中科金辉药业有限公司 | Preparation method of dinitolmide |
| CN115160134A (en) * | 2022-08-10 | 2022-10-11 | 无锡科华生物科技有限公司 | Preparation method of 4-bromo-2-methyl benzoate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0989115A2 (en) * | 1998-09-24 | 2000-03-29 | Showa Denko Kabushiki Kaisha | Process for producing cyanobenzoic acid derivatives |
| CN1720237A (en) * | 2002-12-13 | 2006-01-11 | 弗·哈夫曼-拉罗切有限公司 | 3h-quinazolin-4-one derivatives |
| CN1826111A (en) * | 2003-04-10 | 2006-08-30 | 阿文尼尔药品公司 | Imidazole derivatives for treatment of allergic and hyperproliferative disorders |
| CN101273027A (en) * | 2005-07-29 | 2008-09-24 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis C virus |
| CN103304480A (en) * | 2013-07-09 | 2013-09-18 | 黑龙江胜农科技开发有限公司 | Benzoyl parazole compound as well as synthesis method thereof and application of same as herbicide |
-
2018
- 2018-01-04 CN CN201810007603.2A patent/CN108191667B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0989115A2 (en) * | 1998-09-24 | 2000-03-29 | Showa Denko Kabushiki Kaisha | Process for producing cyanobenzoic acid derivatives |
| CN1720237A (en) * | 2002-12-13 | 2006-01-11 | 弗·哈夫曼-拉罗切有限公司 | 3h-quinazolin-4-one derivatives |
| CN1826111A (en) * | 2003-04-10 | 2006-08-30 | 阿文尼尔药品公司 | Imidazole derivatives for treatment of allergic and hyperproliferative disorders |
| CN101273027A (en) * | 2005-07-29 | 2008-09-24 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis C virus |
| CN103304480A (en) * | 2013-07-09 | 2013-09-18 | 黑龙江胜农科技开发有限公司 | Benzoyl parazole compound as well as synthesis method thereof and application of same as herbicide |
Non-Patent Citations (2)
| Title |
|---|
| SHINICHI IMAMURA等: "Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity", 《J. MED. CHEM.》 * |
| 黄宪: "《新编有机合成化学》", 31 January 2003 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110143923A (en) * | 2018-07-18 | 2019-08-20 | 四川国为制药有限公司 | A kind of higher pharmaceutical composition of safety |
| CN114634422A (en) * | 2022-03-14 | 2022-06-17 | 河北中科金辉药业有限公司 | Preparation method of dinitolmide |
| CN115160134A (en) * | 2022-08-10 | 2022-10-11 | 无锡科华生物科技有限公司 | Preparation method of 4-bromo-2-methyl benzoate |
| CN115160134B (en) * | 2022-08-10 | 2023-10-10 | 无锡科华生物科技有限公司 | Preparation method of 4-bromo-2-methyl benzoate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108191667B (en) | 2021-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108191667A (en) | The preparation method of 2- nitro -4- trifluoromethyl benzoic acid methyl esters | |
| CN101541418B (en) | Conversion of glycerine to dichlorohydrins and epichlorohydrin | |
| CN103382166B (en) | Method for preparing 2, 6-dichlorobenzonitrile | |
| CN101367760A (en) | Synthesis of 2-chlorine apellagrin | |
| CN105344341A (en) | Preparation method of solid catalyst used for synthesizing dimethyl carbonate | |
| CN101851145A (en) | Method for preparing 1,2,3,4-tetrachloro-hexafluoro butane | |
| CN109364868A (en) | A kind of continous way chloro thing process units | |
| CN104557564B (en) | Preparation method of phenylmethylamine | |
| CN109503418A (en) | A kind of preparation process of methyl hydrazine | |
| CN104744211B (en) | An alkynol preparing method | |
| CN101973932A (en) | Preparation method of bisacodyl | |
| CN108530301B (en) | Synthetic method of 2,4, 6-trifluorobenzylamine | |
| CN103012215B (en) | Azo dodecanedioic acid dialkyl ester preparation method | |
| CN102942501B (en) | The production method of Agomelatine is prepared in a kind of hydrogenation | |
| CN110195237A (en) | A method of using bromide as bromating agent, the electro-catalysis in water phase prepares more bromoaniline compounds | |
| CN104045577B (en) | A kind of preparation method of hydrophobic monomer N-alkyl acrylamide | |
| CN101633598A (en) | Method for preparing methane chloride by dimethyl sulfate | |
| CN103102327A (en) | Preparation method of rubber accelerator DZ (N,N-Dicyclohexyl-2-benzothiazolsulfene amide) | |
| CN104649994B (en) | A kind of preparation method of 4-methyl-5-alkoxy-oxazole | |
| CN104447511A (en) | Synthetic method of N-t-butyloxycarboryl-3-piperidone | |
| CN101307016A (en) | Method for synthesizing 2,6-diisopropyl-4-phenoxy phenylthiourea | |
| CN205368191U (en) | N - isopropyl azanol production system | |
| CN106565509A (en) | Preparation method of 2-amino-4-methylamino methyl benzoate hydrochloride | |
| CN103342654A (en) | Novel method for hydrolyzing nitrile group to acylamino | |
| CN103304405B (en) | A kind of method of selective chlorination |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Liang Weiping Inventor after: Xu Yong Inventor after: Zeng Wei Inventor after: Yao Zhongwei Inventor after: Zuo Xiang Inventor after: Cheng Ke Inventor before: Liang Weiping Inventor before: Xu Yong Inventor before: Zeng Wei Inventor before: Yao Zhongwei Inventor before: Zuo Xiang Inventor before: Cheng Ke |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |