CN111253241B - 2,4,5-trifluoro-3-methoxybenzoyl chloride and preparation method of intermediate thereof - Google Patents
2,4,5-trifluoro-3-methoxybenzoyl chloride and preparation method of intermediate thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride and an intermediate thereof, wherein tetrafluorophthalic acid is used as a raw material, and is subjected to defluorination hydroxylation, acidification and decarboxylation reactions to obtain 2,4,5-trifluoro-3-hydroxybenzoic acid, then the 2,4,5-trifluoro-3-hydroxybenzoic acid is reacted with dimethyl carbonate to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride, and finally the 2,4,5-trifluoro-3-methoxybenzoyl chloride is obtained through acyl chlorination. The preparation method disclosed by the invention is simple in preparation process, high in total reaction yield, good in product quality, green and environment-friendly in process route, and has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to 2,4,5-trifluoro-3-methoxybenzoyl chloride and a preparation method of an intermediate thereof.
Background
The quinolone medicine has the advantages of high efficiency, wide antibiotic spectrum, excellent pharmacokinetic characteristic and low toxicity, and has great success in anti-infective treatment. Quinolones have currently been developed for the fourth generation, including moxifloxacin, gatifloxacin, balofloxacin, and the like. 2,4,5-trifluoro-3-methoxybenzoyl chloride is an irreplaceable key raw material for synthesizing the three kinds of the fleroxacins. 2,4,5-trifluoro-3-methoxybenzoyl chloride cas number 112811-66-2, molecular formula C 8 H 4 ClF 3 O 2 Colorless transparent liquid, the structural formula is as follows:
at present, the preparation routes suitable for industrial production reported by domestic and foreign documents mainly comprise the following three routes:
route one:
the method comprises the steps of hydrolyzing tetrafluorophthalic acid serving as a raw material under an alkaline condition to form sodium salt, selectively decarboxylating, acidifying, methylating dimethyl sulfate, and finally performing acyl chlorination to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride. The reaction condition of the route is mild, the total yield is high, and most of domestic producers adopt the process route at present. The method uses highly toxic dimethyl sulfate, which is not environment-friendly and has serious industrial pollution, and simultaneously uses thionyl chloride as an acyl chlorination reagent to generate a large amount of sulfur dioxide (one of six indexes of strict atmosphere control by national environment protection), so that the tail gas aftertreatment is difficult and the energy consumption is high.
And a second route:
the method uses tetrafluorophthalic acid as a raw material, firstly uses methanol as a methylation reagent for methylation reaction under an alkaline condition, then uses tri-n-butylamine for selective decarboxylation, and finally performs acyl chlorination to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride. The preparation of 2,4,5-trifluoro-3-methoxybenzoic acid is described in patent US5488152 with a total yield of 66%. The route adopts methanol methylation to replace dimethyl sulfate, but has the disadvantages of low yield, more complicated treatment, use of highly toxic tri-n-butylamine for decarboxylation, poor selectivity and use of thionyl chloride as an acyl chlorination reagent.
And a third route:
the method takes tetrafluorophthalimide as a raw material, under the alkaline condition, the imide is hydrolyzed, 4-fluorine is selectively hydrolyzed into hydroxyl, after methylation of dimethyl sulfate, tri-n-butylamine is used for selective decarboxylation, and finally acyl chlorination is carried out to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride. The patent CN103450013B describes that 2,4,5-trifluoro-3-methoxybenzoyl chloride is prepared, and the total reaction yield is 55%. The route also adopts dimethyl sulfate, tri-n-butylamine and thionyl chloride as reaction reagents, and has serious toxicity and pollution.
The methylating agent adopted in the existing preparation process is usually dimethyl sulfate, but the dimethyl sulfate is a highly toxic chemical, has genotoxicity, is extremely harmful to human bodies and environment-friendly, and increases the difficulty of post-treatment of the process. In response to this problem, the methylation reagent was optimized by replacing dimethyl sulfate with dimethyl carbonate. Dimethyl carbonate (DMC) is a new green chemical with low toxicity, and Europe lists it as a non-toxic chemical in 1992, so that it is a green chemical product with development prospect, and is an ideal methylating reagent.
Dimethyl carbonate has lower reaction activity than dimethyl sulfate, and if a reaction system does not use a catalyst, the reaction speed is extremely slow, and the reaction is basically not reacted, so that the selection of a proper catalyst is very critical. In patent CN1041516C, a catalyst system composed of metal iodide and alkylation catalyst is adopted, and when a mixture of potassium iodide and 4-dimethylamine aminopyridine is used as the catalyst, the reaction yield is 88%, and the product purity is 95%. Although the reaction selectivity is high, this catalyst system suffers from two major drawbacks: 1. after the catalyst is reacted, a large amount of solid waste is generated, and the post-treatment is complicated. 2. The catalyst used in the system is expensive, and the dosage is large, so that the cost is high, and the system is not beneficial to industrial production.
The methylation reaction of phenol or benzyl alcohol and dimethyl carbonate usually adopts 1,8-diazabicycloundecen-7-ene, triethylamine, tripropylamine and other catalysts, and when the catalysts are applied to the reaction of 2,4,5-trifluoro-3-hydroxybenzoic acid and dimethyl carbonate, the problems of poor reaction selectivity, low product purity and the like can occur. Under the same condition, 1,8-diazabicycloundece-7-ene is used as a catalyst, 2,4,5-trifluoro-3-hydroxybenzoic acid is used as a substrate, the selectivity of the reaction is only about 10%, the content of 2,5-difluoro-3,4-dimethoxybenzoic acid in the finally obtained product after post-treatment is as high as 90%, the content of a target product is only 9%, and the target product is extremely difficult to separate. It is inferred that during methylation, a large amount of methoxy anions may be generated to attack F at the 4-position, and finally, a bis-methoxy byproduct is generated.
Disclosure of Invention
In order to solve the problems in the prior art for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride, the invention provides a green and efficient preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride and a key intermediate thereof, the preparation method takes tetrafluorophthalic acid as a raw material, 2,4,5-trifluoro-3-hydroxybenzoic acid is obtained through defluorination hydroxylation and acidification decarboxylation reaction, 2,4,5-trifluoro-3-methoxybenzoic acid is obtained through reaction with dimethyl carbonate, and 2,4,5-trifluoro-3-methoxybenzoyl chloride is obtained through acyl chlorination.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate comprising:
in the presence of an organic tertiary amine catalyst and an acidic inorganic salt, 2,4,5-trifluoro-3-hydroxybenzoic acid reacts with dimethyl carbonate, and then the intermediate 2,4,5-trifluoro-3-methoxybenzoyl chloride is obtained through hydrolysis, acidification and extraction;
the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate is 2,4,5-trifluoro-3-methoxybenzoic acid
When the catalytic system only contains an organic tertiary amine catalyst, a reaction system generates a large amount of bis-methoxy byproducts, while in the presence of the organic tertiary amine catalyst and an acidic inorganic salt, 2,4,5-trifluoro-3-hydroxybenzoic acid and dimethyl carbonate with more than 2 times of equivalent weight are subjected to methylation reaction, the influence of excessive methoxy anions can be eliminated by adding the acidic inorganic salt, the reaction selectivity and the product purity are improved, and a large amount of methoxy anions are supposed to be generated in the methylation process to attack fluorine of 2,4,5-trifluoro-3-hydroxybenzoic acid, so that the problems of poor selectivity, low product purity and the like of the reaction in the prior art are caused.
The organic tertiary amine catalyst is selected from one of 1,8-diazabicycloundec-7-ene, N-diisopropylethylamine, triethylamine and tripropylamine, and N, N-diisopropylethylamine is preferred. The amount of catalyst used is 0.01 to 0.5 times the molar equivalent, preferably 0.03 to 0.2 times the molar equivalent, of 2,4,5-trifluoro-3-hydroxybenzoic acid.
The acid inorganic salt is selected from potassium dihydrogen phosphate, ferrous sulfate or ammonium nitrate, and the dosage of the acid inorganic salt is 0.1-1 time equivalent, preferably 0.2-0.8 time equivalent of 2,4,5-trifluoro-3-hydroxybenzoic acid.
The reaction solvent is one or more selected from water, dimethyl carbonate, dimethyl sulfoxide, N-dimethylformamide or toluene, and the mass of the added solvent is 3-20 times, preferably 5-15 times that of 2,4,5-trifluoro-3-hydroxybenzoic acid.
The methylation reaction temperature is 100-200 ℃, preferably 120-180 ℃, and the reaction time is 5-11h, preferably 6-8h.
After the methylation reaction is finished, removing the solvent, hydrolyzing with an alkali solution, acidifying, extracting with ethyl acetate, and drying to obtain 2,4,5-trifluoro-3-methoxybenzoic acid. 2.5-15wt%, preferably 5-10wt%, hydrolysis temperature of 20-50 deg.C, preferably 25-45 deg.C, hydrolysis time of 0.5-5h, preferably 1-4h. Acidification is carried out by adjusting the pH to 0.5-5, preferably 0.5-3.
The invention also provides a preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride, which takes the synthesis of the intermediate as a key step and specifically comprises the following steps:
a) Carrying out defluorination hydroxylation reaction on tetrafluorophthalic acid and alkali to obtain reaction liquid containing 2,4,5-trifluoro-3-hydroxyphthalic acid salt;
b) Adding acid into the reaction liquid obtained in the step A to adjust the pH value for decarboxylation reaction, and extracting to obtain 2,4,5-trifluoro-3-hydroxybenzoic acid;
c) 2,4,5-trifluoro-3-hydroxybenzoic acid 2,4,5-trifluoro-3-methoxybenzoic acid was obtained according to the procedure described above;
d) And D, dissolving 2,4,5-trifluoro-3-methoxybenzoic acid obtained in the step C by using a solvent, heating and stirring, adding an acyl chlorination reagent for reaction, and recovering to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride after the reaction is finished.
The reaction route is as follows:
in the dehydrofluorination hydroxylation reaction in step A, sodium hydroxide or potassium hydroxide is used in an amount of 5 to 20 times, preferably 6 to 12 times, the molar amount of tetrafluorophthalic acid. The reaction temperature of the step A is 30-110 ℃, preferably 40-90 ℃, and the reaction time is 4-10 hours, preferably 6-9 hours.
In the decarboxylation reaction in the step B, ammonia water or ammonium salts can be added before the pH is adjusted, wherein the ammonium salt can be ammonium chloride or triethylamine hydrochloride, preferably ammonia water, and the adding amount is 0.1-5.0 times of molar equivalent of tetrafluorophthalic acid, preferably 0.2-2.0 times. The ammonia exists in the form of ammonium ions in a reaction system and mainly plays a role of proton transfer, so that the decarboxylation is promoted to be carried out, if the purity and the yield are not added, the purity is only about 71 percent, the yield is only 69 percent, and the separation is extremely difficult. Hydrochloric acid or sulfuric acid is added to adjust the pH to 0.5-7.0, preferably 1.0-6.0. The reaction temperature of the step B is 100-180 ℃, preferably 140-160 ℃, and the reaction time is 3-10 hours, preferably 4-7 hours.
In the acyl chlorination reaction in the step D, one or more organic solvents of ethyl acetate, dichloromethane or toluene are used as reaction solvents, preferably ethyl acetate, phosgene is firstly dissolved in the organic solvent and then dripped into 2,4,5-trifluoro-3-methoxybenzoic acid for reaction. Phosgene is used in an amount of 1-5 equivalents, preferably 1-2.5 equivalents, of 2,4,5-trifluoro-3-hydroxybenzoic acid. The dosage of the organic solvent is 2,4,5-trifluoro-3-hydroxybenzoic acid equivalent 1.0-2.0 times. The reaction temperature is 30-110 ℃, preferably 40-80 ℃, and the reaction time is 2-10h, preferably 2.5-7.5h. After the reaction is finished, ethyl acetate is recovered under reduced pressure to obtain a 2,4,5-trifluoro-3-methoxybenzoyl chloride crude product, and finally the crude product is rectified to obtain a finished product, wherein the purity of a gas phase is as high as 99.45%.
Compared with the prior art, the invention has the following advantages:
1. in the process of preparing 2,4,5-trifluoro-3-hydroxybenzoic acid, a tri-n-butylamine toxic organic solvent is not used, the method is green and environment-friendly, the yield of a reaction product in the step reaches 90%, and the purity is more than or equal to 96%.
2. Non-toxic dimethyl carbonate is used as a methylating agent to replace traditional highly toxic dimethyl sulfate, so that the method is environment-friendly and reduces the difficulty of post-treatment of waste liquid; and the catalyst used in the methylation reaction is cheap and easy to obtain, the reaction yield of the step is high, the product purity is high, and the catalyst can be put into the next step of reaction without purification.
3. Phosgene is used for replacing thionyl chloride in the acyl chlorination reaction, so that the treatment of sulfur dioxide tail gas is avoided, and the production cost is effectively reduced.
4. The method has simple process, the total yield is 72.97 percent, and the purity of 2,4,5-trifluoro-3-methoxybenzoyl chloride is up to 99.45 percent.
Detailed Description
The following is merely a specific application example of the present invention, and the scope of the present invention is not limited in any way. All the technical solutions formed by equivalent transformation or equivalent replacement fall within the protection scope of the present invention
The purity of the intermediate and final products in the following examples, unless otherwise specified, are referred to as HPLC purity and are compared to the retention time of standards; the yields mentioned are all calculated as pure products.
Example 1: preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 90 ℃, stirred and reacted for 7 hours, and then the reaction is stopped. Adding 27.2g of 25wt% ammonia water into the reaction system, adding concentrated hydrochloric acid to adjust the pH to be about =4.0, heating to 150 ℃, stirring and reacting for 6h under 0.8Mpa, stopping the reaction, cooling to room temperature, adding ethyl acetate to extract for three times, combining organic phases, carrying out reduced pressure distillation (40 ℃ and-0.08 Mpa) to recover ethyl acetate, and after the recovery, carrying out vacuum drying for 4h to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 35.76g, the purity is 96.85%, and the yield is 90.18%.
Adding 35.76g of the brown solid into an autoclave, sequentially adding 150g of water, 150g of DMC (dimethyl carbonate) and 1.20g of DIPEA (N, N-diisopropylethylamine) and 4.25g of monopotassium phosphate, heating to 170 ℃, stirring for reaction for 8h, stopping the reaction, cooling, recovering the solvent under reduced pressure until no obvious liquid flows out to obtain a brownish black oily liquid, adding 144.00g of 10wt% NaOH solution, hydrolyzing at 35 ℃ for 3h, adding hydrochloric acid, adjusting the pH value to be =1.0, extracting with ethyl acetate, recovering and drying to obtain 32.49g of off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid, the purity is 97.45%, and the yield is 85.20%.
32.49g of the above off-white solid, 2,4,5-trifluoro-3-methoxybenzoic acid, 250ml of ethyl acetate were placed in a 1000ml three-necked flask, and 18.00g of phosgene was taken up in 10ml of ethyl acetate. And (3) dropwise adding 2,4,5-trifluoro-3-methoxybenzoic acid ethyl acetate solution, after dropwise adding, heating to 77 ℃, carrying out reflux reaction for 4 hours, recovering ethyl acetate under reduced pressure to obtain a crude product, transferring the crude product into a finished product rectifying still, and rectifying to obtain a finished product, wherein the white transparent liquid 2,4,5-trifluoro-3-methoxybenzoyl chloride is 32.98g, the purity is 99.45%, and the yield is 95.08%.
Example 2: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water and added into a 1500ml three-necked flask, the temperature is raised to 90 ℃, the reaction is stirred and reacted for 7 hours, and the reaction is stopped. And adding concentrated hydrochloric acid to adjust the pH to be about =4.0, heating to 150 ℃, stirring and reacting for 6h under 0.8Mpa, cooling to room temperature after the reaction is finished, adding ethyl acetate to extract for three times, combining organic phases, carrying out reduced pressure distillation (40-0.08 Mpa) to recover the ethyl acetate, and carrying out vacuum drying for 4h after the recovery is finished to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 37.28g with the purity of 71.11%. The yield was 69.03%.
Example 3: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 90 ℃, stirred and reacted for 10 hours, and then the reaction is stopped. Adding 2.14g of ammonium chloride, adding concentrated hydrochloric acid to adjust the pH to be about =3.0, heating to 150 ℃, stirring and reacting at 0.8Mpa for 10h, stopping the reaction, cooling to room temperature, adding ethyl acetate to extract for three times, combining organic phases, recovering the ethyl acetate by reduced pressure distillation (40-0.08 Mpa), and after the recovery is finished, drying in vacuum for 4h to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 36.29g with the purity of 92.78%. The yield thereof was found to be 87.67%.
Example 4: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 90 ℃, stirred and reacted for 6 hours, and then the reaction is stopped. Adding 20.20g of triethylamine, adding concentrated hydrochloric acid to adjust the pH value to be about =3.0, heating to 160 ℃, stirring and reacting for 7h under 0.9Mpa, stopping the reaction, cooling to room temperature, adding ethyl acetate to extract for three times, combining organic phases, recovering the ethyl acetate by reduced pressure distillation (40-0.08 Mpa), and after the recovery is finished, drying for 4h in vacuum to obtain light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 36.45g with the purity of 94.31%. The yield thereof was found to be 89.51%.
Example 5: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 160.0g of sodium hydroxide are weighed, dissolved in 800g of distilled water, added into a 1500ml three-necked flask, heated to 90 ℃, stirred and reacted for 9 hours, and then the reaction is stopped. Adding 30.00g of tripropylamine, adding concentrated hydrochloric acid to adjust the pH value to be about =1.0, heating to 140 ℃, stirring at 1Mpa for reaction for 7h, stopping the reaction, cooling to room temperature, adding ethyl acetate to extract for three times, combining organic phases, recovering the ethyl acetate by reduced pressure distillation (40-0.08 Mpa), and after the recovery is finished, drying in vacuum for 4h to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 36.30g with the purity of 95.59%. The yield thereof was found to be 90.35%.
Example 6: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 90 ℃, stirred and reacted for 6 hours, and then the reaction is stopped. Adding 67.85g of 25wt% ammonia water into the reaction system, adding concentrated hydrochloric acid to adjust the pH to be about =4.0, heating to 150 ℃, stirring and reacting for 6h under 0.8Mpa, stopping the reaction, cooling to room temperature, adding ethyl acetate to extract for three times, combining organic phases, carrying out reduced pressure distillation (40 ℃ and-0.08 Mpa) to recover ethyl acetate, and after the recovery, carrying out vacuum drying for 4h to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 38.32g, the purity is 88.96%, and the yield is 88.77%.
Example 7: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.6g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 90 ℃, stirred and reacted for 6 hours, and then the reaction is stopped. Adding 13.59g of 25wt% ammonia water into the reaction system, adding concentrated hydrochloric acid to adjust the pH to be about =7, heating to 150 ℃, stirring at 0.8Mpa for 6 hours, stopping the reaction, cooling to room temperature, adding ethyl acetate to extract for three times, combining organic phases, carrying out reduced pressure distillation (at 40 ℃ and at-0.08 Mpa) to recover ethyl acetate, and carrying out vacuum drying for 4 hours after recovery to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 37.08g with the purity of 85.27% and the yield of 82.33%
Example 8: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 40 ℃, stirred and reacted for 9 hours, and then the reaction is stopped. Adding 2.72g of 25wt% ammonia water into the reaction system, adding concentrated hydrochloric acid to adjust the pH to be about =4.0, heating to 150 ℃, stirring and reacting for 6h under 0.8Mpa, cooling to room temperature after the reaction is finished, adding ethyl acetate to extract for three times, combining organic phases, carrying out reduced pressure distillation (40 ℃ and-0.08 Mpa) to recover ethyl acetate, and carrying out vacuum drying for 4h after the recovery is finished to obtain a light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 35.64g, the purity is 92.79%, and the yield is 86.11%.
Example 9: preparation of 2,4,5-trifluoro-3-hydroxybenzoic acid
47.60g of tetrafluorophthalic acid and 80.0g of sodium hydroxide are weighed, dissolved in 600g of distilled water, added into a 1500ml three-necked flask, heated to 40 ℃, stirred and reacted for 9 hours, and then the reaction is stopped. Adding 25wt% ammonia water 1.36g into the reaction system, adding concentrated hydrochloric acid to adjust the pH to be about =4.0, heating to 150 ℃, stirring and reacting for 6h under 0.8Mpa, cooling to room temperature after the reaction is finished, adding ethyl acetate to extract for three times, merging organic phases, carrying out reduced pressure distillation (40 ℃ and-0.08 Mpa) to recover ethyl acetate, and carrying out vacuum drying for 4h after the recovery is finished to obtain light brown solid 2,4,5-trifluoro-3-hydroxybenzoic acid 38.92g, the purity is 86.21%, and the yield is 87.37%.
Example 10: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid (obtained according to the preparation method of example 1) was weighed and added to an autoclave, 150.00g water, 150.00g DMC (dimethyl carbonate) and 10.08g DIPEA (N, N-diisopropylethylamine) and 4.25g monopotassium phosphate were sequentially added, the temperature was raised to 170 ℃, stirred and reacted for 5.5 hours, cooled after the reaction was completed, the solvent was recovered under reduced pressure until no significant liquid flowed out, a brownish black oily liquid was obtained, 125g 1wt naoh solution was added, after 35 ℃ hydrolysis for 3 hours, hydrochloric acid was added to adjust pH =1.0, extraction was performed with ethyl acetate, and recovery and drying were performed to obtain an off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid with 26.18g purity of 95.46%, yield of 80.16%.
Example 11: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, 150.00g DMF (N, N-dimethylformamide), 150g DMC (dimethyl carbonate) and 1.20g DIPEA (N, N-diisopropylethylamine) and 4.25g potassium dihydrogen phosphate were added in this order, the temperature was raised to 170 ℃, the reaction was stirred for 8 hours, after the reaction was completed, cooling was performed, the solvent was recovered under reduced pressure until no significant liquid flowed out, a brownish black oily liquid was obtained, 125g10wt NaOH was added to hydrolyze at 35 ℃ for 3 hours, hydrochloric acid was added to adjust the pH =1.0, ethyl acetate was used for extraction, and after recovery and drying, 2,4,5-trifluoro-3-methoxybenzoic acid 27.10g, the purity was 94.55%, and the yield was 82.19%.
Example 12: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, 60g DMC, 240g DMSO, 1.30g DBU (1,8-diazabicycloundecen-7-ene) and 7.80g potassium dihydrogen phosphate were sequentially added, the temperature was raised to 170 ℃, the reaction was stirred for 8 hours, after the reaction was completed, cooling was performed, the solvent was recovered under reduced pressure until no significant liquid flowed out, a brownish black oily liquid was obtained, 125g10wt naoh was added for hydrolysis, hydrochloric acid was added to adjust pH =1.0, extraction was performed with ethyl acetate, and a pale white solid 2,4,5-trifluoro-3-methoxybenzoic acid 27.19g, purity 95.24% and yield 83.06% was obtained by recovery and drying.
Example 13: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed and added to an autoclave, then 200g water, 150g DMC, 1.20g DIPEA, 4.25g potassium dihydrogen phosphate were added in order, the temperature was raised to 170 ℃, stirred and reacted for 10h, after the reaction was completed, cooling was performed, the solvent was recovered under reduced pressure until no clear liquid flowed out, a brownish black oily liquid was obtained, 125g10wt% NaOH was added to hydrolyze, then hydrochloric acid was added to adjust pH =1.5, ethyl acetate was used for extraction, and the off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid 27.11g, purity 94.67%, yield 82.32% was obtained by recovery and drying.
Example 14: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, then 30g DMC, 270g toluene, 1.00g triethylamine and 10.00g potassium dihydrogen phosphate were added in sequence, the temperature was raised to 180 ℃, the reaction was stirred for 9h, after the reaction was completed, cooling was performed, the solvent was recovered under reduced pressure until no significant liquid flow out occurred, a brownish black oily liquid was obtained, 125g10wt% naoh was added for hydrolysis, hydrochloric acid was added to adjust pH =2.0, ethyl acetate was used for extraction, and an off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid 27.12g, purity 93.39%, yield 81.24 was obtained by recovery and drying.
Example 15: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, 60g of DMC, 350g of DMSO, 1.30g of DBU and 9.6g of potassium dihydrogen phosphate were sequentially added, the temperature was raised to 170 ℃, the reaction was stirred for 8 hours, after the reaction was completed, cooling was performed, the solvent was recovered under reduced pressure until no significant liquid flowed out, a brownish black oily liquid was obtained, 125g of 10wt% NaOH was added for hydrolysis, hydrochloric acid was added to adjust pH =1.0, ethyl acetate was used for extraction, and an off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid was obtained by recovering and drying 27.71g, 93.82% in purity and 83.39% in yield.
Example 16: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid is weighed into an autoclave, 50g of DMC, 300g of water, 1.12g of tripropylamine and 17g of monopotassium phosphate are sequentially added, the temperature is increased to 180 ℃, the mixture is stirred and reacted for 9 hours, the mixture is cooled after the reaction is finished, the solvent is recovered under reduced pressure until no obvious liquid flows out, a brownish black oily liquid is obtained, 125g of 10wt% NaOH is added for hydrolysis, hydrochloric acid is added for regulating the pH to be =1.0, ethyl acetate is used for extraction, and the mixture is recovered and dried to obtain an off-white solid, 2,4,5-trifluoro-3-methoxybenzoic acid 26.77g, the purity is 96.47%, and the yield is 82.83%.
Example 17: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid is weighed and added into an autoclave, 400g of DMC, 1.20g of DIPEA and 9.20g of monopotassium phosphate are sequentially added, the temperature is increased to 180 ℃, the reaction is stirred for 9h, the cooling is carried out after the reaction is finished, the solvent is recovered under reduced pressure until no obvious liquid flows out, a brownish black oily liquid is obtained, 125g of 10wt% NaOH is added for hydrolysis, hydrochloric acid is added for regulating the pH to be =1.0, ethyl acetate is used for extraction, and the white solid 2,4,5-trifluoro-3-methoxybenzoic acid 26.99g is obtained after recovery and drying, the purity is 97.66%, and the yield is 84.54%.
Example 18: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid is weighed and added into an autoclave, then 300g of DMC, 1.20g of DIPEA and 15.30g of ferrous sulfate are added in sequence, the temperature is increased to 180 ℃, the reaction is stirred for 8h, the cooling is carried out after the reaction is finished, the solvent is recovered under reduced pressure until no obvious liquid flows out, a brownish black oily liquid is obtained, 125g of 10wt% NaOH is added for hydrolysis, hydrochloric acid is added for regulating the pH to be =1.0, ethyl acetate is used for extraction, and the white solid 2,4,5-trifluoro-3-methoxybenzoic acid 26.19g is obtained after recovery and drying, the purity is 95.45%, and the yield is 80.18%.
Example 19: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid is weighed and added into an autoclave, then 350g of DMC, 1.10g of DIPEA and 2.88g of ammonium nitrate are added in sequence, the temperature is increased to 180 ℃, the stirring reaction is carried out for 9h, after the reaction is finished, the cooling is carried out, the solvent is recovered under reduced pressure until no obvious liquid flows out, a brownish black oily liquid is obtained, 125g of 10wt% NaOH is added for hydrolysis, hydrochloric acid is added for regulating the pH to be =1.0, ethyl acetate is used for extraction, and the white solid 2,4,5-trifluoro-3-methoxybenzoic acid 26.90g, the purity is 96.84%, and the yield is 83.55% is obtained after recovery and drying.
Example 20:2,4,5 preparation of trifluoro-3-methoxybenzoic acid (triethylamine, ferrous sulfate)
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid is weighed and added into an autoclave, then 300g of DMC, 7.89g of triethylamine and 15.00g of ferrous sulfate are added in sequence, the temperature is increased to 180 ℃, the stirring reaction is carried out for 8h, after the reaction is finished, the cooling is carried out, the solvent is recovered under reduced pressure until no obvious liquid flows out, a brownish black oily liquid is obtained, 125g of 10wt% NaOH is added, after the hydrolysis, hydrochloric acid is added, the pH is adjusted again to be =1.0, the extraction is carried out by ethyl acetate, the recovery and the drying are carried out, and 27.78g of off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid is obtained, the purity is 86.56%, and the yield is 77.13%.
Example 21: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid is weighed and added into an autoclave, 350g of DMC, 2.37g of DBU and 2.50g of ammonium nitrate are sequentially added, the temperature is increased to 180 ℃, the reaction is stirred for 9h, the cooling is carried out after the reaction is finished, the solvent is recovered under reduced pressure until no obvious liquid flows out, a brownish black oily liquid is obtained, 125g of 10wt% NaOH is added, hydrochloric acid is added to regulate the pH value to be =1.0, the mixture is extracted by ethyl acetate, and the mixture is recovered and dried to obtain an off-white solid 2,4,5-trifluoro-3-methoxybenzoic acid 27.52g, the purity is 90.47%, and the yield is 79.86%.
Example 22: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, and then 150g water, 150g DMC (dimethyl carbonate) and 10.08g DIPEA (N, N-diisopropylethylamine) and 4.50g potassium dihydrogen phosphate were sequentially added, the temperature was raised to 110 ℃, the reaction was stirred for 8 hours, after the reaction was completed, the reaction was cooled, the solvent was recovered under reduced pressure until no significant liquid flowed out, and a brownish black oily liquid was obtained, and 12510wt% NaOH was added to hydrolyze at 35 ℃ for 3 hours, then hydrochloric acid was added to adjust pH =1.0, extraction was performed with ethyl acetate, and recovery and drying were performed to obtain 2,4,5-trifluoro-3-methoxybenzoic acid as an off-white solid, 30.73g, 89.44% purity, and 88.16 yield.
Example 23: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) of 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, 150g of water, 150g of DMC and 1.20g of DIPEA were sequentially added, the temperature was raised to 170 ℃, the reaction was stirred for 10 hours, after the reaction was completed, the reaction was cooled, the solvent was recovered under reduced pressure until no significant liquid flowed out, a brownish black oily liquid was obtained, 125g of 10wt% NaOH was added for hydrolysis, hydrochloric acid was added to adjust pH =1.0, extraction was performed with ethyl acetate, and recovery and drying were performed to obtain 28.49g of an off-white solid, in which the content of 2,5-difluoro-3,4-dimethoxybenzoic acid was up to 90.13%, and the target product was 8.07%.
Example 24: preparation of 2,4,5-trifluoro-3-methoxybenzoic acid
30.00g (96.85%) 2,4,5-trifluoro-3-hydroxybenzoic acid was weighed into an autoclave, 130.20g DMC, 0.39g potassium iodide and 0.73g 4-dimethylaminopyridine were sequentially added, the temperature was raised to 170 ℃, the reaction was stirred for 8 hours, after the reaction was completed, cooling was performed, the solvent was recovered under reduced pressure until no significant liquid flowed out, a brownish black oily liquid was obtained, 1250 wt% NaOH was added for hydrolysis, hydrochloric acid was added to adjust pH =1.0, ethyl acetate extraction was performed, recovery and drying were performed to obtain 26.15g of an off-white solid, the purity was 94%,2,5-difluoro-3,4-dimethoxybenzoic acid content was 3.01%, and the yield was 78.84%.
Example 25: preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride
25.00g (97.33%) of 2,4,5-trifluoro-3-methoxybenzoic acid and 300ml of methylene chloride were weighed into a 1000ml three-necked flask, and 20.00g of phosgene was absorbed in 10ml of methylene chloride. And (2) dropwise adding 2,4,5-trifluoro-3-methoxybenzoic acid in dichloromethane, after dropwise adding, heating to 40 ℃ for refluxing, carrying out reflux reaction for 5h, after the reaction is finished, decompressing and recovering dichloromethane to obtain a crude product, transferring the crude product into a finished product rectifying kettle for rectifying to obtain a finished product, wherein the white transparent liquid 2,4,5-trifluoro-3-methoxybenzoyl chloride is 26.57g, the purity is 98.48%, and the yield is 98.70%.
Example 26: preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride
25.00g (97.33%) of 2,4,5-trifluoro-3-methoxybenzoic acid and 200ml of toluene were weighed into a 1000ml three-necked flask, and 20.00g of phosgene was absorbed in 10ml of toluene. And (2) dropwise adding 2,4,5-trifluoro-3-methoxybenzoic acid in toluene, after dropwise adding, heating to 110 ℃ for reflux, carrying out reflux reaction for 3 hours, after the reaction is finished, recovering toluene under reduced pressure to obtain a crude product, transferring the crude product into a finished product rectification kettle for rectification to obtain a finished product, wherein the white transparent liquid is 2,4,5-trifluoro-3-methoxybenzoyl chloride 25.31g, the purity is 98.11%, and the yield is 93.67%.
Example 27: preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride
25.00g (97.33%) of the compound 2,4,5-trifluoro-3-methoxybenzoic acid, 250ml ethyl acetate were weighed into a 1000ml three-necked flask, and 3763 g phosgene, 60.07g, was absorbed in 10ml ethyl acetate. And (3) dropwise adding 2,4,5-trifluoro-3-methoxybenzoic acid ethyl acetate solution, after dropwise adding, heating to 77 ℃, carrying out reflux reaction for 4 hours, after the reaction is finished, carrying out reduced pressure recovery on ethyl acetate to obtain a crude product, transferring the crude product into a finished product rectifying kettle for rectification to obtain a finished product, wherein the white transparent liquid 2,4,5-trifluoro-3-methoxybenzoyl chloride is 25.94g, the purity is 97.37%, and the yield is 95.28%.
Example 28: preparation of 2,4,5-trifluoro-3-methoxybenzoyl chloride
25.00g (97.33%) of 2,4,5-trifluoro-3-methoxybenzoic acid and 250ml of ethyl acetate were weighed into a 1000ml three-necked flask, and 20.00g of phosgene was absorbed in 10ml of ethyl acetate. And (2) dropwise adding 2,4,5-trifluoro-3-methoxybenzoic acid ethyl acetate solution, after dropwise adding, heating to 77 ℃, performing reflux reaction for 10 hours, stopping the reaction, recovering ethyl acetate under reduced pressure to obtain a crude product, transferring the crude product into a finished product rectification kettle, and rectifying to obtain a finished product, wherein the white transparent liquid is 2,4,5-trifluoro-3-methoxybenzoyl chloride 25.21g, the purity is 98.39%, and the yield is 93.56%.
Claims (13)
1. A preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate is characterized by comprising the following steps:
in the presence of an organic tertiary amine catalyst and an acidic inorganic salt, 2,4,5-trifluoro-3-hydroxybenzoic acid and dimethyl carbonate are subjected to methylation reaction, and after the reaction is finished, the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate is obtained through hydrolysis, acidification and extraction;
the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate is 2,4,5-trifluoro-3-methoxybenzoic acid;
the methylation reaction temperature is 100-200 ℃;
the organic tertiary amine catalyst is N, N-diisopropylethylamine; the molar ratio of the organic tertiary amine catalyst to 2,4,5-trifluoro-3-hydroxybenzoic acid is 0.03-0.2:1;
the acidic inorganic salt is potassium dihydrogen phosphate; the molar ratio of the acidic inorganic salt to 2,4,5-trifluoro-3-hydroxybenzoic acid is 0.2-0.8:1.
2. the method of preparing the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate of claim 1, wherein the methylation reaction temperature is 120-180 ℃; the methylation reaction time is 5-11h.
3. The method for preparing the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate of claim 1, wherein the hydrolysis is performed under the action of an aqueous solution of NaOH or KOH, the concentration of the aqueous solution of NaOH or KOH being 2.5-15wt%; the molar ratio of NaOH or KOH to 2,4,5-trifluoro-3-hydroxybenzoic acid is 1.0-5.0:1;
the hydrolysis temperature is 20-50 ℃; the hydrolysis time is 0.5-5h;
the pH after acidification is 0.5-5.
4. The process for preparing the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate of claim 3, wherein the concentration of the aqueous NaOH or KOH solution is 5-10wt%; the molar ratio of NaOH or KOH to 2,4,5-trifluoro-3-hydroxybenzoic acid is 2.0-4.0:1;
the hydrolysis temperature is 25-45 ℃; the hydrolysis time is 1-4h;
the pH value after acidification is 0.5-3.
5. The process for preparing the 2,4,5-trifluoro-3-methoxybenzoyl chloride intermediate of claim 1, wherein the solvent for the methylation reaction is one or more of dimethyl carbonate, water, toluene, dimethyl sulfoxide, or N, N-dimethylformamide.
6. A preparation method of 2,4,5-trifluoro-3-methoxybenzoyl chloride is characterized by comprising the following steps:
a) Carrying out defluorination hydroxylation reaction on tetrafluorophthalic acid and alkali to obtain reaction liquid containing 2,4,5-trifluoro-3-hydroxyphthalic acid salt;
b) B, adding acid into the reaction liquid obtained in the step A for decarboxylation reaction, and extracting to obtain 2,4,5-trifluoro-3-hydroxybenzoic acid;
c) Obtaining 2,4,5-trifluoro-3-methoxybenzoic acid by the method of any of claims 1~5;
d) And D, dissolving the 2,4,5-trifluoro-3-methoxybenzoic acid obtained in the step C by using a solvent, heating and stirring, adding an acyl chlorination reagent for reaction, and performing post-treatment after the reaction is finished to obtain the 2,4,5-trifluoro-3-methoxybenzoyl chloride.
7. The process for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride according to claim 6, wherein in step a), said base is sodium hydroxide or potassium hydroxide, and the molar ratio of said base to tetrafluorophthalic acid is 6-12:1.
8. the method for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride according to claim 6 or 7, wherein in step a), the reaction time is 6-9h; the reaction temperature is 40-90 ℃.
9. The method for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride as claimed in claim 6, wherein in step B), said acid is hydrochloric acid or sulfuric acid; the pH after the addition of acid is 1.0-6.0.
10. The method for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride according to claim 6, wherein in step B), ammonia, ammonium chloride or triethylamine hydrochloride is added before the pH is adjusted by adding an acid; the addition amount is 0.2-2.0 times of molar equivalent of tetrafluorophthalic acid.
11. The method for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride as claimed in claim 6, wherein in step B), the reaction temperature is 140-160 ℃; the reaction time is 4-7 hours.
12. The method of claim 6 wherein in step D) the acid chlorination reagent is phosgene; the amount of phosgene used is 1-2.5 times the molar equivalent of 2,4,5-trifluoro-3-hydroxybenzoic acid.
13. The method for preparing 2,4,5-trifluoro-3-methoxybenzoyl chloride according to claim 6, wherein in step D), the reaction temperature is 40-80 ℃; the reaction time is 2.5-7.5h; the solvent is ethyl acetate, dichloromethane or toluene.
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