KR820001236B1 - Process for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid - Google Patents

Abstract

5-Acyl-1-hydrocarbylpyrrole-2-acetic acids were prepd. by Grignard reaction of the 5-cyano-1-hydrocarbylpyrrole-2-acetic acids. Thus, N-methylpyrrole was treated with chloral and NaCN to give 58% 5-cyano-1-methylpyrrole-2-acetic acid, which underwent Grignard reaction with p-BrC6H4Me to give 98% 1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid.

Description

Method for preparing 5-acyl-1-hydrocarbyl pyrrole-2-acetic acid

The present invention relates to a method for producing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid using 5-cyano-1-hydrocarbylpyrrole-2-acetic acid as a starting material.

5-acyl-1-hydrocarbylpyrrole-2-acetic acid is known to have useful pharmacological properties. For example, 1-methyl-5-P-toluoylpyrrole-2-acetic acid has a significant anti-inflammatory effect.

[J. Pharmacologgy and Experimental Therapeutics, 185, 127 (1973)]

Typically 5-acylpyrrole-2-acetic acid, such as 1-methyl-5-aroylpyrrole-2-acetic acid, corresponds to the corresponding pyrrole-2-acetic acid, pyrrole-2-acetic acid ester, or pyrrole-2- Made by acylating acetonitrile. Known methods for preparing the starting pyrrole-2-acetic acid derivatives used in this acylation reaction are as follows.

(1) A method of obtaining 1-methylpyrrole-2-acetic acid ester by reacting diazoacetate with 1-methylpyrrole in the presence of copper powder as a catalyst. [J. Org. Chem., 14,664 (1946)]

(2) From the product obtained by the synthesis of 1-methylpyrrole and oxalyl chloride by the Friedel-Croft reaction to alcohol (1-methylpyrroyl) glyoxalic acid ester, reaction with hydrazine and treatment with potassium hydroxide Method for obtaining 1-methylpyrrole-2-acetic acid. (Wolf-Kishner Reaction) [Liebigs Ann. Chem., 721, 105 (1969).

(3) 1-methylpyrrole-2-acetonitrile was prepared from 1-methylpyrrole, dimethylamine and formaldehyde by the so-called Mannich base (Mannich reaction) and hydrolyzed to obtain 1-methylpyrrole-2-acetic acid. After making, change to methio iodide by methyl iodide and react with sodium cyanide. [J. Amer. Chem. Soc., 73, 4921 (1951).

These methods have the disadvantages of low yield and difficulty in obtaining industrially available amounts for use as reaction starting materials or reagents. Preferred acylation method of the pyrrole-2-acetic acid derivative is as follows.

(1) A method of reacting a pyrrole-D-acetic acid derivative with an aroyl chloride in the presence of an alkyl aluminum chloride. [Ger. Offen 2, 524, 299]

(2) Acylation using anhydrous mixed acid obtained from arylcarboxylic acid and trifluoroacetic anhydride. Japanese Publication 46-418

(3) Acylation using a reaction product obtained from N, N-dimethyl aroyl amide and phosphoryl chloride. Japanese Publication 46-418

(4) Acylation using anhydrous mixtures obtained from arylcarboxylic anhydride, methane sulfonic acid and the like. Japan Publication 50-126660

(5) A method of reacting a pyrrole-2-acetic acid derivative with phosgene to form a 5-chlorocarbyl derivative and reacting with a metal aryl compound. U S 3,846,447.

(6) Aroyl chloride is aroylated in a catalyst-free manner with 1-alkylpyrrole-2-acetic acid derivative using a suitable solvent. [U. S] 3,998,844].

(7) Acylation of suitable pyrrole-2-acetic acid derivatives with various acylating agents in the presence of Lewis acids such as aluminum softened. [U. S 3,752,826: 3,755,307: 3,803,169: 3,803,171].

These methods have the drawback of separating isomers which are low yields or by-products having acyl groups in the 4-position.

The inventors have found high yields using 5-cyano-1-hydrocarbylpyrrole-2-acetic acid, in particular 5-cyano-1-methylpyrrole-2-acetic acid, as readily available starting materials on an industrial scale. Invented a method for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid. In this reaction, 5-cyano-1-hydrocarbylpyrrole-2-acetic acid reacts with Grignard hydrocarbyl pyrrole and hydrolyzes the reaction product.

Preferred starting material, 5-cyano-1-methylpyrrole-2-acetic acid, is 1-methyl-2- (2 ', 2', 2'-trihal) produced from 1-methylpyrrole and trihalo acetaldehyde. It is obtained by reacting rho-1'-hydroxyethyl) pyrrole with a cyanating agent in a basic state.

In this scheme, 1-hydrocarbyl pyrrole such as 1-ethylpyrrole, 1-propylpyrrole, 1-amylpyrrole, 1-phenylpyrrole, 1-cyclohexylpyrrole, 1-benzylpyrrole and 1,3-dimethylpyrrole Other substituents make another 5-cyano-1-hydro carbyl pyrrole-2-acetic acid.

The Grignard compound, which is another starting material in the present invention, is easily prepared from the corresponding organic halide by general Grignard synthesis. Extensive preparations of the Grignard compound are well documented in the literature, for example: Kharasch and Reinmuth, Grignard Reaction of Nonmetallic Substnces, Prentice Hall, New York, 1954: ana Metal-Organic Compounds, (vol. 23 of Advances in Chemistry Series). American Chemical Society, Washington, D. C., 1959, 73-81 pape.

[Assassination Stage]

It is preferable to use a solvent to carry out the acylation step of the present invention. Examples of the solvent include organic quaternary amines containing hydrocarbons such as ether, dioxane, THF, dimethoxyethane. To this solvent Grigdad reagent is added and 5-cyano-1-hydrocarbylpyrrole-2-acetic acid is added. The reaction temperature is good at room temperature or the reflux temperature of the solvent used. In the present invention, the Grignard reagent is preferably added at 2 molar equivalents. One molar equivalent of Grignard reagent is consumed to form carboxylates and the equilibrium is used to introduce acyl groups.

At this stage the reaction mixture is made and hydrolyzed. Hydrolysis is achieved by direct application of products such as hydrochloric acid, sulfuric acid, impressions, oxalin phase and ammonium chloride. From the point of view of the reaction mechanism, the reaction takes place after the formation of the catamine salt as an intermediate as follows.

(R and R 'represent organic groups such as alkyl and aryl, and X is a halogen atom.)

Structural formula (I) compound as a starting material in the present invention is made as follows.

(X represents a halogen atom and R is a hydrocarbon, preferably a lower alkyl group, most preferably a methyl group.)

Harmless substituents (alkyl, etc.) may be present at the 3- and / or 4-positions of the ring.

[First Reaction-Adduct Formation]

In the one-step reaction, it is preferred that the pyrrole reactant reacts with trihalo acetaldehyde to generate adduct (II).

In this reaction, 1-methyl-2- (2 ', 2', 2'-trihalo-1'-hydroxyethyl) pyrrole obtained using 1-methylpyrrole is represented by Structural Formula (II): R = methyl) It is a known compound and its synthesis has reported that 1-methylpyrrole reacts with freshly distilled chloral in the presence of a molar equivalent of zinc chloride, Lewis acid. [R.C. Blinn et al., J. Amer. Chem. Soc. 76, 37 (1954). However, industrial use of this reaction is difficult because the yield is only 26.5%. By further studying this reaction, the inventors have found a way to obtain a compound of formula (II) almost equivalently without adding Lewis acid or other catalysts by treating the reactants at temperatures between -10 ° C and room temperature. . The proportion of this reaction is induced to some extent by the presence of a solvent that does not directly affect the reactions of diethyl ether, dioxane, ethers such as THF, and hydrocarbons such as benzene, toluene, hexane, etc. It is known that it is determined by the nature (or purity) of. Freshly opened chloral do not react with N-methylpyrrole at room temperature and form adducts over time (sometimes several days). In contrast, old bottles of chloral react immediately at room temperature. Assuming that trichloro acetic acid, which is readily produced due to the degradation of chloral, catalyzes the reaction, the present inventors have used organic acids such as trichloro acetic acid, acetic acid and P-toluenesulphonic acid as a reaction mixture for the reaction. Found to add to. Of these three acids, P-toluenesulphonic acid was found to be more effective than the others. By promoting the reaction in the presence of an organic acid or furophene phase added in the form of a positive ion exchange resin (e.g., amberlife), the adduct was easily formed and formed in approximately equivalence ratio.

[2-Step Reaction-Cyanation / Initial Hydrolysis]

It is a gist of the compound of this reaction structure (II) to react with a cyanating agent under a basic state. Examples of cyanide include potassium cyanide, sodium cyanide, copper cyanide, and acetone cyanohydrin. The basic state can be obtained by using a large amount of cyanating agent if it is a base. More preferred is cyanation in the presence of alkali metal salts such as sodium carbonate, potassium carbonate or alkali metal alcohol side such as sodium methoxide, sodium ethoxide, potassium methoxide (in which case the presence of water is essential). It is preferable to use. It is preferable to use a solvent in carrying out the reaction. Examples of the solvent include methanol, alcohols such as ethanol, ether dioxane, ethers such as THF, polar solvents such as dimethylformamide, dimethylsulfoxide and sulfolane and a mixture of the above solvents and water. And so on.

Thus, the best result was obtained by mixing methanol and water as the reaction solvent. The reaction takes place near room temperature and can be heated if necessary.

The 5-cyano-1-hydrocarbylpyrrole-2-acetic acid which is desired to separate the acidic portion by the above-mentioned conditions and alkali extraction and acidification can be selectively obtained.

The invention is illustrated in detail by the following examples.

Example 1 Addition Formation—No Catalyst Added

N-methylpyrrole (810 mg, 10 mmol) solution dissolved in benzene (10 ml) was added dropwise to chloral (1.47 g, 10 mmol) dissolved in benzene (5 ml) treated for 40 minutes on an ice-cold phase. After stirring the mixture at room temperature for 1 hour, water is added and the mixture is extracted with ether.

The extract is dried over sodium sulfate and then concentrated to give oily 1-methyl-2- (2 ', 2', 2'-trichloro-1'-hydroxyethyl) pyrrole (2.04 g).

Yield: 90%

NMR (CCl ₄ ): 83.61 (3H, s), 5.03 (1H, S), 5.95 (1H, m), 6.32 (1Hm), 6.47 (1H, m).

Example 2 Addition Formation—Adding Acid Catalyst

N-methylpyrrole (8.10 mg, 0.1 mmol) solution in ether (50 ml) Chloral (16.21 g, 0.1 mol) solution in ether (50 ml) is added. To this was added P-toluenesulphonic acid (200 mg) and hydroquinone (5 mg). The mixture is then refluxed for 15 hours.

Triethylamine (5 ml) is added and stirred for 5 minutes.

After adding brine (100ml), the organic layer is separated.

After drying over magnesium sulfate, the organic solution was filtered through an activated carbon layer and condensed to give light brown crystals 1-methyl-2- (2 ', 2', 2'-trichloro-1'-hydroxyethyl)- Obtain the pyrrole adduct.

Example 3 Adduct Formation and Cyanide / Base Hydrolysis

N-methylpyrrole (2.43 g, 30.0 mmol) and chloral (4.50 g, 30.5 mmol) react in dioxane (10 ml) at room temperature for 4 hours to form the adduct. This solution is added dropwise to a solution of potassium cyanide (1.90 g, 47.5 mmol) dissolved in methanol (100 ml). Potassium carbonate (8 g. 58 mmol) is added and stirred at room temperature for 5 days. After most of the solvent is removed, water is added and the mixture is washed with methylene chloride.

The methylene chloride layer is dried and concentrated to give starting adduct (7.2 mmol) and 1-methylpyrrole-2-aldehyde (2.6 mmol).

The solution mentioned above is made hydrochloric acid and extracted with methylene chloride. The extract is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography to give 5-cyano-1-methylpyrrole-2-acetic acid (940 mg).

Yield: 25%

m.p 125-126 ℃

NMR (CDCl ₃ ): 83.64 (5H, s), 6.05 (1H, d, J = 4H ₂ ), 6.68 (1H, d, J = 4H ₂ ).

IR (KBr): 3200, 2215, 1740cm ^-1

Example 4 Adduct Formation and Cyanide / Base Hydrolysis

N-methylpyrrole (1.62 g, 20.0 mmol) and chloral (3.20 g, 21.7 mmol) are reacted in dioxane (5 ml) to make an adduct. To this was added potassium cyanide (5.70 g, 88 mmol) and potassium carbonate (2.80 g, 20 mmol) dissolved in methanol (150 ml) and stirred for 4 days. Sodium hydroxide (3.0 g, 75 mmol) is added to the mixture in an equal amount and left for 3 days. The reaction mixture was treated in the same manner as in Example 3 to obtain 5-cyano-1-methylpyrrole-2-acetic acid (1.50 g), which was a well material.

Yield: 50%

Example 5 Addition Formation and Cyanide / Base Hydrolysis

N-methylpyrrole (1.62 g, 20.0 mmol) and chloral (3.20 g, 21.7 mmol) are reacted in dioxane (5 ml) to make an adduct. Potassium cyanide (6.20 g, 95 mmol) and potassium carbonate (2.80 g) dissolved in methanol (100 ml) were added to the solution, and the solution was heated to reflux for 21 hours. The reaction mixture is continuously treated in the manner described in Example 3 to obtain the same product. (880 mg).

Yield: 27%

Example 6 Addition Formation and Cyanide / Base Hydrolysis

A solution of N-methylpyrrole (810 g, 10 mmol) and chloral (1.6 g, 10.7 mmol) of eteph (10 ml) was refluxed for 24 hours. The solvent is removed at room temperature and the residue is dissolved in methanol (30 ml). This solution is added to sodium cyanide (3.0 g, 60 mmol) in water (30 ml). A solution of potassium hydroxide (2.6 g, 40 mmol) dissolved in water (15 ml) is added while heating this solution to 30-35 ° C. for 20 hours on an oil bath. After all additions, the reaction mixture is kept at the same temperature for twice the amount of time added.

The mixture is diluted with water and washed with methylene chloride. (There is very little starting material in this organic layer). The aqueous layer is carefully acidified with hydrochloric acid and then extracted with methylene chloride for several hours. Combine the extracts and wash with brine.

After drying over magnesium sulfate, the organic solution is concentrated. The residue is subjected to silica gel chromatography (nucleic acid ethyl acetate: 5-cyano-1-methylpyrrole-2-acetic acid (945 mg) which is a cyano acid desired as an eluent).

Yield: 58%

Example 7 Cyanide / Base Hydrolysis

The chloral / N-methylpyrrole adduct prepared in Example 6 is cyanoha according to the general procedure in Example 6. Reaction conditions and results are summarized in the following table.

<Production of 5-cyano-1-methylpyrrole-2-acetic acid>

Example 8 Acylation

Prepare Grignard reagent by dissolving magnesium (1.14g, 46.9matom) and P-toluene bromide (8.20g, 47.9mmol) in THF. 5-Cyano-1-methylpyrrole-2-acetic acid (1.61 g, 9.8 mmol) dissolved in THF (5 ml) was added to the above solution and the mixture was refluxed for 2 hours while heating. Acidified with hydrochloric acid and extracted with ether. The ether layer is dried, concentrated and purified by silica gel column chromatography to yield 500 mg of starting nitrile.

The aqueous layer is allowed to stand for two weeks at room temperature. The reaction mixture is extracted with ether and the ether layer is dried and concentrated to give crystals of 1-methine-5-P-toluoyl-pyrrole-2-acetic acid (1.60 g).

Yield: 92%

m.p 155-156 ℃

NMR (CDCl ₃ ): 82.37 (3H, s), 3.69 (2H, s), 3.89 (3H, s), 6.60 (1H, d, J = 4H ₂ ), 6.62 (1H, d, J = 4 Hz), 7.18 (2H, d, JEQUALS Hz), 7.66 (2H, D, JEQUALS 8 Hz): 3425, 2940, 2900, 170, 1600 ^-1 .

Example 9 Acylation

The Grignard reagent is prepared from magnesium (890 mg, 36.6 matom) and P-bromotoluene (6.25 g, 36.5 mmol) as described in Example 8. To this solution was added a solution of 5-cyano-1-methylpyrrole-2-acetic acid (1.50 g, 9.14 mmol) in THF (15 ml) and refluxed for 21 hours while heating the mixture.

To this mixture is added a saturated ether, and then acetic acid (4 ml) and water are added sequentially.

The aqueous layer is washed with methylene chloride and dioxane (100 ml) and concentrated hydrochloric acid (4 ml) is added. This aqueous mixture is left to stand at room temperature for 1 day and then extracted with methylene chloride. The organic layer is concentrated to dryness to obtain 1.57 g of 1-methyl-5-P-toluoylpyrrole-2-acetic acid as a desired substance. Dioxane (50 ml) is further added to the aqueous layer, and the mixed solution is allowed to stand for 2 days and then treated according to the method described above to obtain 400 mg of the desired substance.

Total yield: 84%

Example 10 Adduct Formation-Cation Exchange Resin

To a solution of N-methylpyrrole (1.62 g, 20 mmol) and 1 N-ether (10 ml) was added chloral (3.24 g, 22 mmol) dissolved in ether (10 ml). Emberist (160 mg) is added thereto and the mixture is stirred at reflux for 18 hours. Cool to room temperature and add triethylamine (0.3 ml). The mixture is stirred for 5 minutes and filtered through celite. The filtrate is concentrated under low pressure to give light brown crystals of the crude adduct 1-methyl-2- (2 ', 2', 2'-trichloro-1'-hydroxyethyl) pyrrole (4.68 g).

Example 11 Cyanide / Base Hydrolysis

Dissolve 1-methyl-2- (2 ', 2', 2'-trichloro-1-hydroxyethyl) pyrrole (1,14 g, 5 mmol) prepared in Example 2 in a solvent (15 ml) in the table below. To this solution is added water (15 ml) and alkali metal cyanide (MCN: the amounts are in the table below), and an aqueous potassium hydroxide solution (10 ml) is added to the solution over 6 hours with vigorous stirring (45 ° C). After stirring until the starting material, chloral adduct, was removed, the reaction mixture was diluted with water (100 ml) and extracted twice with ethyl acetate.

The organic extract is washed and dried over anhydrous magnesium sulfate. The solvent is removed at low pressure and the residue is dissolved again in 50 ml of ethyl acetate. A certain amount of solution is taken and treated with diazomethane dissolved in 1N-ether. Excess diazomethane was removed at low pressure, transstyrene was added as an intermediate standard and methyl-5-cyano-1-methylpyrrole-2-acetate (Theory) by GC (2% EGA column, 1M, 160 ° C) Yield, 5 mmol).

<5-cyano-1-methylpyrrole-2-acetic acid>

A) molar ratio with starting 1-methyl-2- (2 ', 2'2'-trichloro-2'-hydroxyethyl) pyrrole

B) Aqueous KOH solution was added for 1.5 hours.

Claims (1)

A process for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid, wherein the reaction product obtained by reacting 5-cyano-1-hydrocarbylpyrrole-2-acetic acid with a Grignard compound is hydrolyzed.