JPS6160819B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (In the formula, Ar is a phenyl group, R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, and X ¹ and X ² are a hydrogen atom or a halogen atom.) This invention relates to silidene acetic acid derivatives.

The cyclohexylidene acetic acid derivative represented by the general formula () of the present invention can be converted into ketoprofen or an analog thereof by repeated dehydrogenation or dehydrohalogenation (see Reference Examples below). Ketoprofen is known as a drug with excellent analgesic and anti-inflammatory effects.

Conventional methods for producing ketoprofen include:
(1) A method in which 3-(α-cyanoethyl)benzoic acid is used as a starting material and is hydrolyzed after a Friedel-Crafts reaction with benzel (see JP-A-48-64059);
(2) By reacting diazomethane with 3-benzoylbenzoic acid chloride, through rearrangement reaction and hydrolysis, 3-benzoylbenzoic acid chloride
- A method of obtaining benzoylphenylacetic acid and further synthesizing it by a reaction such as methylation (see JP-A-46-4973), (3) using 3-acetylbenzophenone, 3-benzoylphenylacetic acid, etc. as a starting material. (4) A method in which 3-bromobenzophenone is used as a starting material and subjected to a Grignard reaction with α-morpholinoacetone, followed by hydrolysis and oxidation reactions (see JP-A-49-93346). (Refer to No. 50-40540), (5) Using m-toluic acid as a starting material, 3-
A method in which benzoylacetonitrile is obtained, followed by methylation and hydrolysis (see JP-A-51-115452), (6) a method in which 1-benzoylcyclohexanone is condensed with pyruvic acid and then heated in the presence of pyridine/hydrochloride (JP-A-51-115452); (See No. 149251, 1983), (7)3
- using propionylbenzophenone as a starting material,
Once 3-(1-propynyl)benzophenone is obtained, it is further reacted with thallium nitrate (see JP-A-52-36642), (8) 3-benzoylbenzaldehyde is reacted with methylthiomethylmethylsulfoxide as a starting material. , a method of synthesizing through steps such as methylation, reduction, and hydrolysis (see JP-A-54-61159), etc. are known.

However, these methods involve steps with low yields (especially methods (1) and (6)), and steps that produce by-products that are difficult to separate (especially methods (2) and (5), which pose an explosion hazard). (In particular, methods (2) and (4), which involve difficult to obtain starting materials or require long steps (in particular, methods (1), (3), (4), (Five),
(7), (8)), require expensive reagents (especially the method
(7)).

In order to overcome these drawbacks, the present inventors
As a result of various studies, it was discovered that ketoprofen or its analogs can be easily derived in a short process by using the compound of the present invention, and the present invention has now been completed.

The reaction formula for one production method of the present invention is as shown in the following formula.

(In the formula, Ar is a phenyl group, R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom or a lower alkyl group, R ³ is a lower alkyl group, R ⁴ is a di-substituted amino group, OR ⁵ or SR ⁶ is a group represented by X ¹ and
X ² is a halogen atom. R ⁵ is a hydroxyl group protecting group, and R ⁶ is a thiol group protecting group. ) [First step] In the first step, 2-cyclohexenone is reacted with a phenylacetonitrile derivative represented by the general formula () in the presence of a base catalyst, and then hydrolyzed to form a 3-cyclohexenone represented by the general formula (). It produces benzoylcyclohexanone. The raw material 2-cyclohexenone is a compound that is easily available, and the compound of the general formula () above can be easily synthesized from the corresponding aldehyde using a known method [J.
See Heterocyclic Chem. 15 881 (1978)].

Specific examples of compounds of general formula () are:
α-(N,N-dimethylamino)benzyl cyanide, α-morpholinobenzyl cyanide, α-methoxybenzyl cyanide, α-(1-ethoxyethoxy)benzyl cyanide, α-methylthiocyanide benzyl, α-ethylthiocyanide benzyl,
Examples include benzyl α-acetoxycyanide.

This step must be carried out in the presence of a base catalyst. Examples of these base catalysts include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride,
Alkali metal hydrides such as potassium hydride, alkali metal amides such as sodium amide and potassium amide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, alkali metal carbonates such as sodium carbonate and potassium carbonate. , sodium cyanide,
Alkali metal cyanides such as potassium cyanide,
Examples include benzyltrimethylammonium hydroxide.

It is desirable to use a solvent to carry out this step;
For example, ether solvents such as diethyl ether, tetrahydrofuran (THF), ethanol, t-
Alcohols such as butyl alcohol, benzene,
Aromatic hydrocarbons such as toluene can be used. The reaction proceeds at a temperature of -30° to 100°C, but a temperature of -5°C to room temperature is preferred in order to improve selectivity.

In this step, the product is then subjected to hydrolysis.
Hydrolysis can be carried out under acidic or basic conditions without isolating the product obtained by reaction under the above conditions.
In addition, when the acetonitrile derivative R ⁴ represented by the general formula () contains a sulfur atom, this hydrolysis reaction can be made to proceed smoothly by using a metal salt such as mercuric chloride as an auxiliary agent. can.

[Second process]

In this step, in the presence of a base, the 3-benzoylcyclohexanone represented by the general formula () obtained in the first step is reacted with the phosphonoacetic acid derivative represented by the general formula (), and the phosphonoacetic acid derivative represented by the general formula (') is reacted. This is a process for producing cyclohexylidene acetic acid derivatives. The phosphonoacetic acid derivative that is a raw material is a compound that can be easily obtained by reacting the corresponding α-haloacetic acid derivative with tri-lower alkyl phosphite. (G.Dallagher, Jr., etc.
Synthesis, 122 (1974)).

These compounds include methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, methyl α-(dimethylphosphono)propionate, ethyl α-(diethylphosphono)propionate, α-(di-n-propylphosphono) Examples include n-propyl propionate, n-butyl α-(di-n-butylphosphono)propionate, ethyl α-(diethylphosphono)butanoate, and ethyl α-(dimethylphosphono)pentanoate.

This step requires performing in the presence of a base. Examples of bases used include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal amides such as sodium amide and potassium amide, and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. be able to.

It is desirable to use a solvent to carry out this step;
For example, ethers such as diethyl ether and tetrahydrofuran (THF), alcohols such as ethanol and t-butyl alcohol, and aromatic hydrocarbons such as benzene and toluene can be used. The reaction proceeds at -10 to 150°C. In order to improve selectivity, the temperature is preferably 0°C to room temperature.

[Third step]

This step is a step of halogenating the cyclohexylidene acetic acid derivative represented by the general formula (') obtained in the second step to produce a halogenated cyclohexylidene acetic acid derivative represented by the general formula ('').

Examples of the halogenating reagent include halogenated imides such as N-bromosuccinimide and N-chlorosuccinimide, chlorine, bromine, bromotrichloromethane, t-butylhypochloride, and trichloromethanesulfonyl chloride. The halogenating reagent is 1 to 5% of the raw material compound.
An equivalent amount is used, generally 1.8 to 3 equivalents.

This step is preferably carried out under radical-generating conditions in order to accelerate the reaction and obtain the product in good yield. The radical generation conditions can be easily achieved, for example, in the presence of a radical generator or under light irradiation. Examples of radical generators include organic peroxides such as benzoyl peroxide, diacetyl peroxide, and di-t-butyl peroxide, azo compounds such as azobisisobutyronitrile, iron chloride, copper chloride, copper oxide, and palladium complexes. , transition metal compounds such as rhodium complexes, and the like.

When carrying out this step, it is desirable to use a solvent. As the solvent, solvents that do not participate in the reaction can be suitably used, such as halogenated carbons such as carbon tetrachloride and chloroform, aromatic hydrocarbons such as benzene, and hydrocarbons such as hexane and cyclohexane.

Although the reaction temperature varies depending on other reaction conditions, it can be carried out at 0°C to 150°C. However, room temperature to the reflux temperature of the solvent are preferred for ease of operation. The present invention will be explained in more detail below using Examples and Reference Examples.

Example 1 Sodium hydride (50%, oil dispersion) 528 mg
After washing (11 mmol) with dry hexane, 22 ml of dry tetrahydrofuran was added and stirred. Ethyl α-(diethylphosphono)propionate 2.618g
A solution of (11 mmol) dissolved in 2 ml of dry tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. 3
- Add dropwise a solution of 2.02 g of benzoylcyclohexanone dissolved in 4 ml of dry tetrahydrofuran,
Stirring was continued for an hour. Thereafter, the reaction solution was poured into dilute hydrochloric acid and extracted with ether. This ether layer was washed with an aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and α
2.334 g of ethyl (3-benzoylcyclohexylidene)propionate was obtained. Yield 82%.

NMR (CDCl ₃ ); δ1.53-3.73 (m, 15H),
3.87~4.4 (m, 2H), 7.3~8.07 (m, 5H). MS (m/e): 286 (M ⁺ ), 240, 135, 105,
77, Example 2 Ethyl α-(3-benzoylcyclohexylidene)propionate (240 mg, 0.84 mmol) and N-bromosuccinimide (3.4 mg, 1.76 mmol) were suspended in 5 ml of carbon tetrachloride, and peroxidized Benzoyl (20
ml) was added, and the mixture was heated under reflux for 1 hour. After cooling,
The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
Ethyl α-(3-benzoyl-3,6-dibromocyclohexylidene)propionate, α-(3-
350 mg of a mixture of ethyl benzoyl-2,3-dibromocyclohexylidene)propionate and ethyl α-(3-benzoyl-2,6-dibromocyclohexylidene)propionate was obtained.

NMR of mixture (CCl ₄ ) δ1.0-1.5 (m, 3H),
1.7-4.4 (m, 12H), 7.2-8.1 (m, 5H). Elemental analysis of mixture: Measured value C; 48.91, H;
4.42, Br35.69. Calculated value C as C ₁₈ H ₂₀ O ₃ Br ₂ ; 48.67, H;
4.54, Br; 35.98. Reference Example 1 Potassium t-
224 mg (2 mmol) of butoxide was added thereto, and 8.08 g (40 mmol) of α-morpholinobenzyl cyanide dissolved in 16 ml of dry tetrahydrofuran was added dropwise under ice-water cooling. After stirring for a while, 1.92 g of 2-cyclohexenone dissolved in dry tetrahydrofuran.
(20 mmol) was slowly added dropwise. After stirring for 5 minutes after the dropwise addition, dilute hydrochloric acid was added to the reaction solution to make it weakly acidic, and the mixture was extracted twice with ethyl acetate. This ethyl acetate layer was washed with an aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 10.55 g of a crude product. Add 50 ml of acetic acid and 4 ml of water to 10.55 g of this crude product, and
The mixture was kept at 80°C and stirred for 18 hours. After the reaction solution was cooled and most of the acetic acid was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer is
It was washed with water, an aqueous sodium carbonate solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3.346 g of 2-benzoylcyclohexanone. Yield 83%.

NMR ( _CDCl3 ); δ1.27-2.7 (m, 8H), 3.43
~3.97 (m, 1H), 7.03~8.06 (m, 5H). Reference Example 2 0.5 ml of dry ethyl alcohol was added dropwise to 50 mg of sodium hydride (50% oil dispersion). Add 2.02 g of α-morpholinobenzyl cyanide to the solution.
(10 mmol) in dry tetrahydrofuran (8 ml) was added dropwise under ice-water cooling. After stirring for a while, a solution of 0.96 g (10 mmol) of 2-cyclohexanone dissolved in 2 ml of dry tetrahydrofuran was slowly added dropwise. The reaction solution was made weakly acidic by adding dilute hydrochloric acid while cooling with ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.055 g of crude product.
Add 3.055 g of this crude product to 30 ml of 2N hydrochloric acid,
The mixture was heated under reflux for 18 hours. The reaction solution was cooled, water was added, and the mixture was extracted with ethyl acetate. This ethyl acetate layer was washed with an aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.914 g of a crude product. The crude product was purified by column chromatography to give 0.965 g of 3-benzoylcyclohexanone. yield
48%.

Reference Example 3 α-(3-
A solution of 1.144 g (4 mmol) of ethyl benzoylcyclohexylidene propionate in dry N,N-dimethylformamide (4 ml) was added dropwise and heated to 150-160°C.
The mixture was heated under reflux for 2.5 hours. Add water to the reaction solution,
The precipitated floating matter was filtered off using a glass filter, and the filtrate was extracted with ether. This ether layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and α-(3-benzoyl-2-
Ethyl cyclohexenylidene) propionate
1.095g was obtained. Yield 96%.

NMR ( _CDCl3 ); δ0.9-2.9 (2d, 12H), 3.83
~4.33 (m, 2H), 6.97~7.70 (m, 6H). Reference Example 4 α-(3-benzoyl-2 obtained in Reference Example 3)
-ethyl cyclohexenylidene)propionate
A mixed solution of 575 mg (2.02 mmol), 58 mg of 10% Pd-carbon powder, and 3 ml of diphenyl ether was heated and stirred at 200°C for 5 hours. The reaction solution was cooled, diethyl ether was added thereto, and then filtered through a glass filter covered with Celite. Diethyl ether was distilled off from the filtrate under reduced pressure to obtain 3.762 g of a diphenyl ether solution of the crude product. This was purified by silica gel chromatography to obtain 398 mg of ethyl α-(3-benzoylphenyl)propionate.
Yield 70%.

NMR (CDCl ₃ ); δ1.20 (t, 3H), 1.47
(d, 3H), 3.65 (q, 1H), 4.04 (q,
2H), 7.2-7.9 (m, 9H). Reference Example 5 350 mg of the bromide mixture obtained in Example 2 was dissolved in 5 ml of dry benzene. 1,5 in this solution
−Diazabicyclo (5.4.0) undecene −5 (383
mg) in dry benzene (2 ml) was added. The reaction mixture was stirred at 50°C overnight, poured into dilute hydrochloric acid, and extracted with ether. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and brine, and then dried. After distilling off the solvent, the crude product was purified by silica gel column chromatography.
90 mg of ethyl α-(3-benzoylphenyl)propionate was obtained. Yield 38%.

Reference example 6 Dissolve 200 mg of sodium hydroxide in 5 ml of water,
α obtained in Reference Example 4 dissolved in 2 ml of dioxane
Ethyl -(3-benzoylphenyl)propionate (282 mg) was added. The mixture was heated to 80° C. for 3 hours, cooled, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine and then dried. The obtained crude product was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain 202 mg of α-(3-benzoylphenyl)propionic acid as colorless crystals. Melting point 94-961℃. The spectral data also matched that of the standard product.

Claims (1)

[Claims] 1. General formula A cyclohexylidene ^{acetic acid} derivative ^{represented by} ).