JP3823385B2 - Process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof.
The aforementioned 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof are useful as starting materials for quinolone carboxylic acid compounds useful as antibacterial agents and antiviral agents, for example. , 5-trifluoro-3-trifluoromethylbenzoic acid. (Refer to Unexamined-Japanese-Patent No. 64-66180, WO96 / 02512).
[0002]
[Prior art]
As a conventional method for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof, for example, the Sandmeyer reaction of 3-amino-2,4,5-trifluorobenzoic acid is used. There are the following methods.
(1) In Japanese Patent Laid-Open No. 3-95179, 3-amino-2,4,5-trifluorobenzoic acid, cuprous iodide, and tertiary butyl nitrite are used. A method for producing trifluoro-3-iodobenzoic acid is disclosed.
[0003]
(2) In JP-A-63-88157 and JP-A-6-25125, 3-amino-2,4-dichloro-5-fluorobenzoic acid is reacted with hydrochloric acid, sodium nitrite and potassium iodide. A process for producing 2,4-dichloro-5-fluoro-3-iodobenzoic acid.
However, the above-mentioned methods (1) and (2) are both low in yield and require a multi-step process to obtain 3-amino-2,4,5-trifluorobenzoic acid and its esters. It was not an industrially satisfactory method.
[0004]
Therefore, both of the known production methods (1) and (2) were unsatisfactory as a method for obtaining 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof.
[0005]
A method for obtaining an iodine compound by reacting an aromatic compound with N-iodosuccinimide in the presence of trifluoromethanesulfonic acid is known (J. Org. Chem., 1993, 58, 3194, J. Chem. Res., Synop., 1977, page 215).
However, there is no report on a compound having a carboxyl group as an aromatic substituent. Further, when these aromatic derivatives are reacted, the place of reaction, that is, regioselectivity and sequential reaction selectivity are problems, and the selectivity varies greatly depending on the aromatic derivative to be reacted.
[0006]
As a result of intensive studies on the applicability of this reaction for the 1,3,4-trifluorobenzene derivative, the present inventors have found that the 2,4,5-trifluorobenzoic acid derivative can selectively introduce iodine into the 3-position. The present invention has been found.
In the present invention, it has also been found that the use of alcohol for the esterification reaction after the reaction facilitates the esterification reaction, which is convenient for isolation and purification.
[0007]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for producing 2,4,5-trifluoro-3-iodobenzoic acid and esters thereof easily and in high yield as an industrial production method.
[0008]
[Means for Solving the Problems]
The first of the present invention is
Production of 2,4,5-trifluoro-3-iodobenzoic acid characterized by reacting 2,4,5-trifluorobenzoic acid and N-iodosuccinimide in the presence of trifluoromethanesulfonic acid Regarding the method,
The second of the present invention is
2,4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid, and then the reaction mixture;
Formula (I)
[0009]
[Chemical 3]
[0010]
(Wherein R represents an alkyl group, a cycloalkyl group or an aralkyl group), and is reacted with an alcohol represented by:
Formula (II)
[0011]
[Formula 4]
[0012]
(Wherein R represents the same meaning as described above), 2,4,5-trifluoro-3-iodobenzoic acid esters,
[0013]
The third aspect of the present invention is
The said alcohol is related with the manufacturing method as described above which is a C1-C4 alkyl alcohol.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
The present invention is, for example, as shown below:
Reaction formula (1)
[0015]
[Chemical formula 5]
[0016]
And the reaction formula (2)
[0017]
[Chemical 6]
[0018]
It can represent with the esterification reaction represented by these.
[0019]
In the iodination reaction of the present invention, 2,4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid to produce 2,4,5-trifluoro-3-iodine. -A step of obtaining dobenzoic acid.
[0020]
2,4,5-trifluorobenzoic acid, trifluoromethanesulfonic acid and N-iodosuccinimide used in the iodination reaction of the present invention are commercially available.
[0021]
The molar ratio of the trifluoromethanesulfonic acid used in the iodination reaction of the present invention is usually in the range of 1 to 20 mol, preferably 2 to 10 mol, relative to 1 mol of 2,4,5-trifluorobenzoic acid. .
[0022]
The molar ratio of N-iodosuccinimide used in the iodination reaction of the present invention is usually in the range of 1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of 2,4,5-trifluorobenzoic acid. is there.
[0023]
In the iodination reaction of the present invention, no solvent other than trifluoromethanesulfonic acid is used.
When this reaction is diluted with another solvent, the reaction does not proceed or becomes extremely slow.
[0024]
In the iodination reaction of the present invention, the reaction temperature can usually be carried out in the range of 0 ° C. to 200 ° C., and preferably in the range of room temperature to 100 ° C.
In the iodination reaction of the present invention, the reaction time greatly depends on the reaction temperature, but is 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 pressure.
[0025]
The iodination reaction of the present invention is carried out in the same procedure as a normal organic reaction except that the iodination reaction is carried out with particular attention to water contamination.
[0026]
The reaction mixture (1) containing 2,4,5-trifluoro-3-iodobenzoic acid obtained by the iodination reaction of the present invention is 2,4,5-trifluoro-3-iodobenzoic acid. Can be used for the following esterification reactions without separation, but after post-treatment operations such as neutralization, concentration, extraction, etc., in the same manner as normal reactions, separation by recrystallization, column purification, etc. Can also be used.
[0027]
In the esterification reaction of the present invention, 2,4,5-trifluoro-3-iodobenzoic acid obtained by the iodination reaction and alcohol are reacted to produce 2,4,5-trifluoro- In this step, 3-iodobenzoate is obtained.
[0028]
The esterification reaction of the present invention directly uses a reaction mixture (1) containing 2,4,5-trifluoro-3-iodobenzoic acid, usually obtained by the iodination reaction. 4,5-trifluoro-3-iodobenzoic acid may be used after separation.
[0029]
In the esterification reaction of the present invention, when alcohols are usually injected into a trifluoromethanesulfonic acid solution, heat is generated. Therefore, a method in which a diluted solution obtained by diluting the reaction mixture (1) with a diluting solvent is dropped into the alcohol is recommended. Is done.
As such a diluting solvent, organic chlorine solvents such as methylene chloride, chloroform and dichloroethane, and aromatic solvents such as benzene, toluene and xylene are usually suitable.
[0030]
The amount of such a dilution solvent used is preferably 0.2 to 10 times the volume of 1 volume of trifluoromethanesulfonic acid used in the iodination reaction.
[0031]
Examples of R shown in the alcohol used in the esterification reaction of the present invention include, for example, a linear or branched saturated alkyl group having 1 to 10 carbon atoms, and a linear or branched structure having 2 to 10 carbon atoms. An unsaturated alkyl group, a cycloalkyl group having 3 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms, preferably a linear or branched alkyl group having 1 to 10 carbon atoms, carbon 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 or a cinnamyl group, and more preferably methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl.
[0032]
Specific examples of the alcohol having R as a substituent include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol. Carbon number such as benzene, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, capryl alcohol, nonyl alcohol, decyl alcohol 1-10 linear or branched saturated alkyl alcohols, unsaturated alkyl alcohols such as allyl alcohol, crotyl alcohol, propargyl alcohol, cyclopentyl alcohol, cyclohexyl alcohol, etc. Alicyclic alcohols, benzyl alcohol, cinnamyl alcohol, etc. Aromatic alcohols are preferred, linear or branched saturated alkyl alcohols having 1 to 10 carbon atoms are more preferred, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, Butyl alcohol, isobutyl alcohol, sec-butyl alcohol, and tert-butyl alcohol are particularly preferred.
[0033]
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 50 mol, relative to 1 mol of 2,4,5-trifluorobenzoic acid reacted. Range.
[0034]
The reaction temperature of the esterification reaction of the present invention can be usually carried out from -40 ° C to the boiling point of the alcohol used. When trifluoromethanesulfonic acid is added to alcohols, it usually generates a considerable amount of heat. Therefore, it is more preferable to first add it after cooling to 0 ° C. or lower, and then heat it to room temperature or near the boiling point of the alcohol 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, but is usually completed in the range of 0.5 to 20 hours.
[0035]
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 pressure.
[0036]
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, extraction, etc., and distillation, column purification, etc. A sufficiently pure target product can be obtained by this method.
[0037]
In addition, since iodine may be liberated during the esterification reaction, it is preferable to remove iodine from the reaction system with sodium thiosulfate or the like during the post-treatment operation.
[0038]
Examples of the 2,4,5-trifluoro-3-iodobenzoates thus obtained include methyl 2,4,5-trifluoro-3-iodobenzoate, 2,4,5- Ethyl 5-trifluoro-3-iodobenzoate, 2,4,5-trifluoro-3-iodobenzoate-n-propyl, 2,4,5-trifluoro-3-iodobenzoate Acid-i-propyl, 2,4,5-trifluoro-3-iodobenzoic acid-n-butyl, 2,4,5-trifluoro-3-iodobenzoic acid-i-butyl, 2, 2,4,5-trifluoro- such as 4,5-trifluoro-3-iodobenzoic acid-s-butyl, 2,4,5-trifluoro-3-iodobenzoic acid-t-butyl C1-C4 alkylester of 3-iodobenzoic acid is mentioned.
[0039]
【The invention's effect】
According to the present invention, 2,4,5-trifluorobenzoic acid and N-iodosuccinimide are reacted in the presence of trifluoromethanesulfonic acid to produce 2,4,5-trifluoro-3-iodo. Debenzoic acid can be easily obtained in a high yield, and the esterification reaction proceeds by reacting 2,4,5-trifluoro-3-iodobenzoic acid with alcohol, 2,4,5-trifluoro-3-iodobenzoic acid esters suitable for isolation and purification can be obtained.
[0040]
【Example】
The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples. The analysis conditions of the liquid chromatograph (hereinafter abbreviated as HPLC) and gas chromatograph (hereinafter abbreviated as GC) in the Examples, Reference Examples and Comparative Examples are as follows.
[0041]
[0042]
[0043]
Example 1
A mixture (1) of 56.14 g (0.375 mol) of trifluoromethanesulfonic acid and 9.41 g (0.053 mol) of 2,4,5-trifluorobenzoic acid was cooled to −5 ° C., and N-iodosuccinimide was obtained. 20.44 g (0.91 mol) was added to obtain a mixture (2). The obtained mixture (2) was stirred at room temperature for 1 hour, and further stirred at 40 to 45 ° C. for 6 hours to be reacted.
[0044]
After completion of the reaction, 20 ml of methylene chloride was added to the resulting reaction mixture (1), and this solution was dropped into 45 ml of ethanol cooled to 0 ° C. Thereafter, the reaction was allowed to stir at 45 ° C. for 4 hours.
To the obtained reaction mixture (2), 100 ml of hexane and 38 ml of 30% aqueous sodium hydroxide solution were added to adjust the pH to around 7. Then 80 ml of saturated aqueous sodium thiosulfate solution was added. The hexane layer was separated, washed with 50 ml of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue was distilled under reduced pressure to obtain 11.07 g of ethyl 2,4,5-trifluoro-3-iodobenzoate as a fraction having a boiling point of 104 ° C./133 Pa (purity 97.5% (HPLC analysis), 0 0.0357 mol]. (Yield 67% based on 2,4,5-trifluorobenzoic acid).
[0045]
Example 2
A mixture (1) of 1552 g (7.23 mol) of trifluoromethanesulfonic acid and 252 g (1.43 mol) of 2,4,5-trifluorobenzoic acid was cooled to −5 ° C., and 483 g of N-iodosuccinimide (2. 15 mol) was added to obtain a mixture (2). The obtained mixture (2) was stirred at room temperature for 2 hours, and further stirred at 45 to 47 ° C. for 3 hours to be reacted.
[0046]
After completion of the reaction, 543 ml of methylene chloride was added to the resulting reaction mixture (1), and this solution was dropped into 1215 ml of ethanol cooled to 0 ° C. Thereafter, the reaction was carried out by stirring at 55 to 56 ° C. for 4.5 hours.
To the obtained reaction mixture (2), 1930 ml of hexane and 960 ml of 30% aqueous sodium hydroxide solution were added to adjust the pH to 6.5. Then, 2002 ml of saturated aqueous sodium thiosulfate solution was added. The hexane layer was separated, and the aqueous layer was extracted with 1700 ml of hexane. The combined hexane layers were washed with 1140 ml of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated residue obtained by performing the above operations three times was distilled under reduced pressure to obtain 1087 g of ethyl 2,4,5-trifluoro-3-iodobenzoate as a fraction having a boiling point of 105 to 108 ° C./187 to 200 Pa. [Purity 97.6% (HPLC analysis), 3.215 mol]. (Yield 74.94% based on 2,4,5-trifluorobenzoic acid).
[0047]
Example 3
A mixture (1) of 1.64 g (10.9 mmol) of trifluoromethanesulfonic acid and 383.8 mg (2.18 mmol) of 2,4,5-trifluorobenzoic acid was cooled to 0 to −5 ° C. -490.4 mg (2.18 mmol) of dosuccinimide was added to obtain a mixture (2). The resulting mixture (2) was reacted by stirring at room temperature for 6 hours.
[0048]
After completion of the reaction, 5 ml of water and 8 ml of ethyl acetate were added to the resulting reaction mixture, and the pH was adjusted to 5.0 with a 30% aqueous NaOH solution. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated. 5 ml of hexane was added to the concentrated residue, the precipitated colorless crystals (succinimide) were filtered, and the filtrate was concentrated to obtain 246 mg of a solid. When this solid was analyzed by HPLC, it contained 24% of the raw material 2,4,5-trifluorobenzoic acid and 76% of 2,4,5-trifluoro-3-iodobenzoic acid.
[0049]
Reference Example 1: Preparation of ethyl 2,4,5-trifluoro-3-trifluoromethylbenzoate To a mixture (1) of cuprous iodide (12.28 g, 65 mmol) and dimethylformamide (2860 ml), methyl fluorosulfonyldifluoroacetate 500 g (2.6 mol) and 441.4 g of ethyl 2,4,5-trifluoro-3-iodobenzoate (purity 97.3%, 1.3 mol) were added and heated to 80-86 ° C., The reaction was stirred for 7 hours.
[0050]
After completion of the reaction, the obtained reaction mixture was added dropwise to a mixture (2) of 3250 ml of hexane and 3250 ml of saturated aqueous sodium hydrogen carbonate. The hexane layer was separated and dried over anhydrous magnesium sulfate. GC analysis revealed that 642 g of the residue obtained by concentrating hexane under reduced pressure contained 278.4 g (1.02 mol) of the desired product, ethyl 2,4,5-trifluoro-3-trifluoromethylbenzoate. .
[0051]
The same operation was performed twice, and the combined concentrate was distilled under reduced pressure with a 30 cm Utmer rectifier. A fraction having a boiling point of 74 to 79 ° C./0.39 kPa was collected. Acquisition amount 567 g, purity 92.2%, 1.927 mol, (acquisition yield 74.1% based on ethyl 2,4,5-trifluoro-3-iodobenzoate).
[0052]
Reference Example 2: Production of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid 567 g of ethyl 2,4,5-trifluoro-3-trifluoromethylbenzoate obtained in Example 2 above (purity) 92.2%, 1.927 mol), a mixture (1) of 1580 ml of acetic acid, 316 ml of water and 733 g of p-toluenesulfonic acid monohydrate was reacted with stirring under heating and refluxing for 8 hours. During this period, 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 to the reaction system twice.
[0053]
After completion of the reaction, the resulting reaction mixture was cooled by adding 1930 ml of water, and 3.85 liters of toluene was added. Liquid separation was performed, and the aqueous layer was further extracted three times with 1.93 liters of toluene. The combined toluene layers were dried over anhydrous magnesium sulfate, filtered and concentrated, and 1.9 liters 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 obtain 401 g of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid (1.64 mol, purity 99.8%).
[0054]
Comparative Example 1: Reaction of 2,4,5-trifluorobromobenzene Mixture of 1.54 g (10.24 mmol) of trifluoromethanesulfonic acid and 432.2 mg (2.05 mmol) of 2,4,5-trifluorobromobenzene (1) was cooled to 0 to -5 ° C, and 460.9 mg (2.05 mol) of N-iodosuccinimide was added to obtain a mixture (2). The resulting mixture (2) was reacted by stirring at room temperature for 6 hours.
[0055]
When the reaction mixture obtained after the reaction was analyzed by HPLC, the raw material 2,4,5-trifluorobromobenzene was 15%, 3-bromo-2,5,6-trifluoroiodobenzene was 20%, -61% of bromo-3,5,6-trifluoro-1,4-diiodobenzene was produced, and there was no selectivity for monobromination.
[0056]
Comparative Example 2: Reaction of 2,4,5-trifluorobenzonitrile A mixture of 3.812 g (25.4 mmol) of trifluoromethanesulfonic acid and 798.1 mg (5.08 mmol) of 2,4,5-trifluorobenzonitrile (1) was cooled to 0 to -5 ° C, and 1143 mg (5.08 mol) of N-iodosuccinimide was added to obtain a mixture (2). The resulting mixture (2) was reacted by stirring at room temperature for 4 hours.
[0057]
After completion of the reaction, the resulting reaction mixture was analyzed by HPLC. The raw material 2,4,5-trifluorobenzonitrile was not reacted.

Claims (3)

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