CN117384029A - 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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- CN117384029A CN117384029A CN202311696277.8A CN202311696277A CN117384029A CN 117384029 A CN117384029 A CN 117384029A CN 202311696277 A CN202311696277 A CN 202311696277A CN 117384029 A CN117384029 A CN 117384029A
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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 59
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000010992 reflux Methods 0.000 claims abstract description 30
- 239000000243 solution Substances 0.000 claims abstract description 26
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 22
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 16
- STZZWJCGRKXEFF-UHFFFAOYSA-N Dichloroacetonitrile Chemical compound ClC(Cl)C#N STZZWJCGRKXEFF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims abstract description 14
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims abstract description 14
- 229940045803 cuprous chloride Drugs 0.000 claims abstract description 14
- LEEYFGDQDBEGPR-UHFFFAOYSA-N 2,4,5-trifluorobenzenediazonium Chemical class FC1=CC(F)=C([N+]#N)C=C1F LEEYFGDQDBEGPR-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 trifluorophenyl oxo acetic acid Chemical compound 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 7
- QMYVWJVVVMIBMM-UHFFFAOYSA-N 2,4,5-trifluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1F QMYVWJVVVMIBMM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007790 solid phase Substances 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 230000000630 rising effect Effects 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 description 5
- AJKNNUJQFALRIK-UHFFFAOYSA-N 1,2,3-trifluorobenzene Chemical compound FC1=CC=CC(F)=C1F AJKNNUJQFALRIK-UHFFFAOYSA-N 0.000 description 2
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 238000007265 chloromethylation reaction Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000007787 solid Substances 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 1
- 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 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 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
- 150000005690 diesters Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000002761 liquid phase assay Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 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 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
-
- 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
- C07C245/20—Diazonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- 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
Abstract
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of 2,4, 5-trifluoro phenylacetic acid, which comprises the following steps: (1) Dissolving 2,4, 5-trifluoroaniline in hydrochloric acid, dropwise adding an aqueous solution of sodium nitrite at the temperature of 0 ℃, and stirring for a period of time at the temperature of 0 ℃ after the dropwise adding is finished to obtain 2,4, 5-trifluorobenzene diazonium salt for later use; (2) Mixing triethylamine and dichloroacetonitrile at the temperature of-5-10 ℃, adding cuprous chloride and 2,4, 5-trifluorobenzene diazonium salt, stirring, then adding hydrochloric acid, heating and refluxing, cooling to the temperature of 0 ℃, and filtering to obtain a solid phase which is a crude trifluorophenyl oxo acetic acid product; (3) And adding sodium hydroxide aqueous solution and hydrazine hydrate solution into the crude trifluorophenyl oxoacetic acid, heating and refluxing, then cooling to room temperature, adjusting pH to neutrality, filtering, washing and drying the collected solid phase to obtain the 2,4, 5-trifluorophenylacetic acid product. The process method is simple to operate, mild in reaction condition, and suitable for industrial production, and the yield of the 2,4, 5-trifluoro-phenylacetic acid product is greatly improved.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of 2,4, 5-trifluoro-phenylacetic acid.
Background
2,4, 5-trifluoro-phenylacetic acid is an important intermediate for synthesizing sitagliptin, and four main synthetic routes are provided at present: (1) The method is characterized in that 1,2, 4-trifluoro-benzene is used as a raw material to be prepared through chloromethylation, cyanidation and hydrolysis, the three wastes in the route are more, and a highly toxic substance sodium cyanide is needed to be used, so that the method is dangerous. (2) Under alkaline condition, 2,4, 5-trifluoro bromobenzene is catalyzed by transition metal to generate coupling reaction with malonic diester, and then is hydrolyzed to obtain 2,4, 5-trifluoro phenylacetic acid. (3) After 2,4, 5-trifluoro bromobenzene is prepared into Grignard reagent, the Grignard reagent is subjected to coupling reaction with allyl bromide, and double bonds are oxidized to obtain 2,4, 5-trifluoro phenylacetic acid. (4) The method still has the defect of more chloromethylation three wastes. Therefore, the invention develops a method for synthesizing trifluoro phenylacetic acid aiming at the technical problems.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: aiming at the defects of the prior art, the synthesis method of the 2,4, 5-trifluoro phenylacetic acid is provided, and the synthesis method is simple in operation, mild in reaction condition and high in synthesis yield.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a method for synthesizing 2,4, 5-trifluorophenylacetic acid, the method comprising the steps of:
(1) Dissolving 2,4, 5-trifluoroaniline in hydrochloric acid, dropwise adding an aqueous solution of sodium nitrite at the temperature of 0 ℃, and stirring for a period of time at the temperature of 0 ℃ after the dropwise adding is finished to obtain a 2,4, 5-trifluorobenzene diazonium salt solution for standby;
(2) Mixing triethylamine and dichloroacetonitrile at the temperature of-5-10 ℃, adding cuprous chloride, stirring and mixing, adding the 2,4, 5-trifluorobenzene diazonium salt solution in the step (1), stirring, adding hydrochloric acid, controlling the heating and refluxing time, cooling to the temperature of 0 ℃ after the reaction is finished, and filtering to obtain a solid phase which is a crude trifluorophenyl oxo acetic acid product;
(3) And (3) adding sodium hydroxide aqueous solution and hydrazine hydrate solution into the crude trifluorophenyl oxoacetic acid product obtained in the step (2), controlling the heating and refluxing time, cooling to room temperature after the reaction is finished, adjusting the pH to be neutral, filtering, and washing and drying the collected solid phase to obtain the 2,4, 5-trifluorophenylacetic acid product.
As an improved technical scheme, the 2,4, 5-trifluoroaniline in the step (1) is used in an amount of 0.5mol, the concentration and the amount of hydrochloric acid are 31wt% and 4.83mol respectively, the concentration of the sodium nitrite aqueous solution is 25wt%, and the amount of the sodium nitrite aqueous solution is 0.5mol.
As an improved technical scheme, the dosage of triethylamine in the step (2) is 5-7 equivalents, the dosage of dichloroacetonitrile is 1.0-1.1 equivalents, the dosage of cuprous chloride is 0.05-0.15 equivalents, the dosage of hydrochloric acid is 0.25-0.75% of the mass of the 2,4, 5-trifluorobenzene diazonium salt solution, and the heating reflux time is controlled to be 2-8 hours.
As a preferred embodiment, the step (2) is carried out by mixing triethylamine with dichloroacetonitrile at 0 ℃.
As a preferable technical scheme, in the step (2), the amount of triethylamine is 6 equivalents, the amount of dichloroacetonitrile is 1.0 equivalents, the amount of cuprous chloride is 0.1 equivalents, and the temperature rising and reflux time is controlled to be 6 hours.
As an improved technical scheme, the dosage of sodium hydroxide in the sodium hydroxide aqueous solution in the step (3) is 3-5 equivalents, and the concentration of the sodium hydroxide aqueous solution is 10wt%; the dosage of the hydrazine hydrate in the hydrazine hydrate solution is 4-6 equivalents, the concentration of the hydrazine hydrate solution is 80wt percent, and the temperature rising and reflux time is controlled to be 3-10 hours.
As a preferable technical scheme, the dosage of the sodium hydroxide aqueous solution in the step (3) is 4 equivalents, the dosage of the hydrazine hydrate solution is 5 equivalents, and the temperature rising and reflux time is controlled to be 8 hours.
The reaction equation involved in the invention is as follows:
step (1)
Step (2)
Step (3)
After the technical scheme is adopted, the invention has the beneficial effects that:
the invention generates a trifluorobenzene positive ion intermediate from 2,4, 5-trifluorobenzene diazonium salt under the catalysis of cuprous chloride, dichloroacetonitrile reacts with trifluorobenzene positive ion under the action of triethylamine to generate intermediate hydrolysis to obtain trifluorophenyl oxo acetic acid, then sodium hydroxide solution and hydrazine hydrate are added, hydrazine hydrate reacts with carbonyl oxygen in the trifluorophenyl oxo acetic acid to generate an imine intermediate, then nitrogen is removed under alkaline conditions to generate 2,4, 5-trifluorophenyl acetic acid sodium, and the pH value is regulated to obtain 2,4, 5-trifluorophenyl acetic acid. The process method is simple to operate, mild in reaction condition, and suitable for industrial production, and the yield of the 2,4, 5-trifluoro-phenylacetic acid product is greatly improved.
Drawings
FIG. 1 is a liquid phase assay of 2,4, 5-trifluorophenylacetic acid product of example 22 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
The synthesis method of the 2,4, 5-trifluoro-phenylacetic acid comprises the following steps:
(1) 73.55g of 2,4, 5-trifluoroaniline is dissolved in 176.42g of 31wt% hydrochloric acid, 137.99g of 25wt% sodium nitrite aqueous solution is added dropwise at 0 ℃, and after the completion of the dropwise addition, the mixture is stirred for 30min at 0 ℃ to obtain 388g of 2,4, 5-trifluorobenzene diazonium salt solution;
(2) Reaction temperature 5 ℃, 252.98g (5.0 eq) of triethylamine and 54.97g (1.0 eq) of dichloroacetonitrile were mixed in a reaction vessel and 4.95g of cuprous chloride (0.10 eq) was added, followed by the slow addition of 389.08g of 2,4, 5-trifluorobenzene diazonium salt (25.07 wt%) from step (1) and stirring for 2h. Adding 194.54g of hydrochloric acid with the mass of 0.5 times of that of the 2,4, 5-trifluorobenzene diazonium salt solution, heating and refluxing for reaction for 4 hours, cooling to 0 ℃, and filtering out solid to obtain a crude trifluorophenyl oxo acetic acid product;
(3) Adding the crude trifluorophenyl oxoacetic acid product obtained in the step (2) into a reaction kettle, adding 600.00g of 10wt% sodium hydroxide aqueous solution (the dosage of sodium hydroxide is 3.0 eq) and 165.44g of 80wt% hydrazine hydrate solution (the dosage of hydrazine hydrate is 5.0 eq), heating and refluxing for 5 hours, cooling to room temperature, adjusting the pH to be neutral by using hydrochloric acid, washing the solid obtained after filtration by using water, and drying to obtain 61.90g of 2,4, 5-trifluorophenylacetic acid product with the yield of 65.12% and the purity of 99.74%.
Example 2
Unlike example 1, the amount of dichloroacetonitrile used in step (2) was 60.47g (1.1 eq) and the remaining conditions were unchanged, 62.12g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 65.35% and a purity of 99.73%.
Example 3
Unlike example 1, the amount of triethylamine in step (2) was 303.57g (6.0 eq) and the remaining conditions were unchanged, 67.17g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 70.66% and a purity of 99.76%.
Example 4
Unlike example 1, the amount of triethylamine in step (2) was 354.17g (7.0 eq) and the remaining conditions were unchanged, to give 67.20g of 2,4, 5-trifluorophenylacetic acid product in 70.69% yield and 99.00% purity.
Example 5
Unlike example 3, the amount of cuprous chloride used in step (2) was 2.48g (0.05 eq) and the remaining conditions were unchanged, yielding 59.97g of 2,4, 5-trifluorophenylacetic acid product in 62.99% yield and 99.52% purity.
Example 6
Unlike example 3, the amount of cuprous chloride used in step (2) was 7.43g (0.15 eq) and the remaining conditions were unchanged, yielding 66.67g of 2,4, 5-trifluorophenylacetic acid product in 70.14% yield and 99.58% purity.
Example 7
Unlike example 3, the reaction temperature in step (2) was 0℃and the remaining conditions were unchanged, 70.62g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 74.29% and a purity of 99.87%.
Example 8
Unlike example 3, the reaction temperature in step (2) was-5℃and the remaining conditions were unchanged, 69.94g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 73.57% and a purity of 99.24%.
Example 9
Unlike example 3, the reaction temperature in step (2) was 10℃and the remaining conditions were unchanged, 60.11g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 63.32% and a purity of 99.98%.
Example 10
Unlike example 7, the reflux reaction time was controlled to 4 hours in step (2) and the remaining conditions were unchanged, to give 71.62g of 2,4, 5-trifluorophenylacetic acid product in 75.34% yield and 99.36% purity.
Example 11
Unlike example 7, the reflux reaction time was controlled to 6 hours in step (2) and the remaining conditions were unchanged, yielding 71.19g of 2,4, 5-trifluorophenylacetic acid product in 74.89% yield and 99.76% purity.
Example 12
Unlike example 10, the amount of hydrochloric acid used in step (2) was 97.27g (0.25 wt%) and the remaining conditions were unchanged, 66.91g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 70.39% and a purity of 99.54%.
Example 13
Unlike example 10, the amount of hydrochloric acid used in step (2) was 291.81g (0.75 wt%) and the remaining conditions were unchanged, to obtain 71.62g of 2,4, 5-trifluorophenylacetic acid product in 75.34% yield and 99.86% purity.
Example 14
Unlike example 10, the reflux time in step (2) was changed to 2 hours, and the remaining conditions were unchanged, 65.06g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 68.44% and a purity of 99.58%.
Example 15
Unlike example 10, the reflux time in step (2) was changed to 6 hours, and the remaining conditions were unchanged, to obtain 73.86g of 2,4, 5-trifluorophenylacetic acid product in a yield of 77.69% and a purity of 99.91%.
Example 16
Unlike example 10, the reflux time in step (2) was changed to 8 hours, and the remaining conditions were unchanged, to obtain 73.86g of 2,4, 5-trifluorophenylacetic acid product in a yield of 77.69% and a purity of 99.01%.
Example 17
In the difference from example 15, the amount of 10% by weight of sodium hydroxide solution in step (2) was 800g (the amount of sodium hydroxide was 4.0 eq), and the remaining conditions were unchanged, to obtain 76.22g of 2,4, 5-trifluorophenylacetic acid product, yield 80.18% and purity 99.23%.
Example 18
Unlike example 15, the amount of 10wt% sodium hydroxide solution in step (3) was 1000g (the amount of sodium hydroxide was 5.0 eq), and the remaining conditions were unchanged, to obtain 75.32g of 2,4, 5-trifluorophenylacetic acid product in 79.23% yield and 99.91% purity.
Example 19
Unlike example 17, the amount of 80wt% hydrazine hydrate solution in step (3) was 125.15g (the amount of hydrazine hydrate was 4.0 eq), and the remaining conditions were unchanged, to obtain 72.71g of 2,4, 5-trifluorophenylacetic acid product, yield 76.49% and purity 99.71%.
Example 20
Unlike example 17, the amount of 80wt% hydrazine hydrate solution in step (2) was 187.735g (hydrazine hydrate amount was 6.0 eq) and the remaining conditions were unchanged, to obtain 75.54g of 2,4, 5-trifluorophenylacetic acid product in 79.46% yield and 99.34% purity.
Example 21
Unlike example 17, the reflux time in step (3) was 3 hours, and the remaining conditions were unchanged, 71.64g of 2,4, 5-trifluorophenylacetic acid product was obtained in a yield of 75.36% and a purity of 99.63%.
Example 22
Unlike example 17, the reflux time in step (2) was 8 hours, and the remaining conditions were unchanged, to obtain 78.76g of 2,4, 5-trifluorophenylacetic acid product in a yield of 82.85 and a purity of 99.79%.
Example 23
Unlike example 17, the reflux time in step (2) was 10 hours, and the remaining conditions were unchanged, to obtain 78.34g of 2,4, 5-trifluorophenylacetic acid product in a yield of 82.41% and a purity of 99.94%.
The following conclusions can be drawn from the above examples:
as is clear from examples 1 and 2, the yield of 2,4, 5-trifluorophenylacetic acid was 65.12% -65.35% in the range of 1.0-1.1eq for dichloroacetonitrile, and the increase in the amount and yield of dichloroacetonitrile did not change much. Therefore, the amount of dichloroacetonitrile is preferably 1.0eq.
As is clear from examples 1 and 3 to 4, the yield of 2,4, 5-trifluorophenylacetic acid was 65.12% -70.69% when the amount of triethylamine was 5.0-7.0 eq. After the amount of triethylamine is more than 6.0eq, the yield is not changed greatly. Therefore, the amount of triethylamine is preferably 6.0eq.
As can be seen from examples 3 and 5-6, the yield of 2,4, 5-trifluoro-phenylacetic acid is 62.99% -70.69% when the cuprous chloride is used in an amount ranging from 0.05eq to 0.15 eq. The yield changes little after the cuprous chloride dosage is more than 0.10eq. Therefore, the amount of cuprous chloride is preferably 0.10eq.
As is clear from examples 3 and 7 to 9, the yield of 2,4, 5-trifluorophenylacetic acid in step (1) was 63.32% -74.29% at a reaction temperature ranging from-5 to 10 ℃. The reaction temperature in the step (1) is 0 ℃ and the yield is up to 74.29 percent. Therefore, the reaction temperature in step (1) is preferably 0 ℃.
As is clear from examples 7 and 10 to 11, the yield of 2,4, 5-trifluorophenylacetic acid in the reaction time range of 2 to 6 hours in the step (1) is 74.29% -75.34%. The reaction time in the step (1) is 4 hours, and the yield is 75.34 percent at the highest. Therefore, the reaction time in step (1) is preferably 4 hours.
As is evident from examples 10, 12-13, the yield of 2,4, 5-trifluorophenylacetic acid in step (1) was in the range of 70.39% -75.34% with a hydrochloric acid usage in the range of 0.25-0.75% by weight. After the amount of hydrochloric acid in the step (1) is more than 0.50wt%, the yield is unchanged, and the maximum is 75.34%. Thus, the amount of hydrochloric acid in step (1) is preferably 0.5wt%.
As is evident from examples 10 and 14 to 16, the yield of 2,4, 5-trifluorophenylacetic acid in step (1) was 68.44% -77.69% over the reflux time period ranging from 2 to 8 hours. The reflux time in the step (1) is 6 hours, and the yield is up to 77.69 percent. Therefore, the reflux time in step (1) is preferably 6 hours.
As is clear from examples 15 and 17 to 18, the yield of 2,4, 5-trifluorophenylacetic acid was 77.69% -80.18% when the amount of 10% sodium hydroxide used in step (2) was 3-5 eq. The highest 77.69% yield of the 10% sodium hydroxide used in the step (2) is 4eq. Therefore, the amount of 10% sodium hydroxide used in step (2) is preferably 4eq.
As is evident from examples 17 and 19 to 20, the yield of 2,4, 5-trifluorophenylacetic acid was 76.49% -80.18% in the amount of 80% by weight of hydrazine hydrate in step (2) ranging from 4 to 6 eq. The yield of the hydrazine hydrate with the dosage of 5eq of 80% in the step (2) is 80.18% at maximum. Therefore, the amount of 80% hydrazine hydrate in step (2) is preferably 5eq.
As is clear from examples 17 and 21 to 23, the yield of 2,4, 5-trifluorophenylacetic acid in the step (2) was 75.36% -82.85% over the reflux time period ranging from 3 to 10 hours. The reflux time in the step (2) is 8 hours, and the yield is up to 82.85 percent. Therefore, the reflux time in step (2) is preferably 8 hours.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (7)
1. A method for synthesizing 2,4, 5-trifluoro-phenylacetic acid, which is characterized by comprising the following steps:
(1) Dissolving 2,4, 5-trifluoroaniline in hydrochloric acid, dropwise adding an aqueous solution of sodium nitrite at the temperature of 0 ℃, and stirring for a period of time at the temperature of 0 ℃ after the dropwise adding is finished to obtain a 2,4, 5-trifluorobenzene diazonium salt solution for standby;
(2) Mixing triethylamine and dichloroacetonitrile at the temperature of-5-10 ℃, adding cuprous chloride, stirring and mixing, adding the 2,4, 5-trifluorobenzene diazonium salt solution in the step (1), stirring, adding hydrochloric acid, controlling the heating and refluxing time, cooling to the temperature of 0 ℃ after the reaction is finished, and filtering to obtain a solid phase which is a crude trifluorophenyl oxo acetic acid product;
(3) And (3) adding sodium hydroxide aqueous solution and hydrazine hydrate solution into the crude trifluorophenyl oxoacetic acid product obtained in the step (2), controlling the heating and refluxing time, cooling to room temperature after the reaction is finished, adjusting the pH to be neutral, filtering, and washing and drying the collected solid phase to obtain the 2,4, 5-trifluorophenylacetic acid product.
2. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (1), the amount of 2,4, 5-trifluoroaniline is 0.5mol, the concentration and amount of hydrochloric acid are 31wt% and 4.83mol, respectively, the concentration of sodium nitrite aqueous solution is 25wt%, and the amount of sodium nitrite aqueous solution is 0.5mol.
3. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein in step (2), the amount of triethylamine is 5-7 equivalents, the amount of dichloroacetonitrile is 1.0-1.1 equivalents, the amount of cuprous chloride is 0.05-0.15 equivalents, the amount of hydrochloric acid is 0.25-0.75% of the mass of 2,4, 5-trifluorobenzodiazonium salt solution, and the heating reflux time is controlled to be 2-8 hours.
4. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein said step (2) comprises mixing triethylamine with dichloroacetonitrile at 0 ℃.
5. A method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 3, wherein in step (2), the amount of triethylamine is 6 equivalents, the amount of dichloroacetonitrile is 1.0 equivalents, the amount of cuprous chloride is 0.1 equivalents, and the temperature-raising reflux time is controlled to be 6 hours.
6. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 1, wherein the amount of sodium hydroxide in said aqueous sodium hydroxide solution in step (3) is 3-5 equivalents, and the concentration of said aqueous sodium hydroxide solution is 10wt%; the dosage of the hydrazine hydrate in the hydrazine hydrate solution is 4-6 equivalents, the concentration of the hydrazine hydrate solution is 80wt percent, and the temperature rising and reflux time is controlled to be 3-10 hours.
7. The method for synthesizing 2,4, 5-trifluorophenylacetic acid according to claim 6, wherein the amount of said aqueous sodium hydroxide solution in step (3) is 4 equivalents, the amount of said hydrazine hydrate solution is 5 equivalents, and the temperature-rising reflux time is controlled to be 8 hours.
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