CN101759597A - Preparation method of 2-trifluoromethyl-4-aminobenzonitrile - Google Patents
Preparation method of 2-trifluoromethyl-4-aminobenzonitrile Download PDFInfo
- Publication number
- CN101759597A CN101759597A CN200910247930A CN200910247930A CN101759597A CN 101759597 A CN101759597 A CN 101759597A CN 200910247930 A CN200910247930 A CN 200910247930A CN 200910247930 A CN200910247930 A CN 200910247930A CN 101759597 A CN101759597 A CN 101759597A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- acid
- reaction
- fluorobenzonitrile
- fluorobenzene
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 2-trifluoromethyl-4-aminobenzonitrile, comprising the following steps of: (a) providing m-trifluoromethyl benzene; (b) carrying out bromination reaction on the m-trifluoromethyl benzene in the presence of an acid and a bromating agent so as to obtain 2-bromine-5-fluorine-benzotrifluoride; (c) carrying out Grignard reaction on the 2-bromine-5-fluorine-benzotrifluoride to prepare a Grignard reagent, and carrying out formylation reaction in the presence of a formylation reagent so as to obtain 2-trifluoromethyl-4-fluorobenzaldehyde; (d) carrying out cyaniding reaction on the 2-trifluoromethyl-4-fluorobenzaldehyde so as to obtain 2-trifluoromethyl-4-fluorobenzonitrile; and (e) reacting the 2-trifluoromethyl-4-fluorobenzonitrile with an ammoniation reagent so as to obtain the 2-trifluoromethyl-4-aminobenzonitrile.
Description
Technical field
The present invention relates to a kind of reaction scheme design of organic synthesis, relate to the preparation method of 2-trifluoromethyl-4-anthranilo nitrile particularly.
Background technology
2-trifluoromethyl-4-anthranilo nitrile is the key intermediate of synthetic drugs bicalutamide.Bicalutamide is a kind of non-reflunomide of androgen antagonist, is widely used in the prevention and the treatment of chronic diseases such as prostate cancer, carcinoma of the pancreas, mammary cancer.Because bicalutamide has good tolerance, take the no any steroidal active effect in back, do not have the side effect of obvious blood vessel and metabolism aspect, so its intermediate 2-trifluoromethyl-4-anthranilo nitrile demand rises sharply.
This intermediate has two kinds of synthetic routes at present.
First kind of route: with the o-trifluoromethyl aniline is the starting point raw material, through diazotization, nitrated, cyano group replace, four steps of iron powder reducing are synthetic.Technological line is as follows:
Second kind of route: with the m-trifluoromethyl fluorobenzene is the starting point raw material, goes on foot synthetic through bromination, cyano group replacement, amino replacement three.Technological line is as follows:
From two kinds of synthetic routes, first kind of route used diazotization reaction, operate loaded down with trivial details, by product is many, yield has only about 60%, product and iron powder mix in the iron powder reducing reaction, must extract repeatedly, operate loaded down with trivial details, and use CuCN, have danger, whole synthesis yield only about 30%, cost is obviously higher, produce large amount of sewage simultaneously, be unsuitable for production.
Second kind of route is with respect to first kind of route, and reactions steps can be simplified, cost reduces relatively, but still uses highly toxic product CuCN, and operation is relatively more dangerous, destroys producing a large amount of waste water.Though be suitable for producing, three waste discharge influences environmental protection.
In sum, this area lacks a kind of simplification reactions steps, the 2-trifluoromethyl of operational safety and environmental protection-4-anthranilo nitrile preparation method.Therefore, this area presses for a kind of simplification reactions steps of exploitation, the 2-trifluoromethyl of operational safety and environmental protection-4-anthranilo nitrile preparation method.
Summary of the invention
The objective of the invention is to obtain a kind of simplification reactions steps, the 2-trifluoromethyl of operational safety and environmental protection-4-anthranilo nitrile preparation method.
A first aspect of the present invention provides the preparation method of a kind of 2-trifluoromethyl-4-anthranilo nitrile, and it comprises the steps:
(a) provide the m-trifluoromethyl fluorobenzene;
(b) bromination reaction takes place in described m-trifluoromethyl fluorobenzene in the presence of acid and bromizating agent, obtains 2-bromo-5-fluoro-phenylfluoroform; (c) described 2-bromo-5-fluoro-phenylfluoroform carries out grignard reaction and is prepared into Grignard reagent, in the presence of formylation reagent formylation reaction takes place, and obtains 2-trifluoromethyl-4-fluorobenzaldehyde;
(d) described 2-trifluoromethyl-4-fluorobenzaldehyde carries out cyanogenation, obtains 2-trifluoromethyl-4-fluorobenzonitrile;
(e) with described 2-trifluoromethyl-4-fluorobenzonitrile and ammonification reagent react, obtain 2-trifluoromethyl-4-aminobenzonitrile.
In a specific embodiment, the preparation method of 2-trifluoromethyl-4-aminobenzonitrile comprises that with the m-trifluoromethyl fluorobenzene be main raw material, goes on foot and synthesizes through bromination, grignard and formylation, cyaniding, amino replacement four, and preparation process is as follows:
(1) bromination: the m-trifluoromethyl fluorobenzene in acid and bromizating agent reaction, is generated 2-bromo-5-fluoride trifluoro toluene;
(2) grignard and formylation: under magnesium chips and organic solvent reaction, make Grignard reagent, make 2-trifluoromethyl-4-fluorobenzaldehyde through successive reaction and DMF (N, dinethylformamide) reaction again;
(3) cyaniding:, generate 2-trifluoromethyl-4-fluorobenzonitrile with 2-trifluoromethyl-4-fluorobenzaldehyde and oxammonium hydrochloride and Lewis acid reaction;
(4) ammonification:, generate 2-trifluoromethyl-4-aminobenzonitrile with 2-trifluoromethyl-4-fluorobenzonitrile and ammonification reagent react.
In a specific embodiment of the present invention, the acid described in the step (b) is mineral acid or organic acid;
Preferably, described mineral acid is one or more or its combination among hydrochloric acid, sulfuric acid, the acid inorganic salt;
Preferably, described organic acid is one or more or its combination among acid organic salt, formic acid, acetate, chlorsulfonic acid, methylsulfonic acid, the trifluoromethanesulfonic acid;
Be more preferably, described acid is the combination of sulfuric acid and Glacial acetic acid.
In a specific embodiment of the present invention, the bromizating agent in the described step (b) is bromine, Hydrogen bromide, C5H6Br2N2O2, N-bromo-succinimide (NBS) or its combination.
In a specific embodiment of the present invention, the bromination reaction temperature in the described step (b) is 10 ℃～80 ℃.
In a specific embodiment of the present invention, in the described step (b), the molar equivalent of m-trifluoromethyl fluorobenzene and acid is 1: 1～1: 5; The molar equivalent of m-trifluoromethyl fluorobenzene and bromizating agent is 1: 0.1～1: 5, preferably 1: 0.5～1: 0.75.
In a specific embodiment of the present invention, the temperature of grignard reaction and formylation reaction is 0 ℃～60 ℃ in the described step (c).
In a specific embodiment of the present invention, in the described step (d), the temperature of reaction of cyanogenation is 20 ℃～100 ℃.
In a specific embodiment of the present invention, in the described step (d), described cyanogenation carries out in the presence of oxammonium hydrochloride and Lewis acid.
In a specific embodiment of the present invention, described 2-trifluoromethyl-4-fluorobenzonitrile is 1: 0.01～1: 0.1 with lewis acidic molar equivalent ratio; 2-trifluoromethyl-4-fluorobenzonitrile is 1: 1～1: 5 with the molar equivalent ratio of oxammonium hydrochloride.
In a specific embodiment of the present invention, described reaction pressure is 5～15kg.
In a preference, described ammonification reagent is ammoniacal liquor or ammonia.
Embodiment
The inventor by improving preparation technology, has obtained a kind of simplification reactions steps, the 2-trifluoromethyl of operational safety and environmental protection-4-anthranilo nitrile preparation method through extensive and deep research.Finished the present invention on this basis.
Technical conceive of the present invention is as follows:
Among the preparation method of 2-trifluoromethyl of the present invention-4-aminobenzonitrile, reaction is a main raw material with the m-trifluoromethyl fluorobenzene, and it is synthetic to replace for four steps through location bromination, grignard and formylation, cyaniding, amino.Avoid the use metal oxide, operated safer more environmental protection.The required reagent such as the vitriol oil, Glacial acetic acid, magnesium chips, formic acid etc. are that product is easily purchased in market in the reaction, low production cost.
Herein, described " bromizating agent " comprises cupric bromide, hydrogen bromide, N-bromo-succinimide (being called for short NBS), bromination dimethyl bromo sulphur (being called for short DMBS), C5H6Br2N2O2, Sodium Bromide, Potassium Bromide, brometo de amonio, bromine chloride; Be preferably bromine, Hydrogen bromide, C5H6Br2N2O2, N-bromo-succinimide (being called for short NBS) or its combination.
Herein, described " formylation reagent " comprises carboxylic acid, carboxylicesters, acid anhydrides, acyl chlorides, methyl iodide, methyl-sulfate, methylcarbonate; Be preferably N, dinethylformamide (DMF).
Herein, described " Lewis acid " comprises aluminum chloride, iron(ic) chloride, boron trifluoride, antimony pentafluoride, formic acid, acetic acid, trifluoromethanesulfonic acid.
Below describe in detail to various aspects of the present invention: specify as nothing, various raw materials of the present invention all can obtain by commercially available; Or prepare according to the ordinary method of this area.Unless otherwise defined or explanation, same meanings of being familiar with of all specialties used herein and scientific words and those skilled in the art.Any in addition method similar or impartial to described content and material all can be applicable in the inventive method.
Step (a)
Raw material of the present invention is the m-trifluoromethyl fluorobenzene.
Described raw material can obtain by commercially available mode, for example Shandong Guangheng Chemicals Co., Ltd. have supply, Huaian create forever chemical company limited have the supply and obtain; Synthetic the obtaining of conventional route that also can be by this area can be raw material with a toluene fluoride for example, through chlorination, fluoridize and make a fluoride trifluoro toluene.
Step (b)
Bromination reaction takes place in m-trifluoromethyl fluorobenzene described in the step of the present invention (b) in the presence of acid and bromizating agent, obtain 2-bromo-5-fluoro-phenylfluoroform.
Particularly, the acid described in the step (b) is mineral acid or organic acid;
Preferably, described mineral acid is one or more or its combination among hydrochloric acid, sulfuric acid, the acid inorganic salt;
Preferably, described organic acid is one or more or its combination among acid organic salt, formic acid, acetate, chlorsulfonic acid, methylsulfonic acid, the trifluoromethanesulfonic acid;
Be more preferably, described acid is the combination of sulfuric acid and Glacial acetic acid.
Particularly, the bromizating agent in the described step (b) is bromine, Hydrogen bromide, C5H6Br2N2O2, N-bromo-succinimide or its combination.
Particularly, the bromination reaction temperature in the described step (b) is 10 ℃～80 ℃, preferred 10 ℃～50 ℃.
Particularly, in the described step (b), the molar equivalent of m-trifluoromethyl fluorobenzene and acid is 1: 1～1: 5; The molar equivalent of m-trifluoromethyl fluorobenzene and bromizating agent is 1: 0.1～1: 5, preferably 1: 0.5～1: 0.75.
Please change according to claim
Step (c)
In the step of the present invention (c), described 2-bromo-5-fluoro-phenylfluoroform carries out grignard reaction and is prepared into Grignard reagent, in the presence of formylation reagent formylation reaction takes place, and obtains 2-trifluoromethyl-4-fluorobenzaldehyde;
Particularly, the temperature of grignard reaction and formylation reaction is 0 ℃～60 ℃ in the described step (c).
Described grignard reaction and formylation reaction can be finished (also promptly continuously) step, also can finish step by step, and be known for those skilled in the art.
The consumption of described formylation reagent 1: 1～1: 5.
Step (d)
In the step of the present invention (d), described 2-trifluoromethyl-4-fluorobenzaldehyde carries out cyanogenation, obtains 2-trifluoromethyl-4-fluorobenzonitrile;
Particularly, in the described step (d), the temperature of reaction of cyanogenation is 20 ℃～100 ℃.
Particularly, in the described step (d), described cyanogenation carries out in the presence of oxammonium hydrochloride and Lewis acid.The cyanating reagent of described cyanation can also adopt sodium cyanide, potassium cyanide, hydrocyanic acid.
More specifically, described 2-trifluoromethyl-4-fluorobenzonitrile is 1: 0.01～1: 0.1 with lewis acidic molar equivalent ratio, preferred 1: 0.05～1: 0.1; 2-trifluoromethyl-4-fluorobenzonitrile is 1: 1～1: 5 with the molar equivalent ratio of oxammonium hydrochloride, preferred 1: 1～1: 1.5.
The inventor finds that wherein the introducing of cyano group avoids using CuCN, through grignard, oxime dehydration preparation, both safety, environmental protection again.
Step (e)
(e) with described 2-trifluoromethyl-4-fluorobenzonitrile and ammonification reagent react, obtain 2-trifluoromethyl-4-aminobenzonitrile.
Particularly, in order to add fast response, described reaction pressure is 5～15kg.
In a preference, described ammonification reagent is ammoniacal liquor or ammonia.Described ammonification reagent can also adopt sodium amide, potassium amide.Wherein working as ammonification reagent is that ammoniacal liquor or ammonia are more economical.
The consumption of described ammonification reagent is not specifically limited, only otherwise goal of the invention of the present invention is produced restriction to get final product.
The temperature of described aminating reaction is decided according to the pressure of aminating reaction without limits.For example can at room temperature get final product.
The contriver also provides a preferred embodiment, and the preparation method of 2-trifluoromethyl-4-aminobenzonitrile comprises that with the m-trifluoromethyl fluorobenzene be main raw material, goes on foot and synthesizes through bromination, grignard and formylation, cyaniding, amino replacement four, and preparation process is as follows;
(1) bromination: the m-trifluoromethyl fluorobenzene in acid and bromizating agent reaction, is generated 2-bromo-5-fluoride trifluoro toluene;
(2) grignard and formylation: under magnesium chips and organic solvent reaction, make Grignard reagent, again through successive reaction and N, dinethylformamide (DMF) reaction makes 2-trifluoromethyl-4-fluorobenzaldehyde;
(3) cyaniding:, generate 2-trifluoromethyl-4-fluorobenzonitrile with 2-trifluoromethyl-4-fluorobenzaldehyde and oxammonium hydrochloride and Lewis acid reaction;
(4) ammonification:, generate 2-trifluoromethyl-4-aminobenzonitrile with 2-trifluoromethyl-4-fluorobenzonitrile and ammonification reagent react.
Advantage
The invention has the advantages that:
1. a kind of economy, environmental protection are provided, are suitable for the preparation method of industrialized 2-trifluoromethyl-4-anthranilo nitrile.
2. the present invention is a main raw material with the m-trifluoromethyl fluorobenzene, the raw material of also using (for example magnesium, tetrahydrofuran (THF) (THF), N, dinethylformamide (DMF), HCOOH, ZnCl
2, NH
3H
2O) etc. all be that product is easily purchased in market, avoided use highly toxic product CuCN in the reaction process, make and produce safer, more environmental protection.Whole piece operational path total recovery reaches 70%～75%, and product purity reaches more than 99%.
3. the inventor finds, wherein the introducing of cyano group avoids using CuCN, through grignard, oxime dehydration preparation, both safety, environmental protection again.
Above-mentioned synthetic method is the synthetic route of part of compounds of the present invention, according to above-mentioned example, those skilled in the art can synthesize other compounds of the present invention by adjusting diverse ways, and perhaps, those skilled in the art can synthesize compound of the present invention according to existing known technology.The synthetic compound can further be further purified by modes such as column chromatography, high performance liquid chromatography or crystallizations.
Synthetic chemistry is transformed, protection functional group methodology (protect or go and protect) is helpful to synthetic application compound, and be technology commonly known in the art, as R.Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the third edition, John Wiley andSons (1999); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents forOrganic Synthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis has open among the John Wiley and Sons (1995).
Other aspects of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is measured according to national standard usually.If there is not a corresponding national standards, then carry out according to general international standard, normal condition or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise all umbers are weight part, and all per-cents are weight percentage, and described polymericular weight is a number-average molecular weight.
Embodiment 1:
The first step location bromination: 300g m-trifluoromethyl fluorobenzene (1.83mol), the 550g vitriol oil (5.61mol), 110g Glacial acetic acid (1.83mol) join in the reactor, stirring is warming up to 20 ℃, add C5H6Br2N2O2 366g (1.28mol) in batches, insulation reaction, ice is separated, wash 2-bromo-5-fluoro-phenylfluoroform 380g (1.56mol), content is more than 95%.
Second step grignard and the formylation: 39g magnesium chips (1.625mol), 1200mlTHF join in the reactor; stirring is warming up to 20 ℃; drip 300g2-bromo-5-fluoro-phenylfluoroform (1.23mol) insulation and drip DMF117g; react and add hydrochloric acid destruction after 2 hours; boil off THF; layering gets 2-trifluoromethyl-4-fluorobenzaldehyde 218g (1.14mol), and content is more than 98%.
The 3rd step cyanogenation: 200g2-trifluoromethyl-4-fluorobenzaldehyde (1.04mol), 7.1g zinc chloride (0.05mol), 80g oxammonium hydrochloride (1.15mol) and 400mlHCOOH mix, be warming up to 65 ℃, insulation reaction, suction filtration, get 2-trifluoromethyl-4-fluorobenzonitrile 178g (0.94mol), purity is more than 98%.
The 4th step aminating reaction: 150g2-trifluoromethyl-4-fluorobenzonitrile (0.79mol) and 300ml ammoniacal liquor join autoclave (in 5～15kg), be warming up to 85 ℃, insulation reaction, suction filtration, ethyl acetate refining 2-trifluoromethyl-4-aminobenzonitrile 140g (0.75mol), purity is greater than 99%.(GC)
Embodiment 2～5
Carry out according to the mode identical with embodiment 1, different is kind, the m-trifluoromethyl fluorobenzene of bromizating agent in the bromination of the first step location: mol ratio, the temperature of reaction of bromizating agent are as shown in table 1.Table 1 also shows the productive rate and the purity of 2-bromo-5-fluoro-phenylfluoroform.
Table 1
| Embodiment | The kind of bromizating agent | M-trifluoromethyl fluorobenzene: the mol ratio of bromizating agent | Temperature of reaction (℃) | Productive rate (%) | Purity (wt%) |
| ??2 | Bromine | ??1∶0.1 | ??10 | ??85.4 | ??94.2 |
| ??3 | Hydrogen bromide | ??1∶0.5 | ??30 | ??85.7 | ??95.1 |
| ??4 | C5H6Br2N2O2 | ??1∶1 | ??50 | ??88.9 | ??97.7 |
| ??5 | N-bromo-succinimide (being called for short NBS) | ??1∶5 | ??80 | ??86.1 | ??95.2 |
Embodiment 6～10
Carry out according to the mode identical with embodiment 1, different is kind, the m-trifluoromethyl fluorobenzene of acid in the bromination of the first step location: the mol ratio of acid is as shown in table 2.Table 2 also shows the productive rate and the purity of 2-bromo-5-fluoro-phenylfluoroform.
Table 2
| Embodiment | The kind of acid | M-trifluoromethyl fluorobenzene: the mol ratio of acid | Productive rate (%) | Purity (wt%) |
| ??6 | Formic acid | ??1∶1 | ??85.4 | ??94.2 |
| ??7 | Acetic acid | ??1∶2 | ??88.7 | ??96.8 |
| Embodiment | The kind of acid | M-trifluoromethyl fluorobenzene: the mol ratio of acid | Productive rate (%) | Purity (wt%) |
| ??8 | Chlorsulfonic acid | ??1∶3 | ??85.9 | ??96.5 |
| ??9 | Trifluoromethanesulfonic acid | ??1∶4 | ??85.1 | ??94.7 |
| ??10 | Sulfuric acid | ??1∶5 | ??87.4 | ??96.7 |
Embodiment 11～15
Carry out according to the mode identical with embodiment 1, kind, the temperature of reaction of different is formylation reagent in the second step grignard and the formylation are as shown in table 3.Table 3 also shows the productive rate and the purity of 2-trifluoromethyl-4-fluorobenzaldehyde.
Table 3
| Embodiment | The kind of formylation reagent | Temperature of reaction (℃) | Productive rate (%) | Purity (wt%) |
| ??11 | Aceticanhydride | ??0 | ??93.4 | ??98.2 |
| ??12 | Acyl chlorides | ??10 | ??94.7 | ??98.7 |
| ??13 | Methyl iodide | ??20 | ??92.9 | ??98.4 |
| ??14 | Methyl-sulfate | ??40 | ??94.1 | ??98.5 |
| ??15 | N, dinethylformamide (DMF) | ??60 | ??95.3 | ??99.2 |
Embodiment 16:
The first step location bromination: 300Kg m-trifluoromethyl fluorobenzene (1.83mol), the 700g vitriol oil (7.14mol), 130g Glacial acetic acid (2.17mol) join in the reactor,
Stirring is warming up to 50 ℃, adds C5H6Br2N2O2 320g in batches, insulation reaction, ice is separated, wash 2-bromo-5-fluoro-phenylfluoroform 370g, content is more than 95%.
Second step grignard and the formylation: 38g magnesium chips (1.58mol), 1000mlTHF join to stir in the reactor and are warming up to 30 ℃; drip 300g2-bromo-5-fluoro-phenylfluoroform (1.23mol); after the insulation reaction 8 hours; be cooled to 20 ℃; insulation drips DMF120g; react and boil off THF after 2 hours, layering gets 2-trifluoromethyl-4-fluorobenzaldehyde 220g (1.15mol), and content is more than 98%.
The 3rd step cyanogenation: 200g2-trifluoromethyl-4-fluorobenzaldehyde (1.04mol), 8g zinc chloride, 85g oxammonium hydrochloride and 400mlHCOOH mix, and are warming up to 80 ℃, insulation reaction, hydrolysis, suction filtration gets 2-trifluoromethyl-4-fluorobenzonitrile 180g (0.95mol), and purity is more than 98%.
The 4th step aminating reaction: 150g2-trifluoromethyl-4-fluorobenzonitrile (0.79mol) and 600ml ammoniacal liquor join in the autoclave, are warming up to 95 ℃,
Reacted 8 hours, suction filtration, ethyl acetate refining finished product 2-trifluoromethyl-4-aminobenzonitrile 135g (0.73mol), purity is greater than 99%.(GC)
Embodiment 17～21
Carry out according to the mode identical with embodiment 16, different is lewis acidic kind, 2-trifluoromethyl-4-fluorobenzaldehyde in the 3rd step cyanogenation: lewis acidic mol ratio, 2-trifluoromethyl-4-fluorobenzaldehyde: mol ratio, the temperature of reaction of oxammonium hydrochloride are as shown in table 4.Table 4 also shows the productive rate and the purity of 2-trifluoromethyl-4-fluorobenzonitrile.
Table 4
| Embodiment | Lewis acidic kind | 2-trifluoromethyl-4-fluorobenzaldehyde: lewis acidic mol ratio | 2-trifluoromethyl-4-fluorobenzaldehyde: the mol ratio of oxammonium hydrochloride | Temperature of reaction (℃) | Productive rate (%) | Purity (wt%) |
| ??17 | Aceticanhydride | ??1∶0.01 | ??1∶1 | ??0 | ??83.4 | ??98.7 |
| ??18 | Aluminum chloride | ??1∶0.03 | ??1∶2 | ??10 | ??84.2 | ??98.2 |
| ??19 | Boron trifluoride | ??1∶0.05 | ??1∶3 | ??20 | ??82.5 | ??98.4 |
| ??20 | Antimony pentafluoride | ??1∶0.08 | ??1∶4 | ??40 | ??84.1 | ??98.2 |
| ??21 | Trifluoromethanesulfonic acid | ??1∶0.1 | ??1∶5 | ??60 | ??85.5 | ??98.5 |
Embodiment 22～25
Carry out according to the mode identical with embodiment 16, kind, the reaction pressure of different is ammonification reagent in the 4th step aminating reaction are as shown in table 5.Table 5 also shows the productive rate and the purity of 2-trifluoromethyl-4-aminobenzonitrile.
Table 5
| Embodiment | The kind of ammonification reagent | Reaction pressure (kg) | Productive rate (%) | Purity (wt%) |
| ??17 | Sodium amide | ??5 | ??93.4 | ??99.3 |
| ??18 | Potassium amide | ??8 | ??94.2 | ??99.1 |
| Embodiment | The kind of ammonification reagent | Reaction pressure (kg) | Productive rate (%) | Purity (wt%) |
| ??19 | Ammoniacal liquor | ??11 | ??92.8 | ??99.7 |
| ??20 | Ammonia | ??15 | ??94.1 | ??99.8 |
The above only is preferred embodiment of the present invention, be not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people finish, if it is defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition after having read foregoing of the present invention, those skilled in the art can make various changes or modifications the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. the preparation method of 2-trifluoromethyl-4-anthranilo nitrile is characterized in that, comprises the steps:
(a) provide the m-trifluoromethyl fluorobenzene;
(b) bromination reaction takes place in described m-trifluoromethyl fluorobenzene in the presence of acid and bromizating agent, obtains 2-bromo-5-fluoro-phenylfluoroform; (c) described 2-bromo-5-fluoro-phenylfluoroform carries out grignard reaction and is prepared into Grignard reagent, in the presence of formylation reagent formylation reaction takes place, and obtains 2-trifluoromethyl-4-fluorobenzaldehyde;
(d) described 2-trifluoromethyl-4-fluorobenzaldehyde carries out cyanogenation, obtains 2-trifluoromethyl-4-fluorobenzonitrile;
(e) with described 2-trifluoromethyl-4-fluorobenzonitrile and ammonification reagent react, obtain 2-trifluoromethyl-4-aminobenzonitrile.
2. the method for claim 1 is characterized in that, the acid described in the step (b) is mineral acid or organic acid;
Preferably, described mineral acid is one or more or its combination among hydrochloric acid, sulfuric acid, the acid inorganic salt;
Preferably, described organic acid is one or more or its combination among acid organic salt, formic acid, acetate, chlorsulfonic acid, methylsulfonic acid, the trifluoromethanesulfonic acid;
Be more preferably, described acid is the combination of sulfuric acid and Glacial acetic acid.
3. the method for claim 1 is characterized in that, the bromizating agent in the described step (b) is bromine, Hydrogen bromide, C5H6Br2N2O2, N-bromo-succinimide (NBS) or its combination.
4. the method for claim 1 is characterized in that, the bromination reaction temperature in the described step (b) is 10 ℃～80 ℃.
5. the method for claim 1 is characterized in that, in the described step (b), the molar equivalent of m-trifluoromethyl fluorobenzene and acid is 1: 1～1: 5; The molar equivalent of m-trifluoromethyl fluorobenzene and bromizating agent is 1: 0.1～1: 5, preferably 1: 0.5～1: 0.75.
6. the method for claim 1 is characterized in that, the temperature of grignard reaction and formylation reaction is 0 ℃～60 ℃ in the described step (c).
7. the method for claim 1 is characterized in that, in the described step (d), the temperature of reaction of cyanogenation is 20 ℃～100 ℃.
8. the method for claim 1 is characterized in that, in the described step (d), described cyanogenation carries out in the presence of oxammonium hydrochloride and Lewis acid.
9. method as claimed in claim 8 is characterized in that, described 2-trifluoromethyl-4-fluorobenzonitrile is 1: 0.01～1: 0.1 with lewis acidic molar equivalent ratio; 2-trifluoromethyl-4-fluorobenzonitrile is 1: 1～1: 5 with the molar equivalent ratio of oxammonium hydrochloride.
10. the method for claim 1 is characterized in that, described reaction pressure is 5～15kg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910247930 CN101759597B (en) | 2009-12-31 | 2009-12-31 | Preparation method of 2-trifluoromethyl-4-aminobenzonitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910247930 CN101759597B (en) | 2009-12-31 | 2009-12-31 | Preparation method of 2-trifluoromethyl-4-aminobenzonitrile |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101759597A true CN101759597A (en) | 2010-06-30 |
| CN101759597B CN101759597B (en) | 2013-09-04 |
Family
ID=42490999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910247930 Active CN101759597B (en) | 2009-12-31 | 2009-12-31 | Preparation method of 2-trifluoromethyl-4-aminobenzonitrile |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101759597B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875414A (en) * | 2012-10-16 | 2013-01-16 | 常州华生精细化工有限公司 | Preparation method of 4-amino-2-trifluoromethyl cyanophenyl |
| CN102951996A (en) * | 2012-11-15 | 2013-03-06 | 大连九信生物化工科技有限公司 | Synthesis method of 2-bromo-5-fluorobenzotrifluoride |
| CN104610015A (en) * | 2014-11-05 | 2015-05-13 | 江苏辉丰农化股份有限公司 | Preparation method of 2-bromine-5-fluorine trifluorotoluene |
| CN105152853A (en) * | 2015-09-25 | 2015-12-16 | 江苏永创医药科技股份有限公司 | Method for preparing 2-bromine-5-fluorobenzotrifluoride |
| CN107337576A (en) * | 2017-06-17 | 2017-11-10 | 盐城师范学院 | Constant temperature catalyzing synthesizes the fluoride trifluoro toluene of 2 bromine 5 |
| CN108623496A (en) * | 2017-03-22 | 2018-10-09 | 上海特化医药科技有限公司 | The preparation method of 3- ethyl -4- fluorobenzonitriles |
| CN111072517A (en) * | 2019-12-31 | 2020-04-28 | 常州沃腾化工科技有限公司 | Preparation method of 4-amino-2-trifluoromethyl benzonitrile |
| CN114920622A (en) * | 2022-02-19 | 2022-08-19 | 忠同科技(大连)有限公司 | Process method for preparing bromopentafluorobenzene |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE28864T1 (en) * | 1982-07-23 | 1987-08-15 | Ici Plc | AMIDE DERIVATIVES. |
| CN1810775B (en) * | 2006-02-21 | 2012-05-09 | 唐保清 | Preparation process of 4-amino-2-trifluoromethyl benzonitrile |
-
2009
- 2009-12-31 CN CN 200910247930 patent/CN101759597B/en active Active
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875414A (en) * | 2012-10-16 | 2013-01-16 | 常州华生精细化工有限公司 | Preparation method of 4-amino-2-trifluoromethyl cyanophenyl |
| CN102951996A (en) * | 2012-11-15 | 2013-03-06 | 大连九信生物化工科技有限公司 | Synthesis method of 2-bromo-5-fluorobenzotrifluoride |
| CN104610015A (en) * | 2014-11-05 | 2015-05-13 | 江苏辉丰农化股份有限公司 | Preparation method of 2-bromine-5-fluorine trifluorotoluene |
| CN105152853A (en) * | 2015-09-25 | 2015-12-16 | 江苏永创医药科技股份有限公司 | Method for preparing 2-bromine-5-fluorobenzotrifluoride |
| CN108623496A (en) * | 2017-03-22 | 2018-10-09 | 上海特化医药科技有限公司 | The preparation method of 3- ethyl -4- fluorobenzonitriles |
| CN108623496B (en) * | 2017-03-22 | 2022-11-08 | 上海特化医药科技有限公司 | Preparation method of 3-ethyl-4-fluorobenzonitrile |
| CN107337576A (en) * | 2017-06-17 | 2017-11-10 | 盐城师范学院 | Constant temperature catalyzing synthesizes the fluoride trifluoro toluene of 2 bromine 5 |
| CN111072517A (en) * | 2019-12-31 | 2020-04-28 | 常州沃腾化工科技有限公司 | Preparation method of 4-amino-2-trifluoromethyl benzonitrile |
| CN111072517B (en) * | 2019-12-31 | 2022-08-30 | 常州沃腾化工科技有限公司 | Preparation method of 4-amino-2-trifluoromethyl benzonitrile |
| CN114920622A (en) * | 2022-02-19 | 2022-08-19 | 忠同科技(大连)有限公司 | Process method for preparing bromopentafluorobenzene |
| CN114920622B (en) * | 2022-02-19 | 2024-04-05 | 忠同科技(大连)有限公司 | Technological method for preparing pentafluorobromide benzene |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101759597B (en) | 2013-09-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101759597B (en) | Preparation method of 2-trifluoromethyl-4-aminobenzonitrile | |
| KR102286085B1 (en) | Method for synthesizing terephthaloyl chloride by continuous flow in a microchannel reactor | |
| CN101367736B (en) | Synthesis of 2-aminobiphenyl compounds | |
| CN101133016A (en) | Method for producing substituted biphenyls | |
| CN101665394B (en) | Method for directly preparing alpha-fluoro acetophenone by acetophenone one-pot method | |
| CN112457153B (en) | Industrial preparation method of 2,4, 5-trifluoro-phenylacetic acid | |
| CN101693652B (en) | Process for preparing high-pure 4-hydroxybenzophenone | |
| WO2014071545A1 (en) | Preparation method for 2-bromo-3-fluorobenzoic acid | |
| CN104610012A (en) | Synthetic method for stable isotope labeled halobenzene | |
| CN100551923C (en) | Friedel-crafts process for the preparation of thioxanthones | |
| CN101648890A (en) | Synthesis method of 2-fluoro-4-nitrobenzonitrile | |
| CN108530301A (en) | A kind of synthetic method of tri- fluorin benzyl amines of 2,4,6- | |
| CN101693651B (en) | Synthetic method of 4-biphenylcarboxaldehyde | |
| CN115850018A (en) | Synthesis method of 1,2, 4-trifluorobenzene | |
| CN107602339B (en) | Method for synthesizing 4-hydroxymethyl biphenyl | |
| CN110229129B (en) | Equipment and method for preparing 4-chlorophthalic anhydride | |
| CN101318974B (en) | Process for synthesizing methyl tin chloride | |
| WO1988007519A1 (en) | Process for preparing 3-chloro-4-fluoronitrobenzene | |
| US2778847A (en) | Process for producing acrylonitrile | |
| CA2502360C (en) | Process for producing acetylene compound | |
| JP3729884B2 (en) | Method for producing fluorophenols | |
| CN102936188A (en) | Propynol glycidyl ether synthesis method | |
| CN102786399A (en) | New synthesis method for benflumetol intermediate 2,7-dichloro-4-chloroacetylfluorene | |
| JP3581391B2 (en) | Method for producing fluorophenols | |
| CN100389104C (en) | Process for preparation of 2,6-dichloroaniline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee | ||
| CP03 | Change of name, title or address |
Address after: 200331 No. 200, Wuwei Road, Shanghai, Putuo District Patentee after: SHANGHAI CHEMSPEC Corp. Address before: 200333 Shanghai city Putuo District Tong Pu Lu Lane 1273 No. 3 Patentee before: Shanghai Kangpeng Chemical Co.,Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20160308 Address after: 200331 No. 200, Wuwei Road, Shanghai, Putuo District Patentee after: SHANGHAI CHEMSPEC Corp. Patentee after: SHANGHAI WANSHUO CHEMICAL CO.,LTD. Address before: 200331 No. 200, Wuwei Road, Shanghai, Putuo District Patentee before: SHANGHAI CHEMSPEC Corp. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 2003 2001 No. 200 Wuwei Road, Putuo District, Shanghai Co-patentee after: Shanghai Wanshou Pharmaceutical Co.,Ltd. Patentee after: Shanghai Kangpeng Science and Technology Co.,Ltd. Address before: 2003 2001 No. 200 Wuwei Road, Putuo District, Shanghai Co-patentee before: SHANGHAI WANSHUO CHEMICAL CO.,LTD. Patentee before: SHANGHAI CHEMSPEC Corp. |