CN116730824B - Synthesis method of 2,4, 5-trifluoro phenylacetic acid - Google Patents
Synthesis method of 2,4, 5-trifluoro phenylacetic acid Download PDFInfo
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- 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 23
- 238000001308 synthesis method Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 claims abstract description 38
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 26
- -1 2,4, 5-trifluoro-phenethyl Chemical group 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 claims abstract description 15
- 230000003647 oxidation Effects 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000011684 sodium molybdate Substances 0.000 claims abstract description 10
- 235000015393 sodium molybdate Nutrition 0.000 claims abstract description 10
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 230000001105 regulatory effect Effects 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000000047 product Substances 0.000 claims description 41
- 230000035484 reaction time Effects 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- OSQPRQRJSJMQRJ-UHFFFAOYSA-N 2-(2,3,4-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C(F)=C1F OSQPRQRJSJMQRJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 16
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 abstract 1
- 229940049953 phenylacetate Drugs 0.000 abstract 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 25
- 238000001514 detection method Methods 0.000 description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- 230000007423 decrease Effects 0.000 description 4
- 241000486679 Antitype Species 0.000 description 2
- 238000010464 Blanc reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 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 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-Phenylethanol Natural products OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010405 reoxidation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
- C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The application belongs to the technical field of organic chemical industry, and discloses a method for synthesizing 2,4, 5-trifluoro-phenylacetic acid, which comprises the steps of mixing 1,2, 4-trifluoro-benzene with a catalyst AlCl 3 Mixing, dripping ethylene oxide liquid at the temperature of 5 ℃, and heating to perform Friedel-crafts alkylation reaction to prepare 2,4, 5-trifluoro-phenethyl alcohol; reacting 2,4, 5-trifluoro-phenethyl alcohol with hydrogen peroxide under the catalysis of sodium molybdate to obtain an oxidation product 2,4, 5-trifluoro-phenethyl acid; filtering 2,4, 5-trifluoro phenylacetic acid, adding into sodium hydroxide solution, stirring while maintaining temperature, cooling, standing to obtain liquid, regulating acid, crystallizing to obtain sodium trifluoro phenylacetate as free acid, filtering, and drying to obtain 2,4, 5-trifluoro phenylacetic acid solid. The method has the advantages of simple process operation, good selectivity, high safety, readily available raw materials, environmental friendliness, high total yield and good industrial prospect.
Description
Technical Field
The application belongs to the technical field of organic chemical industry and also belongs to the technical field of synthesis of pharmaceutical raw materials, and in particular relates 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-trifluorophenylacetic acid is an intermediate of sitagliptin, an anti-type II diabetes drug, developed by Merck, america, and used as a dipeptidyl peptidase-4 inhibitor for the treatment of type II diabetes, and for the prevention and treatment of type II diabetes, hyperglycemia, insulin resistance, obesity, and hypertension, as well as certain complications. The current widely adopted route for producing 2,4, 5-trifluoro-phenylacetic acid is to take 1,2, 4-trifluoro-benzene as raw material, generate benzyl chloride through Blanc chloromethylation, and then catalyze and oxidize to obtain 2,4, 5-trifluoro-phenylacetic acid product, or to obtain 1,2, 4-trifluoro-phenylacetonitrile through Friedel-Crafts alkylation and then hydrolyze to prepare 2,4, 5-trifluoro-phenylacetic acid.
Various problems exist in the production route, so that the method is not suitable for industrial large-scale production, such as the unavoidable use of high toxic substances such as carbon monoxide, sodium cyanide and other raw materials in a Blanc chloromethylation reoxidation route, and meanwhile, expensive catalysts such as tetracarbonyl cobalt salt are also needed for catalysis, or the cost problem and yield problem of raw material chloroacetonitrile faced in a route for obtaining trifluorobenzyl cyanide for reolysis in Friedel-Crafts alkylation, and the problems of post-treatment difficulty and the like caused by high-risk raw materials all cause the increase of the comprehensive cost of the product, so that the production does not have price advantages.
Disclosure of Invention
The technical problems to be solved by the application are as follows: the synthesis method of the 2,4, 5-trifluoro phenylacetic acid overcomes the defects in the prior art, has simple process operation, good selectivity, high safety, easily obtained raw materials, environmental friendliness, high total yield and good industrialization prospect.
Reaction principle:
1,2, 4-trifluoro benzene is used as a raw material, anhydrous aluminum chloride is used for catalyzing ethylene oxide to carry out Friedel-crafts alkylation reaction to generate 2,4, 5-trifluoro benzene ethanol, and hydrogen peroxide is used for oxidizing to generate 2,4, 5-trifluoro benzene acetic acid. The process route is as follows:
in order to solve the technical problems, the technical scheme of the application is as follows:
the synthesis method of the 2,4, 5-trifluoro-phenylacetic acid comprises the following steps:
a. 1,2, 4-trifluoro benzene and catalyst AlCl 3 Mixing in a reaction kettle in a molar ratio of 1:0.2-0.4, dropwise adding ethylene oxide liquid at a temperature of 5 ℃, wherein the molar ratio of 1:0.15-0.3 of 1,2, 4-trifluoro benzene to ethylene oxide, sealing the reaction kettle, heating the reaction kettle to 100-120 ℃ for Friedel-crafts alkylation reaction, and reacting for 20-40 min to prepare 2,4, 5-trifluoro benzene ethanol;
b. mixing the 2,4, 5-trifluoro-phenethyl alcohol obtained in the step a with an oxidant hydrogen peroxide solution, wherein the molar ratio of the 2,4, 5-trifluoro-phenethyl alcohol to the hydrogen peroxide is 1:0.75-1.5, and reacting under the catalysis of sodium molybdate (the addition amount is 0.012-0.018 of the molar equivalent of the 2,4, 5-trifluoro-phenethyl alcohol), wherein the reaction temperature is 30-60 ℃, stirring is 100-1000 rpm, and the reaction time is 4-5 h, so as to obtain an oxidation product 2,4, 5-trifluoro-phenethyl acid;
c. filtering the oxidation product 2,4, 5-trifluoro phenylacetic acid obtained in the step b to obtain an oxidation product filter cake; adding the oxidation product filter cake into 10% sodium hydroxide solution with the mass concentration of 1:20, then carrying out heat preservation and stirring for 3-5 h at 70-90 ℃, converting the trifluoro phenylacetic acid into corresponding sodium salt, dissolving the corresponding sodium salt in water, cooling, standing and subdividing the solution, regulating the pH value of a water layer to 1-3 by hydrochloric acid, carrying out heat preservation and stirring for 1.5-2.5 h at the temperature below 8-12 ℃, converting the trifluoro phenylacetic acid sodium into free acid, crystallizing, filtering and drying to obtain 2,4, 5-trifluoro phenylacetic acid solid.
Preferably, in the step a, 1,2, 4-trifluoro-benzene and catalyst AlCl 3 The molar ratio of 1:0.35, the molar ratio of 1,2, 4-trifluoro benzene to ethylene oxide is 1:0.2, and the temperature of the ethylene oxide liquid is 0 ℃; the reaction temperature of Friedel-crafts alkylation reaction is 110 ℃, and the reaction time is 30min.
Preferably, in the step b, the molar ratio of the 2,4, 5-trifluoro-phenethyl alcohol to the hydrogen peroxide is 1:1, the addition amount of sodium molybdate is 0.015 of the molar equivalent of the 2,4, 5-trifluoro-phenethyl alcohol, the reaction temperature is 40 ℃, and the reaction time is 5 hours.
Preferably, the hydrogen peroxide solution in the step b is a hydrogen peroxide solution with a mass concentration of 30%.
Preferably, the oxidation product filter cake in the step c and the sodium hydroxide solution are stirred for 4 hours at the temperature of 80 ℃; the pH value of the water layer is regulated to 2 by hydrochloric acid, and the materials after the acid regulation are stirred for 2 hours under the temperature of 10 ℃.
Further, in the step c, the hydrochloric acid is hydrochloric acid with a mass concentration of 10%.
Due to the adoption of the technical scheme, the application has the beneficial effects that:
1. according to the application, 1,2, 4-trifluorobenzene is used as a raw material, anhydrous aluminum chloride is used for catalyzing ethylene oxide, and hydrogen peroxide is oxidized under the catalysis of sodium molybdate to generate 2,4, 5-trifluorophenylacetic acid, so that the raw material is easy to obtain, the process is simple to operate, the Friedel-crafts alkylation is carried out at a temperature rise, the reaction time is greatly shortened, and the reaction efficiency and the yield are improved;
2. the application also avoids the use of high-toxic raw materials in the traditional process, and is more green and safer than the traditional route and is environment-friendly; meanwhile, the reaction selectivity is good, the yield is high, and the recovery of the later raw materials is simpler, so that the three wastes after the reaction are easier to treat and are more suitable for industrialization.
In a word, the method has the advantages of simple process operation, good selectivity, high safety, readily available raw materials, environmental friendliness, high total yield and good industrial prospect.
Detailed Description
The application is further illustrated by the following examples.
Example 1
Fully stirring and mixing 100.00g of 1,2, 4-trifluoro benzene and 30.29g (0.3 molar equivalent) of anhydrous aluminum chloride in an anhydrous sealed reaction kettle, cooling the materials to 5 ℃, dropwise adding 6.67g (0.2 molar equivalent) of ethylene oxide liquid at 0 ℃ into the mixed liquid, heating to 110 ℃ after the dropwise adding is completed, preserving heat for 30min, and separating 24.95g of intermediate 2,4, 5-trifluoro phenethyl alcohol by hydrolysis and liquid separation distillation of the mixed liquid after the reaction is completed;
adding 16.06g (1.0 molar equivalent) of 30% hydrogen peroxide solution and 0.4g of catalyst sodium molybdate into 24.95g of 2,4, 5-trifluoro-phenethyl alcohol obtained by distillation, heating to 40 ℃ under stirring at the speed of 1000rpm, preserving heat, stirring and oxidizing for 4 hours, and filtering the feed liquid after the reaction is completed to obtain an oxidized product filter cake;
adding the oxidized product filter cake into 300ml of 10% sodium hydroxide solution with mass concentration, keeping the temperature at 80 ℃ and stirring for 4 hours, converting the trifluoro phenylacetic acid into the corresponding sodium salt and dissolving the corresponding sodium salt in water, cooling, standing and subdividing the solution, adjusting the pH of a water layer to 2 by hydrochloric acid, keeping the temperature below 10 ℃ and stirring the acid-adjusted material for 2 hours, crystallizing, filtering and drying after converting the trifluoro sodium phenylacetate into the free acid of the trifluoro sodium acetate, weighing to obtain 24.08g of the product with the molar yield of 90.27% and the gas phase detection purity of 99.90%.
Example 2
The procedure of this example was repeated except that the catalyst was used in an amount of 35.33g (0.35 molar equivalent), and the other steps were the same, to obtain 23.86g of a product, a molar yield of 89.48% and a gas phase purity of 99.94%.
Example 3
The procedure of this example was repeated except that the catalyst was used in an amount of 20.19g (0.1 molar equivalent), and the other steps were the same, to obtain 12.65g of a product having a molar yield of 47.42% and a gas phase purity of 99.91%.
Example 4
The procedure of this example was repeated except that the catalyst was used in an amount of 40.38g (0.4 molar equivalent) and the other steps were the same, to obtain 22.92g of a product, the molar yield was 85.92% and the purity of the gas phase detection was 99.86%.
Example 5
The difference between the method of this example and example 1 is that the amount of ethylene oxide used is 5.00g (0.15 molar equivalent), and the other steps are the same, giving 23.29g of the product with a molar yield of 87.32% and a gas phase purity of 99.87%.
Example 6
The difference between the method of this example and example 1 is that the amount of ethylene oxide used is 8.34g (0.25 molar equivalent), and the other steps are the same, giving 24.08g of the product with a molar yield of 90.30% and a gas phase purity of 99.79%.
Example 7
The difference between the method of this example and example 1 is that the amount of ethylene oxide used is 10.01g (0.30 molar equivalent), and the other steps are the same, giving 23.48g of the product with a molar yield of 88.03% and a gas phase purity of 99.85%.
Example 8
The difference between the method and example 1 is that the Friedel-crafts alkylation reaction temperature is 100 ℃, the other steps are the same, 17.94g of product is obtained, the molar yield is 67.25%, and the gas phase detection purity is 99.88%.
Example 9
The difference between the method and example 1 is that the Friedel-crafts alkylation reaction temperature is 120 ℃, and the other steps are the same, so that 3.68g of product is obtained, the molar yield is 13.79%, and the gas phase detection purity is 99.90%.
Example 10
The difference between the method and example 1 is that the Friedel-crafts alkylation reaction time is 10min, the other steps are the same, 22.61g of product is obtained, the molar yield is 84.79%, and the gas phase detection purity is 99.85%.
Example 11
The difference between the method and example 1 is that the Friedel-crafts alkylation reaction time is 20min, and other steps are the same, 23.97g of product is obtained, the molar yield is 89.89%, and the gas phase detection purity is 99.92%.
Example 12
The difference between the method and example 1 is that the Friedel-crafts alkylation reaction time is 40min, and other steps are the same, so as to obtain 23.37g of the product, wherein the molar yield is 87.63%, and the gas phase detection purity is 99.87%.
Example 13
The difference between the method and example 1 is that the oxidation reaction temperature is 30℃and the other steps are the same, so that 21.78g of the product is obtained, the molar yield is 81.65%, and the gas phase detection purity is 99.79%.
Example 14
The difference between the method and example 1 is that the oxidation reaction temperature is 50℃and the other steps are the same, so that 24.05g of the product is obtained, the molar yield is 90.18%, and the gas phase detection purity is 99.86%.
Example 15
The difference between the method and example 1 is that the oxidation reaction temperature is 60℃and the other steps are the same, so that 20.31g of the product is obtained, the molar yield is 76.15%, and the gas phase detection purity is 99.89%.
Example 16
The procedure of this example was repeated except that the amount of the 30% hydrogen peroxide solution used was 12.04g (0.75 molar equivalent), and the other steps were the same, to obtain 18.65g of a product having a molar yield of 69.91% and a gas phase purity of 99.79%.
Example 17
The difference between the method of this example and example 1 is that the 30% hydrogen peroxide solution is used in an amount of 24.09g (1.5 molar equivalents), and the other steps are the same, to obtain 23.98g of the product, a molar yield of 89.91%, and a gas phase purity of 99.75%.
Example 18
The procedure of this example was repeated except that the amount of the 30% hydrogen peroxide solution used was 32.11g (2.0 molar equivalents), and the other steps were the same, to obtain 22.84g of a product, a molar yield of 85.63% and a gas phase purity of 99.81%.
Example 19
The difference between the method of this example and example 1 is that the amount of sodium molybdate used as the oxidation catalyst is 0.35g (0.012 molar equivalent), and the other steps are the same, so that 16.55g of the product is obtained, the molar yield is 62.05%, and the gas phase detection purity is 99.75%.
Example 20
The difference between the method of this example and example 1 is that the amount of sodium molybdate used as the oxidation catalyst is 0.53g (0.018 molar equivalent), and the other steps are the same, to give 24.08g of the product in a molar yield of 90.27% and a gas phase purity of 99.88%.
Example 21
The difference between the method and example 1 is that the oxidation reaction time is 3 hours, the other steps are the same, 21.20g of the product is obtained, the molar yield is 79.47%, and the gas phase detection purity is 99.85%.
Example 22
The difference between the method and example 1 is that the oxidation reaction time is 5 hours, and the other steps are the same, so that 23.84g of the product is obtained, the molar yield is 89.39%, and the gas phase detection purity is 99.94%.
Example 23
The difference between the method and example 1 is that the oxidation reaction time is 6 hours, and the other steps are the same, so as to obtain 22.74g of the product, the molar yield is 85.25%, and the gas phase detection purity is 99.87%.
Results and analysis:
the experimental conditions and results of examples 1-23 were counted to obtain the results shown in Table 1:
as is clear from examples 1/2/3/4, with respect to the amount of the catalyst to be charged, if the amount of the catalyst to be charged is too small, the reaction is difficult to proceed, the yield of the reaction is greatly reduced, and if the amount of the catalyst to be charged is too large, the yield of the reaction is also reduced, the gas phase purity of the product is also affected, and the ratio of the optimum amount of the catalyst to be charged to the raw material 1,2, 4-trifluorobenzene by mole is 0.35:1;
as can be seen from examples 1/5/6/7, ethylene oxide needs to be controlled at a proper amount, when the ethylene oxide is excessively fed, not only is a higher yield not obtained, but also the gas phase purity of the product is reduced to some extent, whereas if the ethylene oxide is excessively fed, the yield of the reaction is reduced, so that the ratio of the optimal amount of the reaction to the 1,2, 4-trifluorobenzene serving as a raw material is 0.2:1 in terms of mole;
as is clear from examples 1/8/9, the reaction temperature of Friedel-crafts alkylation is preferably controlled at 110 ℃, from experimental phenomena and analysis of results, when the temperature is too low, the reaction proceeds very slowly, the same reaction time can proceed only a small part of the reaction, and when the reaction temperature is increased, more side reactions may occur to lower the reaction yield, so that the most suitable reaction temperature is 110 ℃;
as can be seen from examples 1/10/11/12, when the Friedel-crafts reaction time is too short, the reaction cannot be thoroughly performed, resulting in a reduced reaction yield, whereas extending the reaction time beyond 30min cannot continue to improve the reaction yield, but rather, the development yield is reduced due to the occurrence of side reactions of the product, so that the most suitable reaction time is 30min;
as is clear from examples 1/13/14/15, the reaction is not carried out thoroughly when the temperature of the oxidation reaction is too low, resulting in a decrease in the reaction yield, while the reaction temperature is too high, resulting in a decrease in the reaction yield due to decomposition of the oxidizing agent, so that the most suitable temperature for the oxidation reaction is 40 ℃;
as is clear from examples 1/16/17/18, too much oxidant is fed in the oxidation reaction, not only the yield of the reaction cannot be improved but also the yield is reduced, but too little oxidant is fed, which results in incomplete reaction, so that the most suitable amount of hydrogen peroxide to be fed is the same as the amount of 2,4, 5-trifluorophenethyl alcohol to be fed in terms of moles;
as is clear from examples 1/19/20, when the amount of the oxidation catalyst to be fed is too low, the reaction cannot be thoroughly carried out, the reaction yield is reduced, and when the amount of the catalyst to be fed is more, the reaction yield is not improved, and the most suitable amount of the oxidation catalyst to be fed is 0.015 molar equivalent of the oxidation substrate comprehensively considering the yield and the raw material cost;
as is clear from examples 1/21/22/23, when the oxidation reaction time is insufficient, the reaction cannot be completely performed, the reaction yield decreases, and when the reaction time is too long, the reaction yield and the product purity decrease, so that the most suitable oxidation reaction time is 5 hours.
It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (5)
1. The synthesis method of the 2,4, 5-trifluoro-phenylacetic acid is characterized by comprising the following steps:
a. 1,2, 4-trifluoro benzene and catalyst AlCl 3 Mixing in a reaction kettle in a molar ratio of 1:0.2-0.4, dropwise adding ethylene oxide liquid at a temperature of 5 ℃, wherein the molar ratio of 1:0.15-0.3 of 1,2, 4-trifluoro benzene to ethylene oxide, sealing the reaction kettle, heating the reaction kettle to 100-120 ℃ for Friedel-crafts alkylation reaction, and reacting for 20-40 min to prepare 2,4, 5-trifluoro benzene ethanol;
b. mixing the 2,4, 5-trifluoro-phenethyl alcohol obtained in the step a with an oxidant hydrogen peroxide solution, wherein the molar ratio of the 2,4, 5-trifluoro-phenethyl alcohol to the hydrogen peroxide is 1:0.75-1.5, and reacting under the catalysis of sodium molybdate, wherein the adding amount of the sodium molybdate is 0.012-0.018 of the molar equivalent of the 2,4, 5-trifluoro-phenethyl alcohol, the reaction temperature is 30-60 ℃, the stirring is carried out at 100-1000 rpm, the reaction time is 4-5 h, and the oxidized product 2,4, 5-trifluoro-phenethyl acid is obtained;
c. filtering the oxidation product 2,4, 5-trifluoro phenylacetic acid obtained in the step b to obtain an oxidation product filter cake; adding the oxidation product filter cake into 10% sodium hydroxide solution with the mass concentration of 1:20, then carrying out heat preservation and stirring for 3-5 h at 70-90 ℃, converting the trifluoro phenylacetic acid into corresponding sodium salt, dissolving the corresponding sodium salt in water, cooling, standing and subdividing the solution, regulating the pH value of a water layer to 1-3 by hydrochloric acid, carrying out heat preservation and stirring for 1.5-2.5 h at the temperature below 8-12 ℃, converting the trifluoro phenylacetic acid sodium into free acid, crystallizing, filtering and drying to obtain 2,4, 5-trifluoro phenylacetic acid solid.
2. The method for synthesizing 2,4, 5-trifluoro-phenylacetic acid according to claim 1, wherein the method comprises the following steps: the 1,2, 4-trifluoro-benzene and the catalyst AlCl in the step a 3 The molar ratio of 1:0.35, the molar ratio of 1,2, 4-trifluoro benzene to ethylene oxide is 1:0.2, and the temperature of the ethylene oxide liquid is 0 ℃; the reaction temperature of Friedel-crafts alkylation reaction is 110 ℃, and the reaction time is 30min.
3. The method for synthesizing 2,4, 5-trifluoro-phenylacetic acid according to claim 1, wherein the method comprises the following steps: in the step b, the molar ratio of the 2,4, 5-trifluoro-phenethyl alcohol to the hydrogen peroxide is 1:1, the addition amount of sodium molybdate is 0.015 of the molar equivalent of the 2,4, 5-trifluoro-phenethyl alcohol, the reaction temperature is 40 ℃, and the reaction time is 5 hours.
4. The method for synthesizing 2,4, 5-trifluoro-phenylacetic acid according to claim 1, wherein the method comprises the following steps: the hydrogen peroxide solution in the step b is a hydrogen peroxide solution with the mass concentration of 30 percent.
5. The method for synthesizing 2,4, 5-trifluoro-phenylacetic acid according to claim 1, wherein the method comprises the following steps: the oxidation product filter cake in the step c and sodium hydroxide solution are stirred for 4 hours at the temperature of 80 ℃; the pH value of the water layer is regulated to 2 by hydrochloric acid, and the materials after the acid regulation are stirred for 2 hours under the temperature of 10 ℃.
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| CN106748716A (en) * | 2016-11-14 | 2017-05-31 | 江苏汉阔生物有限公司 | A kind of new method for preparing 2,4,5 trifluoro benzene acetic acids |
| WO2022257519A1 (en) * | 2021-06-10 | 2022-12-15 | 南京斯贝源医药科技有限公司 | Process for preparing hydroxytyrosol |
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| CN106748716A (en) * | 2016-11-14 | 2017-05-31 | 江苏汉阔生物有限公司 | A kind of new method for preparing 2,4,5 trifluoro benzene acetic acids |
| WO2022257519A1 (en) * | 2021-06-10 | 2022-12-15 | 南京斯贝源医药科技有限公司 | Process for preparing hydroxytyrosol |
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