CN1068867C - Preparation of 2,3,4,5-tetrafluorobenzoic acid - Google Patents

Abstract

The invention relates to a preparation method of 2,3,4,5-tetrafluorobenzoic acid.

The present invention uses 3,4,5,6-tetrachlorophthalic anhydride and aniline as raw materials to obtain the target product-2,3,4,5-tetrachlorophthalic anhydride through processes such as condensation, fluorination, ring opening, decarboxylation and hydrolysis. Fluorobenzoic acid. Since this method uses aniline as the raw material for the condensation reaction, the existence of the benzene ring will produce a conjugation effect and an induction effect, so that the fluorination and decarboxylation reactions can be carried out at a lower temperature; at the same time, the solvent used in the decarboxylation process is non- The protic polar solvent enables the decarboxylation process to be carried out under normal pressure, so that the operating conditions of the entire preparation process are relatively mild, and the purity of the product is high. It is a preparation method with broad industrial application prospects.

Description

The preparation method of 2,3,4,5-tetrafluorobenzoic acid

The invention belongs to the field of synthesis of pharmaceutical intermediates and relates to a preparation method of 2,3,4,5-tetrafluorobenzoic acid.

2,3,4,5-Tetrafluorobenzoic acid is an important drug intermediate, which is widely used in the process of drug synthesis, especially in the preparation of third-generation quinolone antibacterial drugs such as Levefloxacin (Levefloxacin) , important raw material of fleroxacin (dofloxacin, Fleroxacin), lomefloxacin (Lomefloxacin), rufloxacin (Rufloxacin), sparfloxacin (also known as sifloxacin, Spsrfloxacin). Its structural formula is as follows:

At present, existing many documents have reported the method for synthesizing 2,3,4,5-tetrafluorobenzoic acid, comparatively typical have following several kinds:

(1) JP0125737, JP6185349, JP6261948, EP194671, and DE3810093 respectively disclose a kind of 2,3,4,5-tetrafluorophthalic acid as raw material and tertiary amines such as n-tributylamine and n-trioctylamine as catalyst and concurrently. Solvent or in the presence of Lewis acid, a method of removing a carboxyl group with a metal ion as a catalyst to obtain 2,3,4,5-tetrafluorobenzoic acid. In the decarboxylation reaction of this method, expensive high-boiling tertiary amines such as n-tributylamine and n-trioctylamine are used as solvents and catalysts, which brings difficulties to their recycling, and will inevitably produce a small amount of deep decarboxylation during the reaction process. By-products such as 1,2,3,4-tetrafluorobenzene must undergo repeated extraction or rectification to obtain pure target products. The above-mentioned defects have brought insurmountable difficulties to the industrialization of the method.

(2) Japanese Patent JP 90 145538 discloses another synthetic method, which uses 3,4,5,6-tetrachlorophthalic anhydride and methylamine as raw materials to react in a polar solvent to generate N-formaldehyde 3,4,5,6-tetrachlorophthalimide, and then KF fluorination to obtain fluoride, the resulting fluoride reacts with lye to obtain a ring-opened product, and then high pressure in an aqueous solution of organic tertiary amine Decarboxylation, and finally hydrolysis in sulfuric acid solution to obtain the target product. In order to improve the reactivity of the fluorinating agent KF in this method, sulfolane with a high boiling point is selected as a solvent, and the reaction temperature is relatively high, which causes serious coking of the product during the reaction and post-treatment process, making it difficult to obtain a fluorinated product with higher purity; at the same time, The decarboxylation reaction takes water as the medium and tertiary organic amine as the catalyst, and is carried out under the condition of sealing, pressurizing and raising the temperature to 150°C. The higher reaction pressure greatly increases the risk factors in the industrialization process.

In summary, research and development of a synthesis method of 2,3,4,5-tetrafluorobenzoic acid with mild reaction conditions, simple process, and safety has become an urgent need of the industry.

The object of the present invention is to disclose a kind of with 3,4,5,6-tetrachlorophthalic anhydride and aniline as raw material, react under normal pressure and generate 2,3,4,5-tetrafluorobenzoic acid new Synthetic methods to overcome the shortcomings of the prior art and meet the needs of industrial sectors.

The concept of the present invention is as follows: 3,4,5,6-tetrachlorophthalic anhydride and aniline are used as raw materials for condensation reaction to obtain N-phenyl-3,4,5,6-tetrachlorophthalic anhydride Phthalimide, and then react with KF in an aprotic polar solvent to generate N-phenyl-3,4,5,6-tetrafluorophthalimide, which is dissolved in alkali and used Acidification gives N-phenyl-2,3,4,5-tetrafluorophthalic acid, which is decarboxylated in an aprotic polar solvent such as dimethyl sulfoxide (DMSO) to give N-phenyl-3,4 , 5,6-tetrafluorobenzamide, and finally the decarboxylated product was hydrolyzed in an aqueous mineral acid solution to obtain the target product-2,3,4,5-tetrafluorobenzoic acid.

Since this method uses aniline as the raw material for the condensation reaction, the existence of the benzene ring will produce a conjugation effect and an induction effect, so that the fluorination and decarboxylation reactions can be carried out at a lower temperature; at the same time, the solvent used in the decarboxylation process is non- The proton polar solvent enables the decarboxylation process to be carried out under normal pressure, so that the reaction conditions of the whole preparation process are relatively mild, and the purity of the product is also high.

According to above-mentioned design, the contriver has proposed following with 3,4,5,6-tetrachlorophthalic anhydride and aniline as raw material, prepares the technical scheme of 2,3,4,5-tetrafluorobenzoic acid through a large number of tests :

反应的工艺条件是这样的：(1) Condensation reaction: use 3,4,5,6-tetrachlorophthalic anhydride as raw material, and perform condensation reaction with aniline in a solvent to obtain N-phenyl-3,4,5,6-tetrachloro Phthalimide, the reaction formula is:

The process conditions of the reaction are as follows:

The solvent is a polar organic solvent, commonly used are acetic acid, dioxane, etc., react at reflux temperature for 6 to 10 hours, and then collect the product -N-phenyl-3,4,5 from the reaction mixture ,6-Tetrachlorophthalimide. The optimal ratio of 3,4,5,6-tetrachlorophthalic anhydride to aniline is 1:(1~1.5) (molar ratio), and the amount of solvent used is raw material:solvent=1:(4~8) (weight ratio);

反应的工艺条件是这样的：(2) Fluorination reaction: In an aprotic polar solvent, the condensation product -N-phenyl-3,4,5,6-tetrachlorophthalimide and a fluorinating agent are subjected to a fluorination reaction, and the reaction The formula is:

The process conditions of the reaction are as follows:

The reaction temperature is 140-155° C., the reaction time is 7-15 hours, and the product is collected from the mixture after the reaction. The consumption of aprotic polar solvent is 4～15 times (mass) of raw material consumption;

Said aprotic polar solvent is one of sulfolane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide;

Said fluorinating agent can adopt palladium fluoride and potassium fluoride etc., considers from economic point of view, is advisable with potassium fluoride (KF), preferably selects the KF of highly active spray drying for use.

In order to increase the reaction rate, an appropriate amount of phase transfer catalyst can be added to the reaction system. The phase transfer catalyst is a quaternary ammonium salt compound, such as tetramethylammonium chloride, tetrabutylammonium bromide, hexadecyltrimethyl bromide Ammonium chloride, etc., or quaternary phosphonium salt compounds, such as tetraphenylphosphonium bromide, tributylphenylphosphonium bromide, etc., polyethylene glycol compounds, such as PEG6000, etc., or their mixtures can also be used, and the addition amount is 0.6% of raw material mass;

(3) ring-opening reaction: the fluoride obtained in step (2) is reacted with an alkali solution to open the imide ring on the fluoride, and then use acid for acid analysis. The reaction formula is: The process conditions of the reaction are as follows:

Said alkali can adopt the hydroxide of alkali metal, as potassium hydroxide (sodium), or be carbonate such as potassium carbonate (sodium), potassium bicarbonate (sodium), and suitable concentration is 5～20% (wt %) aqueous solution, the dosage is: fluoride: alkali solution = 1: (1.1-1.2) (molar ratio); the acid used for acid analysis is generally inorganic acid, such as hydrochloric acid, sulfuric acid, etc., and the suitable concentration is 10-15 % (wt%) aqueous solution, its consumption is: fluoride: acid solution=1: (1.1～1.5) (molar ratio); Reaction temperature is 50～100 ℃, adopts conventional method to collect from the mixture after reaction and form thing.

(4) decarboxylation reaction: the ring-opened product obtained in step (3) is placed in a tertiary amine or an aprotic polar solvent to carry out a decarboxylation reaction, and its reaction formula is: The process conditions of the reaction are as follows:

The reaction temperature is 80-150°C, the reaction time is 1-5 hours, the amount of the solvent added is 5-10 times the weight of the ring-opened compound, and the product is collected from the mixture by a conventional method after the reaction.

Said tertiary amine solvent can be one or more in n-tributylamine, triethylamine, n-trioctylamine, more preferred solvent is an aprotic polar solvent, such as N-methylpyrrolidone , dimethyl sulfoxide, etc.:

反应的工艺条件是这样的：(5) Hydrolysis reaction: the decarboxylation product is placed in an acidic aqueous solution and hydrolyzed to obtain the said target product of the present invention-2,3,4,5-tetrafluorobenzoic acid, and its reaction formula is:

The process conditions of the reaction are as follows:

Reaction temperature is 80～150 ℃, and said acidic solution is mineral acids such as sulfuric acid, hydrochloric acid or hydrobromic acid, and its concentration is generally 30～50% (wt%), and addition is: decarboxylation product: acid solution=1: (5～10) (weight), the reaction time is 15～25 hours, adopts conventional method to collect the resultant from the mixture after the reaction finishes, and is target product—a kind of off-white solid compound.

The present invention will be further described below through examples, but examples do not limit the protection scope of the present invention.

Example 1

(1) In a reaction kettle with condensing reflux, stirring and heating devices, add 4000 grams of acetic acid, 260 grams of aniline (2.8mol), 715 grams (2.5mol) of 3,4,5,6-tetrachlorophthalate Formic anhydride was refluxed for 6 hours under the protection of nitrogen, and the reactant was filtered, washed with water, and dried to obtain 880 g of light yellow solid condensate. Melting point: 271°C, yield 97.5%.

Example 2

500 grams (0.722mol) of the condensate obtained in Example 1, 1130 grams of potassium fluoride, 4000 ml of N,N-dimethylformamide (DMF) and 3 grams of catalyst PEG6000 were placed in the above-mentioned reactor for 10 hours, and the reaction The temperature is 150°C, and through liquid chromatography analysis, the conversion rate of the raw material is 100%, the formation rate of the product is 86%, and the partial fluoride is 5%. After the reactant is purified, 245 grams of beige solid fluoride is obtained, the content was 98.5%, and the yield was 60%, [MS: C ₁₄ H ₅ F ₄ NO ₂ (M, 295,100; M ⁺ 1,296, 20.899; MC ₈ H ₅ NO ₂ , 148, 53.198; MC ₇ H ₅ NO, 176 , 16.102; MC ₈ F ₄ NO ₂ , 77, 17.118)].

Example 3

The operation process is the same as in Example 2, the solvent is changed into 4000ml of dimethyl sulfoxide, reacted for 10 hours, and analyzed by liquid chromatography, the conversion rate of the raw material is 100%, the formation rate of the product is 83%, and the partial fluoride is 6 %, the reactant was purified to obtain 230 grams of beige solid fluoride, with a content of 97.8%, 1.2% of partial fluoride, and a yield of 56%.

Example 4

Place 475 grams (1.61 mol) of the beige solid fluoride obtained in Example 2, 1350 ml of water, and 135 grams of KOH in the above-mentioned reactor for 1 hour, the reaction temperature is 95 ° C, the reactant is cooled to 25 ° C, and concentrated hydrochloric acid is added dropwise Until all the off-white solids were precipitated, 495 grams of off-white solid ring-opened compounds were obtained after filtration, washing and drying. Melting point: 195°C, yield 98%.

Example 5

500 grams (1.60mol) of off-white solid ring-opened compound and 4200ml dimethyl sulfoxide (DMSO) obtained in Example 4 were placed in the reactor described in Example 1, and reacted for 10 hours under nitrogen protection, and the reaction temperature was 130°C. Through liquid chromatography analysis, the conversion rate of the raw material is 92%, the generation rate of the decarboxylation product is 82%, and the ring-closed product is 6%. After the reactants were purified, 265 grams of decarboxylated off-white solids were obtained, the content was 99%, the yield was 61.7%, melting point: 151°C, [MS: C ₁₃ H ₇ F ₄ NO (M, 269,39.591; MC ₆ H ₆ N, 177,100; MC ₇ H ₆ NO, 149, 17.461)].

Example 6

The solvent among the embodiment 5 was changed to 5000ml n-tributylamine, reacted for 18 hours, and the others were the same as in the embodiment 5. Analysis by liquid chromatography showed that the conversion rate of the raw material was 91%, the formation rate of the decarboxylation product was 77%, and the ring-closed product was 9%. The reactants were purified to obtain 236 grams of decarboxylated off-white solids with a content of 99% and a yield of 55%.

Example 7

The solvent in Example 5 was changed to 4200ml N-methyl-2-pyrrolidone, and reacted for 2 hours, and the others were the same as in Example 5. Through liquid chromatography analysis, the conversion rate of the raw material is 90%, the generation rate of the decarboxylation product is 80%, and the ring-closed product is 7%. The reactant was purified to obtain 252 grams of decarboxylated off-white solid, with a content of 99% and a yield of 58%.

Example 8

The hydrobromic acid of 265 grams, 500ml (40%) of the off-white decarboxylation compound gained in Example 5 is placed in the above-mentioned reactor, and reacted for 24 hours at 130° C., and after cooling, the white precipitate is filtered out, and the filter cake is used After dissolving 10% NaOH solution, extract it with 300ml ethyl acetate. After separating the organic phase, use concentrated hydrochloric acid to precipitate all the products in the aqueous phase, filter, wash, and vacuum-dry to obtain off-white target products 2, 3, 4, 161.5 grams of 5-tetrafluorobenzoic acid. Melting point: 88-88.6°C, analyzed by liquid chromatography, the content is 99%, and the yield is 85%;

[MS:C ₇ H ₂ F ₄ O ₂ ,M/e(%),194(76.626)[M+],195(6.642)[M++1],177(100)[M+-OH],149( 56.72)[M+-COOH], 45(19.530)[M+-C ₆ HF ₄ ];

IR(cm ^-1 ):3400,1705,1515,1480,1395,1100,1040,900,740,710,695;

F content (measured value): 39.03%, (theoretical value): 39.17%.

Example 9

The operation process is the same as in Example 8, with 5000ml of sulfuric acid (35%) replacing hydrobromic acid, reacting for 30 hours at 130°C, and extracting the reaction solution with 250ml of methyl chloride to obtain off-white target product 2,3,4,5-tetra Fluorobenzoic acid 178.4 grams. Yield: 92%, melting point: 87.8-88.4°C, content: 98.5% (liquid chromatography), F content (measured value): 39.0%, (theoretical value): 39.17%.

Example 10

The operation process is the same as in Example 2, adding 1 gram of cetyltrimethylammonium bromide and 2 grams of PEG6000, and reacting for 10 hours. Through liquid chromatography analysis, the conversion rate of the raw material is 100%, and the formation rate of the product is 83%. , part of the fluoride is 6%, and the reactant is purified to obtain 228 grams of beige solid fluoride, the content is 97.0%, the part of the fluoride is 1.1%, and the yield is 55.5%.

Claims (2)

1. the preparation method of a 2,3,4,5 tetra fluoro benzoic acid, it is characterized in that: with 3,4,5,6-tetrachlorophthalic tetrachlorophthalic anhydrid and aniline are raw material, mainly carry out following reaction successively:

(1) condensation reaction: 3,4,5,6-tetrachlorophthalic tetrachlorophthalic anhydrid and aniline carry out condensation reaction in polar organic solvent, and reaction formula is:

The processing condition of reaction are:

Under reflux temperature, reacted 6～10 hours, 3,4,5, the mol ratio of 6-tetrachlorophthalic tetrachlorophthalic anhydrid and aniline is 1: 1～1.15; Said polar organic solvent is an acetate Huo diox;

(2) fluoridation: in aprotic polar solvent, condensation product and Potassium monofluoride carry out fluoridation, and reaction formula is:

The processing condition of reaction are:

140～155 ℃ of down reactions 7～15 hours, said aprotic polar solvent is tetramethylene sulfone, dimethyl sulfoxide (DMSO), N, a kind of in N '-dimethyl formamide or the N,N-dimethylacetamide;

(3) ring-opening reaction: with fluorochemical and alkaline solution reaction, use acid out again, its reaction formula is:

The processing condition of reaction are:

Said alkali is a kind of in potassium hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, saleratus or the sodium bicarbonate; Said acid is a kind of in hydrochloric acid, the sulfuric acid; Temperature of reaction is 50～100 ℃:

(4) decarboxylic reaction: place solvent to carry out decarboxylic reaction the ring-opening product of step (3) gained, its reaction formula is:

The processing condition of reaction are:

Temperature of reaction is 80～150 ℃, and the reaction times is 1～5 hour, and the add-on of solvent is 5～10 times of opened loop compound weight; Said solvent is positive Tributylamine, triethylamine, positive trioctylamine, N, one or more in N '-dimethyl formamide, N-methyl arsenic pyrrolidone, the dimethyl sulfoxide (DMSO);

(5) hydrolysis reaction: place acidic aqueous solution to be hydrolyzed decarboxylate, collect resultant from reaction solution, its reaction formula is:

The processing condition of reaction are:

Temperature of reaction is 80～150 ℃, and said acidic solution is a kind of in sulfuric acid, hydrochloric acid or the Hydrogen bromide, and the reaction times is 15～25 hours.

2. the method for claim 1, it is characterized in that: in fluorination reaction process, add phase-transfer catalyst, said phase-transfer catalyst is one or more among tetramethyl ammonium chloride, Tetrabutyl amonium bromide, cetyl trimethylammonium bromide, 4-phenyl phosphonium bromide, tributyl phenyl phosphonium bromide, the PEG6000, and addition is 0.6% of a raw material weight.