JPH02145538A - Preparation of fluorinated benzoic acids and intermediates thereof - Google Patents

Abstract

PURPOSE:To provide the subject compound in a high yield by a low temperature reaction without using any reactant having a high toxicity by reacting a halogenated phthalimide as a starting raw material with a fluorination agent and subsequently converting the prepared fluorinated phthalic imide as an intermediate. CONSTITUTION:A halogenated phthalimide of formula I (X is Cl or Br; n is 1-4; R is 1-12C alkyl) (e.g. N-methyl-tetrachlorophthalimide) is reacted with a fluorinating agent (e.g. potassium fluoride) to prepare a fluorinated phthalimide of formula II (e.g. N-methyl-tetrafluorophthalimide). This intermediate is subsequently preferably hydrolyzed to form a compound of formula III, which is decarbonated into a compound of formula IV and further hydrolyzed into a fluorinated benzoic acid of formula V (e.g. 2,3,4,5-tetrafluorobenzoic acid). The preparation process is profitable because the process can be performed at a low temperature without passing through any poisonous intermediate.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to fluorinated benzoic acids useful as intermediates for pharmaceuticals and methods for producing intermediates thereof.

[Prior art] A method for obtaining fluorinated benzoic acids such as tetrafluorobenzoic acid involves chlorinating phthalonitrile to convert it to tetrachlorophthalonitrile, followed by fluorination and hydrolysis.
A method of decarboxylation (JP-A No. 61-85349, etc.) is known.

[Problem to be solved by the invention] In the method using phthalonitrile as a starting material, a gas phase chlorination reaction is required to obtain tetrachlorophthalonitrile, and in this case, the product tetrachlorophthalonitrile is toxic. is high and has problems in handling. In addition, this chlorination reaction has many problems as an industrial process, such as the need to vaporize phthalonitrile, which has a high melting point, and the deactivation of the chlorination catalyst.

"Means for Solving the Problems" The present invention has been made to solve many drawbacks of the prior art, such as the toxicity of intermediate products and process problems. The represented halogenated phthalimide is reacted with a fluorinating agent, and the following - machining allowance (■)
A method for obtaining a fluorinated phthalimide which is an intermediate of fluorinated Yasui and aromatic acids represented by the formula, and a method for converting the obtained fluorinated phthalimide to obtain a fluorinated benzoic acid represented by the following formula (1u). It is something.

The conversion of the compound of general formula (11) to the compound of (l■) is preferably carried out via the following compound (tV) and compound (V). Compound (1v) is converted from compound (1
By hydrolysis of r), compound (V) is converted to compound (1v)
can be obtained by decarboxylation of A typical manufacturing route of the present invention is shown below.

(■) (IV) (V) Decarboxylation of compounds (1v) to (V) and hydrolysis of compounds (V) to (III>) may be performed simultaneously, and decarboxylation 1. before hydrolysis or after hydrolysis. It may also be decarboxylated.

Starting point: The halogenated phthalimides can be easily obtained from readily available and inexpensive halogenated phthalic anhydride. This imidization reaction is carried out by reacting halogenated phthalic anhydride with a primary amine. The amount of amine used is 11 u.The amount of amine used is
The appropriate reaction temperature is 100 to 250°C, preferably 120 to 170°C, when 0.4 to 3 times the mole, preferably 0.7 to 1.5 times the mole is used.

Fluorination of halogenated phthalic fmide I can be carried out by reacting a halogenated phthalimide with a fluorinating agent such as an alkali metal fluoride without a solvent or in an aprotic solvent. As the alkali metal fluoride, spray-dried potassium fluoride is preferred, and 1 to 5 times the mole, preferably 1 to 2 (1'f mole) is used relative to the halogen atom to be substituted. A catalyst may also be added.

Examples of such phase transfer catalysts include quaternary ammonium salts such as tetramethylammonium chloride and tetrabutylammonium bromide, and quaternary phosphonium salts such as tetrabutylphosponium bromide and tetraphenylphosphonium bromide. The amount used is 0.01 to 100% by weight, preferably 0.01 to 100% by weight, based on the raw material.
It is 1-20% heavy view fire protection. Aprotic solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethylphosphorotriamide, N-methyl-2-pyrrolidone, acetonitrile, benzonitrile, dioxane, diglyme, Tetraglyme etc. can be used, preferably sulfolane, N,
N-dimethylformamide is suitable, and the amount used is 0.5 to 10 times, preferably 1 to 5 times the weight of the raw materials.

The hydrolysis reaction of fluorinated phthalimides can be carried out under aqueous acidic or alkaline conditions. Suitable acids to be used are hydrochloric acid, phosphoric acid, and sulfuric acid. As the alkali, sodium or potassium hydrogen carbonate, sodium or potassium carbonate, sodium or potassium hydroxide, etc. are suitable.The reaction temperature is 30 to 120'C, and this can be adjusted as appropriate depending on the type and concentration of the acid and alkali used. Can be changed.

The decarboxylation reaction of the compound (mV) is 80-22 in aqueous medium.
This can be done by heating to a temperature in the range of 0°C. In addition, at this time, a catalyst may be added as a reaction aid. Examples of these catalysts include tertiary amines such as triethylamine and tributylamine, ammonia, hydroxides of alkali metals or alkaline earth metals, and carbonic acid. Salts, bicarbonates, sulfates, nitrates, etc. can be used.

The hydrolysis reaction of fluorinated benzamides (compound ①) can be carried out under aqueous acidic or alkaline conditions.

Suitable acids to be used are hydrochloric acid, phosphoric acid, and sulfuric acid. As the alkali, sodium or potassium hydrogen carbonate, sodium or potassium carbonate, sodium or potassium hydroxide, etc. are suitable.The reaction temperature is suitable in the range of 30 to 200°C.
This depends on the type and concentration of acid and alkali used.
It can be changed as appropriate.

[Examples] Examples of the present invention will be described in more detail below.

Reference Example 1 1 with a stirrer and a reflux condenser! In a glass flask, add 80 g of tetrachlorophthalic anhydride (0
, 280), 23.8 g of 40% methylamine aqueous solution (
0,308 mo 1 ) and 160 g of sulfolane were charged, and the temperature was raised to 120° C. over 2 hours while stirring vigorously.

After that, remove the reflux condenser and raise the temperature to 150℃ over 2 hours while distilling off the water.After cooling,
The precipitate was filtered and recrystallized to give 71.5 g of N-
Methyl-tetrachlorophthalimide was obtained. Yield 85%
.

Example 1 500 with agitator and reflux condenser
In a m1 glass flask, 80 g (0,265 m o 1) of N-methyl-tetrachlorophthalimide and 69. 5g (1.1gBm, ol) and 250g of sulfolane were added, stirred vigorously and
Liquid chromatography analysis of the 0 reaction crude liquid obtained by reacting at 5°C for 4 hours revealed that the reaction rate of N-methyl-tetrachlorophthalimide was 100% and the selectivity to N-methyl-tetrafluorophthalimide was 81.9. %Met. In addition, partially fluorinated products were observed.

Example 2 300 with agitator and reflux condenser
In a m1 glass flask, 50 g (0,215 rnol) of N-methyl-tetrafluorophthalimide, 22.5 g (0,225 mol) of potassium bicarbonate, and 10 g of water were added.
0 g was charged and reacted at 80° C. for 4 hours with vigorous stirring. After cooling, the mixture was acidified by adding concentrated hydrochloric acid dropwise to precipitate the product to obtain N-methyl-tetrafluorophthalamic acid. Yield 95%.

Example 3 N-methyl-
10 g of tetrafluorophthalamic acid, 10 g of tributylamine, and 50 g of water were charged, and the mixture was reacted at 140° C. for 5 hours with vigorous stirring. Analysis of the product by liquid chromatography and IeF-NMR revealed that the reaction rate of raw material (IV) was 90% and the selectivity to N-methyl-tetrafluorobenzamide was 72%.

Example 4 5 g of N-methyl-tetrafluorobenzamide, concentrated sulfur M
20 g and 30 g of water were placed in a 100 ml glass flask and reacted at 120° C. for 10 hours with vigorous stirring. After cooling, the product is filtered and dried2. 3. 4.
4.4 g of 5-tetrafluorobenzoic acid was obtained. Yield 9
4%.

[Effects of the Invention] Compared to conventional methods, the method of the present invention does not require the use of highly toxic reactants, can be carried out at lower temperatures, and is an excellent method with a high yield.

Claims (1)

[Claims] 1. A halogenated phthalimide represented by the following general formula (I) is reacted with a fluorinating agent to form the following general formula (II).
A method for producing fluorinated phthalimides, which comprises obtaining fluorinated phthalimides represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, x is Cl or Br, n is an integer of 1 to 4, and R is an alkyl group having 1 to 12 carbon atoms.) ▲Mathematical formulas, chemical formulas, tables, etc. etc.▼(II) (In the formula, Y is F, n is an integer of 1 to 4, and R is a carbon number of 1 to 1.
2 shows the alkyl group. ) 2. A halogenated phthalimide represented by the following general formula (I) is reacted with a fluorinating agent to form the following general formula (II).
After obtaining the fluorinated phthalimide represented by the following formula (III
) A method for producing fluorinated benzoic acids, characterized by obtaining fluorinated benzoic acids represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is Cl or Br, n is an integer of 1 to 4, and R is an alkyl group having 1 to 12 carbon atoms.) ▲Mathematical formulas, chemical formulas, There are tables, etc.▼(II) (In the formula, Y is F, n is an integer from 1 to 4, and R is a carbon number of 1 to 1.
2 shows the alkyl group. ) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, Y is F and n is an integer from 1 to 4)