JPH0684331B2 - Process for producing aromatic substituted alkylcarboxylic acid compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an aromatic-substituted alkylcarboxylic acid compound.

More specifically, it is a method for producing an aromatic substituted alkylcarboxylic acid compound used as an antipyretic analgesic and anti-inflammatory agent such as common names such as alclofenac, ibuprofen, naproxen, flurbiprofen and ketoprofen.

[Conventional technology]

Conventionally, the following method (Japanese Patent Publication No. Sho 43-22297) is known as a typical method for producing an aromatic-substituted alkylcarboxylic acid.

Further, in JP-A-60-11439, hexamethylphosphoric triamide or N-methylpyrrolidone is used as a solvent, and copper iodide is used as a catalyst, and a cyanoacetic acid ester is allowed to act on an aryl halide to isolate a product. Methods for deriving 1,2-arylalkylcarboxylic acids are described.

[Problems to be solved by the invention]

However, the former typical production method has a very long process, and the yield is naturally low, which is not industrially advantageous. In the latter method, in addition to the use of a special solvent, the addition amount of the catalyst is extremely large (for example, 2 mol is added to 1 mol of the aryl halide), and it cannot be said that it is a catalytic reaction in fact.

[Means for solving problems]

As a result of various studies, the inventors of the present invention obtained an aromatic-substituted alkylcarboxylic acid in a small number of steps and in a high yield without isolation of an intermediate, when an extremely small amount of a specific palladium-phosphorus catalyst was used. The inventors have found out that, and have reached the present invention.

That is, in the present invention, in the presence of a catalyst, a basic condensing agent and a solvent, the general formula [I] Ar-X [I] (wherein Ar represents a substituted aryl group or a substituted or unsubstituted heterocyclic group, X Represents a bromine atom or an iodine atom respectively)
The aromatic halide represented by the general formula [II] [Wherein R represents a hydrogen atom or a methyl group, Y represents a cyan group or a group-COOR ¹ (R ¹ represents an alkyl group, an aralkyl group or an aryl group)], using a nitrile compound represented by the general formula [ IIIa] to [IIIc] L ₂ Pd (II) ▲ X ^* ₂ ▼ [IIIa] L ₄ Pd (O) [IIIb] QaPd (II) ▲ X ^* _b ▼ + L [IIIc] [where L is (R ² , R ³ or R ⁴ represents a group independently selected from an alkyl group, an alkenyl group, an aralkyl group, an aryl group, a cycloalkyl group, an alkoxy group or an aryloxy group,
R ^2, R ³ or R ⁴ is mutually bonded with R ^2, R ³ or R ⁴ other molecules,
At least a ligand represented by the structure may be in) one of L ₂ to form an alkylene group or an alkylene ether group, Q is a nitrile, isonitriles, .pi.-allyl, 1,5
-Diene, 1,3-diene, benzoquinone or olefin, provided that these compounds form a Pd (II) complex, X ^* is a halogen atom, and the group -OOCR ⁵ (R ⁵ is a lower alkyl group ) Or A and b each represent an integer of 1 or 2] and the reaction is carried out with at least one divalent or O-valent palladium compound, and the corresponding aromatic-substituted malonnitrile or cyanacetic acid ester is reacted. Then, this compound is (a) hydrolyzed in the presence of an acid or alkali and decarboxylated by heating, or (b) methylated with methyl halide in the presence of a basic condensing agent, and then heated after hydrolysis. General formula [IV] characterized by decarboxylation (Wherein Ar and R have the same meaning as described above), and a method for producing an aromatic-substituted alkylcarboxylic acid compound.

The catalyst used in the method of the present invention has the formula L ₂ Pd (II)
A palladium compound represented by ▲ X ^* ₂ ▼, L ₄ Pd (O) or QaPd (II) ▲ X ^* ₂ ▼ + L. Pd (II) represents divalent palladium and Pd (O) represents O-valent palladium. L means a ligand having one phosphorus atom in one molecule, and a ligand having two phosphorus atoms in one molecule can also be represented as L ₂ . Further, if even a small amount of L ₂ Pd (II) ▲ X ^* ₂ ▼ is formed in the reaction system, L ₂ and Pd (II) ▲ X ^* ₂ ▼ can be added separately, and in this case, the catalyst system (L ₂ ＋ Pd (II) ▲ X
^* ₂ ▼) also has the same meaning as L ₂ Pd (II) ▲ X ^* ₂ ▼.

General formula L ₂ Pd (II) ▲ X ^* ₂ ▼, L ₄ Pd (O) or QaPd (II)
In the palladium compound represented by ▲ X ^* ₂ ▼ + L, L
Or, as the ligand of L ₂ , for example, (CH ₃ ) ₃ P, (C ₂ H ₅ ) ₃ P, (CH
₂ = CHCH ₂ ) ₃ P, (C ₃ H ₇ ) ₃ P, (C ₄ H ₉ ) ₃ P, (C ₅ H ₁₁ ) ₃ P, (C ₆ H ₁₃ ) ₃ P,
(C ₇ H ₁₅ ) ₃ P, (C ₈ H ₁₇ ) ₃ P, (C ₆ H ₁₁ ) ₃ P, (C ₆ H ₅ ) ₃ P, (CH ₃ C ₆ H ₄ )
₃ P, (ClC ₆ H ₄ ) ₃ P, (CH ₃ OC ₆ H ₄ ) ₃ P, (C ₆ H ₅ CH ₂ ) ₃ P, (C ₄ H ₉ ) ₂ (C ₆ H
₅ ) P, (C ₄ H ₉ ) (C ₆ H ₅ ) ₂ P, (CH ₃ OC ₆ H ₄ ) (C ₆ H ₅ ) ₂ P, (C ₆ H ₅ ) ₂ PCH ₂ C
_{H 2 P (C 6 H 5} ) 2, (C ₆ H ₅ ) ₂ PCH ₂ CH ₂ OCH ₂ CH ₂ P (C ₆ H ₅ ) ₂ , (CH ₃ O) ₃ P, (C ₂ H ₅ O) ₃ P,
(C ₃ H ₇ O) ₃ P, (C ₄ H ₉ O) ₃ P, (C ₅ H ₁₁ O) ₃ P, (C ₈ H ₁₇ O) ₃ P, (C ₆ H ₅ CH ₂
O) ₃ P, (C ₆ H ₅ O) ₃ P, (CH ₃ C ₆ H ₄ O) ₃ P, (ClC ₆ H ₄ O) ₃ P, (CH ₃ OC ₆ H
₄ O) ₃ P, (CH ₃ O) (C ₆ H ₅ ) ₂ P, (C ₄ H ₉ O) ₂ (C ₆ H ₅ ) P, (CH ₃ C ₆ H ₄ O) (C ₆
Examples thereof include phosphorus compounds such as H ₅ ) ₂ P and (C ₄ H ₉ O) (C ₆ H ₅ O) ₂ P.

In the palladium complex represented by the general formula QaPd (II) ▲ X ^* _b ▼, Q is, for example, benzonitrile, benzoisonitrile, π-allyl, cyclohexadiene, cyclooctadiene, norbornadiene, butadiene, tetraphenylcyclobutadiene, benzoquinone. ,styrene,
π-Cyclopentadienyl, etc. are included, and these compounds have nitrile Pd due to the presence of Pd (II) compounds.
(II) complex, isonitrile Pd (II) complex, π-allyl Pd
(II) complex, 1,5-diene Pd (II) complex, 1,3-diene Pd
(II) complex, benzoquinone Pd (II) complex, olefin Pd
(II) forms a complex. In the general formula [IIIc], it means that the phosphorus compound [L] is added to the Pd (II) complex and used.

Further, as X ^* , chlorine atom, bromine atom, iodine atom, group —OOCCH ₃ , group —OOCC ₂ H ₅ , group —OOCC ₃ H ₇ , group —OOCC ₄ H ₉ , And so on.

In the method of the present invention, the aromatic halide represented by the general formula [I], which is reacted with the nitrile compound represented by the general formula [II], is a substituted aryl halide or a heterocyclic halide. And so on. A bromine compound corresponding to the above-exemplified iodine compound can also be used in the production method of the present invention. When a carbonyl group or an allyl ether group is present in the molecule of the aromatic halide exemplified above, it is preferably converted into a ketal group, a benzyl ether group or the like in advance for protection and used for the reaction.

In the method of the present invention, examples of the nitrile compound to be reacted with the aromatic halide include malon nitrile such as malon nitrile and methyl malon nitrile, methyl cyanoacetate, ethyl methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, butyl cyanoacetate and cyanide. Examples thereof include cyanoacetic acid esters such as octyl acetate, benzyl cyanoacetate and phenyl cyanoacetate.

Examples of the basic condensing agent that is present when the aromatic halide and the nitrile compound are reacted include alkali metals such as sodium and potassium, sodium methoxy, ethoxy sodium, irisopropoxy sodium, t-butoxy potassium, and t-amyloxy sodium. Examples thereof include alkali metal alcoholates, potassium amides, lithium amides, alkali amides such as sodium amides, sodium hydride, and triphenylmethyl sodium.

Examples of the reaction solvent include tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethyl ether, dibutyl ether, dioxane, hexamethylphosphortriamide, dimethylformamide, and a mixed solvent thereof with a hydrocarbon.

The reaction temperature is 20 to 150 ° C, preferably 50 to 80 ° C,
The reaction time varies depending on the temperature, but is, for example, 70 ° C. for 4 hours or longer. It is desirable to carry out the reaction under an inert gas atmosphere.

When reacting an aromatic halide with a nitrile compound,
Addition amount of palladium compound catalyst to 1 mol of both raw materials
It is 1/10 to 1/10000 mol, preferably 1/50 to 1/500 mol. When the general formula QaPd (II) ▲ X ^* _b ▼ + L is used for the catalyst, the addition ratio of the divalent palladium complex and the ligand compound (L) may be arbitrary, but preferably 1: 2 (mol Ratio).

The aromatic-substituted malonnitrile or cyanoacetic acid ester thus obtained is hydrolyzed in the presence of (a) acid or alkali and decarboxylated by heating, or (b) in the presence of a basic condensing agent. Methylated with methyl halide,
After hydrolysis and decarboxylation by heating, an aromatic substituted alkylcarboxylic acid compound represented by the general formula [IV] can be obtained.

Hydrolysis is usually carried out in the presence of an acidic aqueous solution obtained by diluting an acid such as hydrochloric acid or sulfuric acid with water, or an alkaline aqueous solution obtained by diluting an alkali such as sodium hydroxide or potassium hydroxide with water.
The concentration is not particularly limited, but both aqueous solutions are 5 to 20 N.

The decarboxylation reaction is easily performed by heating an acidic or alkaline aqueous solution after hydrolysis. The heating temperature is 80 to 150 ° C, preferably 110 to 130 ° C. A heating time of 15 hours or less is sufficient.

Methylation of aromatic substituted malon nitrile or cyanoacetic acid ester is performed by reacting methyl halide in the presence of a basic condensing agent and a solvent. As the basic condensing agent, the same ones as those used in the reaction of the aromatic halide and the nitrile compound are used, and as the solvent, the same ones as those used in the same reaction as well as methanol, ethanol, propanol and the like are used. Alcohol is used. Examples of methyl halides include methyl iodide and methyl bromide. The reaction is carried out at 20 to 150 ° C, preferably 50 to 80 ° C, and is completed in several hours.

If necessary, the aromatic-substituted alkylcarboxylic acid compound thus obtained is purified by a method such as recrystallization or column chromatography.

〔effect〕

According to the method of the present invention, an aromatic halide and a nitrile compound can be reacted using an extremely small amount of catalyst,
Furthermore, since aromatic substituted malon nitrile or cyanoacetic acid ester can be obtained in high yield and high purity, the subsequent methylation, hydrolysis and decarboxylation steps can be performed without isolation and purification. Therefore, the conventional process can be greatly simplified and is an industrially extremely advantageous method.

The aromatic-substituted alkylcarboxylic acid compound obtained by the present invention is used as it is or as an esterification, sodium salt, calcium salt, etc., for example, rheumatoid arthritis, other arthritis associated with collagen pain, upper respiratory tract inflammation, low back pain, etc. Extinction,
It is used as an antipyretic analgesic and anti-inflammatory agent applicable to analgesia, trauma, anti-inflammatory after surgery and tooth extraction, and analgesia.

Next, the present invention will be described with reference to examples.

Example 1 Synthesis of ibuprofen (method A) In a three-necked flask equipped with a reflux condenser, a stirrer, a dropping funnel and a thermometer, 2469 mg of potassium t-butoxide in a nitrogen stream.
(22mmol), triphenylphosphine 105mg (0.4mmol)
And tetrahydrofuran (40 ml) were added, and a solution of malonnitrile (740 mg, 11 mmol) in tetrahydrofuran (10 m
l) was added slowly. Then, 2601 mg (10 mmol) of p-isobutylphenyliodite and 45 mg (0.2 mmol) of palladium diacetate were added, and the mixture was reacted under reflux for 5 hours.
After cooling to room temperature, the reaction mixture was treated with dilute hydrochloric acid and extracted with ether. The ether solution was concentrated. To this concentrate was slowly added 20 ml of an ethanol solution of 748 mg (0.11 mmol) of sodium ethoxy, and then methyl iodide 17 was added.
03 mg (0.12 mmol) was added. After reacting the mixture under reflux for 3 hours, the alcohol was distilled off. Water on this residue
25 ml of concentrated sulfuric acid and 25 ml of concentrated sulfuric acid were added, and decarboxylation was carried out simultaneously with hydrolysis at 120 to 130 ° C for 12 hours. Cool to room temperature and extract the product with ether. For purification, the ether was distilled off,
The products were separated by silica gel column chromatography. 2- (4-isobutylphenyl) propionic acid (common name: ibuprofen) having a melting point of 76 ° C, eluted with a methylene chloride solvent
1450 mg (yield 70%) was obtained.

Example 2 Synthesis of flurbiprofen (method B) In a reaction vessel similar to that in Example 1, 2470 mg (22 mmol) of potassium t-butoxide and 40 ml of ethylene glycol dimethyl ether were placed in a nitrogen stream, and ethyl cyanoacetate 1450 was added thereto.
A solution of mg (13 mmol) of ethylene glycol dimethyl ether (10 ml) was gradually added. Next, 2-fluoro-4-iodobiphenyl 2981 mg (10 mmol) and dichlorobis (triphenylphosphine) palladium catalyst 300 mg (0.43 mmo
l) was added and reacted at 70 ° C. for 8 hours while stirring. The reaction mixture was treated with diluted hydrochloric acid, extracted with ether and then concentrated. To this concentrate, 20 ml of an ethanol solution of 748 mg (0.11 mmol) of sodium ethoxy was added slowly, and then 1703 mg (0.12 mmol) of methyl iodide was added. After reacting the mixture under reflux for 3 hours, the alcohol was distilled off. This residue was hydrolyzed with an aqueous sulfuric acid solution in the same manner as in Example 1,
Decarboxylation and purification separation were carried out to obtain 1590 mg (yield 65%) of 2- (2-fluoro-4-biphenyl) propionic acid (common name: flurbiprofen) having a melting point of 114 ° C.

Example 3 Synthesis of ketoprofen (method C) 3 in a three-necked flask equipped with a dehydrator, a thermometer and a stirrer
-Iodobenzophenone 3081 mg (10 mmol), ethylene glycol 1860 mg (30 mmol) and p-toluenesulfonic acid
100 mg was added, dissolved in 20 ml of benzene, and dehydrated under reflux for 15 hours. (Dehydration amount 0.18 ml / theoretical dehydration amount 0.18 ml).
The solvent was distilled off from the obtained benzene solution of 3-iodobenzophenone ethylene ketal.

In a reaction vessel similar to that of Example 1, 530 mg (22 mmol) of sodium hydride and 40 ml of tetrahydrofuran were placed in a nitrogen stream, and a tetrahydrofuran solution of 740 mg (11 mmol) of malonnitrile was gradually added dropwise thereto. After the generation of hydrogen subsided, a solution of 3-iodobenzophenone ethylene ketal (10 mmol) obtained above in tetrahydrofuran (20 ml) and dichlorobis (triphenylphosphine)
100 mg (0.14 mmol) of palladium catalyst was added, and the mixture was reacted for 5 hours while refluxing and stirring. After the reaction mixture was cooled to room temperature, it was treated with dilute hydrochloric acid to remove the ketal protecting group to give a carbonyl group, and then extracted with ether and concentrated. 20 ml of an ethanol solution of 748 mg (0.11 mmol) of sodium ethoxy was slowly added to the residue, and then 1703 mg (0.12 mmol) of iodomethyl was added. After refluxing this mixture for 3 hours, the alcohol was distilled off. This residue was hydrolyzed with an aqueous sulfuric acid solution, decarboxylated, and treated in the same manner as in Example 1.
Purified and separated, 1526 mg (yield: 3-benzoylhydratropic acid (common name: ketoprofen) with a melting point of 95 ° C.
60%).

Example 4 Synthesis of Alcrofenac (Method D) Sodium hydride was placed in the reaction vessel of Example 1 in a nitrogen stream.
Add 530 mg (22 mmol) and 40 ml of tetrahydrofuran,
A tetrahydrofuran solution (10 ml) of 740 mg (11 mmol) of malon nitrile was gradually added thereto. After the generation of hydrogen subsided, 3446 mg (10 mmol) of benzyl (2-chloro-4-iodo) phenyl ether and 100 mg (0.14 mmol) of dichlorobis (triphenylphosphine) palladium were added, and the mixture was refluxed with tetrahydrofuran while stirring. Five
Reacted for hours. After cooling to room temperature, the reaction mixture was treated with dilute hydrochloric acid and extracted with ether.

After concentrating the ether solution, 25 ml of anhydrous n-butanol was added, and while maintaining the temperature at 50 ° C, sodium 230 mg (10 mmol)
Was quickly added to carry out the reaction. After the sodium had completely disappeared, it was cooled and neutralized with dilute hydrochloric acid. After drying the organic layer, n-butanol was completely distilled off. The reaction mixture was dissolved in 20 ml of acetone, 1380 mg of potassium carbonate, 80 mg of potassium iodide and 840 mg (11 mmol) of allyl chloride were added at once, and the mixture was reacted under reflux for 8 hours. After cooling to room temperature, an excess was performed, and acetone was distilled off from the liquid acetone solution. 25 ml of water and 25 ml of concentrated sulfuric acid were added to the reaction product, and decarboxylation was carried out simultaneously with hydrolysis at 120-130 ℃ for 12 hours. Thereafter, in the same manner as in Example 1, extraction with ether,
Purified and separated, 4-allyloxy-, melting point 92-93 ℃
1670 mg (yield 73%) of 3-chlorophenylacetic acid (conventional name: alclofenac) was obtained.

Examples 5-10 10 mmo of aromatic halide described in Table 1-1 and Table 1-2
l, a nitrile compound and a catalyst, and then the above
The aromatic substituted alkylcarboxylic acid of the present invention was obtained according to the method.

The methods A to D mean the following.

Method A: After reaction with malonnitrile, methylation, hydrolysis and decarboxylation were carried out.

Method B: After reaction with cyanoacetic acid ester, methylation was carried out, followed by hydrolysis and decarboxylation.

Method C: The carbonyl group was previously protected, and after reaction with malonnitrile, methylation was carried out, followed by hydrolysis and decarboxylation.

Method D: After reaction with malonnitrile, introduction of an allyl group,
Hydrolysis and decarboxylation were performed.

The above results are summarized in Tables 1-1 and 1-2.

(Note) The symbols in Tables 1-1 to 1-2 represent the following.

Ph: phenyl, Et: ethyl group, Me: methyl group, COD: cyclooctadiene, CHD: cyclohexadiene.

Examples 11 to 17 The same reaction vessel as in Example 1 was charged with the basic condensing agent and solvent shown in Table 2 below, and a solution of 740 mg (11 mmol) malonnitrile was gradually added. Next, 2981 mg (10 mmol) of 2-fluoro-4-iodobiphenyl and the catalyst shown in Table 2 below were added and reacted. Thereafter, in the same manner as in Example 1, methylation,
Hydrolysis, decarboxylation, separation and purification, melting point 113-114
Thus, 2- (2- (fluoro-4-biphenyl) propionic acid (reaction product) at ℃ was obtained.

The results are shown in Table 2.

(Note) The symbols in Table 2 indicate the following.

Me: methyl group, Et: ethyl group, Bu: butyl group, Ph: phenyl group,
acac: acetylacetonate group, COD: cyclooctadiene, NBD: nobornadiene.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07C 59/84 8930-4H C07D 207/20 8217-4C 209/46 9284-4C 333/22 // B01J 31/22 X 8017-4G 31/24 X 8017-4G C07B 61/00 300

Claims (1)

[Claims] 1. A compound represented by the general formula [I] Ar-X [I] (wherein Ar represents a substituted aryl group or a substituted or unsubstituted heterocyclic group, and X represents the presence of a catalyst, a basic condensing agent and a solvent). Indicates a bromine atom or an iodine atom, respectively)
The aromatic halide represented by the general formula [II] [Wherein R represents a hydrogen atom or a methyl group, Y represents a cyan group or a group-COOR ¹ (R ¹ represents an alkyl group, an aralkyl group or an aryl group)], using a nitrile compound represented by the general formula [ IIIa] to [IIIc] L ₂ Pd (II) ▲ X ^* ₂ ▼ [IIIa] L ₄ Pd (O) [IIIb] QaPd (II) ▲ X ^* _b ▼ + L [IIIc] [where L is (R ² , R ³ or R ⁴ represents a group independently selected from an alkyl group, an alkenyl group, an aralkyl group, an aryl group, a cycloalkyl group, an alkoxy group or an aryloxy group,
R ^2, R ³ or R ⁴ is mutually bonded with R ^2, R ³ or R ⁴ other molecules,
At least a ligand represented by the structure may be in) one of L ₂ to form an alkylene group or an alkylene ether group, Q is a nitrile, isonitriles, .pi.-allyl, 1,5
-Diene, 1,3-diene, benzoquinone or olefin, provided that these compounds form a Pd (II) complex, X ^* is a halogen atom, and -OOCR ⁵ (R ⁵ is a lower alkyl group) ) Or A and b each represent an integer of 1 or 2] and are reacted with at least one divalent or O-valent palladium compound, and the corresponding aromatic-substituted malonnitrile or cyanoacetic acid ester is reacted. Then, this compound is (a) hydrolyzed in the presence of an acid or alkali and decarboxylated by heating, or (b) methylated with methyl halide in the presence of a basic condensing agent, and then heated after hydrolysis. General formula [IV] characterized by decarboxylation A method for producing an aromatic-substituted alkylcarboxylic acid compound represented by the formula (wherein Ar and R have the same meanings as described above).