JPH0696545B2 - Process for producing 3,5,6-trifluoro-4-hydroxyphthalic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] (Field of Industrial Application) The present invention relates to a method for producing 3,5,6-trifluoro-4-hydroxyphthalic acid, more specifically, a quinolonecarboxylic acid-based compound. The present invention relates to a method for producing 3,5,6-trifluoro-4-hydroxyphthalic acid, which is useful as a raw material for producing antibacterial agents.

(Conventional Technology and Problems Thereof) Conventional synthetic antibacterial agents have the following formula: Nalidixic acid represented by the following formula: Pipemidic acid represented by the following formula: And the following formula: Norfloxacin and the like shown in have been developed and used for the treatment of various infectious diseases.

Further, as improving various properties of the antibacterial agent,
A quinolonecarboxylic acid type antibacterial agent having an oxygen atom at the 8-position has been developed (for example, Japanese Patent Publication No. 61-11955).

On the other hand, 2,4,5-trifluoro-3-hydroxybenzoic acid obtained by decarboxylation of 3,5,6-trifluoro-4-hydroxyphthalic acid is a quinolonecarboxylic acid derivative having an oxygen atom at the 8-position. Is useful as a synthetic intermediate, and has already been applied for a patent by the applicant of the present application as Japanese Patent Application No. 61-287763.

The manufacturing method of 3,5,6-trifluoro-4-hydroxyphthalic acid used as a manufacturing raw material here is Osadchii, SA,
Barkhash, VA; Zh.Org.khim., 6 (8), 1636 (1970) (Chemical Abstract, 73 , 109544p). According to this document, tetrafluorophthalic anhydride and pentafluorophenylacetic acid are reacted in triethylamine-acetic anhydride to give triethylamine of 5-hydroxy-4,6,7-trifluoro-3- (pentafluorobenzylidene) phthalide. Salt and 3,5,6-trifluoro-4-
A triethylamine salt of hydroxyphthalic anhydride is obtained. The by-product 3,5,6-trifluoro-4-hydroxyphthalic acid triethylamine salt was treated with an acid in an aqueous solution to obtain 3,5,6-trifluoro-4-hydroxyphthalic acid. There is.

However, this method has the following three additional reaction products:
The product is 5,6-trifluoro-4-hydroxyphthalic acid, and the yield is low and the reaction is complicated.

In addition, Ishikawa, Suzuki, Tanabe et al., Journal of the Chemical Society of Japan, page 200 (1976
(Year) describes a method for synthesizing 3,5,6-trifluoro-4-methoxyphthalic acid dimethyl ester. From this compound, a known method (for example, hydrolysis with an alkaline aqueous solution)
3,5,6-trifluoro-4-methoxyphthalic acid, and then reacted with a strong acid such as hydrobromic acid)
It is possible to obtain 5,6-trifluoro-4-hydroxyphthalic acid.

However, in this method, tetrafluorophthalic acid is once converted into a methyl ester and then reacted to obtain 3,5,6-trifluoro-4-methoxyphthalic acid dimethyl ester. In order to obtain 6-trifluoro-4-hydroxyphthalic acid, it is necessary to remove three methyl groups, which is not a very rational method.

Under the circumstances, the inventors of the present invention have earnestly studied the industrial production method of 3,5,6-trifluoro-4-hydroxyphthalic acid, and as a result, have completed the present invention.

[Structure of Invention] (Means and Actions for Solving Problems) The method for producing 3,5,6-trifluoro-4-hydroxyphthalic acid of the present invention is 3,4,5,6-tetrafluorophthalic acid. The acid and the alkaline compound in water or an aqueous solvent, 70-12
It is characterized by reacting at 0 ° C. and then treating with an acidic aqueous solution.

Examples of the alkaline compound used in the present invention include alkali metal hydroxides such as lithium hydroxide,
Sodium hydroxide, potassium hydroxide and cesium hydroxide; hydrogen carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate; carbonates such as potassium carbonate and sodium carbonate; and the like. It is industrially preferable to use sodium hydroxide or potassium hydroxide. The amount of the alkaline compound is theoretically required to be 4 mol or more per 1 mol of tetrafluorophthalic acid. The concentration of the alkaline compound in the reaction solution is preferably within the range of 5 to 40% by weight.

This reaction is carried out in water or an aqueous solvent, and the amount of the solvent is preferably in the range of 3 to 100 times by weight based on tetrafluorophthalic acid. As the aqueous solvent, water and a mixture with a solvent which dissolves in water at an arbitrary ratio and does not react under alkaline conditions can be used. Specific examples of the aqueous solvent include a mixture of alcohols such as methanol and ethanol, ethers such as dioxane, and water. The water content is preferably 10% or more. The reaction temperature is 70 to 120 ° C, preferably 80 to 95 ° C. The reaction time depends on the reaction temperature, but is usually completed in 0.5 to 20 hours.

When the reaction temperature is lower than 70 ° C, the reaction rate is remarkably reduced, and when the temperature is higher than 120 ° C, the production of by-products is increased, and the target 3,5,6-trifluoro-4-hydroxy is obtained. The yield of the alkali salt of phthalic acid decreases.

An acidic aqueous solution is added to the aqueous solution of the salt of 3,5,6-trifluoro-4-hydroxyphthalic acid thus produced so as to have a pH of 1 to 4, to produce 3,5,6-trifluoro-4-hydroxyphthalic acid. Let Any acid can be used as long as it can neutralize the alkalinity, and for example, an aqueous solution of sulfuric acid or hydrochloric acid can be used. After acid precipitation, the resulting 3,5,6-trifluoro-4-hydroxyphthalic acid was extracted into an organic layer using a solvent such as ether or ethyl acetate, and after liquid separation, evaporation to dryness was performed. The target substance can be isolated. The 3,5,6-trifluoro-4-hydroxyphthalic acid thus obtained is a white, highly pure substance.

(Examples) Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.

Example 1 2 g (30.7 mmol) of 86% potassium hydroxide was dissolved in 10 ml of water,
Heated to 90 ° C. While stirring, 1.0 g (4.20 mmol) of 3,4,5,6-tetrafluorophthalic acid was gradually added to this solution at 90 ° C.
And reacted for 9 hours. After cooling, concentrated hydrochloric acid was added to this reaction aqueous solution to adjust the pH to 2, to obtain 3,5,6-trifluoro-4-hydroxyphthalic acid. To this, 15 ml of ether was added, and 3,5,6-trifluoro-4-hydroxyphthalic acid was extracted into the organic layer. This extraction operation was repeated 5 times, and the obtained ether layer was dried over anhydrous sodium sulfate, evaporated to dryness and washed with chloroform to give white 3,5,6-trifluoro-4.
-1.05 g of hydroxyphthalic acid monohydrate was obtained. Yield 98%.
Melting point 171-172 ° C. Carbon 13 NMR (in CD ₃ OD) δppm111.
8 (m, C-1), 120.0 (m, C-2), 140.2 (m, C-4), 143.5 (m,
¹ J _CF 249.1Hz, C-5), 147.1 (m, ¹ J _CF 250.6Hz, C-3), 147.9
(M, ¹ J _CF 253.5Hz, C-6), 165.4, 166.4 (m, COOH). Mass Spec M ⁺ 236.

Reference example 3,5,6-trifluoro-4-hydroxyphthalic acid (II)
Using the starting material as a starting material, the antimicrobial agent ofloxacin (III) (9)
-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6 -Carboxylic acid), which is an important intermediate in the synthesis of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1, 4] Ethyl (IV) benzoxazine-6-carboxylate was synthesized according to the following reaction formula.

Step 1 0.47 g of 3,5,6-trifluoro-4-hydroxyphthalic acid and 10 ml of water were placed in a sealed tube, which was replaced with nitrogen and heated at 140 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to precipitate crystals. The crystals are filtered and washed (chloroform
5 ml) and then dried. 0.35 g of 2,4,5-trifluoro-3-hydroxybenzoic acid was obtained as colorless crystals. Yield 90
%. Melting point 144-146 ° C. Proton NMR spectrum (in CD ₃ O
D) δppm 7.25 (m, 1H, ³ J _HF 10.74Hz, ⁴ J _HF 8.30Hz, ⁴ J _HF 5.86
Hz) Aromatic proton, 4.94 (bs, 1H) hydroxy proton. Mass Spec M ⁺ 192.

Step 2 2,4,5-Trifluoro-3-hydroxybenzoic acid (I) 1
Acetic anhydride (40 ml) was added to 2.6 g (0.066 mol), and the mixture was heated under reflux for 15 hours. The reaction mixture was poured into ice water, extracted with chloroform, the chloroform layer was washed with water, dried and concentrated under reduced pressure, and the residue was washed with n-hexane,
3-acetoxy-2,4,5-trifluorobenzoic acid (V)
6.10 g was obtained as a colorless powder.

Mass spectrum (CI): m / e 235 (M ⁺ +1), 217 (M ⁺ -OH), 175
(M ⁺ -CH ₃ COO) Step 3-7 3-acetoxy-2,4,5-trifluorobenzoic acid (V)
6.10 g (0.026 mol) was dissolved in 200 ml of benzene, 15 ml of thionyl chloride was added, and the mixture was heated under reflux for 4 hours. After the reaction, benzene and excess thionyl chloride were completely distilled off under reduced pressure, and 3-
Acetoxy-2,4,5-trifluorobenzoic acid chloride (V
I) got.

On the other hand, 3.17 g (0.028 mol) of magnesium ethoxide and 4.30 g (0.027 mol) of diethyl malonate were heated under reflux in 100 ml of anhydrous diethyl ether for 3 hours to obtain a diethyl ether suspension of diethyl ethoxymagnesium malonate. . To this, a solution of the acid chloride in 50 ml of anhydrous diethyl ether was added dropwise with stirring at room temperature, and after completion of the addition, the mixture was further stirred at room temperature for 1 hour. After completion of the reaction, 1N hydrochloric acid was added to acidify and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure to give 3-acetoxy-
Diethyl 2,4,5-trifluorobenzoylmalonate (VI
I) 10.39 g was obtained as a yellow oil.

The yellow oil was then dissolved in 120 ml dioxane,
p-toluenesulfonic acid monohydrate 4.90 g (0.026 mol)
Was added and the mixture was heated under reflux for 15 hours. After completion of the reaction, dioxane was distilled off under reduced pressure, 100 ml of water and 2.15 g (0.026 mol) of sodium hydrogencarbonate were added to the residue, and this mixture was extracted with chloroform. After washing the chloroform layer with water and drying,
Evaporation under reduced pressure gave 7.64 g of ethyl 3-acetoxy-2,4,5-trifluorobenzoylacetate (VIII) as a red oil.

Ethyl 3-acetoxy-2,4,5-trifluorobenzoylacetate (VIII) thus obtained 7.64 g (0.025 mol)
To the mixture, add 20 ml of acetic anhydride and 6 ml of ethyl orthoformate, and
After heating under reflux for an hour, the mixture was concentrated under reduced pressure. Dichloromethane residue
Dissolved in 50 ml, DL-2-aminopropanol 1.91 g (0.026
Mol) was added and the mixture was allowed to stand at room temperature overnight. Dichloromethane was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 1: 1 mixture) to give 2- (3-acetoxy-2,4,5-trifluorobenzoyl) -3. -(2-hydroxy-1-methylethyl)
Obtained 4.37 g of ethyl aminoacrylate (X) as a pale yellow oil.

Mass spectrometry: m / e 389 (M ⁺ ), 358 (M ⁺ −CH ₂ OH), 43 (+ COC
H ₃ ) Step 8 2- (3-acetoxy-2,4,5-obtained as described above
Trifluorobenzoyl) -3- (2-hydroxy-1)
-Methylethyl) aminoacrylate (X) 4.30 g
(0.011 mol) dissolved in 30 ml of dimethylformamide,
Add potassium fluoride 1.92g (0.033mol), 140-150
The mixture was stirred at ° C for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure,
Water was added to the residue and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried, and concentrated under reduced pressure.

The residue was then washed with ethanol and the crude crystals obtained were recrystallized from acetone to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2, 3-d
1.40 g of ethyl [IV] [1,4] benzoxazine-6-carboxylate (IV) was obtained as fine brown fine needle crystals.

Melting point: 255 to 256 ° C. Elemental analysis value (%): CH ₁₅ H ₁₃ F ₂ NO ₄ CHN theoretical value 58.25 4.24 4.53 measured value 58.09 4.14 4.24 [Effect of the invention] According to the present invention, a simple means is used. , High-purity 3,5,6-
Trifluoro-4-hydroxyphthalic acid can be obtained in high yield.

Claims (2)

[Claims] 1. 1,4,5,6-Tetrafluorophthalic acid and an alkaline compound in water or an aqueous solvent in an amount of 70 to 120
A method for producing 3,5,6-trifluoro-4-hydroxyphthalic acid, which comprises reacting at 0 ° C and then treating with an acidic aqueous solution. 2. The method according to claim 1, wherein the alkaline compound is an alkali metal hydroxide, hydrogen carbonate or carbonate.