CN117466729A - Synthesis method of 2,4, 5-trifluoro phenylacetic acid - Google Patents
Synthesis method of 2,4, 5-trifluoro phenylacetic acid Download PDFInfo
- Publication number
- CN117466729A CN117466729A CN202311823401.2A CN202311823401A CN117466729A CN 117466729 A CN117466729 A CN 117466729A CN 202311823401 A CN202311823401 A CN 202311823401A CN 117466729 A CN117466729 A CN 117466729A
- Authority
- CN
- China
- Prior art keywords
- reaction
- trifluoro
- sulfuric acid
- trifluorophenylacetic
- synthesizing
- 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.)
- Withdrawn
Links
- YSQLGGQUQDTBSL-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(F)C=C1F YSQLGGQUQDTBSL-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 119
- 238000000034 method Methods 0.000 claims abstract description 48
- DLKNOGQOOZFICZ-UHFFFAOYSA-N 2,4,5-trifluorobenzonitrile Chemical compound FC1=CC(F)=C(C#N)C=C1F DLKNOGQOOZFICZ-UHFFFAOYSA-N 0.000 claims abstract description 46
- BLJQJQNRXILVTA-UHFFFAOYSA-N (2,4,5-trifluorophenyl)methanamine Chemical compound NCC1=CC(F)=C(F)C=C1F BLJQJQNRXILVTA-UHFFFAOYSA-N 0.000 claims abstract description 35
- QMYVWJVVVMIBMM-UHFFFAOYSA-N 2,4,5-trifluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1F QMYVWJVVVMIBMM-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 20
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 81
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 54
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 33
- 235000010288 sodium nitrite Nutrition 0.000 claims description 27
- 230000035484 reaction time Effects 0.000 claims description 26
- 238000006460 hydrolysis reaction Methods 0.000 claims description 25
- JTYBTJVFXUKNKW-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetonitrile Chemical compound FC1=CC(F)=C(CC#N)C=C1F JTYBTJVFXUKNKW-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000007333 cyanation reaction Methods 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 7
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 7
- 229940112669 cuprous oxide Drugs 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000004321 preservation Methods 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 28
- 239000000463 material Substances 0.000 description 14
- 239000012954 diazonium Substances 0.000 description 11
- 150000001989 diazonium salts Chemical class 0.000 description 11
- 230000008569 process Effects 0.000 description 10
- -1 1,2, 4-trifluorobenzyl chloride Chemical compound 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 230000003595 spectral effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000010464 Blanc reaction Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 3
- 229960004034 sitagliptin Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ROJNMGYMBLNTPK-UHFFFAOYSA-N 1,2,4-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C=C1F ROJNMGYMBLNTPK-UHFFFAOYSA-N 0.000 description 2
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 2
- 241000486679 Antitype Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 238000007171 acid catalysis Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 239000002912 waste gas Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- UXKZFJDNFBNQHE-RITPCOANSA-N [(1s,4r)-4-aminocyclopent-2-en-1-yl]methanol Chemical compound N[C@@H]1C[C@H](CO)C=C1 UXKZFJDNFBNQHE-RITPCOANSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of 2,4, 5-trifluorophenylacetic acid, which adopts a brand-new synthesis route, takes 2,4, 5-trifluoroaniline as a raw material, synthesizes 2,4, 5-trifluorobenzonitrile through diazotization reaction and cyanidation reaction, then reduces the 2,4, 5-trifluorobenzonitrile into 2,4, 5-trifluorobenzylamine through catalytic hydrogenation reaction, synthesizes 2,4, 5-trifluorobenzonitrile through secondary cyanidation reaction, and finally hydrolyzes the 2,4, 5-trifluorobenzonitrile to synthesize the target product 2,4, 5-trifluorophenylacetic acid; compared with the existing synthesis method, the method has the advantages of high reaction selectivity, high product yield, high molar yield up to 99.49%, low production cost, high economy, environmental protection and high feasibility of industrial application, and belongs to the technical field of organic synthesis.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and also relates to the technical field of synthesis of pharmaceutical raw materials, in particular to a method for synthesizing an intermediate 2,4, 5-trifluoro-phenylacetic acid of sitagliptin as an anti-type II diabetes drug.
Background
2,4, 5-trifluoro-phenylacetic acid is an intermediate of sitagliptin which is a dipeptidyl peptidase-4 inhibitor developed by Merck corporation in the United states and is an anti-type II diabetes drug, and can prevent and treat type II diabetes, hyperglycemia, insulin resistance, obesity and hypertension and certain complications, so that the research of the synthesis method of 2,4, 5-trifluoro-phenylacetic acid has important significance for researching sitagliptin.
The widely adopted synthetic route of the 2,4, 5-trifluorophenylacetic acid at present is that 2, 4-dichlorobenzene is taken as a raw material to obtain 2,4, 5-trifluoronitrobenzene through nitration and fluorination, the nitro is subjected to hydrogenation reduction and diazo reduction to complete denitration, 1,2, 4-trifluorobenzene is obtained, 1,2, 4-trifluorobenzene is subjected to Blanc chloromethylation to generate 1,2, 4-trifluorobenzyl chloride, then 2,4, 5-trifluorobenzyl cyanide is generated through substitution, and finally 2,4, 5-trifluorobenzyl cyanide is hydrolyzed to obtain 2,4, 5-trifluorophenylacetic acid. The reaction route is as follows:
the above route is capable of successfully synthesizing 2,4, 5-trifluorophenylacetic acid, but the above route has some key problems: firstly, in the process of generating 1,2, 4-trifluoro-benzyl chloride by Blanc chloromethylation, the risk of isomerization exists, and the isomer 2,3, 6-trifluoro-benzyl chloride is easy to generate, so that the selectivity of the reaction is low, the product yield is low, the comprehensive cost of the product is increased, and the production process does not have the price advantage; secondly, in the denitration process of 2,4, 5-trifluoro nitrobenzene, a reducing agent is additionally added to provide hydrogen atoms, so that the production cost is further increased.
Based on the above circumstances, there is an urgent need to develop a new synthesis method of 2,4, 5-trifluorophenylacetic acid.
Disclosure of Invention
In order to solve the technical problems, the technical scheme adopted by the application is to provide a synthesis method of 2,4, 5-trifluoro-phenylacetic acid, so as to solve the technical problems of low reaction selectivity, low product yield and high production cost of the existing synthesis method of 2,4, 5-trifluoro-phenylacetic acid.
The embodiment of the application provides a synthesis method of 2,4, 5-trifluoro-phenylacetic acid, which comprises the following steps:
(1) Adding 2,4, 5-trifluoroaniline and sodium nitrite into sulfuric acid, and carrying out diazotization reaction by heat preservation and stirring; after the reaction is finished, adding potassium cyanide and cuprous oxide, and carrying out a cyanation reaction by stirring under heat preservation to obtain 2,4, 5-trifluoro-benzonitrile;
(2) Adding 2,4, 5-trifluoro-benzonitrile and palladium carbon into methanol, heating in hydrogen atmosphere to perform catalytic hydrogenation reaction to obtain 2,4, 5-trifluoro-benzylamine; adding 2,4, 5-trifluoro benzylamine and sodium nitrite into sulfuric acid, adding potassium cyanide, and performing secondary cyanidation reaction at a constant temperature to obtain 2,4, 5-trifluoro benzyl cyanide;
(3) Adding 2,4, 5-trifluorobenzyl cyanide into sulfuric acid, heating and preserving heat to perform hydrolysis reaction to obtain 2,4, 5-trifluorophenylacetic acid.
Preferably, in the step (1), sulfuric acid is a 50% sulfuric acid solution, and the molar ratio of 2,4, 5-trifluoroaniline to sulfuric acid is 1:3,2,4, 5-trifluoroaniline to sodium nitrite is 1:0.9-1:1.2.
Preferably, in the step (1), the reaction temperature of the diazotization reaction is-5 ℃ and the reaction time is 10min.
Preferably, in the step (1), the molar ratio of the 2,4, 5-trifluoroaniline to the potassium cyanide is 1:0.9-1:1.1, and the mass of the cuprous oxide is 1% of the mass of the 2,4, 5-trifluoroaniline.
Preferably, in the step (1), the reaction temperature of the cyanation reaction is 0-20 ℃ and the reaction time is 30min.
Preferably, in the step (2), the mass ratio of the 2,4, 5-trifluoro-benzonitrile to the methanol is 1:1,2,4, 5-trifluoro-benzonitrile to palladium carbon is 1:0.001-1:0.002.
Preferably, in the step (2), the reaction temperature of the catalytic hydrogenation reaction is 80-120 ℃, the reaction time is 2 hours, and the hydrogen pressure is 1-3 Mpa.
Preferably, in the step (2), sulfuric acid is a 50% sulfuric acid solution, the mass ratio of 2,4, 5-trifluorobenzylamine to sulfuric acid is 1:1, the molar ratio of 2,4, 5-trifluorobenzylamine to sodium nitrite is 1:1.0-1:1.2, and the molar ratio of 2,4, 5-trifluorobenzylamine to potassium cyanide is 1:1.0-1:1.1.
Preferably, in the step (2), the reaction temperature of the secondary cyanation reaction is 10-30 ℃ and the reaction time is 30min.
Preferably, in the step (3), sulfuric acid is a 50% sulfuric acid solution, the molar ratio of 2,4, 5-trifluorobenzyl cyanide to sulfuric acid is 1:0.5-1:2.0, the reaction temperature of the hydrolysis reaction is 70-90 ℃, and the reaction time is 4-8 h.
The invention provides a synthesis method of 2,4, 5-trifluorophenylacetic acid, which adopts a brand-new synthesis route, takes 2,4, 5-trifluoroaniline as a raw material, synthesizes 2,4, 5-trifluorobenzonitrile through diazotization reaction and cyanidation reaction, then reduces the 2,4, 5-trifluorobenzonitrile into 2,4, 5-trifluorobenzylamine through catalytic hydrogenation reaction, synthesizes 2,4, 5-trifluorobenzonitrile through secondary cyanidation reaction, and finally hydrolyzes the 2,4, 5-trifluorobenzonitrile to synthesize the target product 2,4, 5-trifluorophenylacetic acid.
Compared with the existing synthesis method, the invention has the beneficial effects that:
(1) According to the invention, after diazonium salt is synthesized through diazotization, a hydrogen atom is not introduced by using a reducing agent, but a cyano group is introduced to a benzene ring by using potassium cyanide, so that the isomerization phenomenon caused by Blanc chloromethylation is fundamentally avoided, the reaction selectivity is improved, and the product yield is improved; in addition, lewis acid catalysis is not needed in the reaction, so that the production cost is reduced, a large amount of dangerous hydrogen chloride waste water and gas are avoided, the post-treatment difficulty is reduced, further subsequent reaction and purification are easy, and the reaction is safe and environment-friendly, so that the reaction has the advantage of industrial production;
(2) The invention synthesizes 2,4, 5-trifluoro-benzonitrile through cyanidation reaction, then synthesizes 2,4, 5-trifluoro-benzonitrile through catalytic hydrogenation reaction, at the moment, diazonium salt is acted by aromatic ring, is stable under the reaction condition, and is decomposed to generate N 2 The reaction with potassium cyanide directly generates 2,4, 5-trifluorobenzyl cyanide (the reaction mechanism is as follows), and carbonium ions are not generated when diazonium salts are decomposed, so that a series of reactions such as substitution, rearrangement, elimination and the like of the carbonium ions are avoided, a single product can be efficiently generated, the reaction selectivity is higher, and the yield of the product is also higher; the reaction mechanism of 2,4, 5-trifluoro-benzyl amine to 2,4, 5-trifluoro-benzyl acetonitrile is as follows:
the method has the advantages of high reaction selectivity, high product yield, high molar yield up to 99.49%, low production cost, high economy, environmental protection and high feasibility of industrial application.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following description will briefly introduce the drawings that are needed in the embodiments or the description of the prior art, it is obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a liquid chromatogram of the product prepared in example 24 of the present application;
FIG. 2 is a liquid chromatogram of a 2,4, 5-trifluorophenylacetic acid standard;
FIG. 3 is a graph showing the comparison of the spectral peaks of the product prepared in example 24 of the present application with 2,4, 5-trifluorophenylacetic acid standard; wherein, (1) is the product obtained in example 24; (2) is a 2,4, 5-trifluoro phenylacetic acid standard.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects to be solved by the present application more clear, the present application is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the present application.
The invention provides a method for synthesizing 2,4, 5-trifluoro-phenylacetic acid, which takes 2,4, 5-trifluoro-aniline as a raw material, synthesizes 2,4, 5-trifluoro-benzonitrile through diazotization reaction and cyanidation reaction, then reduces the 2,4, 5-trifluoro-benzonitrile into 2,4, 5-trifluoro-benzylamine through catalytic hydrogenation reaction, synthesizes 2,4, 5-trifluoro-phenylacetonitrile through secondary cyanidation reaction, and finally hydrolyzes the 2,4, 5-trifluoro-phenylacetonitrile to synthesize the target product 2,4, 5-trifluoro-phenylacetic acid.
In order to confirm the effect of the present invention, examples 1 to 30 are described below.
Diazotisation-cyanation
Example 1
(1) 203.94g (2.0378 mol) of 98% concentrated sulfuric acid and 199.86g of water were charged into a water-free sealed reactor to prepare a 50% sulfuric acid solution.
(2) Cooling 50% sulfuric acid solution to 0 ℃, adding 100.00g (0.6798 mol) of 2,4, 5-trifluoroaniline, uniformly mixing, adding 46.91g (0.6799 mol) of sodium nitrite, stirring to fully mix, preserving heat at 0 ℃ and stirring for 10min, and carrying out diazotization reaction to obtain diazonium salt materials;
heating diazonium salt material to 10 ℃, adding 1g of cuprous oxide powder as a catalyst, uniformly stirring, adding 44.27g (0.6416 mol) of potassium cyanide, and stirring at 10 ℃ for 30min for cyanidation; after the cyanation reaction is finished, the reaction material is kept stand for liquid separation, the lower layer oil phase is taken out, the lower layer oil phase is washed by purified water, 106.74g of 2,4, 5-trifluoro-benzonitrile is obtained after dehydration, and the molar yield is calculated to be 99.95%.
The reaction equation is as follows:
example 2
The difference between the present method and example 1 is that 42.22g (0.6119 mol) of sodium nitrite is added in the step (2), and the other steps are the same, whereby 93.87g of 2,4, 5-trifluorobenzonitrile is obtained, and the molar yield thereof is calculated to be 87.90%.
Example 3
This example was conducted in the same manner as in example 1 except that 51.60g (0.7479 mol) of sodium nitrite was added in step (2), 106.74g of 2,4, 5-trifluorobenzonitrile was obtained, and the molar yield was found to be 99.95%.
Example 4
The difference between the present method and example 1 is that 56.29g (0.8159 mol) of sodium nitrite is added in the step (2), and the other steps are the same, whereby 106.72g of 2,4, 5-trifluorobenzonitrile is obtained, and the molar yield thereof is calculated to be 99.93%.
From examples 1 to 4, it is understood that, with respect to the amount of sodium nitrite to be charged, if the amount of sodium nitrite to be charged is too small, the diazotization reaction is difficult to proceed, the yield of the reaction is lowered, while if the amount of sodium nitrite to be charged is too large, the yield of the reaction is not improved, the waste of raw materials is caused, and the yield of the reaction is slightly lowered, and the most suitable amount of sodium nitrite to be charged is 1.0 to 1.1 equivalent of the raw material 2,4, 5-trifluoroaniline by mole; therefore, from the viewpoint of cost reduction, the molar ratio of 2,4, 5-trifluoroaniline to sodium nitrite is preferably 1:1.0.
Example 5
Unlike example 1, in step (2), the diazotization reaction was carried out at-5℃and other steps were carried out in the same manner to obtain 85.93g of 2,4, 5-trifluorobenzonitrile, and the molar yield was 80.47%.
Example 6
The difference between the present method and example 1 is that in step (2), the diazotization reaction temperature was 5℃and the other steps were the same, 48.76g of 2,4, 5-trifluorobenzonitrile was obtained, and the molar yield was 45.66%.
As is clear from examples 1 and 5 to 6, the reaction temperature of diazotization needs to be controlled to be 0℃and the reaction proceeds slowly (-5 ℃) and cannot be completed under the same conditions, while the reaction temperature of too high (5 ℃) causes unstable diazonium salt materials and decomposition, resulting in a decrease in the reaction yield, and therefore, the reaction temperature of diazotization is preferably 0 ℃.
Example 7
The difference between the present method and example 1 is that 39.84g (0.6118 mol) of potassium cyanide was added in the step (2), and the other steps were the same, whereby 96.08g of 2,4, 5-trifluorobenzonitrile was obtained, and the molar yield thereof was calculated to be 89.97%.
Example 8
The difference between the present method and example 1 is that 48.70g (0.7479 mol) of potassium cyanide was added in the step (2), and the other steps were the same, whereby 106.71g of 2,4, 5-trifluorobenzonitrile was obtained, and the molar yield was 99.93%.
As is clear from examples 1 and 7 to 8, in the cyanation reaction, the amount of potassium cyanide fed should be 1.0 equivalent of 2,4, 5-trifluoroaniline on a molar basis, and when the amount of potassium cyanide fed is not enough to be 0.9 equivalent, the reaction cannot be completely carried out, and some raw materials remain, and when the amount of potassium cyanide fed is too much to be 1.1 equivalent, potassium cyanide remains, so that the difficulty in material treatment increases; thus, the most suitable potassium cyanide feed amount is 1.0 equivalent of the molar amount of 2,4, 5-trifluoroaniline, i.e., the molar ratio of 2,4, 5-trifluoroaniline to potassium cyanide is preferably 1:1.0.
Example 9
The difference between the present method and example 1 is that in step (2), the cyanation reaction temperature was 0℃and the other steps were the same, and 72.50g of 2,4, 5-trifluorobenzonitrile was obtained, and the molar yield was 67.89%.
Example 10
The difference between the present method and example 1 is that in step (2), the cyanation reaction temperature was 20℃and the other steps were the same, 92.51g of 2,4, 5-trifluorobenzonitrile was obtained, and the molar yield was 86.62%.
As is clear from examples 1 and 9 to 10, when the temperature of the cyanation reaction is too low, the reaction cannot be conducted thoroughly, resulting in a decrease in the reaction yield, and when the reaction temperature is too high, the diazonium salt material is deteriorated, resulting in a decrease in the yield, so that the reaction temperature of the cyanation reaction is preferably 10 ℃.
In order to more intuitively compare the effect of the process parameters of examples 1 to 10 on the molar yield of 2,4, 5-trifluorobenzonitrile, the following Table 1 was now formed.
TABLE 1 influence of the process parameters of examples 1 to 10 on the molar yield of 2,4, 5-trifluorobenzonitrile
As can be seen from Table 1, preferred reaction conditions for the diazotisation reaction are: the molar ratio of 2,4, 5-trifluoroaniline to sulfuric acid is 1:3, the molar ratio of 2,4, 5-trifluoroaniline to sodium nitrite is 1:1.0, the reaction temperature is 0 ℃, and the reaction time is 10min; preferred reaction conditions for the cyanation reaction are: the molar ratio of the 2,4, 5-trifluoroaniline to the potassium cyanide is 1:1.0, the mass of the cuprous oxide is 1% of the mass of the 2,4, 5-trifluoroaniline, the reaction temperature is 10 ℃, and the reaction time is 30min.
(II) catalytic hydrogenation reaction
Example 11
Taking 100g of dehydrated 2,4, 5-trifluoro-benzonitrile prepared in example 1, adding 100g of methanol solvent into a high-pressure reaction kettle, adding 2,4, 5-trifluoro-benzonitrile and 0.2g of palladium-carbon catalyst, closing the kettle, filling hydrogen into the kettle until the pressure in the kettle is 2MPa, heating the reaction kettle to 100 ℃, and preserving heat for 2 hours to perform catalytic hydrogenation reaction; after the reaction is finished, cooling, decompressing, recovering hydrogen, opening the kettle to obtain a reaction material, filtering the reaction material, separating a catalyst, distilling filtrate, separating a methanol solvent to obtain 102.53g of a product 2,4, 5-trifluoro-benzylamine, and calculating the molar yield of the product to be 99.96%.
The reaction equation is as follows:
example 12
This example was conducted in the same manner as in example 11 except that 0.1g of a palladium-carbon catalyst was added, and 74.40g of 2,4, 5-trifluorobenzyl amine was obtained, whereby the molar yield was 72.54%.
As is clear from examples 11 to 12, in the catalytic hydrogenation reaction, too low an amount of the palladium-carbon catalyst may cause incomplete reaction and lower the reaction yield, and therefore, the most suitable catalyst addition amount is 0.002 equivalent of 2,4, 5-trifluorobenzonitrile added by mass, i.e., the mass ratio of 2,4, 5-trifluorobenzonitrile to palladium-carbon is preferably 1:0.002.
Example 13
The difference between the present method and example 11 is that in step (2), the catalytic hydrogenation reaction temperature was 80℃and the other steps were the same, whereby 3.35g of 2,4, 5-trifluorobenzylamine was obtained, and the molar yield was 3.27%.
Example 14
The difference between the present method and example 11 is that in step (2), the catalytic hydrogenation reaction temperature was 120℃and the other steps were the same, thereby obtaining 54.30g of 2,4, 5-trifluorobenzylamine, and the molar yield was 52.95%.
As is clear from examples 11 and 13 to 14, when the temperature of the catalytic hydrogenation reaction is too low, the reaction does not proceed substantially, and when the reaction temperature is too high, the reaction yield is also lowered, and therefore, the reaction temperature of the catalytic hydrogenation reaction is preferably 100 ℃.
Example 15
The difference between the method of this embodiment and example 11 is that in step (2), hydrogen was introduced into the reactor until the pressure in the reactor became 1MPa, and the other steps were the same, whereby 83.05g of 2,4, 5-trifluorobenzylamine was obtained, and the molar yield was 80.97%.
Example 16
The difference between the present method and example 11 is that in step (2), hydrogen was introduced into the reactor until the pressure in the reactor became 3MPa, and 102.45g of 2,4, 5-trifluorobenzylamine was obtained in the same manner as in the other steps, and the molar yield was 99.89%.
As is clear from examples 11 and 15 to 16, in the catalytic hydrogenation reaction, when the hydrogen gas charging pressure is too low, the reaction cannot be completely performed, resulting in a low reaction yield, and when the hydrogen gas charging pressure reaches 2 to 3MPa, the reaction can be normally performed, resulting in a high yield, and therefore, the most suitable hydrogen gas charging pressure is 2 to 3MPa, and the hydrogen gas pressure is preferably 2MPa from the viewpoint of cost reduction.
In order to more intuitively compare the effect of the process parameters of examples 11-16 on the molar yield of 2,4, 5-trifluorobenzylamine, the following Table 2 was now formed.
TABLE 2 influence of the process parameters of examples 11 to 16 on the molar yield of 2,4, 5-trifluorobenzylamine
As can be seen from Table 2, the preferred reaction conditions for the catalytic hydrogenation reaction are: the mass ratio of the 2,4, 5-trifluoro-benzonitrile to the methanol is 1:1,2,4, 5-trifluoro-benzonitrile to palladium-carbon is 1:0.002, the reaction temperature is 100 ℃, the reaction time is 2h, and the hydrogen pressure is 2MPa.
(III) Secondary cyanidation
Example 17
100g (0.6206 mol) of 2,4, 5-trifluoro-benzylamine prepared in example 11 is taken and mixed with 100g of 50% sulfuric acid, then 47.11g (0.6828 mol) of sodium nitrite is added, after uniform stirring, 42.44g (0.6518 mol) of potassium cyanide is added, and the mixture is kept at 20 ℃ for 30min for secondary cyanidation; after the reaction, the reaction mass was filtered, the filter cake was washed with acetonitrile, and then air-blown and dried under normal pressure to obtain 101.66g of 2,4, 5-trifluorobenzyl cyanide as a product, the molar yield of which was 95.72%.
The reaction equation is as follows:
example 18
The procedure of this example was repeated except for adding 42.83g (0.6208 mol) of sodium nitrite to obtain 99.29g of 2,4, 5-trifluorobenzyl cyanide, which was found to give a molar yield of 93.49%.
Example 19
This example was conducted in the same manner as in example 17 except that 51.39g (0.7448 mol) of sodium nitrite was added, 101.57g of 2,4, 5-trifluorobenzyl cyanide was obtained, and the molar yield was calculated to be 95.63%.
As is clear from examples 17 to 19, in the case where the amount of sodium nitrite to be fed in the secondary cyanation reaction is too low, diazonium salt cannot be obtained by sufficient reaction, and therefore, the most suitable amount of sodium nitrite to be fed is 1.1 to 1.2 equivalents of 2,4, 5-trifluorobenzylamine on a molar basis, and the molar ratio of 2,4, 5-trifluorobenzylamine to sodium nitrite is preferably 1:1.1 from the viewpoint of cost reduction.
Example 20
The procedure of this example was repeated except for adding 40.42g (0.6207 mol) of potassium cyanide and the same procedure was repeated except that 98.23g of 2,4, 5-trifluorobenzyl cyanide was obtained, whereby the molar yield was 92.49%.
Example 21
The procedure of this example was repeated except for adding 44.46g (0.6828 mol) of potassium cyanide and the same procedure was repeated except that 100.91g of 2,4, 5-trifluorobenzyl cyanide was obtained, whereby the molar yield was 92.02%.
As is clear from examples 17 and 20 to 21, in the secondary cyanation reaction, when the amount of potassium cyanide to be fed is too low, a part of 2,4, 5-trifluorobenzylamine is not reacted, resulting in a low reaction yield, and when the amount of potassium cyanide to be fed is too large, the reaction yield cannot be improved, and the excessive potassium cyanide causes difficulty in material handling, so that the most suitable amount of potassium cyanide to be fed is 1.05 equivalents of 2,4, 5-trifluorobenzylamine on a molar basis, i.e., the molar ratio of 2,4, 5-trifluorobenzylamine to potassium cyanide is preferably 1:1.05.
Example 22
The difference between the present method and example 17 is that the temperature of the secondary cyanation reaction is 10℃and the other steps are the same, and 73.06g of 2,4, 5-trifluorobenzyl cyanide is obtained, and the molar yield is 68.79%.
Example 23
The difference between the present method and example 17 is that the temperature of the secondary cyanation reaction is 30℃and the other steps are the same, and 84.58g of 2,4, 5-trifluorobenzyl cyanide is obtained, and the molar yield is 79.64%.
As is clear from examples 17 and 22 to 23, the reaction temperature of the secondary cyanation reaction should be controlled to 20℃and, when the reaction temperature is too low, the reaction proceeds slowly, and when the reaction temperature is too high, the reaction yield decreases, and therefore, the reaction temperature of the secondary cyanation reaction is preferably 20 ℃.
In order to more intuitively compare the effect of the process parameters of examples 17 to 23 on the molar yield of 2,4, 5-trifluorobenzyl cyanide, the following Table 3 was now formed.
TABLE 3 influence of the process parameters of examples 17 to 23 on the molar yield of 2,4, 5-trifluorobenzyl cyanide
As can be seen from Table 3, the preferred reaction conditions for the secondary cyanation reaction are: the mass ratio of 2,4, 5-trifluoro-benzylamine to 50% sulfuric acid is 1:1,2,4, 5-trifluoro-benzylamine to sodium nitrite is 1:1.1, the molar ratio of 2,4, 5-trifluoro-benzylamine to potassium cyanide is 1:1.05, the reaction temperature is 20 ℃, and the reaction time is 30min.
(IV) hydrolysis reaction
Example 24
Taking 100g (0.5844 mol) of 2,4, 5-trifluorobenzyl cyanide prepared in example 17, adding the mixture into 114.54g (0.5839 mol) of 50% sulfuric acid, uniformly mixing, heating to 80 ℃, and preserving heat for 6 hours to perform hydrolysis reaction; after the reaction is finished, the temperature is reduced, the reaction materials are filtered, filter cakes are washed by water and acetonitrile in sequence, and then dried, thus obtaining 110.54g of 2,4, 5-trifluoro-phenylacetic acid, and the molar yield is calculated to be 99.49%.
The reaction equation is as follows:
example 25
This example was conducted in the same manner as in example 24 except that 57.27g (0.2920 mol) of 50% sulfuric acid was added, and 54.73g of 2,4, 5-trifluorophenylacetic acid was obtained, whereby the molar yield was 49.26%.
Example 26
The procedure of this example was repeated except that 229.08g (1.1678 mol) of 50% sulfuric acid was added to give 86.59g of 2,4, 5-trifluorophenylacetic acid, and the molar yield was 77.94%.
As is clear from examples 24 to 26, in the hydrolysis reaction, when the amount of sulfuric acid fed is too low, hydrolysis is not complete, and a large amount of raw materials are not hydrolyzed, and when the amount of sulfuric acid fed is too high, the oxidizing property of the system is too strong, so that a part of the materials are deteriorated, and 2,4, 5-trifluorophenylacetic acid cannot be produced, and therefore, the most suitable amount of sulfuric acid fed is 1.0 equivalent of 2,4, 5-trifluorophenylacetonitrile on a molar basis, i.e., the molar ratio of 2,4, 5-trifluorophenylacetonitrile to sulfuric acid is preferably 1:1.0.
Example 27
The procedure of this example was repeated except that the hydrolysis time was 4 hours and the other steps were the same, to obtain 102.84g of 2,4, 5-trifluorophenylacetic acid, and the molar yield was 92.57%.
Example 28
The difference between the present method and example 24 is that the hydrolysis reaction time is 8 hours, and the other steps are the same, thereby obtaining 110.45g of 2,4, 5-trifluorophenylacetic acid, and the molar yield is 99.41%.
As is clear from examples 24 and 27 to 28, the reaction time of the hydrolysis reaction should be controlled to be 6 hours, and when the hydrolysis reaction time is too short, the hydrolysis reaction is not thorough, which results in low reaction yield, and the hydrolysis reaction time reaches 6 hours, and the hydrolysis reaction time is prolonged without increasing the reaction yield, so the reaction time of the hydrolysis reaction is preferably 6 hours.
Example 29
The difference between the present method and example 24 is that the hydrolysis reaction temperature is 70℃and the other steps are the same, thereby obtaining 109.76g of 2,4, 5-trifluorophenylacetic acid, and the molar yield is 98.79%.
Example 30
The present method was conducted in the same manner as in example 24 except that the temperature of the hydrolysis reaction was 90℃and the other steps were conducted in the same manner, 94.37g of 2,4, 5-trifluorophenylacetic acid was obtained, and the molar yield was 84.94%.
As is clear from examples 24 and 29 to 30, when the reaction temperature of the hydrolysis reaction is 90 ℃, the yield of the hydrolysis reaction is greatly reduced, and the raw material is wasted, whereas when the reaction temperature of the hydrolysis reaction is 70 ℃, the reaction rate of the hydrolysis reaction is reduced, and the reaction yield is slightly reduced, and therefore, the reaction temperature of the hydrolysis reaction is preferably 80 ℃.
In order to more intuitively compare the effect of the process parameters of examples 24 to 30 on the molar yield of 2,4, 5-trifluorophenylacetic acid, table 4 below was now formed.
TABLE 4 influence of the process parameters of examples 24 to 30 on the molar yield of 2,4, 5-trifluorophenylacetic acid
As can be seen from Table 4, the preferred reaction conditions for the hydrolysis reaction are: the molar ratio of the 2,4, 5-trifluorobenzyl acetonitrile to the sulfuric acid is 1:1.0, the reaction temperature is 80 ℃, and the reaction time is 6 hours.
From the above, it can be seen from tables 1 to 4 that preferred synthesis conditions for 2,4, 5-trifluorophenylacetic acid are:
diazotization reaction: the molar ratio of 2,4, 5-trifluoroaniline to sulfuric acid is 1:3, the molar ratio of 2,4, 5-trifluoroaniline to sodium nitrite is 1:1.0, the reaction temperature is 0 ℃, and the reaction time is 10min; and (3) cyaniding reaction: the molar ratio of the 2,4, 5-trifluoroaniline to the potassium cyanide is 1:1.0, the mass of the cuprous oxide is 1% of the mass of the 2,4, 5-trifluoroaniline, the reaction temperature is 10 ℃, and the reaction time is 30min;
catalytic hydrogenation reaction: the mass ratio of the 2,4, 5-trifluoro-benzonitrile to the methanol is 1:1,2,4, 5-trifluoro-benzonitrile to palladium-carbon is 1:0.002, the reaction temperature is 100 ℃, the reaction time is 2h, and the hydrogen pressure is 2MPa;
secondary cyanidation reaction: the mass ratio of 2,4, 5-trifluoro-benzylamine to 50% sulfuric acid is 1:1,2,4, 5-trifluoro-benzylamine to sodium nitrite is 1:1.1, the molar ratio of 2,4, 5-trifluoro-benzylamine to potassium cyanide is 1:1.05, the reaction temperature is 20 ℃, and the reaction time is 30min;
hydrolysis reaction: the molar ratio of the 2,4, 5-trifluorobenzyl acetonitrile to the sulfuric acid is 1:1.0, the reaction temperature is 80 ℃, and the reaction time is 6 hours;
in this case, the molar yield of 2,4, 5-trifluorophenylacetic acid was as high as 99.49%.
The product obtained in example 24 was examined to obtain a liquid chromatogram as shown in FIG. 1, and a 2,4, 5-trifluorophenylacetic acid standard purchased from Allatin corporation was examined to obtain a liquid chromatogram as shown in FIG. 2. As can be seen from FIG. 1, the peak with the peak time of 7.677min is a solvent peak, the spectral peak time of 9.882min is a product, and as can be seen from FIG. 2, the spectral peak time of 9.888min is a 2,4, 5-trifluorophenylacetic acid standard, the peak time of the product prepared in example 24 is approximately the same as the peak time of the 2,4, 5-trifluorophenylacetic acid standard. The comparison of the spectral peaks of the product prepared in example 24 and the 2,4, 5-trifluorophenylacetic acid standard substance shows a comparison chart of the spectral peaks of the product and the standard substance, shown in fig. 3, wherein (1) is the product prepared in example 24, and (2) is the standard substance of 2,4, 5-trifluorophenylacetic acid. As can be seen in FIG. 3, the spectral peaks of the two materials are substantially coincident together, thus indicating that the two materials are the same material, i.e., the product of example 24 is 2,4, 5-trifluorophenylacetic acid.
The invention provides a synthesis method of 2,4, 5-trifluorophenylacetic acid, which adopts a brand-new synthesis route, takes 2,4, 5-trifluoroaniline as a raw material, synthesizes 2,4, 5-trifluorobenzonitrile through diazotization reaction and cyanidation reaction, then reduces the 2,4, 5-trifluorobenzonitrile into 2,4, 5-trifluorobenzylamine through catalytic hydrogenation reaction, synthesizes 2,4, 5-trifluorobenzonitrile through secondary cyanidation reaction, and finally hydrolyzes the 2,4, 5-trifluorobenzonitrile to synthesize the target product 2,4, 5-trifluorophenylacetic acid.
Compared with the existing synthesis method, (1) after diazonium salt is synthesized through diazotization, hydrogen atoms are not introduced by using a reducing agent, cyano groups are introduced to benzene rings by using potassium cyanide, so that isomerization phenomenon caused by Blanc chloromethylation is fundamentally avoided, the reaction selectivity is improved, and the product yield is improved; in addition, lewis acid catalysis is not needed in the reaction, so that the production cost is reduced, a large amount of dangerous hydrogen chloride waste water and gas are avoided, the post-treatment difficulty is reduced, further subsequent reaction and purification are easy, and the reaction is safe and environment-friendly, so that the reaction has the advantage of industrial production; (2) The invention is characterized in thatSynthesizing 2,4, 5-trifluoro-benzonitrile through cyanidation, and synthesizing 2,4, 5-trifluoro-benzonitrile through catalytic hydrogenation, wherein diazonium salt is subjected to aromatic ring, is relatively stable under the reaction condition, and is decomposed to generate N 2 2,4, 5-trifluorobenzyl cyanide is directly generated after the reaction with potassium cyanide, carbonium ions are not generated when diazonium salts are decomposed, a series of reactions such as substitution, rearrangement, elimination and the like of the carbonium ions are avoided, and a single product can be efficiently generated, so that the selectivity of the reaction is higher, and the yield of the product is also higher; the method has the advantages of high reaction selectivity, high product yield, high molar yield up to 99.49%, low production cost, high economy, environmental protection and high feasibility of industrial application.
It should be noted that: the raw materials and the devices used in the invention are conventional commercial products unless specified otherwise, and the methods used in the invention are conventional methods unless specified otherwise.
The above embodiments are only for illustrating the technical solution of the present application, and are not limiting; although the present application has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present application, and are intended to be included in the scope of the present application.
Claims (10)
1. The synthesis method of the 2,4, 5-trifluoro-phenylacetic acid is characterized by comprising the following steps:
(1) Adding 2,4, 5-trifluoroaniline and sodium nitrite into sulfuric acid, and carrying out diazotization reaction by heat preservation and stirring; after the reaction is finished, adding potassium cyanide and cuprous oxide, and carrying out a cyanation reaction by stirring under heat preservation to obtain 2,4, 5-trifluoro-benzonitrile;
(2) Adding 2,4, 5-trifluoro-benzonitrile and palladium carbon into methanol, heating in hydrogen atmosphere to perform catalytic hydrogenation reaction to obtain 2,4, 5-trifluoro-benzylamine; adding 2,4, 5-trifluoro benzylamine and sodium nitrite into sulfuric acid, adding potassium cyanide, and performing secondary cyanidation reaction at a constant temperature to obtain 2,4, 5-trifluoro benzyl cyanide;
(3) Adding 2,4, 5-trifluorobenzyl cyanide into sulfuric acid, heating and preserving heat to perform hydrolysis reaction to obtain 2,4, 5-trifluorophenylacetic acid.
2. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (1), sulfuric acid is a 50% sulfuric acid solution, and the molar ratio of 2,4, 5-trifluoroaniline to sulfuric acid is 1:3,2,4, 5-trifluoroaniline to sodium nitrite is 1:0.9-1:1.2.
3. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (1), the reaction temperature of the diazotization reaction is-5 to 5 ℃ and the reaction time is 10 minutes.
4. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (1), the molar ratio of 2,4, 5-trifluoroaniline to potassium cyanide is 1:0.9-1:1.1, and the mass of cuprous oxide is 1% of the mass of 2,4, 5-trifluoroaniline.
5. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (1), the reaction temperature of the cyanation reaction is 0-20 ℃ and the reaction time is 30min.
6. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (2), the mass ratio of 2,4, 5-trifluorobenzonitrile to methanol is 1:1,2,4, 5-trifluorobenzonitrile to palladium on carbon is 1:0.001-1:0.002.
7. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (2), the reaction temperature of the catalytic hydrogenation reaction is 80-120 ℃, the reaction time is 2h, and the hydrogen pressure is 1-3 Mpa.
8. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (2), sulfuric acid is a 50% sulfuric acid solution, the mass ratio of 2,4, 5-trifluorobenzylamine to sulfuric acid is 1:1,2,4, 5-trifluorobenzylamine to sodium nitrite is 1:1.0-1:1.2, and the molar ratio of 2,4, 5-trifluorobenzylamine to potassium cyanide is 1:1.0-1:1.1.
9. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (2), the reaction temperature of the secondary cyanation reaction is 10-30 ℃ and the reaction time is 30min.
10. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (3), sulfuric acid is a 50% sulfuric acid solution, the molar ratio of 2,4, 5-trifluorophenylacetonitrile to sulfuric acid is 1:0.5-1:2.0, the reaction temperature of the hydrolysis reaction is 70-90 ℃, and the reaction time is 4-8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311823401.2A CN117466729A (en) | 2023-12-28 | 2023-12-28 | Synthesis method of 2,4, 5-trifluoro phenylacetic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311823401.2A CN117466729A (en) | 2023-12-28 | 2023-12-28 | Synthesis method of 2,4, 5-trifluoro phenylacetic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117466729A true CN117466729A (en) | 2024-01-30 |
Family
ID=89638224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311823401.2A Withdrawn CN117466729A (en) | 2023-12-28 | 2023-12-28 | Synthesis method of 2,4, 5-trifluoro phenylacetic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117466729A (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5673064A (en) * | 1979-11-21 | 1981-06-17 | Teikoku Hormone Mfg Co Ltd | Isoquinoline derivative |
| US4337256A (en) * | 1978-12-27 | 1982-06-29 | Teikoku Hormone Manufacturing Co., Ltd. | 1-Phenyl isoquinoline-5-acetic acid compounds and analgesic compositions thereof |
| CN1261875A (en) * | 1997-07-01 | 2000-08-02 | 拜尔公司 | Method for production of 2,4,5-trifluorobenzonitrile |
| 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 |
| CN106518839A (en) * | 2017-01-11 | 2017-03-22 | 鲁东大学 | Green preparation technology of 2-thiopheneacetic acid |
| CN112457153A (en) * | 2020-11-10 | 2021-03-09 | 杭州臻挚生物科技有限公司 | Industrial preparation method of 2,4, 5-trifluoro-phenylacetic acid |
| CN112851493A (en) * | 2020-11-10 | 2021-05-28 | 杭州臻挚生物科技有限公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
| CN115052627A (en) * | 2019-12-17 | 2022-09-13 | 凯麦拉医疗公司 | IRAK degrading agents and uses thereof |
| CN115677477A (en) * | 2022-09-26 | 2023-02-03 | 上海康鹏科技股份有限公司 | Preparation method of 2,4, 5-trifluoro-phenylacetic acid and intermediate thereof |
-
2023
- 2023-12-28 CN CN202311823401.2A patent/CN117466729A/en not_active Withdrawn
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4337256A (en) * | 1978-12-27 | 1982-06-29 | Teikoku Hormone Manufacturing Co., Ltd. | 1-Phenyl isoquinoline-5-acetic acid compounds and analgesic compositions thereof |
| JPS5673064A (en) * | 1979-11-21 | 1981-06-17 | Teikoku Hormone Mfg Co Ltd | Isoquinoline derivative |
| CN1261875A (en) * | 1997-07-01 | 2000-08-02 | 拜尔公司 | Method for production of 2,4,5-trifluorobenzonitrile |
| 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 |
| CN106518839A (en) * | 2017-01-11 | 2017-03-22 | 鲁东大学 | Green preparation technology of 2-thiopheneacetic acid |
| CN115052627A (en) * | 2019-12-17 | 2022-09-13 | 凯麦拉医疗公司 | IRAK degrading agents and uses thereof |
| CN112457153A (en) * | 2020-11-10 | 2021-03-09 | 杭州臻挚生物科技有限公司 | Industrial preparation method of 2,4, 5-trifluoro-phenylacetic acid |
| CN112851493A (en) * | 2020-11-10 | 2021-05-28 | 杭州臻挚生物科技有限公司 | Preparation method of 2,4, 5-trifluorophenylacetic acid |
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
| CN115677477A (en) * | 2022-09-26 | 2023-02-03 | 上海康鹏科技股份有限公司 | Preparation method of 2,4, 5-trifluoro-phenylacetic acid and intermediate thereof |
Non-Patent Citations (4)
| Title |
|---|
| CAPDEVIELLE, P. ET AL: "Mechanism of primary aliphatic amine oxidation to nitriles by the cuprous chloride/dioxygen/pyridine system", 《TETRAHEDRON LETTERS》, vol. 31, no. 23, 31 December 1990 (1990-12-31), pages 3305 - 3308 * |
| CHEMICALBOOK: "2, 4, 5-三氟苯乙腈", 化学品安全技术说明书, 15 July 2019 (2019-07-15), pages 1 * |
| LUECKE, DANIEL ET AL: "Total synthesis of Pericoannosin A", 《ORGANIC LETTERS》, vol. 20, no. 15, 13 July 2018 (2018-07-13), pages 4475 - 4477 * |
| 何敬文编: "《药物合成反应》", 31 December 1995, 中国医药科技出版社, pages: 104 - 107 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113429295B (en) | Method for preparing m-phenylenediamine by continuous catalytic hydrogenation based on fixed bed microreactor | |
| CN104628548B (en) | Method for preparing acetophenone by bionic catalytic oxidation of ethylbenzene | |
| CN113929553B (en) | Synthetic method of 2, 4-dichlorofluorobenzene | |
| CN111100035A (en) | Preparation method of 3-hydroxypropionitrile | |
| CN110563554B (en) | Method for producing adiponitrile | |
| CN108863754B (en) | Preparation method of cobalt (II) acetylacetonate | |
| JPH04210933A (en) | Process for producing tert-butyl alcohol | |
| CN117466729A (en) | Synthesis method of 2,4, 5-trifluoro phenylacetic acid | |
| CN103265441B (en) | Preparation method of 2,5-dimethoxyl-4-chloroaniline | |
| CN116730824A (en) | Synthesis method of 2,4, 5-trifluoro phenylacetic acid | |
| CN108299259B (en) | Preparation method of 2-amino-5-thiophenyl- (2-methoxy) acetanilide | |
| CN105175247B (en) | A kind of preparation method of 2 methylbutanoic acid | |
| CN111116378A (en) | Method for synthesizing 1, 8-diaminonaphthalene by selective reduction of 1, 8-dinitronaphthalene | |
| CN111662182A (en) | Method for producing phenylenediamine by dinitrobenzene solvent-free hydrogenation continuous reaction | |
| JP2002249467A (en) | Method for producing 4-aminodiphenylamine | |
| CN102584879B (en) | Preparation method of aluminium triethyl | |
| JPH04149160A (en) | Production of 1-amino-4-alkoxybenzene compounds | |
| CN115594601B (en) | Method for preparing Saimiqili intermediate 2-methyl-4-aminophenol | |
| JPS6311346B2 (en) | ||
| JPH06306020A (en) | Production of 4-aminodiphenylamine | |
| CN108947849A (en) | A kind of method of solvent-free catalytic hydrogenation production 2,4 difluorobenzene amine | |
| CN115466255B (en) | Tropine and synthetic method thereof | |
| CN112341361A (en) | Preparation method of mandelonitrile | |
| CN108863715B (en) | Method for preparing dihydronopol by hydrogenation reduction of nopol | |
| CN112479931A (en) | Synthesis process of cyclohexyl |
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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20240130 |