JPH0416466B2 - - Google Patents

Description

Detailed Description of the Invention The present invention provides a general formula useful as an intermediate for pharmaceuticals, agricultural chemicals, etc. (In the formula, R represents a lower alkyl group, X represents a halogen atom, and n represents 0, 1 or 2) and a method for producing the same.

The compound of the present invention can be prepared by, for example, decarboxylating the 2nd position and then acylating the 1st position.
The agricultural and horticultural fungicides described in 7967255-51066, 55-57508, etc. can be produced with good yield.

As a method for producing the above-mentioned pyrrole derivative fungicide, a method shown in the following reaction formula is known.

(In the formula, X and n have the same meanings as above,
R' represents H, lower alkyl or methoxymethyl. ) However, in this production method, the pyrrole derivative represented by the formula () can be obtained by reacting the compound () with the compound () without passing through the compound of the present invention, but the yield varies depending on the type of Xn and the reaction conditions. Not only is the yield low at ~70%, but compound (), which is an important raw material compound, is known to be produced by the method shown in the reaction formula below, but the yield is low and the cost is high. It had the following drawbacks.

The present inventors have completed the present invention through repeated studies on a method for producing the pyrrole derivatives in good yield using readily available and inexpensive raw materials.

The compounds of the present invention have the general formula (In the formula, X and n have the same meanings as above, and Z represents a halogen atom, a nitrile group, or a sulfonyl group represented by the formula SO ₂ r (r represents an alkyl group or an aryl group). By reacting cinnamnitrile and isocyanoacetic esters represented by the general formula () CNCH ₂ COOR (in the formula, R has the same meaning as above) in an organic solvent in the presence of a base or a catalyst. can be manufactured.

As the base, an organic or inorganic base such as sodium hydride, sodium alkoxide, potassium alkoxide, metallic sodium, potassium carbonate or sodium carbonate is used. When using sodium hydride, alcoholate, metallic sodium, etc. as the base, non-hydrogen solvents such as benzene, toluene, ether, tetrahydrofuran, dimethoxyethane, etc. can be used as the organic solvent, but dimethoxyethane, dimethylsulfoxide, dimethylformamide, etc. It is preferable to use an anion-stabilizing solvent or a mixed solvent to which isocyanoacetate and an equivalent amount of dimethyl sulfoxide or dimethyl formamide are added. When sodium carbonate is used as the base, methanol, ethanol, etc. can also be used in addition to the above-mentioned solvents, and it is particularly preferable to use aqueous ethanol. As a catalyst, a copper compound that forms a complex with isocyanoacetic acid esters, such as cuprous oxide, is used.

The reaction temperature varies depending on the base, solvent, etc. used, but is usually carried out at room temperature or under mild conditions of 0°C to 45°C under cooling. However, when the reaction is carried out in a sodium carbonate-hydrated ethanol system, heating under reflux is also possible.

As Z in the cinnamnitrile represented by the above general formula (), functional groups that can be used as leaving groups such as chlorine, bromine, nitrile, methanesulfonyl, ethanesulfonyl, and tosyl can be used, but sulfonic acid-containing groups can be used. It is preferable to use

The structure of the compound of the present invention has been determined by MASS, NMR, and IR.
This was determined from the results of spectral analysis.

Hereinafter, the method for producing the compound of the present invention will be explained in more detail with reference to Examples.

Example 1 4.7 g of α-cyano-O-chlorocinnamonitrile and 1.1 g of 60% sodium hydride in a 30 ml four-necked flask.
g, prepare 15 ml of dry tetrahydrofuran and prepare 5 to 10 g.
3.1 g of isocyanoacetic acid ethyl ester dissolved in 5 ml of dry tetrahydrofuran was added dropwise under a nitrogen atmosphere at a reaction temperature of 10° C. or lower. After the dropwise addition, the mixture was stirred at room temperature for 3 hours to complete the reaction and the precipitated crystals were separated. The solution was dried under reduced pressure, dissolved in benzene, washed with water, dried, and dried again under reduced pressure. The obtained crude crystals were recrystallized from ethanol to obtain 3 g of 3-cyano-4-(2-chlorophenyl)-5-carboethoxypyrrole. Yield 44% Example 2 α-Chlor-O-chlorcinnamonitrile 2g
(0.01 mol) and ethyl isocyanoacetate 1.3 g
(0.0115 mol) in 30 ml of dry benzene was dissolved in 0.6 g of 50% sodium hydride in a stream of _N2 .
(0.0125 mol) of dry benzene and 20 ml of
It was added dropwise to a suspension of 10 ml of DMSO at a temperature of 0° to 5°C to cause a reaction. Thereafter, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 50 ml of ice water, extracted twice with 30 ml of ethyl acetate, and the organic layer was washed twice with 30 ml of saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography using benzene as a developing solvent to obtain 1 g of 2-ethoxycarbonyl-3-(2-chlorophenyl)-4-cyanopyrrole. Yield 38% mp136-138℃ Example 3 2.5 g (0.015 mol) of α-chlorcinnamonitrile and 2.1 g of ethyl isocyanoacetate
(0.0185 mol) of dried dimethoxyethane 25 ml
1.1 g of 50% NaH in a _N2 stream
(0.0229 mol) of dry dimethoxyethane 15 ml
was gradually added dropwise to the suspension so that the reaction temperature did not exceed 45°C. Thereafter, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 30 ml of ice water, extracted with 50 ml of ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography using benzene as a developing solvent, resulting in 2-ethoxycarbonyl-3-
1.3 g of phenyl-4-cyanopyrrole was obtained. Yield 36.1% mp156-158℃ Example 4 α-Tosyl-O-chlorcinnamonitrile 2g
(0.0063 mol) and ethyl isocyanoacetate 0.9
g (0.0079 mol) of dried dimethoxyethane 30
0.4 g of 50% NaH in a stream of _N2
(0.0083 mol) of dry dimethoxyethane 10 ml
was gradually added dropwise to the suspension so that the reaction temperature did not exceed 45°C. Thereafter, the mixture was stirred at room temperature for 30 minutes. After the reaction, the precipitated sodium p-toluenefluinate was separated, the liquid was concentrated, the residue was dissolved in 50 ml of ethyl acetate, washed with saturated brine, and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were dissolved in a mixed solvent of n-hexane/benzene (2:1).
Wash with 10 ml of 2-ethoxycarbonyl-3-
(2-chlorophenyl)-4-cyanopyrrole 0.9
I got g. The washing liquid was concentrated, and the residue was purified by silica gel column chromatography using benzene as a developing solvent to obtain 0.53 g of secondary crystals.

Yield 82.7% mp136-138℃ Example 5 3 g (0.0106 mol) α-tosyl-cinnamonitrile and 1.4 g ethyl isocyanoacetate
(0.0123 mol) of dried dimethoxyethane 20 ml
0.6 g of 50% NaH under a stream of _N2
(0.0125 mol) of dry dimethoxyethane 10 ml
was gradually added dropwise to the suspension so that the reaction temperature did not exceed 43°C. Thereafter, the mixture was stirred at room temperature for 1 hour. After the reaction, the precipitated sodium p-toluenesulfinate was separated, the liquid was concentrated, and the residue was dissolved in 30 ml of ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. . The obtained crude crystals were mixed with n-hexane and benzene in a mixed solvent of 1:1.
Washing with 10 ml gave 1.8 g of 2-ethoxycarbonyl-3-phenyl-4-cyanopyrrole. The washing liquid was concentrated, and the residue was purified by silica gel column chromatography using benzene as a developing solvent to obtain 0.128 g of secondary crystals. yield
75.8% mp156−158℃ Example 6 A solution of 2 g (0.00828 mol) of α-methylsulfonyl-0-chlorocinnamonitrile and 1 g (0.0088 mol) of ethyl isocyanoacetate in 25 ml of dry dimethoxyethane was prepared at 50% concentration in a stream _{of N2} .
The mixture was gradually added dropwise to a suspension of 0.4 g (0.0083 mol) of NaH in 10 ml of dry dimethoxyethane so that the reaction temperature did not exceed 40°C. Thereafter, the mixture was stirred at room temperature for 30 minutes. After the reaction, the precipitated sodium methanesulfinate was separated and the liquid was concentrated.
- The mineral oil component was removed by washing twice with 40 ml of hexane, then the residue was dissolved in 35 ml of ethyl acetate, washed with saturated brine, then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were washed with 10 ml of a mixed solvent of 1:1 n-hexane and Hensen,
1.5 g of 2-ethoxycarbonyl-3-(2-chlorophenyl)-4-cyanopyrrole was obtained. The washing liquid was concentrated and the residue was purified by silica gel column chromatography using benzene as a developing solvent.
0.36g of secondary crystals was obtained. Yield 82.7% mp140−
141℃ Example 7 2 g (0.00828 mol) of α-methylsulfonyl-0-chlorocinnamonitrile and 0.95 g (0.0084 mol) of ethyl isocyanoacetate were added to 40 ml of ethanol.
0.53 g of sodium carbonate in solution dissolved in ml
(0.005 mol) was added and heated under reflux for 50 minutes. After the reaction was completed, the mixture was cooled to room temperature and the precipitated sodium carbonate crystals were removed. acetic acid ethyl ester in liquid
After adding 30 ml and filtering, the liquid was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude crystals were washed with a mixed solvent of 7:3 of n-hexane-benzene to obtain 1.55 g of 2-ethoxycarbonyl-3-(2-chlorophenyl)-4-cyanopyrrole. The washing liquid was concentrated and purified by column chromatography using benzene as a developing solvent to obtain 0.1 g of secondary crystals. Yield 72.7
% Example 8 α-Tosyl-0-chlorcinnamonitrile 6.35
(0.02 mol), ethyl isocyanoacetate 2.26 g
(0.02 mol), sodium carbonate 1.06g (0.01 mol),
A suspension consisting of 30 ml of ethanol and 10 ml of water was heated under reflux for 30 minutes while stirring. Ethanol was distilled off from the reaction solution using a rotary evaporator, and the residue was extracted with benzene. The benzene layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The obtained crystals were washed with n-hexane to give 5.5 g of 2-ethoxycarbonyl-3-(2-chlorophenyl)-
4-cyanopyrrole was obtained. High performance liquid chromatography Purity 92.3% Yield 92.3% Reference example 1 8 ml of ethanol, 16.3 ml of water, sodium hydroxide
2-ethoxycarbonyl-3-(2-chlorophenyl)-4- in a solution consisting of 1.6 g (0.04 mol)
5.49 g (0.02 mol) of cyanopyrrole was added, and the mixture was heated under reflux for 5 hours while stirring. After the reaction solution was cooled, it was poured into ice water, and then hydrochloric acid was added to make it acidic. This was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and dried using a vacuum pump to give 4.52 g of 2-carboxy-3-(2-chlorophenyl)-4.
- Cyanopyrrole was obtained. Yield 91.3% Decomposition point
215.1℃ (This product has a purity that can be used in the next step without any particular purification.) Reference example 2 2-carboxy-3-(2-chlorophenyl)-
A mixture consisting of 9.86 g (0.04 mol) of 4-cyanopyrrole, 20 ml of quinoline, and 0.64 g (0.008 mol) of cupric oxide was heated at 150 to 60° C. for 2.5 hours with stirring. After the reaction solution was cooled to room temperature, it was poured into ice water containing 20 g of concentrated hydrochloric acid. After extraction with 200 ml of ethyl acetate, the organic layer was washed with saturated brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 8.0 g of a crude product.

The crude product was purified by silica gel column chromatography (eluent: benzene) to obtain 7.03 g of 3-(2-chlorophenyl)-4-cyanopyrrole.

Yield 86.8% Melting point 139.4℃

Claims (1)

[Claims] 1 (1) General formula (In the formula, R represents a lower alkyl group, X represents a halogen atom, and n represents 0, 1 or 2). 2 General formula {In the formula, X is a halogen atom, and n is 0, 1 or 2
, Z is a halogen atom, a cyano group, or a formula SO ₂ r (r
represents an alkyl group or an aryl group. ) represents a sulfonyl group. } and isocyanoacetic acid esters represented by the general formula CNCH ₂ COOR () (in which R represents a lower alkyl group). (In the formula, X, R and n have the same meanings as above.)
A method for producing a compound represented by 3. The manufacturing method according to claim 2, wherein the reaction is carried out in the presence of a base in an organic solvent. 4. The manufacturing method according to claim 2, wherein the reaction is carried out in an organic solvent in the presence of a catalyst. 5. The manufacturing method according to claim 2, 3 or 4, wherein Z is SO ₂ r (r represents an alkyl group or an aryl group).