JPH1067706A - Production of 2,4,5-trifluoro-3-iodobenzoic acid and its ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a 2,4,5-trifluoro-3-iodobenzoic acid and its ester which are useful as a material for 2,4,5-trifluoro-3-trifluoromethyl benzoic acids used as a starting material for production of antimicrobial and antiviral agents, easily and at a high yield. SOLUTION: This 2,4,5-trifluoro-3-iodobenzoic acid of formula I (R is an alkyl, cycloalkyl or aralkyl) is produced by making a 2,4,5-trifluoroiodobenzoic acid of formula II with a N-iodosuccinimide of formula III in the presence of trifluoromethane sulfonic acid. Furthermore, a 2,4,5-trifluoro-3-iodobenzoic ester of formula IV is obtained by reaction of a reactant mixture that contains a compound of formula I with an alcohol of the formula of R-OH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof. 2,4,5-trifluoro-
3-Iodobenzoic acid and its esters are, for example,
It is a raw material of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid useful as a starting material of a quinolone carboxylic acid compound useful as an antibacterial agent and an antiviral agent. (Japanese Unexamined Patent Publication No. Sho 64-66180, WO 96/0
No. 2512).

[0002]

2. Description of the Related Art Conventional 2,4,5-trifluoro-3-
Examples of the method for producing iodobenzoic acids and esters thereof include the following method using the Sandmeyer reaction of 3-amino-2,4,5-trifluorobenzoic acids. (1) JP-A-3-95179 discloses 3-amino-
A method for producing 2,4,5-trifluoro-3-iodobenzoic acid using 2,4,5-trifluorobenzoic acid, cuprous iodide and tert-butyl nitrite is disclosed. ing.

(2) JP-A-63-88157 and JP-A-6-25125 disclose 3-amino-2,
A method for producing 2,4-dichloro-5-fluoro-3-iodobenzoic acid from 4-dichloro-5-fluorobenzoic acid by reacting it with hydrochloric acid, sodium nitrite and potassium iodide is disclosed. However, the aforementioned method (1),
In (2), the yield is low and 3-amino-
This method was not industrially satisfactory in that a multi-step process was required to obtain 2,4,5-trifluorobenzoic acid and its esters.

Therefore, any of the known production methods (1) and (2) is unsatisfactory as a method for obtaining 2,4,5-trifluoro-3-iodobenzoic acid and its esters.

A method of obtaining an iodine compound by reacting an aromatic compound with N-iodosuccinimide in the presence of trifluoromethanesulfonic acid is known (J. Org. Che).
m. 1993, 58, 3194; Che
m. Res. , Synop. , 1977, p. 215). However, there is no report on a compound having a carboxyl group as an aromatic substituent. Further, when reacting these aromatic derivatives, the place where they react, that is, regioselectivity and sequential reaction selectivity are problematic, and the selectivity greatly changes depending on the aromatic derivative to be reacted.

The present inventors have conducted intensive studies on the applicability of this reaction to 1,3,4-trifluorobenzene derivatives, and as a result, the 2,4,5-trifluorobenzoic acid derivative selectively selected iodine at the 3-position. The inventors have found that the compound can be introduced, and have reached the present invention. In the present invention, it has also been found that the use of an alcohol in the esterification reaction after the reaction facilitates the esterification reaction, and is convenient for isolation and purification.

[0007]

SUMMARY OF THE INVENTION The present invention provides a process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof easily and in high yield as an industrial production process. The purpose is to provide.

[0008]

SUMMARY OF THE INVENTION The first aspect of the present invention is as follows.
A method for producing 2,4,5-trifluoro-3-iodobenzoic acid, comprising reacting 4,5-trifluorobenzoic acid with N-iodosuccinimide in the presence of trifluoromethanesulfonic acid. The second of the present invention is 2,
4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid, and the reaction mixture is reacted with a compound of the formula (I)

[0009]

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Wherein R represents an alkyl group, a cycloalkyl group or an aralkyl group, wherein the compound is reacted with an alcohol represented by the general formula (II):

[0011]

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Wherein R represents the same meaning as described above, and a process for producing 2,4,5-trifluoro-3-iodobenzoic acid esters represented by the formula:

A third aspect of the present invention relates to the above-mentioned production method, wherein the alcohol is an alkyl alcohol having 1 to 4 carbon atoms.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides, for example, the following reaction scheme (1):

[0015]

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And the reaction formula (2)

[0017]

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It can be represented by an esterification reaction represented by

The iodination reaction of the present invention is carried out by reacting 2,4,5-trifluorobenzoic acid with N-iodosuccinimide in the presence of trifluoromethanesulfonic acid.
In this step, 4,5-trifluoro-3-iodobenzoic acid is obtained.

The 2,4,5-trifluorobenzoic acid, trifluoromethanesulfonic acid, and N-iodosuccinimide used in the iodination reaction of the present invention are commercially available.

The molar ratio of trifluoromethanesulfonic acid used in the iodination reaction of the present invention is 2, 4, 5
-1 to 20 moles per mole of trifluorobenzoic acid
It is in the molar range, preferably 2-10 mol.

The N used in the iodination reaction of the present invention
The molar ratio of -iodosuccinimide is usually in the range of 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of 2,4,5-trifluorobenzoic acid.

No solvent other than trifluoromethanesulfonic acid is used in the iodination reaction of the present invention. When this reaction is diluted with another solvent, the reaction does not proceed or becomes extremely slow.

The iodination reaction of the present invention can be carried out at a reaction temperature of usually 0 ° C. to 200 ° C., preferably from room temperature to 100 ° C. In the iodination reaction of the present invention, the reaction time greatly depends on the reaction temperature,
The range is 0.5 to 20 hours. The reaction pressure of the esterification reaction of the present invention is usually carried out at atmospheric pressure, but under reduced pressure,
The reaction can be performed under pressure.

The iodination reaction of the present invention is carried out by the same procedure as that of a usual organic reaction, except that the iodination reaction is carried out with particular attention to the incorporation of water.

The iodination reaction of the present invention,
The reaction mixture (1) containing 2,4,5-trifluoro-3-iodobenzoic acid was 2,4,5-trifluoro-3-
Without separation of iodobenzoic acid, it can be used in the following esterification reaction, but after the post-treatment operations such as neutralization, concentration and extraction as in the ordinary reaction, recrystallization, column purification, etc. It can be used even if separated.

In the esterification reaction of the present invention, the 2,4,5-trifluoro-3-iodobenzoic acid obtained in the above-mentioned iodination reaction is reacted with alcohol to give 2,4,5- This is a step of obtaining trifluoro-3-iodobenzoate.

In the esterification reaction of the present invention, usually, the reaction mixture (1) containing 2,4,5-trifluoro-3-iodobenzoic acid obtained by the above-mentioned iodination reaction is directly used. , 2,4,5-trifluoro-3-iodobenzoic acid may be used after separation.

In the esterification reaction of the present invention, when alcohols are generally injected into a trifluoromethanesulfonic acid solution, heat is generated. Therefore, a diluted solution obtained by diluting the reaction mixture (1) with a diluting solvent is dropped into the alcohol. A method is recommended. Such a diluting solvent is usually methylene chloride,
Organic chlorine solvents such as chloroform and dichloroethane, and aromatic solvents such as benzene, toluene and xylene are preferred.

The amount of the diluting solvent used is preferably 0.2 to 10 times the volume of the trifluoromethanesulfonic acid used in the iodination reaction.

R represented by the alcohol used in the esterification reaction of the present invention is, for example, a linear or branched saturated alkyl group having 1 to 10 carbon atoms, a linear or branched saturated alkyl group having 2 to 10 carbon atoms. Examples thereof include a branched unsaturated alkyl group, a cycloalkyl group having 3 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms, and preferably a linear or branched alkyl having 1 to 10 carbon atoms. A linear or branched unsaturated alkyl group having 3 to 4 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, a benzyl group, a cinnamyl group, and more preferably methyl, ethyl, propyl, or isopropyl. , Butyl, isobutyl, sec-butyl and tert-butyl.

Such an alcohol having R as a substituent
Specific examples of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol,
Butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, caprylic alcohol , Nonyl alcohol, decyl alcohol
Linear or branched saturated alkyl alcohols having 1 to 10 carbon atoms, such as allyl alcohol, crotyl alcohol
Alkyl alcohols such as cyclopropyl, propargyl alcohol, alicyclic alcohols such as cyclopentyl alcohol and cyclohexyl alcohol, aromatic alcohols such as benzyl alcohol and cinnamyl alcohol. Are preferred, and straight-chain or branched saturated alkyl alcohols having 1 to 10 carbon atoms are more preferred.
Particularly preferred are ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol and tert-butyl alcohol.

The molar ratio of the alcohol used in the esterification reaction of the present invention is usually in the range of 1 to 100 mol, preferably 5 to 1 mol of the reacted 2,4,5-trifluorobenzoic acid. ５０50 mol.

The reaction temperature of the esterification reaction of the present invention can be carried out usually from -40 ° C. to the boiling point of the alcohol used. Addition of trifluoromethanesulfonic acid to alcohols generally generates a considerable amount of heat. Therefore, it is more preferable to cool the mixture to 0 ° C. or less at first, and then heat the mixture to room temperature or near the boiling point of the alcohol to be used. The reaction time of the esterification reaction of the present invention varies depending on the reaction temperature, the amount of trifluoromethanesulfonic acid, and the amount of alcohol,
Usually ends in the range of 0.5 to 20 hours.

The reaction pressure of the esterification reaction of the present invention is usually carried out under atmospheric pressure, but the reaction can be carried out under reduced pressure or under increased pressure.

The isolation of the product from the reaction mixture (2) obtained by the esterification reaction of the present invention is carried out by post-treatment operations such as neutralization, concentration and extraction, followed by distillation, A sufficiently pure target product can be obtained by a method such as column purification.

Since iodine may be released during the esterification reaction, it is preferable to remove iodine from the reaction system with sodium thiosulfate or the like during the post-treatment.

The 2,4,5-trifluoro-3-iodobenzoic acid esters thus obtained include, for example, methyl 2,4,5-trifluoro-3-iodobenzoate, Ethyl 2,4,5-trifluoro-3-iodobenzoate, n-propyl 2,4,5-trifluoro-3-iodobenzoate, 2,4,5-trifluoro-3-iodo -I-propyl 2-benzoate, n-butyl 2,4,5-trifluoro-3-iodobenzoate, i-butyl 2,4,5-trifluoro-3-iodobenzoate , 2,
4,5-trifluoro-3-iodobenzoic acid-s-butyl, 2,4,5-trifluoro-3-iodobenzoic acid-
Examples thereof include alkyl esters of 2,4,5-trifluoro-3-iodobenzoic acid having 1 to 4 carbon atoms, such as t-butyl.

[0039]

According to the present invention, by reacting 2,4,5-trifluorobenzoic acid with N-iodosuccinimide in the presence of trifluoromethanesulfonic acid,
2,4,5-Trifluoro-3-iodobenzoic acid can be easily obtained in high yield, and 2,4,5-trifluoro-3-iodobenzoic acid and alcohol And the esterification reaction proceeds, and 2,4,5-trifluoro-3-iodobenzoic acid esters suitable for isolation and purification can be obtained.

[0040]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the present invention. The analysis conditions of a liquid chromatograph (hereinafter abbreviated as HPLC) and a gas chromatograph (hereinafter abbreviated as GC) in Examples, Reference Examples and Comparative Examples are as follows.

HPLC analysis conditions Column: TSK-gel ODS-80TM (trade name:
4.6 mmφ × 250 mm Temperature; 40 ° C. Eluent; acetonitrile: water: acetic acid = 50: 50: 1
(V / v) Flow rate: 1 ml / min Detection wavelength: 275 nm Internal standard substance: 1-phenyl-1-butanone

GC analysis conditions Column: PEG-20M (trade name: manufactured by GL Science Co., Ltd.) Carrier: Uniport HP (trade name: manufactured by GL Science Co., Ltd.) (60/80 mesh), 3.5 mmφ × 2 m column Temperature: 100 to 200 ° C (7.5 ° C / min) Injection section temperature: 220 ° C Detector temperature; 220 ° C (FID) Carrier gas; Nitrogen

Example 1 56.14 g of trifluoromethanesulfonic acid (0.37
5 mol) and 2,4,5-trifluorobenzoic acid 9.4
The mixture (1) with 1 g (0.053 mol) was cooled to −5 ° C., and 20.44 g (0.9%) of N-iodosuccinimide was added.
1 mol) was added to obtain a mixture (2). The obtained mixture (2) was stirred at room temperature for 1 hour, and further reacted at 40 to 45 ° C. for 6 hours.

After completion of the reaction, 20 ml of methylene chloride was added to the obtained reaction mixture (1).
Was dropped into 45 ml of cooled ethanol.
Thereafter, the mixture was reacted by stirring at 45 ° C. for 4 hours. 100 ml of hexane and 30% were added to the obtained reaction mixture (2).
38 ml of an aqueous sodium hydroxide solution was added to adjust the pH to around 7. Then a saturated aqueous solution of sodium thiosulfate 8
0 ml was added. The hexane layer was separated, washed with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under reduced pressure to obtain a fraction having a boiling point of 104 ° C./133 Pa.
Ethyl 4,5-trifluoro-3-iodobenzoate 1
1.07 g [purity 97.5% (HPLC analysis);
0.0357 mol]. (Yield 67% based on 2,4,5-trifluorobenzoic acid).

Example 2 1552 g of trifluoromethanesulfonic acid (7.23 m
ol) and 252 g of 2,4,5-trifluorobenzoic acid
(1.43 mol) was cooled to −5 ° C., and 483 g of N-iodosuccinimide (2.15 mol) was obtained.
l) was added to obtain a mixture (2). After stirring the obtained mixture (2) at room temperature for 2 hours, the mixture was further heated at 45 to 47 ° C for 3 hours.
The mixture was stirred for an hour to react.

After completion of the reaction, 543 ml of methylene chloride was added to the obtained reaction mixture (1).
The solution was added dropwise to 1215 ml of ethanol cooled to ° C. Thereafter, the mixture was stirred and reacted at 55 to 56 ° C. for 4.5 hours. 1930 ml of hexane and 960 ml of a 30% aqueous sodium hydroxide solution were added to the resulting reaction mixture (2) to adjust the pH to 6.5. Then, 2002 ml of a saturated aqueous solution of sodium thiosulfate was added.
The hexane layer was separated, and the aqueous layer was extracted with 1700 ml of hexane. The combined hexane layer was washed with 1140 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue obtained by performing the above operation three times was distilled under reduced pressure, and the boiling point was 105 to 10.
1087 g of ethyl 2,4,5-trifluoro-3-iodobenzoate was obtained as a fraction at 8 ° C./187 to 200 Pa [purity 97.6% (HPLC analysis), 3.215 mo
l]. (Yield 74.94% based on 2,4,5-trifluorobenzoic acid).

Example 3 1.64 g (10.9 m) of trifluoromethanesulfonic acid
mol) and 2,4,5-trifluorobenzoic acid 383.
The mixture (1) with 8 mg (2.18 mmol) was treated with 0 to-
Cool to 5 ° C. and 490.4 mg of N-iodosuccinimide
(2.18 mmol) was added to obtain a mixture (2). The obtained mixture (2) was reacted by stirring at room temperature for 6 hours.

After completion of the reaction, 5 ml of water and 8 ml of ethyl acetate were added to the obtained reaction mixture.
The pH was adjusted to 5.0 with 0% aqueous NaOH. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated. Hexane (5 ml) was added to the concentrated residue, and the precipitated colorless crystals (succinimide) were filtered. The filtrate was concentrated to give a solid 2
46 mg were obtained. When this solid was analyzed by HPLC, the raw material 2,4,5-trifluorobenzoic acid was 24%, 2,2
It contained 76% of 4,5-trifluoro-3-iodobenzoic acid.

Reference Example 1 2,4,5-trifluoro-3
-Production of ethyl trifluoromethylbenzoate 500 g (2.6 mol) of methyl fluorosulfonyldifluoroacetate was added to a mixture (1) of 12.28 g (65 mmol) of cuprous iodide and 2860 ml of dimethylformamide.
1) and 441.4 g of ethyl 2,4,5-trifluoro-3-iodobenzoate (purity 97.3%, 1.3 mol)
Was heated to 80 to 86 ° C., and the mixture was stirred and reacted for 7 hours.

After completion of the reaction, the obtained reaction mixture was mixed with 3250 ml of hexane and a saturated aqueous solution of sodium hydrogencarbonate 3 times.
The mixture was dropped into 250 ml of the mixture (2). The hexane layer was separated and dried over anhydrous magnesium sulfate. Hexane was concentrated under reduced pressure and 642 g of the residue was added to 2,4,
It was found by GC analysis that 278.4 g (1.02 mol) of ethyl 5-trifluoro-3-trifluoromethylbenzoate was contained.

The same operation was performed twice, and the combined concentrate was distilled under reduced pressure with a 30 cm Uttmer rectifier. A fraction having a boiling point of 74-79 ° C./0.39 kPa was collected. Acquisition amount 567 g, purity 92.2%, 1.927 mol,
(Acquisition yield based on ethyl 2,4,5-trifluoro-3-iodobenzoate 74.1%).

Reference Example 2: 2,4,5-trifluoro-3
Production of -trifluoromethylbenzoic acid 2,4,5-trifluoro-3 obtained in Example 2 above
-567 g of ethyl trifluoromethylbenzoate (purity 9
A mixture (1) of 2.2%, 1.927 mol), 1580 ml of acetic acid, 316 ml of water, and 733 g of p-toluenesulfonic acid monohydrate was reacted by heating under reflux with stirring for 8 hours. During this time, 250 ml of the solvent was distilled off from the reaction system, and a mixture (2) of 280 ml of acetic acid and 42 ml of water was added twice to the reaction system.

After completion of the reaction, water 19 was added to the obtained reaction mixture.
30 ml was added and the mixture was cooled, and 3.85 liter of toluene was added. The layers were separated and the aqueous layer was further diluted with 1.93 of toluene.
Extracted three times with liters. The combined toluene layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and 1.9 liter of hexane was added to the concentrated residue and heated. The obtained homogeneous solution was cooled to 0 to -6.5 ° C to precipitate crystals. The obtained crystals were filtered, washed with hexane, and air-dried to give 2,4,5.
-Trifluoro-3-trifluoromethylbenzoic acid 40
1 g (1.64 mol, purity 99.8%) was obtained.

Comparative Example 1 Reaction of 2,4,5-trifluorobromobenzene 1.54 g of trifluoromethanesulfonic acid (10.24
mmol) and 432.2 mg (2.05 mmol) of 2,4,5-trifluorobromobenzene (1)
Is cooled to 0-5 ° C, and N-iodosuccinimide 46 is cooled.
0.9 mg (2.05 mol) was added to obtain a mixture (2). The obtained mixture (2) was reacted by stirring at room temperature for 6 hours.

After the completion of the reaction, the obtained reaction mixture was washed with HP
When analyzed by LC, the raw materials 2,4,5-trifluorobromobenzene were 15%, 3-bromo-2,5,6-trifluoroiodobenzene was 20%, 2-bromo-3,
5,6-trifluoro-1,4-diiodobenzene is 6
1% was produced, and there was no selectivity for monobromination.

Comparative Example 2 Reaction of 2,4,5-trifluorobenzonitrile 3.812 g of trifluoromethanesulfonic acid (25.4
mmol) and 798.1 mg (5.08 mmol) of 2,4,5-trifluorobenzonitrile (1)
Is cooled to 0-5 ° C and N-iodosuccinimide 114 is added.
3 mg (5.08 mol) was added to obtain a mixture (2). The obtained mixture (2) was stirred and reacted at room temperature for 4 hours.

After the completion of the reaction, the obtained reaction mixture was washed with HP
When analyzed by LC, the starting material 2,4,5-trifluorobenzonitrile was not reacted.

Claims (3)

[Claims] (1) 2,4,5-trifluorobenzoic acid and N-
A method for producing 2,4,5-trifluoro-3-iodobenzoic acid, comprising reacting iodosuccinimide with trifluoromethanesulfonic acid. (2) 2,4,5-trifluorobenzoic acid and N-
Iodosuccinimide is reacted with trifluoromethanesulfonic acid in the presence of trifluoromethanesulfonic acid, and then reacted with a reaction mixture of the general formula (I). (Wherein R represents an alkyl group, a cycloalkyl group or an aralkyl group), characterized by reacting with an alcohol represented by the general formula (II): (Wherein, R has the same meaning as described above),
A method for producing 4,5-trifluoro-3-iodobenzoic acid esters. 3. The method according to claim 2, wherein said alcohols are alkyl alcohols having 1 to 4 carbon atoms. [0001]