DE1770984A1 - Aroyl substituted pyrroles - Google Patents

Description

: Cologne, July 18, 1968

Sl / pz / I67

McNeil Laboratories, Inc., 110 Camp Hill Road, Port Washington

Pennsylvania, U.S.A.

Aroyl substituted pyrroles

The invention relates to 5-aroyl-pyrrole-alkane-carboxylic acids, their derivatives and therapeutically useful salts, of the formulas

"2

-cl

^(Ia) s  Ii (*>>

Ar-cl Ji-CH-R ₀ Ar-C ^

R, lower alkyl radical

methyl

^Π 3.-Ar ₁ -C

H.

in which Ar is a phenyl radical or one with one or more the substituents: halogen radicals, lower alkyl, lower ■ alkoxy, nitro, amino, methylthio groups or cyano radicals, substituted Phenyl radical,

Ar, a phenyl radical or one with one or more the substituents: halogen radicals, lower alkyl and lower alkoxy radicals, substituted phenyl radical, R a hydrogen atom or a lower alkyl radical, R, a hydrogen atom, a lower alkyl radical or benzyl

R ₂ one of the radicals CN, COOH, COO- (lower alkyl), CONHg,

CONH- (lower alkyl) and CON- (lower alkyl) ₂ and

R ^ one of the radicals COOH, COO- (lower alkyl), CONH ₃ , CONH-

(lower alkyl) and CON- (lower alkyl) ₂ , with the proviso that

1. R for a hydrogen atom, R for a lower alkyl radical and Rp for a -CN radical, a -COOH group or a -COO- (lower alkyl) group when Ar is a nitro-substituted phenyl radical or an amino-substituted one Denotes phenyl radical;

2. that R, for a lower alkyl radical and R ~ for a -COOH- or -COO- (lower alkyl) group when Ar is a cyanophenyl or methylthiophenyl radical; and

5 · that R stands for a hydrogen atom when R, a Means hydrogen atom.

The derivatives of these 5-aroyl-pyrrole-alkane-carboxylic acids are in particular Ester / nitriles, amides and substituted amides.

The non-toxic, therapeutically useful ones according to the invention Salts of these acids are salts with suitable organic or inorganic bases.

The "lower alkyl" and "lower alkoxy" groups mentioned here can be straight-chain or branched saturated hydrocarbon radicals having 1 to about 6 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, butyl, Pentyl, hexyl and similar alkyl radicals, or the corresponding alkoxy radicals such as methoxy, ethoxy, propoxy,

7 0 9 8 H / 1 7 3 7

- -7) -

Isopropoxy residues etc.

The compounds of the invention can be prepared using various synthetic methods. For example, compounds of the formula I ~ a in which R _{2 stands} for a -CN radical or a -COO- (lower alkyl) radical are generally produced by a Friedel-Crafts reaction between a benzoyl halide, preferably the chloride (II ) and a derivative of pyrrole-2-acetic acid of the formula (HI), in which R ^{r is} a cyano radical or a lower alkoxycarbonyl radical, in the presence of a Lewis acid, preferably a metal halide such as aluminum chloride. Suitable solvents are those which are usually used in Friedel-Grafts reactions, such as, for example, methylene chloride, 1,2-dichloroethane, carbon disulfide, nitrobenzene and the like. The acid derivative (IV) thus obtained can then be converted into the corresponding free carboxylic acid by conventional hydrolysis , for example by heating a solution of the derivative (IV) in aqueous methanol with an alkali metal hydroxide to form the alkali salt of the acid and then acidifying the mixture. The reactions described can be illustrated by the following equation.

O tr a RO

η U yt it

■ + * k N ^ A-GH-

Ar-C-Cl + * ^ N ^ a-CH-R ¹ AlCl, Ar-C- "

^ N

R ₁ - ■ .. S _R.

(II) (III) ^λ (IV)

If

NaOHv BCl ν Ar-C - * ^ N ^ JU CH-COOH

I "I

R ι

The benzoyl chlorides (II) are - generally known and can by converting the corresponding benzoic acid into the Acid chloride can be prepared by conventional methods such as the method shown in Example 81.

On the other hand, nitriles and carboxylic acids are used to produce the nitriles of formula (Ia), in which R is a lower alkyl radical

BATH ORIGINAL

means a derivative of 5-benzoyl-pyrrole-2-acetic acid of the formula:

Ar'-C -JL JL-CHp-R '(V)

in which R ^{1 has} the meaning mentioned, R "is a lower alkyl radical or benzyl radical and Ar ^{1 is} a phenyl radical or a phenyl radical substituted by halogen, lower alkyl, lower alkoxy radicals or cyano groups, alkylated using conventional alkylation processes, for example with a lower one Alkyl halide as an alkylating agent in the presence of a strong base such as sodium amide or sodium hydride, the corresponding nitriles and esters being obtained:

______ (lower alkyl)

s Π 71 '

Ar'- CJC JL-CH-R ¹ (VI)

R "
which are converted into the corresponding acids by conventional hydrolysis.

The carboxylic acid derivative (V) can be obtained by the above-described Friedel-Crafts reaction can be obtained.

The acetonitriles of the formula (VI) in which R "is lower Means alkyl radical, are also by customary N-alkylation of an N-unsubstituted 5-benzoyl-pyrrole-2-acetonitrile of the formula:

Ar '-CA ^ ^ J-CH ₂ -CN (VIl)

obtained, to which a customary C-alkylation of the thus obtained N-alkyl-5-benzoyl-pyrrole-2-acetonitrile follows.

209815/1737

After the N-alkylation or C-alkylation stage has ended can the corresponding carboxylic acids through customary hydrolysis processes can be obtained.

The nitriles, ESter and carboxylic acids of the formula (la) in which Ar is an amino-substituted phenyl radical are preferred from the corresponding 5-nitrobenzoyl-1-lower alkyl-pyrrole-2-acetic acid esters or nitriles, prepared according to the following reaction scheme, in which the corresponding Parade derivatives are listed as examples. (R * -V has the meaning already mentioned):

O ₂ N

-CH ₀ -R '

AlCl

Alkyl

Alkyl

Η _Λ Ν

CH ₀ -R 'hydrolysis

Alkyl

GOOH

In the previous reaction sequence, the nitro function is used of 5-nitrobenzoyl-1-lower alkyl-pyrrole-2-acetic acid ester or nitrile, (produced by the Friedel-Crafts reaction was obtained), catalytically hydrogenated, for example with hydrogen and palladium on carbon as a catalyst. This produces the corresponding 5-aminobenzoyl-low Alkyl-pyrrole-2-acetic acid ester or the corresponding Nitrile, which then becomes the corresponding free acid is hydrolyzed or saponified.

Esterification of the carboxylic acids of the formula Ia with a slight excess of a suitable lower alkanol results the corresponding esters, in those cases in which Rp denotes the radical -COO-lower alkyl. Preferably receives the methyl ester of the formula Ia by the Friedel-Crafts reaction described above between a suitable Benzoylhalogeriid II and a suitable methyl-pyrrole-2-

209816/17 J7. ^ _{0 0R1GINAL}

The primary amides of the formula Ia are obtained in a simple manner • way by partial hydrolysis of the corresponding nitriles of the formula Ia. The conversion of nitriles into amides takes place by conventional methods, for example by treatment of the nitrile with aqueous sodium hydroxide at reflux for a relatively short period, i.e. a treatment period, which is sufficient for partial hydrolysis to the amide stage, as opposed to complete hydrolysis to the stage the carboxylic acid. The corresponding amides substituted with lower alkyl radicals are preferably obtained by that one first converts the carboxylic acid function of carboxylic acids of the formula Ia into the corresponding acid chloride function transferred what, for example, by treating the carboxylic acid or its alkali salt mitihionylchlorid or oxalylchloride takes place, and the carboxylic acid chloride thus obtained with a suitable lower alkylamine or the lower Alkyl amine to form the corresponding N-alkyl or N, -N-dialkylamides of the formula Ia.

The compounds of the formula Ib, in which R, the radical -COO- (low Alkyl), preferably an ethoxycarbonyl radical, and Ar does not represent an aminophenyl radical, are preferred by Friedel-Crafts reaction between a suitable Benzoyl halide, preferably the chloride VIII and a lower alkyl-1-lower alkyl-pyrrole-2-propionate IX manufactured. The usual hydrolysis of the thus obtained lower alkyl - 5-benzoyl-1-lower alkyl-pyrrole-2-propionate X leads to the corresponding free carboxylic acids of the formula Ib. The free. Acids can in turn by conventional methods using ammonia or a suitable one Alkyl or dialkylamine in the corresponding amides of the Formula Ib will be transferred:

0

"Ii ii

Ar-C-Cl + .U ₁ NJUCH ₀ CH ₀ -C OO alkyl AlCl, (VIII) alkyl ( _IX ) >

.JJi-J- CH ₂ CH ₂ -COCAIlCyI hydrolysis * Ar-C Jl JjLCHgCHg-COOH alkyl _Ä M * A.if *> - M «if ■ ^A Wl

- 7 -. ■ .. ■ · ■■■

The compounds of the formula Ib in which Ar is an aminophenyl-. rest is, are preferably from the corresponding lower alkyl esters of 5-nitrobenzoyl-l- (lower alkyl) -pyrröl-2-propionic acids (which are obtained by customary Friedel Crafts reaction of a nitrobenzoyl chloride with an alkylprofdonate IX), by converting the nitro function into a Amino function according to the above for the compounds _; of the formula Ia described Heakti ons schema tiered,! ie with the help of catalytic hydrogenation and subsequent hydrolysis.

The alkyl propionates IX can be prepared by first treating a suitable N-alkylpyrrole-2-aldehyde "M" with a suitable alkoxycarbonyl-methylene-triphenylphosphorane (R. Jones et al., Cänad. "Tour. Chem., 18 , 883 (1965)) and then the resulting alkyl 2- (1-alkyl-2-pyrrolyl) acrylate, hydrogenated to the desired alkyl propionate IX, the double bond of the acrylate function being saturated ».

The compounds of the formula Xe are selected from the point of view of suitability

l-Aryl-1,2,3-butanetrione-2 »oxime (XI) and a suitable di« ' allyl ester of acetone dicarboxylic acid (XIl) prepared as starting materials. Both connections are made accordingly

a Knorr ¹ see pyrrole synthesis in glacial acetic acid in the presence ^! ■ "

of zinc dust reacted with each other * with ring closure to I m

the corresponding pyrrole, namely the Alkyipster from 5- t

ί ti

Aroyl-3 * alkoxycarbonyl- ⁱ l-methylpyrrole-2-oacetic acid (XIII) j * ■ takes place. Hydrolysis of the latter compound with moderately concentrated alkalis, for example with 25 to 50%,! [. aqueous sodium hydroxide, leads to the corresponding. '.-Free dicarboxylic acid XIV, which then with the aid of an acidic: partially esterified% solution of a lower alcohol again' * ■ is to the corresponding alkyl ester of 5-Ärayl-3 ~ carboxy - to obtain methylpyrrole ^ -acetic XV - ^. Decarboxylation of the carboxy group in the J position is then carried out by heating the compound in a suitable basic solvent such as quinoline. The received ^!

2098 1 S / 1 737

BATH ORIGINAL

Alkyl ester of 5-aroyl-4-methylpyrrole-essi @ acid XVI then hydrolyzed in the customary manner to give the desired free acids XVII of the formula Ic. The acids in turn can esterified with the aid of lower alkenols to give the corresponding lower alkyl esters of the formula Ic or by customary processes using ammonia or a suitable alkyl or dialkylamine into the corresponding amides of Formula Ic are converted. The reaction sequence described can be illustrated by the following equation:

Me

Ar -ΟΙ ti

C = O

C = NOH

(χι)

COO

O = C

CHgCOO ethyl
(XII)

·, Zn * HOAc /

0 ti

Ar ₁ -C

Me

COO ethyl CH ₂ COO ethyl

(XIII)

0 Me

hydrolysis

Ar, - ¹

COOH

CHpCOOH ethanol
H ⁺

0 Me

Ar _n -C

(XV)

COOH CH _o C00 Ethyl

0 vMe 0 Me

CH ₂ COO Ethyl Hydrolysis ^ _kv J

(XVI)

(XVII)

CH ₂ COOH

209815/1737

SAD ORIGINAL

The compounds of the formula Id are derived from the known Pyrrole ester, the ethyl ester of 2,4-dimethylpyrrole-3-acetic acid (XVIII) prepared according to a Friedel-Crafts reaction using a suitable benzoyl halide, preferably the chloride (XIX), as acylating agent, is acylated. The methyl group in the 2-position of the 3-ethyl-5-benzoyl-2,4-dimethylpyrrole-3-acetate obtained in this way (XX) is then made by treating this ester (XX) with sulfuryl chloride in an inert solvent such as Ether, perchlorinated, the corresponding ethyl 5-benzoyl-4-methyl-2-trichloromethyl-pyrrole-2-acetate (XXl) arises. The hydrolysis of the latter compound, for example ™ takes place for a few hours by refluxing in aqueous dioxane or 1,2-dimethoxyethane, the results Dicarboxylic acids STbenzoyl ^ -methyl ^ -carboxy-pyrrole-J-acetic acid. (XXII) .. The carboxylic acid function in the 2-position is then removed, for example by heating in a suitable basic organic solvents, such as quinoline, in order to give the desired free acids (XXIII) of the formula Ic to get. These acids in turn can be converted into the corresponding esters and amides of the formula Ic in the customary manner will. This reaction sequence described can by the following formula scheme can be illustrated:

H ₀ COO ethyl 0 0 Me CH ₀ COO ethyl

⁺ Ar ^ -C-Cl AlCl, Ar -, -

J- ^ N. -L

^H "■ - .. ■ 7 H

(XVIII) (XIX) (XX)

0 MoCH ₂ COO ethyl O Me CH ₂ COOH

SOCl ₂ Ar ₁ -CC ^ A ₀₀₁ hydrolysis ι A ^ -cJjjl · COOH

H ^J ■ ' H

(XXI) (XXII)

-CO ₂

^H 209816 / 173-7

(XXIII)

ßAD ORIGINAL

- Io -

The corresponding salts of the acids of the formulas Ia, b, c and d, are easily obtained by treating the acids with an equivalent amount of a suitable base, for example an alkali or alkaline earth metal hydroxide, such as sodium hydroxide, Potassium hydroxide, barium hydroxide, calcium hydroxide, i.a. or with an organic amine e.g. a lower Alkylamine such as ethylamine, propylamine, etc. or others Amines such as benzylamine, piperidine, pyrrolidine and others.

The compounds of the invention of the formulas Ia, b, c., and d and their therapeutically active salts have valuable pharmacological properties which they use make suitable in common pharmaceutical drug formulations. It was found that these compounds possess anti-inflammatory activity, as in the standard kaolin-induced paw edema test is shown in the rat and the cotton ball granuloma test with doses between 5 to 10 mg / kg body weight.

The experiment with kaolin-induced rat paw edema measures the ability of a compound administered in a single oral dose to prevent swelling of the rat paw into which a standard amount (0.1 ml) of a sodium kaolin suspension in saline has been injected . For comparison purposes, the activity of the test compound is measured in comparison with the activity of the known anti-inflammatory agent phenylbutazone. Male Holtzmann rats were used for the experiment. In this experiment, it was found, for example, that the compound 5- (p ~ CM.orbenzoyl) -lmethyl-pyrrole-2-acetic acid had an anti-inflammatory effect of about 55 % at a dose of 12.5 mg / kg, about 47 % at 25% mg / kg and 45 to 53 % inhibitory effect in doses of fib to 100 mg / kg, while phenylbutazone has an inhibiting effect of about 3 ° to 40 % at 100 mg / kg.

BAD ORiGiNAL

209815/173?

The ability is tested in the cotton ball granuloma test. . a compound that is male daily for 7 days Holtzmann rats are administered orally to inhibit the formation of granuloma tissue in or around a cotton ball, which are implanted in the animal's chest region under the skin became. This inhibitory effect is compared with control tests carried out using water became. This method is by Charles A. Winter and co-workers in J. Pharmacol., 14l, 3β9 (Ι9β>) »t> e. The study of the changes is used to determine the significance of the results obtained determine. For example / in this test at Use of the compound 5- (p-anisoyl) -l-methylpyrrole-2-acetic acid a granuloma weighs about 71 mg in one Dose of 25 mg / kg obtained, compared with a granuloma weight of Ho mg in the control experiments with Water ^ and the compound 5- (p-0hlorbenzoyl) -l-methylpyrrole-2-acetonitrile gave a granuloma weight of about 98 mg at a dose of 100 mg / kg compared to II5 mg in the control experiments with water.

The table below is the anti-inflammatory activity various compounds of the formulas Ia, b, 0 and d are listed. These compounds are exemplary of the valuable properties of all compounds that come under the formulas Ia, b, c and d and the pharmaceutically suitable basic salts of these compounds, without the invention to limit it.

209815/1737

SAD ORIGINAL

- 12 - 25th 1770984 Table 1 25th 25th Inhibiting effect 25th Average of .25 Io rats 25 - 47 Kaolin-induced rat paw edema test 25th 41 Dose (p.o) 25th 44 mg / kg loo 51 25th 42 5- {p-chlorobenzoyl5-l-methylpyrrole-2-acetic acid € loo 42 5- (m-chlorobenzoyl) - " 25th 42 5- (o-chlorobenzoyl) " 44 5. (2 ^! , 4'-dichlorobenzoyl) "· 5o 55 5- (p ~ bromobenzoyl) " 23 5- (p-fluorobenzoyl) " 25th 2o 5 ~ (p-methoxybenzoyl) " 25th ' 58 5- (p-methylbenzoyl) " 5- (p-nitrobenzoyl) " loo 56 "5- (p-aminobenzoyl)" 5o 5- (p-cyanobenzoyl) " 22nd 5- ^ enzoyl ^M 25th 32 5- (p-chlorobenzoyl) -a-methyl-1-raethylpyrrole-2- acetic acid 25th 43 5- (p-chlorobenzoyl) -α-ethyl-l-methylpyrrole-2- 5o 23 acetic acid 5- (p-chlorobenzoyl) pyrrole-2-acetic acid 25th 5- (p-chlorobenzoyl) -l-a-thylpyrrole ^ -acetic- acid 25th 38 l-Benzyl-5 '"(p-chlorobenzoyl) -pyrrole-2-vinegar-
acid 55 fithyl-5- ^(p-c hlorbenzoyl) -l-methylpyrrole-2- 25th • acetate 25th Methyl-5- (p-chlorobenzoyl) -l-methylpyrrole-2- 5o acetate loo 36 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetamide 5- (p-chlorobenzoyl) -N-ethyl ~ l ~ methylpyrrole-2- BAD ORJGJNAL 63 acetamide 5- (p-chlorobenzoyl) -Ν, Ν-diethyl-l-niethylpyrrole- 2-acetamide 5- (p-chlorobenzoyl) -l-methylpyrrole-2-propion- acid 5- (p-chlorobenzoyl) -4-methylpyrrole - ^ - vinegar- acid 5-benzoyl-4-methylpyrrole-2-acetic acid 209815/1737

■ - 13 - ■

As anti-inflammatory agents, the compounds are the Formulas Ia, b, c and d and their salts are valuable for "Ent-, ignition change and to alleviate the symptoms of rheumatism ■■ · ■; ■ table, artritic and other inflammatory conditions. The compounds can be used in therapeutic doses in conventional pharmaceutical formulations for oral and parenteral use Application are given, for example tablets * capsules, j Solutions, suspensions, preparations, injectable formul- ' rungen, etc.,

From the previously described method for producing the Compounds according to the invention can be seen that number λ rich of the compounds of the formulas Ia, b, e and d also as intermediates are useful for the synthesis of other of these compounds. For example, the nitriles and esters represent of the formulas IV, V, VI, and VII valuable intermediates for the synthesis of the corresponding acids. In addition, the 5-nitrobenzoyl compounds of the formulas Ia and Ib are valuable Intermediate products in the process of conversion into the corresponding 5-aminobenzpyl compounds. In addition, are the acids represented by formulas la, b, c and d important intermediates for the conversion into the corresponding EsteijAmide and base salts.

The invention is illustrated by the following examples. M example 1

Ethyl 5 "(p-chlorobenzoyl) -l-methylpyrrole-2-acetate; To a solution of 22.0 g (0.131 mol) ethyl N-methylpyrrole-2-acetate and 2.4.5 g (o., 14 mol) of ρ-chlorobenzoyl chloride in 120 ml. carbon disulfide is added a 35 ° g (α, 262 mol) of anhydrous aluminum chloride over the course of 20 minutes, cooling at intervals to keep the temperature at 25 ° C. The mixture becomes Stirred for an additional 20 minutes, then decant and discard the solvent carbon disulfide, wash the red gummy residue with hexane and dilute hydrochloric acid, add ice to the mixture, and extract the mixture with ether.

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8AD ORIGINAL

The ethereal solution is extracted by shaking with an aqueous solution of dimethylaminopropylamine and washed first with dilute hydrochloric acid and then with brine. The solution is dried over magnesium sulfate and treated with animal charcoal. After the animal charcoal has been removed, the solvent is evaporated in vacuo, leaving a partially crystalline * red 'oil as a residue. This product is extracted with 100 ml of boiling pentane each time. The combined pentane extracts are evaporated in vacuo and the residue is crystallized from 60 ml of cold methanol. The pesticide obtained is isolated and washed with cold methanol. Ethyl-5- ( p-chlorobenzoyl) -lmethylpyrrol-2-acetate as a white crystalline solid of melting point 74 to 76 ⁰ C. by recrystallization from Methylcyklohexan the melting point is increased to 78 to 8o ° C.

* Example 2

5- (p-Chlorobenzoyl) -l-methylpyrrole-2-acetic acid and its sodium salt.

A suspension of 5.06 g (o, ol mol) of ethyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetate in 25 ml of 0.5 η sodium hydroxide is refluxed for 10 minutes. About 2/5 of this solution is cooled, washed with ether and then acidified with dilute hydrochloric acid. The solid precipitate obtained is isolated by filtration, dried and recrystallized from aqueous ethanol. In this case, the desired product, 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetic acid having a melting point of 189 to 19I ⁰ C is obtained. After recrystallization from ethanol-water of the melting point is 188 to I90 ⁰ C. The remaining third of the solution is cooled in an ice bath, the sodium salt of the acid yellow off. falls and is recovered by filtration.

Analysis: Calculated for C ^ ₁ HgClNO _3: C, 6o.54; H, 4.36; N, 5.05 % found C, 6o.54; H, 4.37; N, 5.14 %.

20941 S / 173-7 _ßAD0RIQ1NAu

Example '3

According to the method described in the preceding examples, with the modification that instead of the _{p-chlorobenzoyl chloride used in Example I 1} , an equivalent amount of benzoyl chloride is used, the corresponding products are ethyl-S-benzoyl-1-ffle.thyl ^ yrrol- gt-acefca ^ and 5- "benzoyl-l-methyl-pyrrole-2-acetic acid.

Example 4 '

5-benzoyl-1 "iuethylpyrrole" 2-acetonitrile

9 ml (0.07 mol) of benzoyl chloride are added to a cooled suspension of 9.7 g (0.07 mol) of aluminum chloride in 45 ml of methylene chloride. The solution obtained is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 150 ml of methylene chloride while the acid mixture is cooled from the outside with an ammonium chloride ice bath (temperature below 5 ° C.) after the addition is complete; the reaction mixture was stirred for 15 minutes at 0 ° C. and then poured into an ice bath acidified with 3 η hydrochloric acid. The acid fraction is 3 times mili methyl ^ nchlorid extracted, the organic fractions are combined and washed successively with N, N-dimethyl-l, 3-propane <AEI M washed amine and 3 π hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated to give an oily residue which is chromatographed on the column on neutral aluminum oxide using hexane, benzene and ethyl acetate as successively applied eluents. The first fractions with an ultraviolet absorption in the range of 24o to 26o mu contain the desired product. These fractions are combined and the solvent is evaporated. After trituration with methanol, the oily residue gives the crystalline product, S-banzoyl-1-methylpyrrole ^ -acetonitrile with a melting point of 10 ° to 108 ° G.

209815/1737

BATH ORIGINAL

Example 5

g-Senzoyl-1-methylpyrrole-g-acetic acid .

A suspension of 2.42 g (o _# ll mol) of S-benzoyl-1-methylpyrrOl-2-aoetonitrile, 0.9 g (d, 22 mol) of sodium hydroxide, 6 ml of water and 0.5 ml of ethanol is used for 1 hour stirred and heated to reflux. The resulting solution is cooled and extracted with water and chloroform. The aqueous fraction is mixed with 3 η hydrochloric acid. Here, a white solid, 5-ß-aoyl-1-methyl-graft-acetic acid, fills out, which is filtered off and washed with a hexahydrate solution. The product has a melting point of 144 to 145 ° C.

Analysis t calculated for found

ϊ C, 69.12; H, 509J N, C, 69.2 ^; H, 5.47; N,

Example 6

5- (m-chlorobenzoyl) l-methylpyrrole-2-aoetonitrile .

25 g (0.12 mol) of m-chlorobenzoyl chloride are added dropwise to a cooled suspension of 16.6 g (0.12 mol) of aluminum chloride in 60 ml of 1-, 2-dichloroethane. The suspension obtained is added dropwise to a cooled solution of 15 g (0.12 mol) of 1-methylpyrrole-2-aeetonitrile in 60 ml of 1,2-dichloroethane. The reaction mixture is stirred at room temperature for about 20 minutes and then heated and refluxed for 5 minutes. The reaction is terminated by pouring the mixture onto ice acidified with 3η hydrochloric acid. The 2 fractions obtained are separated from one another. The aqueous fraction is washed with chloroform. The organic fractions are combined and washed successively with N, N-dimethyl-lj ^ -propanediamine, J5 η hydrochloric acid and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate. That

209815/1737

Solvent is evaporated and the residue obtained triturated with cold methanol. The red-boiled product is obtained in the form of a precipitate which is filtered off and is set aside. The iuethanolischen filtrate is im Concentrated vacuum and the remaining oily residue on a column charged with neutral aluminum oxide chromatographed using hexane ^ nzene and ether as sequential eluents. About 2.5 S. of the desired product are made by evaporating the first ethereal fractions that receive the compound. The solids are combined and recrystallized from methanol. This gives 3.6 g of 5- (m-chlorobenzoyl) -lmethylpyrrole ^ 2-acetonitrile with a melting point of 122 to

Analysis8 calculated for C ₁ ^ H ₁₁ ClNgQj N, lo, 83 $ found N, lo, 52 #.

Example 7

^ - (m-ChlorbQytzoyl) -l-methylpyrrole-2-acetic acid.

A mixture of 2.8 g (ο, σΐ mol) 5- {m-chlorobenzoyl) -l ~ methylpyrrole-2-acetonitrile, 22 ml 1 η sodium hydroxide solution and 5 ml ethanol is refluxed for 15 hours with stirring. A certain proportion of the ethanol is evaporated. The remaining solution is poured onto ice acidified with dilute hydrochloric acid. It is striking a white solid, 5- (m-chlorobenzoyl) -l-methylpyrrole-2-acetic acid from which is recrystallized 2 times from methanol / water "and then has a melting point of 165 ⁰ Q. '

Analysis: calculated for ^C ₁ 4 ^H ₁ 2 ^C1NO 3 ^? °> - ⁶⁰ ^ i H, 4.36; N, 5.o5 found C, 6σ.6ΐ; Η, 4.4α; Ν, 4.87

20981 S /

BADORfQlNAL

Example 8

Α »The procedure according to Example 6 is repeated with the exception that instead of m-chlorobenzoyl chloride an equivalent Amount of p-bromobenzoyl chloride and p-fluorobenzoyl chloride used will. In this way the following products are obtained:

S-Cp ^ BrorabenzoylJ-l-methylpyrrole - ^ - acetonitrile, Pp Ij59-14l ° C and 5- (p-pluorbenzoyl) -l-methylpyrrole-2-acetonitrile, Pp 134-156 ⁰ C.

B, Following the procedure of Example 7 using an equivalent amount of the acetonitrile just mentioned instead of 5 ~ (m-chlorobenzoyl) ~ 1-methylpyrrole-2-acetonitrile the following corresponding acids? 5- (p-Bromobenzoyl) -l-methylpyrrole-2-acetic acid, pp 188 ° C and 5- (p-Pluorbenzoyl) -l-methylpyrrole-2-acetic acid, pp 164-105 ° C.

Example 9

G" ( o-chlorobenzoyl) -l-methylpyrrole-2-acetonitrile.

To a cooled suspension of 14 g (0.15 mol) of aluminum chloride 18.5 g (0.15 mol) of o-chlorobenzoyl chloride are added dropwise to 45 ml of dichloroethane. The received Solution is added dropwise to a cooled (0 ° C) solution of 1-methylpyrrole-2-acetonitrile in 45 ml of dichloroethane, the temperature being kept at lo ° C. The mixture is stirred at room temperature for about 20 minutes

; and then refluxed for 5 minutes. Then it will Poured onto ice acidified with 3 η hydrochloric acid and the 2 layers obtained separated from one another. the aqueous fraction is extracted twice with chloroform. The organic fractions are combined and washed twice with N, N-dimethyl-l, 3-propanediamine, Washed once with 3 η hydrochloric acid and once with saturated sodium chloride solution.

20981S / 1737 bad original

The organic fraction is dried over anhydrous magnesium sulfate. The solvent is evaporated and the oil obtained on a column sent with neutral aluminum oxide using benzene and ether as Eluent chromatographed «The first substance-. - ■■ '■ contained fractions contain the desired product « The solvent is evaporated and the oil obtained is allowed to pass through -Treatment with methanol crystallizes »The solid, 5- (o- '! ChlorbenzoslJ-l-methylpyrrole-S-acetonitrile, is made by Recrystallize from BenEol-Öyelohexan-. solution cleaned and has a melting point of 80 to 85 ° C. ■ "

Example Io -

5 ". (O-chlorobenzoyl) -l * -methylpyrrole-g-acetic acid"

A solution of 2.4 g (0.09 mol) of S-tomethylpyrrole-2-acetonitrile 18 ml 1 η .Natriumhydfojcyd and 18 ml of 95 # strength ethanol is stirred for 7 hours refluxed. The ethanol is evaporated and the obtained solid residue dissolved in water and washed with chloroform. The aqueous layer is acidified with 3 η hydrochloric acid. An oil precipitates out and crystallizes after rubbing. The solid obtained is filtered off and washed with water and hexane. The solid is duroh uni-. crystallize from methanol-water and then from ether-: Purified hexane. Fp: 14o to 1 * H ° C.

Analysis; for C ₁₁₁ H ₁₂ ClNO: C, 60.5h ', H, 4.3β> Ν »5 · ο5 % found C, 60.55; H, K.kj ' _t N, 4.91 : ■%,

Example 11

5- (2 ¹ , 4 '-Dichlorobenzoyl) ■ »l-methylpyrrole-2-ac.etonitrii.

To an aqueous solution of 16.6 g (0.125 mol) of aluminum chloride in 60 ml of 1,2-dichloroethane are 2β, 2 g (o, 125 mol) 2,4-DLchlorobenzoyiohloride given. The solution obtained gives

209 81 B / 1737

BATH ORIQIMAL

- 2ο -

slowly to a solution of 15 g (0.125 mol) of 1-methylpyrrole-2-acetonitrile in βο ml of 1,2-dichloroethane, the reaction mixture being cooled from the outside with an ice bath. When the addition is complete, the mixture is stirred at room temperature for 40 minutes and then refluxed for 3 minutes, then poured onto ice acidified with dilute hydrochloric acid. The organic phase is separated off and washed successively with N, N-dimethyll # 3-propanediamine, 3 η hydrochloric acid and saturated sodium chloride solution * It is then dried over magnesium sulphate and the solvent is evaporated. The red oily residue obtained is chromatographed on a column charged with neutral aluminum oxide and eluted with benzene and ether. The first fractions containing a substance give, after evaporation of the solvent, a white pesticide, 5- (2 ^l , V-dichlorobenzoyl) -l-methylpyrrole-2-acetonitrile. The product is purified by recrystallization from methanol and then has a melting point of 129 to 150 ° C.

Analysis 1 calculated for C ₁ ^ H ₁₀ ClpN ₂ O: N, 9.56 %, found N, 9.51 %.

Example 12

5- (2 ', 4 ^t -f3dohlorbenzoyl) -l-methylpyrrole-2-acetic acid.

A solution of 4.3 g (0.55 mol) of 5- (2 ^t , 4 ^t -dichlorobenzoyl) -lmethylpyrrole-2-acetonitrile in 1 ml of 1 η sodium hydroxide and 30 ml of 95 tiger ethanol is refluxed overnight. The solution is concentrated and poured into dilute hydrochloric acid. A white pesticide, 5- (2 ^?, 4 ^! Dichlorobenzoyl) -l-methylpyrrole-2-acetic acid, precipitates out and recrystallizes from isopropanol and methanol. Fpi I65 - 166 ° C.

Analysis Calculated for C ₁ ^ H ₁₁ Cl ₂ NO ₃ : C, 53.86; H, 3.55; N, 4.68 found C, 53.97; H, 3.66; N, 4.69

209815/1737

BATH ORIGINAL Example 13

5- (p-Toluo-yl) -1-methylpyrrole-2-acetonitrile.

3o.8 g (0.2 mol) of p-toluoyl chloride are added dropwise to a cooled suspension of 26.6 g (0.2 mol) of aluminum chloride in 80 ml of dichloroethane. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 80 ml of dichloroethane, which is cooled externally with an ice bath. When the addition is complete, the resulting mixture is stirred at room temperature for 20 minutes and then refluxed for 3 minutes. The solution is then poured onto ice acidified with dilute hydrochloric acid. The organic and the aqueous fraction are separated from one another. The aqueous fraction is extracted once with chloroform. The organic fractions are combined and washed successively with N, N-dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated. After the residue has been triturated with methanol, a solid crystallizes out, 5- (p-toluoyl) -l-methylpyrrole-2-acetonitrile, which is removed by filtration and purified by recrystallization from benzene. Additional product is isolated from the mother liquors, which are combined and concentrated in vacuo. The oily residue obtained is chromatographed on neutral aluminum oxide on the column, hexane, benzene and ether being used as successive eluting agents. The product is isolated by concentrating the first main fractions containing substance (10 % ether in benzene). The solids are combined and recrystallized from methanol and then from benzene-hexane. Fp: Io2 - Io5 ° C.

example lK

5- (p-Toluoyl) -l-methylpyrrole-2-acetic acid,

209Ö1B / 1 737

BATH ORIGINAL

A solution of 5.67 g (o, ol5 mol) 5- (p-4Poluoyl) -l-methylpyrrole-2- acetonitrile, 24 ml 1 η sodium hydroxide and 5o ml 95 J # igem ethanol is stirred for 24 hours on Heated to reflux. The resulting solution is poured onto ice acidified with dilute hydrochloric acid. A white plague precipitates, which is extracted with ether will. The ethereal phase is washed with a saturated solution of sodium chloride and over anhydrous magnesium sulfate dried. After evaporation of the solvent, a white solid is obtained, 5- (p-lbluoyl) -l-methylpyrrole-2-acetic acid, which is recrystallized 2 times from isopropanol. Pp: 155 - 157 ° C.

Example 15

A. The procedure of Example 11 is repeated with the exception that instead of 2,4-D.ichlorbenzoyl chloride one equivalent amount of o-toluoyl chloride, m-toluoyl chloride, p-Kthylbenzoylchloride and 3,4-Dimethylbenzoylohlorid used will. The corresponding 5- (o-toluoyl) -, 5- (m-toluoyl) -, 5- (p-ethylbenzoyl) - and 5- (3 '/ 4' brain ethylbenzoyl) derivatives obtained from 1-methylpyrrole-2-acetonitrile.

B. The process of Example 12 is repeated, using ^{an equivalent amount of each of the acetonitriles just described instead of 5- (2 ', 4 1} -dichlorobenzoylJ-1-methylpyrrole-2-acetonitrile. The corresponding products are obtained 5- (o-oiioyl) -, 5- (m-oluoyl) -, 5- (p-Xthylbenzoyl) - and 5- (3 ', 4S ¹ Hnlethylbenzoyl) derivatives ^of 1-, methylpyrrole-2-acetic acid.

Example l6 Methyl 5- (p-anisoyl) -l-niethylpyrrole-2-acetate.

A solution of 17.0 g (0.1 mol) of p-anisoyl chloride and 13.2 g (0.1 mol) of aluminum chloride in 2oo ml of methylene chloride during an addition time of 5 minutes to an ice bath

209-15 / 1737

BATH ORIGINAL

~ 23 -

temperature-held solution of methyl l-methylpyrrole-2-acetate given in loo ml of methylene chloride. The mixture is stirred for 25 minutes and diluted with dilute hydrochloric acid Poured acidified ice. The organic layer is separated and the aqueous layer with methylene chloride washed. The combined organic solutions are successively diluted with a solution of dimethylaminopropylamine Washed hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. That Solvent is evaporated in vacuo. A dark oily residue remains, which crystallizes from 40 ml of cold methanol will. The pesticide is isolated by filtration, washed with cold methanol and recrystallized from methanol, white crystalline methyl 5- (p-anysoyl) -lmethylpyrrole-2-acetate, with a melting point of Io4 - Io5 ° C, .- j results.

Example 17

5- (p-Anisoyl) -l-methylpyrrole ^ -esslgic acid. j

A solution of j5> ° S (o, olo5 mol) methyl-5- (anisoyl) -l- j methylpyrrole-2-acetate in 12 ml (o, ol2 mol) 1 η sodium hydroxide solution and 5 ml 95% Ethanol is refluxed for 3 minutes. The solution is diluted with water and the ethanol is then evaporated in vacuo. The solution is filtered and the filtrate is acidified with dilute hydrochloric acid. The precipitated solid is filtered through ·! isolated, dried and recrystallized from methanol-water, about 2.4 g (yield 87 %) of 5- (p-anisoyl) -l-methylpyrr61-2-acetic acid being obtained in the form of a white solid. Pp: I7o - 171 ° C.

Analysis: Calculated for C ₁₅ Ii NO ^: c, 65.92; H, 5.5 ?; N, 5.135 * Found C, 66.oi; H, 5.62JN, $ 5.12.

Example 13

209815/1737

By repeating the steps described in Examples 16 and 17; Procedure, except that at the beginning instead of

6AD ORIGINAL.

- 2t -

p-anisoyl chloride an equivalent amount of m-anisoyl chloride or p-Äthoxybenzoylchlorid is used as Esters the corresponding 5- (m-anisoyl) and 5- (p-ethoxybenzoyl) derivatives of methyl-1-methylpyrrole-2-acetate and, as acids, the corresponding 5- (m-anisoyl) and 5- (p-ethoxybenzoyl) derivatives obtained from l-methylpyrrole-2-acetic acid.

Example 19

5- (3 ^! -Chlor-p-toluoyl) -l-methylpyrrole-2-acetonitrile.

21.4 g (0.14 mol) of 3-chloro-4-methylbenzoyl chloride are added to a suspension of 15.2 g (0.114 mol) of aluminum chloride in 50 ml of 1,2-dichloroethane. The solution obtained is added dropwise to a cooled solution of 15.7 g (0.14 mol) of 1-methylpyrrole-2-acetonitrile in 50 ml of 1,2-dichloroethane. When the addition is complete, the mixture is stirred for 10 minutes at room temperature and then refluxed for 15 minutes. It is poured onto ice acidified with dilute hydrochloric acid. The organic phase is separated off and washed successively with NiN-dimethyl-l ^ -propanediamine, j5 hydrochloric acid and saturated sodium chloride solution. Then it is dried over anhydrous magnesium sulfate and the solvent is evaporated. A white pesticide, 5- (3'-chloro-p-toluoylJ-l-methylpyrrole-2-acetonitrile, precipitates from the remaining oily residue after trituration with methanol. This pesticide is purified by recrystallization from methanol and then has a melting point of 116-118 ° C,

Analysis; calcd for C ₁₅ H ₁ ^ ClN ₂ O: N, I0.26 % found N, I0.38 %.

Example 2o S-Q'-chloro-p-toluoylj-l-methylpyrrole - ^ - acetic acid.

A solution of 5.5 g (ο, οοΐ ^ mol) 5- (J ' ¹ -chloro-p-toluoyl) -lmethylpyrrole-2-acetonitrile in 18 ml of 95% ethanol and

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BATH ORIGINAL

26 ml of 1 η sodium hydroxide is refluxed overnight. The reaction mixture is then cooled and poured into dilute hydrochloric acid. The received white precipitate, 5- (3'-chloro-p-toluoylI-1-methylpyrrole-2-acetic acid is filtered off and purified by recrystallization once from isopropanol. Fp; 176-178 C.

Example 21

By repeating the Friedel- : Crafts reactions with an equivalent amount of the corresponding substituted benzoyl chloride will be the following 5-aroyl derivatives of methyl l-methylpyrrole-2-acetate are obtained:

Methyl 5- (3 ', 4 ¹ -dimethoxybenzoyl) -1-methylpyrrole-2-acetate; Methyl 5- (j ^r , 5'-dinitrobenzoyl) -1 ~ methylpyrrole-2-acetate; Methyl 5- (3 ¹ _T bromo-4 ^f -chlorobenzoyl) -l-methylpyrrole-2-acetateJ methyl-5- (2 ^f , 3 ', 5'-tribromobenzoyl) -l-methylpyrrole-2-acetate and methyl 5 - (> f, 4 '* 5'-trimethoxybenzoyl) -l-methylpyrrole-2-acetate.

Example 22

The conversion of an acetic acid ester group into an acetic acid group following the hydrolysis procedure described in Example 27 using equivalent amounts of each of Pyrrolaoetate obtained in Example 21 was repeated. As jev / in a hurry Products are the corresponding 5-aroyl-1-methylpyrrole-2-acetic acids obtain,

Example 23

^ - (p-Nitrobenzoyl) -l-methylpyrrole-2-acetonitrile.

A solution of 46.4 g (0.25 mol) of p-nitrobenzoyl chloride in 100 ml of 1,2-dichloroethane is added in portions to form a suspension of 52.2 g (0.25 mol) of aluminum chloride in 100 ml of 1,2-dioloroethane gp give. This Qemlsch is added drop by drop to one cooled solution of>, o g (0.25 mol) of l-iiethylpyrrole-2-aeetonitrile in 100 ml of 1,2-dlohlorethane. After the addition is complete

209815/1737

BAD ORiGlNAl.

the mixture is stirred at room temperature for 20 minutes and then refluxed for 5 minutes. It is poured into an ice bath acidified with 15 η hydrochloric acid. The organic phase is separated off and washed successively with N, N-dimethyl-l ^ -propanediamine, 15 N hydrochloric acid and saturated sodium chloride solution. Then it is dried over magnesium sulfate and the solvent evaporated in vacuo. The semi-solid residue obtained is triturated with cold methanol, from which the desired product, 5- (p-nitrobenzoyl) -l-methylpyrrole-2-acetonitrile, crystallizes out. It is removed by filtration and purified by recrystallization from ethanol. Mp: 167-I69 ⁰ C.

Example 24 5- (p-aminobenzoyl) -l-methylpyrrole-2-acetonitrile,

A solution of 7 g (ο, ο2β mol) 5- (p-nitrobenzoyl) -l-methylpyrrole-2-acetonitrile in 45o ml of ethyl acetate, which contains 1 g of palladium on carbon as a catalyst, is in a Parr shaking autoclave under a hydrogen pressure of 5.1 at hydrogenated until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the solvent evaporated in vacuo. About 6.0 g (97 % yield) of a yellow solid, 5- (p-aminobenzoyl) -l-methylpyrrole-2-acetonitrile, are obtained. Mp: 137-142 ° C.

Example 25 5- (p-aminobenzoyl) -l-methylpyrrole-2-acetic acid.

A suspension of 6.0 g (0.025 mol) of 5- (p-aminobenzoyl) -lmethylpyrro: te-acetonitrile, 25 ml of 95% ethanol and 25 ml of 1 η sodium hydroxide are refluxed overnight. The ethanol is then evaporated in vacuo and the remaining suspension is poured onto ice, which is mixed with dilute hydrogen chloride acid was brewed to a pH of 5. The solid obtained is between sodium bicarbonate solution and chloroform distributed. The insoluble substances are removed from the 2-phase table

209815/1737

BATH ORIGINAL

filtered off. The sodium carbonate layer is separated off , and slowly acidified with dilute hydrochloric acid. The solids precipitating at different pH values are removed by filtration. The desired product, 5- (p-amino-benzoyl) -l-methylpyrrole-2-acetic acid, is obtained a pH of J. It has a melting point of 173-175 ° C.

Example 26 Ethyl 5- (p-nitrobenzoyl) -l-methylpyrrole-2-acetate.

A solution of 5.5 g (0.03 mol) of p-nitrobenzoylochloride in 60 ml of methylene chloride becomes a suspension of 3.9 g (0.03 mol) of aluminum chloride in 2o ml of methylene chloride. The suspension obtained is added dropwise a cooled solution (-15 ° C) of ethyl 1-methylpyrrole-2-acetate in 5o ml of methylene chloride, the solution is 15 minutes stirred for a long time at a temperature of -lo ° C and for 15 minutes at room temperature. The reaction mixture is in a mixture of ice and dilute hydrochloric acid poured. The organic phase is separated and successively with NiN-dimethyl-l ^ -propanediamine, 5 η chlorine | hydrochloric acid and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate dries and the solvent evaporates in vacuo. A j crystallizes from the remaining oily residue Solid, ethyl-5- (p-nitro-benzoyl) -l-methylpyrrole-2- ' acetate, which is isolated by recrystallization from methanol! will. Fp; Io3 to Io6 ° C. J.

Example 27 j

5- (p-nitrobenzoyl) -l-m'ethylpyrrole-2-acetic acid.

A solution of 3.2 g (o, ol mol) of ethyl 5- (p-nitrobenzoyl) -l-methylpyrroie acetate and 25 ml of ethanol is heated to reflux temperature. This solution is added dropwise

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BATH ORIGINAL

Io ml of 1 η sodium hydroxide solution. After the addition is complete the ethanol is evaporated and the residue acidified with dilute hydrochloric acid. The received Pest substance, 5- (p-nitrobenzoyl) -l-methylpyrrole-2-acetic acid is separated off by filtration and purified by recrystallization from ethanol. Mp »192-195 ° C.

Example 28 Ethyl 5- (p-cyanobenzoyl) -l-methylpyrrole-2-aoetate.

A solution of 5, above (0.03 mol) of p-Cyanoberizoylchlorid in 60 ml of methylene chloride is added to a suspension of 4o g of aluminum chloride in J> o ml of methylene chloride. The mixture obtained is added dropwise to a cooled solution of 5.0 g (0.05 mol) of ethyl 1-methylpyrrole-2-acetate in 15 ml of methylene chloride. The resulting mixture is stirred at room temperature for 20 minutes and then poured onto ice acidified with dilute hydrochloric acid. The organic phase is separated off, washed successively with Ν, Ν / dimethylaminopropylamine, 3 η hydrochloric acid and saline solution and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo. The solid obtained, which separates out of the oily residue on standing, is recrystallized from methanol. This gives pure ethyl 5- (p-cyanobenzoyl) -l-methyl-pyrrole-2-acetate with a melting point of 11.7 to 120 ° C.

Example 29 S-fp-Cyanobenzoylj-l-methylpyrrole ^ -acetic acid.

A solution of 0.5 g (o, ool7 mol) of ethyl 5- (p-oyanobenzoyl) -l-methylpyrrole-2-acetate in 3 ml of ethanol is heated to reflux temperature and 1.7 ml of sodium hydroxide solution is added added dropwise. The mixture is on for 3 minutes

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BATH ORIGINAL

Maintained reflux and then the ethanol evaporated in vacuo. The residue is diluted with water and acidified with dilute hydrochloric acid. 5- (p-Cy & nobenzoyl) -l-methylpyrrole-2-acetic acid precipitates out in the form of a white solid, which is isolated by filtration and dried. Mp 196-198 ⁰ C.

Example 3o Methyl - ^ - (p-methylthiobenzoyl) -l-methylpyrrole-2-acetate.

The compound is obtained by repeating the procedure described in Example 26 when in place of p-anlsoyl chloride an equivalent amount of p-mathylthiobenzoyl chloride is used.

Example 31

^ - (p-ethyl thiobenzoyl) -l-methylpyrrole-2-acetic acid. Prepared by repeating the hydrolysis procedure described in Example 27, with the modification that the hydrolysis of an equivalent amount of the ester obtained in Example 30 is carried out.

Example 32 -

Ethyl 5- (p-chlorobenzoyl) -α-methyl-1-methylpyrrole-2-acetate.

A solution of 6.68 g (0.0219 mol) of ethyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetate in 50 ml of ether becomes a solution of 0.94 g (0.024 mol) of sodium amide in about 150 ml of liquid Ammonia at -33 ° C, given. The mixture is refluxed for 15 minutes and then 3, Io g (o, o219 Mol) methyl iodide added. The mixture is for 1 hour touched; then the ammonia is allowed to evaporate. Ether and sufficient ammonium chloride are given to neutralize all of them Anlons too. The mixture is dissolved in dilute hydrogen chloride

2 0 9 8 15/1737

BATH ORIGINAL

- 3ο -

acid poured and the essential solution separated and with Sodium bisulfite solution, sodium bicarbonate solution and saline solution washed. Dry them over anhydrous magnesium sulfate and evaporate the solvent, leaving about 6.8 g of an oily residue are obtained which crystallizes on standing. The plague is sequentially recrystallized from cyclohexane and methanol, ethyl 5- (p-chlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetate obtained as a white crystalline pest, which has a melting point of 67 - 68 ° C.

Example 33 S-Cp-chlorobenzoylj-a-methyl-1-methylpyrrole ^ -acetic acid.

A solution of 4.05 g (o, ol26 mol) of ethyl 5- (p-chlorobenzoyl) -. A-methyl-1-methylpyrrole-2-acetate, 15 ml of 1 η sodium hydroxide solution and 2 ml of ethanol are refluxed for 30 minutes. The solution is cooled, diluted with water and filtered off. The piltrate is made with dilute hydrochloric acid acidified. The precipitated pesticide is isolated and recrystallized from methanol-water. You get one white crystalline solid, 5- (p-chlorobenzoyl) -α-methyll-methylpyrrole-2-acetic acid with a melting point of 135 - 136 ° C.

Analysis: Calculated for C ₁₅ H ₁ → ClNO ₃ : C, 61.76; H, 4.83; N, 4.82 % found C, 61.68; H, 4.86; N, 4.89 %>

Example 34

5- (p-Chlorobenzoyl) -q-methyl-1-methylpyrrole-2-acetonitrile.

To a suspension of Natriurahydrid (. 12.2 g of 5 wt -Jo ° HaH in mineral oil) in i, 2-Dirnethoxyäthan is added 5- _(p-t Chlorbei zoy '..) - l-iuethylpyrrol-2-acetonitrile (02 , 6 g, 0.24 mol) in 1,2-Dimetho: yäbhan during an addition period of half an hour at room temperature. When the addition is complete, the mixture becomes

209815/1737 bad original

? '. ■ ■ ■ ■■

Stirred for one hour and then 35 g (0.25 mol) ■ · methyl iodide too. The reaction mixture is an additional 3 hours stirred long, concentrated under reduced pressure, diluted with water and extracted with chloroform. After this Drying, the chloroform is removed, leaving a brown solid residue. After triturating the residue with cold methanol, yellow crystals of 5- (p-6hlorbeazoyl) -a-methyl-1-methylpyrrole-2-acetonitrile are obtained with a melting point of 145 to 143 ° C. After recrystallizing twice from methanol the melting point is 151 * 5 to 152.5 ° C.

Example 35 5- (p-Chlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid.

A sample of 27.1 g ( ^{0.1 mol) 5- (p-G} nlorbenzoyl) - <x-methyll-methylpyrrole-2-acetonitrile is refluxed for 16 hours with 8 g (0.2 mol) sodium hydroxide in 35o ml of aqueous ethanol hydrolyzed. After concentrating in vacuo, the sodium salt separates out, which is filtered off and dissolved in water. After acidifying with dilute hydrochloric acid, the corresponding acid precipitates, S-iP-chlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid «The originally basic filtrates are also acidified with chloro- ^! , form extracted and concentrated. The remaining solid 'm is combined with the previously obtained from Peststoff and i methanol-water recrystallized "This gives the pure product, S-Cp-ChlorbenzoylJ-a-methyl-l-methylpyrrole-ß-acetic | acid with a melting point of 139 to 14 ° C .;

Example 36

5- (p »chlorobenzoyl) -q-ethyl-1-methylpyrrole - ^ - acetic acid.

A solution of 6.5 g (0.021 mol) of ethyl 5- (p-chlorobenzoyl) ~ linethylpyrrole-2-acetate in 60 ml of ether is refluxed to a suspension of 1.25 g (0.032 mol) of sodium amide in 150 ml given liquid ammonia. After Io minutes you give

2098 15/1737

BATH ORIGINAL

4.98 g (0.052 mol) of ethyl iodide was added. The mixture is 1.5 hours stirred for a long time and another l, o g (o, o64 mol) of ethyl iodide are added added. Then it is stirred for a further 30 minutes and Ammonium chloride is added to neutralize the anions. The mixture is allowed to warm to room temperature and the ammonia to evaporate. Then ether is added and the mixture

-acid
poured into dilute hydrogen chloride. The ethereal layer is separated and the aqueous layer is washed with ether. The combined ether solutions are washed successively with sodium bisulfite solution and sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo, about 7 * 4 g of a yellow oily residue result, the ethyl 5- (pchlorbehzoyl) -a-ethyl-1-methylpyrrole-2-acetate, which as such for the subsequent conversion into the free acid is used.

A sample of 6.9 g of the oily residue is placed in Jo ml Dissolve ethanol and add 11.4 ml of 1 η sodium hydroxide. The mixture is refluxed for 1 hour. Then it will be the solvent removed in vacuo and the residue partitioned between ether and water. The aqueous layer becomes separated and acidified with dilute hydrochloric acid. The separated oil, which is separated off, crystallizes after rubbing with the formation of a pesticide, 5- (p-chlorobenzoyl) -dc-ethyl-1-methylpyrrole-2-acetic acid), which is isolated and dried. The melting point is I08 to 112 ° C. According to successive steps of recrystallization from ether-mathylcyclohexane, Benzene-hexane, methylcyclohexane and ether-hexane, is the Melting point Ho to Il4 ° C.

Analysis? calculated for found

: C, 62.84JH, 5.27; N, 4.58 % C, 63.oi; H, 5.56; N, 4.6l #

Example 37

The processes for the alkylation and conversion of the ester in the acid according to example j? 6 are repeated with the wall

20981 5/1737

BATH ORIGINAL

. treatment that an equivalent amount of a corresponding 5-a-royl-methylpyrrole-2-acetic acid alkyl ester and an equivalent amount of a corresponding alkyl halide as an alkylating agent was used . In this way the following products are obtained:

5-Benzoyl-a- (n-butyl) -l-methylpyrrole-2-acetic acid i 5- (p-methoxybenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid; 5- * Benzoyl-a- (n-propyl) -l-methylpyrrole-2-acetic acid and 5 ~ (p-Cyanobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid.

Example 38

The procedures described in Examples 34 and 35 for Alkylation and conversion of the nitrile into the acid are repeated with the modification that equivalent amounts of one corresponding 5-aroyl-1-methylpyrrole-2-acetonitrile and a corresponding alkyl halide is used as the alkylating agent. In this way, pan receives the following products:

5- (m-chlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid 5- (p-fluorobenzoyl) -a-ethyl-1-methylpyrrole-2-acetic acid; 5- (p-methylbenzoyl) a-ethyl-1-methylpyrrole-2-acetic acid; 5- (2 ^f , 4 ^t -dichlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid and 5- (3'-chloro-4 ¹ -methylbenzoylJ-a-ethyl-1-methylpyrrole-S-esigsture.

Example 39

5- (p-chlorobenzoyl) pyrrole-2-acetonitrile.

To a cooled suspension of 26.8o g (0.2 mol) of aluminum chloride 35 g (0.2 mol) of p-chlorobenzoyl chloride are added dropwise to 1 ml of methylene chloride. The mixture is added dropwise to a solution of 21.22 g (0.2 mol) of pyrrole-2-aeetonitrile given in 125 ml of methylene chloride, which can be obtained from the outside with the help of an ammonium chloride ice bath. When the addition is complete, the reaction mixture is cooled at 0 ° C. for 10 minutes and

209815/1737

then poured onto ice acidified with dilute hydrochloric acid. 5- ^(p-c hlorbenzoyl) pyrrole-2-aeetonitril a solid precipitates in the form which was filtered off »washed with hot methanol and dried. Fp: 2o3 to 2o5 ° C.

Example 4o 5- (p * chlorobenzoyl) pyrrole-2-ebsigic acid.

A solution of 3.6 g (o, ol5 mol) 5- (p-chlorobenzoyl) .- pyrrole-2-acetonitrile, jüo ml 1 η sodium hydroxide solution and ^ o ml 95 # ethanol are stirred for 6 hours on the Rüokfluss heated. The ethanol is evaporated in vacuo. The solid obtained is dissolved in water and the solution of insoluble constituents filtered off. The Plltrat will then acidified with dilute hydrochloric acid. 5- (p-chlorobenzoyl) pyrrole-2-acetic acid separates out in the form of a white solid, which is obtained by recrystallization from acetone Water (lil) is purified. Mp: 21o ° C.

Example 4l

The method of preparation described in Example 39 is used of 5-aroyl-1-R, -pyrrole-2-acetonitrile, in which R, is hydrogen. By repeating this procedure with the modification that instead of p-chlorobenzoyl chloride an equivalent amount of a corresponding benzoyl chloride is used, the following pyrrole acetone trilei are obtained as products

5-Benzoyl-pyrrole-2-aoetonitrile \

5- (p-fluorobenzoyl) -pyrrole-2-acetonitrileJ 5- (p-methylbenzoyl) -pyrrole-2-acetonitrile; 5- (p-methoxybenzoyl) pyrrole-2-aoetonitrile; 5- (3 ¹ -chloro-4 ¹ -methylbenzoyl) -pyrrole-2-acetonitrile and 5- (2 ', ^ ¹ -dichlorobenzoyl) -pyrrole-2-acetonitrile.

Example 42

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The method according to Example ko is repeated, with instead

BAO ORIGINAL

■ "■■ ίίΐ ... ν I, ¹ ; T ■

- 55 -. ■ ■

of 5- (p-CJilorbenzoyl) -pyrrol-2-ace1? onitril an equivalent Amount of each of the pyrrole-acetone trils obtained according to Example 4l is used. One receives as a corresponding Products:

5-benzoyl-pyrrole-2-acetic acid e ',
5- (p-pluobenzoyl) pyrrole-2-acetic acid;

5- (p-methylbenzoyl) pyrrole-2-acetic acid; .:

5- (p-methoxybenzoyl) pyrrole-2-acetic acid; 5_ (3'_Chlor-4 ^t -methylbenzoyl) -pyrrole-2-acetic acid and 5- (2 ', 4' ~ dichlorobenzoyl) -pyrrole-2-acetic acid,

Example 43

5- (p-Chlorobenzoyl) -l-ethylpyrrole-2-aoetonitrile.

A mixture of 24.4 g (0.1 mol) 5- (p-chlorobenzoyl) pyrrole-2-f acetonitrile, 41.7 g (0.15 mol) potassium carbonate and 16.1 gj (0.15 mol) Ethyl iodide in 300 ml of methyl ethyl ketone is over! Heated to reflux overnight. The reaction mixture is then poured into water and extracted with chloroform. The organic solutions are combined, dried over anhydrous magnesium sulfate and the solvent is evaporated off in vacuo. The residue is recrystallized from 2- propanol, 15 g of the crude solid being obtained. The plague ^! A is sublimed over Naoht at 140 ° C and 0.025 mm Hg. The sublimate is recrystallized successively from 2-propanol, benzene and hexane. This gives 5- (p-chlorobenzoyl) -lethylpyrrole-2-acetonitrile as a white pesticide with a melting point of 145 to 147 ° C.

Analysis; calculated for CLp-H ^ -zClNgO: N, lo.27 % found: N, lo.54 %

Example 44

5- (p-chlorobenzoyl) -l-ethylpyrrole-2-acetic acid.

A suspension of 3 * 52 g (0.01.3 Hol) 5- (p-chlorobenzoyl) -1 ethylpyrrole-2-acetonitrile in 26 ml of 1 η sodium hydroxide and

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BATH ORIGINAL

50 ml of ethanol are refluxed for 6 hours. The mixture is then diluted with water and cooled. A solid precipitates out, which is filtered off and set aside is provided. The ethanol is removed from the piltrate in vacuo. The isolated precipitate becomes the concentrated piltrate and the mixture extracted with chloroform. The aqueous phase is separated off with dilute hydrogen chloride acidified and the resulting precipitate (A) isolated by filtration and dried. The chloroform phase is evaporated and the residue with 12 ml of sodium hydroxide and 24 ml of ethanol 6 Heated for hours on the Rüuki'Iuss. The ethanol is in Evaporated in vacuo and the remaining solution diluted with water and washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and the precipitated solid (B) is isolated and dried. the Both parts of the acidic substance (A and B) are combined with one another and recrystallized from aqueous isopropanol. 5- (p-Chlorobenzoyl) -l-ethylpyrrole-2-acetic acid is obtained in the form of a white solid with the melting point 149 to 155 ° C.

Analysis; calculated for found

Example 45

C, 61.751; H, 4.85; N, 4.80 % C, 6I.78; H, 4.94; 'N, 4.96 %

The method for N-alkylation described in Example 4j5 is used to prepare SA.royl-lR ^ pyrrole-a-aoetonitriles which R _{1 is} a lower alkyl radical. By repeating this process with a corresponding N-unsubstituted 5-aroyl-pyrrole-2-acetonitrile and an equivalent amount of a corresponding alkyl halide as the N-alkylating agent, the following products are obtained

5-benzoyl-ethylpyrrole-2-acetonitrile; 5- (p-Methylbenzoyl) -1- (n-propyl) -pyrrole-2-ace toni -trll ', 5- (p-Methoxybenzoy]) -1-ethylpyrrole -2-aoetoaitrll and 5- (2', 4 '-Dichlorbeuzoyl) -l- (n-butv].) Pyrrole-2-aeetoni-tril.

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y) (

209815 /

-butv]

1737

BATH ORIGINAL Example 46

The procedure described in Example 44 for converting nitriles into carboxylic acids is repeated with the modification that an equivalent amount of each of the acetonitriles obtained in Example 45 is used as the starting material. The following corresponding connections are obtained:

5-benzoyl-1-ethylpyrrole-2-acetic acid,
5- (p-methylbenzoyl) -1- (n-propyl) pyrrole-2-acetic acid, 5- (p-methoxybenzoyl) -l-ethylpyrrole-2-acetic acid and 5- (2 ', 4'-dichlorobenzoyl) -l - (n-butyl) pyrrole-2-acetic acid.

Example 47

The alkylation and conversion procedures according to the examples 34 and 35, are repeated with the modification that instead of the acetonitriles used as starting materials in Example 34 equivalent amounts of each of those obtained in Examples 43 and 45 Alfcylpyrrol-acetonitrile can be used and an equivalent Amount of an appropriate alkyl halide is used as the alkylating agent. The following corresponding ones are obtained Links:

5- (p-chlorobenzoyl) -a-methyl-l-ethylpyrrole-2-acetic acid, 5-benzoyia-ethyl-l-ethylpyrrole-2-acetic acid 5- (p-methylbenzoyl) -a-ethyl-l- (n- propyl) pyrrole-2-acetic acid and 5- (2 ', 4 ¹ -dichlorobenzoyl) -a-methyl-1- (n-butylpyrrole> 2-acetic acid.

Example 48

!, - Benzyl-5- (p-chlorobenzoyl) -pyrrole-2-acetoneltrile.

A solution of 8.43 ml (0.0663 mol) of p-chlorobenzoyl chloride and 8.8 g (0.0663) aluminum chloride in 100 ml 1.247 dichloroethane become a solution of 13.0 g (0.0663 mol) of 1-benzylpyrrole-2-acetonitrile in 50 ml 1,2- ^ chloroethane at 5 ° C for 5 min.

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given. The mixture is stirred for 15 minutes and then rapidly heated to reflux for 15 minutes. That The reaction mixture is poured into a mixture of ice and hydrochloric acid poured and then filtered off. The aqueous layer is separated and washed with chloroform. The United organic solutions are successively mixed with Ν, Ν-dimethylaminopropylamine solution, diluted hydrochloric acid and brine, and then washed over anhydrous magnesium sulfate dried. The solvent is evaporated and the oily residue is dissolved in benzene-methylcyclohexane and covered with crystals inoculated by l-lenzyl-4- (p-chlorobenzoyl) -pyrrole-2-aoetonitrile. After the crystallization of the last-mentioned compound has ended, the mother liquor is filtered, evaporated and the residue crystallizes from methanol. The crystals thus obtained are recrystallized from methanol, whereby l-Benzyl-5- (p-chlorobenzoyl) -pyrrole-2-aoetonitrile in the form of a yellow solid with a melting point of Io4 to 106 ° C.

Example 49

l-benzyl-5- (p-chlorobenzoyl) pyrrole ^ -acetic acid.

A suspension of 5.0 g (0.09 mol) of l-benzyl-5- (p-chlorobenzoyl) pyrrole-2-acetonitrile in 20 ml of ethanol and 18 ml (0.08 mol) of 1 η sodium hydroxide is used for 6 hours heated to reflux. The mixture is diluted with water and the ethanol evaporated in vacuo. The solution is washed with chloroform and ether and acidified with 5 η hydrochloric acid. The precipitated solid is isolated and dried in vacuo. About 2.8 g (91 % yield) of l-lenzyl-5- (p-chlorobenzoyl) -pyrrole-2-acetic acid are obtained as white crystals with a melting point of 162 to 16 ° C.

Analysis » Calculated for: C ₂₀ H ₁₅ ClNO ,: C, 67.70; H, 4.56; N, 5.96 % Found: C, 67.79; H, 4.65; N, 3.97 %

Example 5o 209815/1737

According to the procedure described in Example 48 5-aroyl

lR, -pyrrole - ^ - acetonitrile prepared, in which R _{1 is} a benzyl radical. For example, by repeating this process with an equivalent amount of a corresponding benzoyl chloride instead of p-chlorobenzoyl chloride, the following corresponding compounds are obtained:

l-Benzyl-5-benzoyl-pyrrole-2-acetonitrile! |
l-benzyl-5- (p-bromobenzoyl) r-pyrrole-2-acetonitrile; l »benzyl-5- (p-ethoxybenzoyl) -pyrrole-2-acetonitrile; 1-benzyl-5- (2 ¹ , 4'-dichlorobenzoyl) -pyrrole-2-aoetonitrile and 1-benzyl-5- (J ', 4'-dimethylbenzoyl) -pyrrole-2-acetonitrile.

Example 51

The procedure described in Example 49 for converting the Nitriles to free carboxylic acids are made using equivalent amounts of each of the acetonitriles obtained in Example 50 repeated as starting products. The corresponding l-benzyl-5-aroylpyrrole-2-acetic acids are obtained as the respective end products. '

i Example 52 !

The alkylation and conversion processes described in Examples J4 and 35 are repeated with the modification that equivalent amounts of a corresponding 1-benzyl-5-aroyl- Λ pyrrole-2-acetonitrile and an equivalent amount of a corresponding alkyl halide are used as the alkylating agent ' will. The following corresponding compounds are obtained: j

l-Benzyl-5r (p-chlorobenzoyl) -α-methyl-pyrrole-2-acetic acidJ <. l-Benzyl-5-benzoyl-a- (n-propyl) -pyrrole-2-acylic acidJ j

l-benzyl-5- (p-bromobenzoyl) -a-ethyl-pyrrole-2-acetic acid; \ l-Benzyl-5- (p-ethoxybenzoyl) -a-methyl-pyrrole-2-acetic acid; l-Benzyl-5- (2 ^f , 4'-dichlorobenzoyl) -a-ethyl-pyrrole-2-acetic acid and l-benzyl-5- (5 ¹ , 4'-dimethylbenzoyl) -a-methyl-pyrrole-2-acetic acid .

Example 53 209815/1737

5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetonitrile.

By slowly adding 278 g (1.53 IJqI) of p-chlorobenzoylchloride

- 4ο -

to 21ο g (l, 58 mol) of aluminum chloride in 75 ° ml of ethylene chloride an acylation solution is produced.

2 0 9 8 1 B / 1 7 3 7

The resulting solution is added to a solution of 190 g (1.58 mol) of N-methylpyrrole-2-acetonitrile in 750 ml of ethylene chloride. The temperature is maintained during äsr addition to 20 to 22 ⁰ C and the solution is stirred for another hour at room temperature. The solution is then heated rapidly to 74 to 76 ^° C. At this temperature, a strong evolution of gaseous hydrogen chloride takes place. The temperature is maintained for about 5 minutes and the solution is then rapidly cooled and poured into ice water. The product obtained is extracted with methylene chloride and washed with water. The organic solution then becomes

,. from

shaken with an excess of an aqueous solution / N, N-dimethylaminopropylamine and then with dilute hydrochloric acid in order to remove excess p-chlorobenzoyl chloride. After a final wash with saline solution, the solution is dried over anhydrous magnesium sulfate. Distilling off the solvent leaves a residue which crystallizes. After recrystallization from methanol, the desired product, 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetonitrile with a melting point of 120 to 124 ^° C. is obtained. After two further recrystallizations from methanol, the melting point is 127 to

Example 54 |

5- (p-Chlorobenzoyl) -l-methylpyrrole-2-acetic acid A mixture of 129 g (0.52 mol) 5-fa-chlorobenzoyl) -l-methylpyrrole-2-acetonitrll and 88 g (1.1 mol) 50 #iger sodium hydroxide solution in 800 ml of ethanol and 500 ml of water are heated under reflux for about 18 hours with stirring, with slow evolution of ammonia. The solution is then ^{cooled to about 50 °} C. and acidified by adding 110 ml of concentrated hydrochloric acid. The mixture is cooled and the precipitated product, 5- (p-

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Chlorobenzoyl) -l-methylpyrrole-2-acetic acid is filtered off and recrystallized from methanol. The melting point is 193 to 195 C (with decomposition). A second portion of the product is obtained by concentrating the mother liquor, so that an overall yield of 61%, based on the theoretical yield, results.

Analysis: calculated for Ο, ^ Η ,, ClN (U: N, 5.05 % found: N, 5 · θ6 %

Example 55

Ethyl 5- (p-chlorobenzoyl) -l-methyl-pyrrole-2-acetate A suspension of 55 »4 g of 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetic acid, 44 ml of absolute ethanol, 1 g of p -Toluo ^ / acid and 650 ml of benzene is refluxed for 7 hours with azeotropic removal of water. The reaction mixture is filtered, washed with sodium bicarbonate solution, over

dried anhydrous magnesium sulfate / and the solvent removed in vacuo. The crystalline residue is recrystallized twice from cyclohexane, ethyl 5- (p-chlorobenzoyl) -l-methyl-2-acetate as a yellow solid with a melting point of 74 to 76 ^° C. being obtained.

Example 56

The procedure described in Example 55 is repeated with the modification that an equivalent amount of isopropanol and n-butanol are used instead of the ethanol. You get in this way the corresponding isopropyl and n-butyl esters of 5-lp-chlorobenzoyl) -l-methylpyrrole-2-acetic acid.

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Example 57 A. Methyl-1-methylpyrrole-2-acetate

450 ml of an ether-ischm solution of diazomethane, which consists of ² ^ 3 g (0.2 mol) of N-methyl-N-nitroso-p-toluenesulfonamide according to the in Organic Synthesis, Volume 4, John Wiley and Sons, page 250 to 252 (1963) is obtained, is added dropwise to a cooled solution of 18.1 g (0.13 mol) of 1-methylpyrrole-2-acetic acid in 100 ml of aqueous methanol, the temperature being maintained at about 0.degree . After the evolution of gas has ceased, the mixture is washed three times with saturated sodium bicarbonate solution and once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent, about 14.5 g of an oily residue of methyl 1-methylpyrrole-2-acetate are obtained, which is used in the process described in Example 47 without further purification.

B methyl pyrrole-2-acetate is obtained by the process described in Example 57 A with the modification that an equivalent amount of pyrrole-2-acetic acid is used instead of 1-methylpyrrole-2-acetic acid.

Example 58

A methyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-aoetate 10.5 g of p-chlorobenzoyl chloride are added dropwise to a cooled suspension of 8 g (0.06 mol) of aluminum chloride in 60 ml of methylene chloride. The resulting solution is quickly but dropwise added to a solution of 7 * 6 g (0.05 mol) of methyl 1-methylpyrrole-2-acetate in 30 ml of methylene chloride,

vfobei keeping the temperature below 10 ° C. The reaction mixture is stirred for 20 minutes and then in 3N hydrochloric acid poured and the resulting mixture with Kther

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extracted. The ethereal fraction is successively treated with NjN-dimethyl-1 ^ -propanediamine, with J5 η-hydrochloric acid and washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo and the pesticide obtained, methyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetate, by recrystallization purified from methanol. Pp 122 to 125 ° C.

B methyl 5- (p-chlorobenzoyl) pyrrole-2-acetate is obtained by repeating the procedure described in Example 28 A with the exception that instead of methyl 1-methyl- ^ pyrrole-2-acetate, an equivalent amount of Methyl pyrrole-2-acetate is used.

Example 59

By repeating those described in Example 58 A and B. Method with the modification that instead of p-chlorobenzoyl chloride using an equivalent amount of a corresponding benzoyl chloride, the following corresponding ones are obtained Links:

Methyl 5-benzoyl-pyrrole-2-acetate,
Methyl 5-benzoyl-1-methylpyrrole-2-acetate, P methyl 5- (p-bromobenzoyl) -l-methylpyrrole-2-acetate, methyl 5- (p-methoxybenzoyl) -l-methylpyrrole-2-acetate and methyl 5- (2 *, 4'-dichlorobenzoyl) pyrrole-2-acetate.

Example 60

^ - (p-Chlorobenzoyl) -l-methylpyrrole-2-acetamide A mixture of 12.4 g (0.05 mol) of 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetonitrile and 8 g of a 50 #igen Sodium hydroxide solution in 50 ml of water and 75 ml of methyl alcohol is 45 minutes

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refluxed for a long time with stirring. The solid obtained is filtered off from the hot solution and crystallized from dimethylformamide. This gives 8.5 g (62 %) of 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetamide with a melting point of 250 to 253 ° C. (decomposition).

Analysis: calculated for C ₁ ^ H ₁ -ClN ₂ O ₂ ϊ Ν, 10

Found: N, $ 9-97

Example 6l

According to the process described in Example 60, the nitrile function of the compounds according to the invention is hydrolyzed to an amide function (for example “R ₂ ”). For example, by repeating this process with an equivalent amount of a corresponding 5-aroyl-IR ₁ ~ 2-alkanonitrile as the starting compound, the following corresponding compounds are obtained:

5-benzoyl-1-methylpyrrole-2-acetamide, 5- (p-chlorobenzoyl) -pyrrole-2-acetamide, 5 - (? '- chloro-p-toluoyl) -l-methylpyrrole-2-acetamide, 5- (p-methoxybenzoyl) -pyrrole-2-acetamide,

5- (p-chlorobenzoyl) -l-ethylpyrrole-2-acetamide and ™

1-Benzyl-5- (p-chlorobenzoyl) -pyrrole-2-acetamide.

Example 62

5- (p-Chlorobenzoyl) -N-ethyl-1-methylpyrrole-2-acetamide A suspension of 6.0 g (0.02 mol) of the sodium salt of 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetic acid in 100 ml of dry benzene is treated with 2.1 ml (0.025 mol) of oxalyl chloride in 100 ml of benzene. The mixture is stirred for three hours, filtered, evaporated in vacuo and the residue

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taken up in benzene. The benzene mixture is poured into 50 ml of a solution of 70 % ethylamine in 200 ml of water, the precipitated solid is filtered off and dried. After recrystallization from Sthanol obtained about 2.0 g of 5- (p-chlorobenzoyl) -N-ethyl-l-methylpyrrole-2-acetamide in the form of white needles with a melting point of I87 to I88 ⁰ C.

Analysis: calculated for C ₁ ^ H ₁ found

Example M 63

: C, 63.05JH, 5.62; N, 9.20 : C, 63.06; H, 5.61; N, 9.14

5- (p-chlorobenzoyl) -N, N-diethyl-1-methylpyrrole-2-acetamide To a solution of 6.1 g (0.02 mol) 5- (p-chlorobenzoyl) -lmethylpyrrole-2-acetic acid in 100 3.8 ml (0.03 mol) of thionyl chloride are added to ml of chloroform. The mixture is refluxed with stirring overnight. The solvent is then evaporated and the residue is quickly added to a solution of 22 ml of diethylamine in 50 ml of water , while the mixture is cooled from the outside with an ice bath. It is striking 5- (p-chlorobenzoyl) -N, N-diethyl-l-methylpyrrole-2-acetamide as a solid, which is isolated and purified by recrystallization from Methyleyelohexan (under treatment of the solution with animal charcoal). Fp 82 to 85 ⁰ C.

Analysis: calculated for found

Example 64

: C, 64.96; H, 6.36; N, 8.4l % : C, 65.02; H, 6.38; N, 8.20Y *

Following the process according to Examples 62 and 63 are obtained using an equivalent amount of a corresponding 5-aroyl-pyrrole-2-alkanecarboxylic acid or a salt thereof

20981 5/1737

Acid and an equivalent amount of a corresponding primary or secondary alkylarain as starting materials the following corresponding compounds;

S-Benzoyl-N-ethyl-l-methylpyrrole - ^ - acetamide, 5-benzoyl-N, N-diethylpyrrole-2-acetamide, l-benzyl5- (p-chlorobenzoyl) -N-isopropylpyrrole-2-acetamide _i 5- (p-Toluoyl) -N, N-dimethyl-1-methylpyrrole-2-acetamide, 5- (p-chlorobenzoyl) -l-ethyl-N- (n-butyl) -pyrrole-2-aeetamide and 5- (p -Chlorobenzoyl) -N-ethyl-a-methyl-1-methylpyrrole-2-acetamide.

Example 65 *

It is carried out according to the procedure described by R. Jones and J. Lindner in Canadian Journal of Chemistry, 18, page 883 (1965) for the reaction of N-alkylpyrrole-2-aldehydes with Kthoxycarbonylmethylene triphenylphosphorane to ethyl-2- (1-alkyl-2-pyrrolyl) acylaea worked. This process is used to prepare the 1-methyl, 1- (n-butyl) and 1-isoamyl derivatives of ethyl 2- (2-pyrrolyl) acrylate applied.

Example 66 Ethyl 2- (1-methyl-2-pyrrolyl) propionate

A solution of 62.4 (0.35 mol) ethyl 2-l-methyl-2-pyrrolyl) acrylate in 350 ml of 95% ethanol is in a Parr shaking autoclave using 3 g of platinum oxide as a catalyst, hydrated. The hydrogenation is done overnight under a hydrogen pressure of 2.25 at continued. The mixture is filtered and the filtrate concentrated in vacuo. The leftover yellow oil is dissolved in ether and successively saturated with 3N hydrochloric acid Sodium bicarbonate solution and saturated sodium chloride solution. The essential

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Solution is dried over anhydrous magnesium sulfate. After evaporation of the ether, about 42 g of ethyl 2- (1-methyl-2-pyrrolyl) propionate are obtained in the form of a clear oil.

Example 6?

Ethyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-propionate To a suspension of 26.6 g (0.2 mol) of aluminum chloride in 100 ml of methylene chloride are added 34.8 g (0.2 mol) of p- Chlorobenzoyl chloride. The resulting solution is added dropwise to a solution of 26.8 g (0.2 mol) of ethyl 2- (L-methyl-2-pyrrolyl) propionate in 100 ml of methylene chloride, the reaction mixture being cooled from the outside with an ice bath . When the addition is complete, the reaction mixture is stirred for 10 minutes and then poured onto ice acidified with dilute hydrochloric acid. The two factions are separated from each other. The organic fraction is washed successively with N, N-dimethyl-1,3-propanediamine, 3N-hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. A solid crystallizes from the oily residue obtained and is isolated and purified by recrystallization from methanol. Mp 71.5 to 73 ° C.

Example 68

5- (p-Chlorobenzoyl) -l-methylpyrrole-2-propionic acid A suspension of 8.0 g (0.025 mol) of ethyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-propionate in 15 ml of ethanol and 30 ml 1 N sodium hydroxide solution is refluxed for one hour.

The ethanol is then evaporated and the remaining solution poured into dilute hydrochloric acid. The received white precipitate is filtered off and recrystallized

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177098A

Purified from isopropanol. One obtains 5- (p-chlorobenzoyl) -lmethylpyrrol-2-propionic acid with a melting point of 188-191 ⁰ C.

Example 69

The successive processes according to Examples 66, 67 and 68 are repeated, with the change that equivalent amounts of 1- (n-butyl) and 1-Isoamyl derivatives of ethyl 2- (2-pyrrolyl) aerylate are used will. The following products are available:

Ethyl 2- (l-n-butyl-2-pyrrolyl) propionate, ethyl 2- (l-isoamyl-2-pyrrolyl) propionate, Ethyl 5- (p-chlorobenzoyl) -l-n-butylpyrrole-2-propionate, A * ethyl 5- (p-chlorobenzoyl) -l-isoamylpyrrole-2-propionate, 5- (p-chlorobenzoyl) -l-n-butylpyrrole-2-propionic acid and 5- (p-chlorobenzoyl) -l-isoamylpyrrole-2-propionic acid.

Example 70

A The acylation procedure described in Example 68 is repeated except that an equivalent Amount of a corresponding ethyl 2- (1-alkyl-2-pyrrolyl) propionate and an equivalent amount of a corresponding benzoyl chloride is used as acylating agent.Man receives the following corresponding connections on this catfish:

Ethyl 5- (p-methylbenzoyl) -l-methylpyrrole-2-propionate, ethyl 5- (p-ethuxybenzoyl) -ln-butylpyrrole-2-propionate, Äühyl-S-iaS ^ '- dichlorobenzoyl) -l-methylpyrrole -2-propionate, ethyl 5- (p-cyanobenzoyl) -l-isoamylpyrrrole-2-propionate, ethyl 5- (p-methylthiobenzoyl) -l-methylpyrrole-2-proplonate, ethyl 5- (p-nitrobenzoyl) -imethylpyrrole-2-propionate and ethyl 5- (y, h * , 5 * -trimethoxybenzoyl) -l-methylpyrrole-2-propionate.

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B. The procedure described in Example 68 is repeated for converting an ester to a carboxylic acid using an equivalent amount of each of the propionic acid esters obtained in Example 70A in place of that originally used Esters. The corresponding 5-aroyl-1-alkylpyrrole-2-propionic acids are obtained as compounds.

C By using an equivalent amount of ethyl 5- (pnitrobenzoyl) -l-methylpyrrole-2-propionate instead of 5- (p-nitrobenzoyl) l-methylpyrrole-2-acetonitrile in the hydrogenation process according to Example 24, the compound ethyl 5- (p-aminobenzoyl) -l-methylpyrrole-2-propionate is obtained.

D The hydrolysis procedure described in Example 68 is followed using an equivalent amount of that in Example 70 C obtained ester instead of the one originally used Esters repeated. In this way, 5- (p-aminobenzoyl) -l-methylpyrrole-2-propionic acid is obtained.

Example 71

One applies the through Ceresol in Ber., Vol. £ Γ, page 815 (1884) method described the reaction of l-aryl-1,3 "butan ion with nitrous acid to give the corresponding 1-aryl l, 2,3-trione butane -2-oximes, and receives in this catfish following links:

1 Phenyl-1,2,> butanetrione-2-oxime, Pp 120 - 131 ° C j 1-p-chlorophenyl-1,2,3-foutantrione-2 <- oximj 1-p-methylphenyl-1,2,3-butanetrione-2-oxtm and 1-p-Methoxyphenyl-1,2,3-butanetrione-2-oxime.

Example 72

A Ethyl-5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate

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A solution of 71 g (0.57 mol) of l-phenyl-l ^^ - butantrione-2-oxime in 350 ml of glacial acetic acid and 50 ml of water is added to 75.5 g of the diethyl ester of acetone dicarboxylic acid in 350 ml of glacial acetic acid at a temperature of 70 ⁰ C given. At the same time are a mixture of 73 g (1 * 12 mol) of zinc dust and 91.5 g (1.12 mol) of anhydrous sodium acetate in portions to such a rate that the temperature is maintained at about 100 ⁰ C-. After the additions are complete (about 45 minutes), the mixture is refluxed for one hour and poured into ice water. The semi-solid crude product obtained is isolated by filtration and recrystallized twice from methanol. Kthyl-S-benzoyl-I-ethoxycarbonyl ^ -methylpyrrole · ^ - acetate with a melting point of 152 to 15 ² I- ⁰ C. is obtained.

Analysis: Calculated for C ₁₉ H ₂₁ NO ₅ : C, 66.46; H, 6.I6; N, 4.08 % found: C, 66.50; H, 6.20; N, 4.17 %

B By repeating the procedure described in Example 72 A with an equivalent amount of the 1-p-chlorophenyl, 1-p-methylphenyl and 1-p-methoxyphenyl derivatives of 1,2,3-butanetrione-2-oxime the corresponding Kthyl ^ -aroyl ^ -ethoxycarbonyl ^ -methylpyrrole-2-acetate are obtained as the respective products.

Example 73

A 5-Benzoyl-3-carboxy-4-methylpyrrole-2-acetic acid A mixture of 3 »4 g of ethyl-5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, 10 g of 50% sodium hydroxide solution and 10 ml Water is refluxed for two hours. The reaction mixture is then diluted with water and acidified with dilute hydrochloric acid. The precipitated pesticide is isolated by filtration, air-dried and converted from acetone-water.

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crystallized. The end product obtained is S-4-methylpyrrole-2-acetic acid in the form of white crystals with a melting point of 250 to 253 ° C.

B The hydrolysis process according to Example 73 A is repeated, with the modification that an equivalent amount of each of the esters obtained in Example 72B is used. In this way the corresponding 5-p-chlorobenzoyl, 5-p-methylbenzoyl and 5-p-methoxybenzoyl derivatives are obtained as the respective end products 3-carboxy-4-methylpyrrole-2-acetic acid.

Example 74

A solution of 8.0 g (0.028 mol) of S-pyrrole-2-acetic acid in 80 ml of a 0.5 show ethanol Hydrogen chloride solution is refluxed for 90 minutes. The solution is treated with animal charcoal, filtered and the filtrate is evaporated in vacuo. What remains is a crystalline one Residue which is recrystallized from acetone «One receives ethyl ^ -benzoyl-J-carboxy - ^ - methylpyrrole - ^ - aoetat with the Melting point 18 to 185 ° C.

B The procedure sur partial reesterification ψ described in Example 64 A is repeated using a tbfttivalenten amount of the corresponding 73 B obtained in Example acids. The corresponding ethyl ^ -aroyl- ^ - carboxy- ^ methylpyrrole - ^ - aoetate are obtained in this way.

Example 75 A 5-Benzoyl-4-methylpyrrole-2-acetylic acid A solution of 4.13 g (0.0131 mol) of ethyl-S-bewilöyl-J-carboxy-

4-methylpyrrole-2-acetate in 8o ml of quinoline is in presence

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BATH ORIGINAL

heating a copper trace on l8o to 183 ⁰ C for 5 hours. The equipment is poured into dilute hydrochloric acid and extracted three times with ether. The essential extracts are combined and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuo, 4 g of ethyl S-benzoyl - ^ - methylpyrrole - ^ - acetate are obtained in the form of a semi-solid product, which is used for the subsequent hydrolysis without further purification.

The entire semi-solid product is dissolved in 20 ml of ethanol and 20 ml of 1N sodium hydroxide solution are added. The mixture is refluxed for JO minutes. The solvent is then evaporated off in vacuo and the residue is dissolved in water and washed with ether. The aqueous solution is acidified with dilute hydrochloric acid and the resulting crystalline plague (1.6 g, yield 50 %) is isolated by filtration and air-dried. The product obtained, 5-benzoyl-4-methylpyrrole-2-acetic acid, is recrystallized three times from acetone-water while treating with animal charcoal. Mp 167-168 ° C.

B The procedure described in Example 75 A is performed under

Using an equivalent amount of the corresponding one in | Example 74 B repeated. The corresponding 5-p-chlorobenzoyl-, 5-p-methylbenzoyl- and 5-p-Methoxybenzoyl derivatives of 4-methylpyrrole-2-acetic acid obtain.

C Lower alkyl esters of the acids obtained in A and B in this example, for example the ethyl, isopropyl and n-butyl esters are made by conventional esterification processes prepared using a suitable lower alkanol.

209815/1737

ßAO ORIGINAL

D Primary, secondary and tertiary amides of the acids obtained in this example according to A and B are conventionally Process prepared, for example by treatment with thionyl chloride and treatment of the acid chlorides thus obtained with ammonia, a primary, lower alkylamine or a secondary lower alkylamine. In this way one obtains:

5-Benzoyl-N, N-diethyl-4-methylpyrrole-2-acetamide, 5- (p-chlorobenzoyl) - ^ l-methylpyrrole ^ -acetamide, 5- (p-Methylbenzoyl) -N-methyl-4-methylpyrrole-2-acetamide and fc 5- (p ~ methoxybenzoyl) -N-ethyl-4-methylpyrrole-2-acetamide.

Example 76

A ethyl 5- (p-chlorobenzoyl) -2,4-dimethylpyrrole-3-acetate To a solution of 29 g (0.17 mol) p-chlorobenzoyl chloride and 28.0 g (0.15 mol) ethyl-2, 4-dimethylpyrrole-5-acetate in 100 ml of carbon disulfide are added 41.2.5 g (0.31 mol) of anhydrous aluminum chloride. The reaction mixture is cooled externally with an ice bath. The mixture is stirred for 15 minutes, after which the solvent is decanted off and the remaining pesticide is treated with ice acidified with η-hydrochloric acid. The acidic mixture P is extracted three times with ether. The combined ether extracts are washed successively with N, N-dimethyl-1,3-propanediamine, 15 n-hydrochloric acid and a saturated solution of sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuo. The remaining pesticide is recrystallized from methanol, ethyl 5- (p-chlorobenzoyl) -2,4-dimethylpyrrole-3-aoetate with a melting point of 126 to 129 ° C. being obtained.

B By repeating the procedure described in Example 76A Procedure, with the exception that as acylating agent a equivalent amount of a corresponding benzoyl chloride

209815/1737 _{BAD 0R1G | NAl} _

is used, you get the following connections:

Ethyl ^ -benzoyl ^^ - dimethylpyrrole-J-acetate, ethyl-5- (p-methoxybenzoyl) -2, ^ - dimethylpyrrole-J-acetate, ethyl-5- (2 \ 4 ^f -diohlorbenzoyl ^^ - dimethylpyrrole ^ - acetate, ethyl 5- (3'-chloro-4 ¹ -methylbenzoyl) -2,4-dimethylpyrrole-3-acetate

Example 77

A ethyl 5- (p-chlorobenzoyl) -4-methyl-2-trichloromethylpyrrole- 3-acetate

209815/1737

BATH ORIGINAL

To a suspension of 9 * 6 g (0.03 mol) of ethyl 5- (p-chlorobenzoyl) -2,4-dimethylpyrrole-3-acetate in 75 ml of ether is added dropwise 7.8 ml of sulfuryl chloride, while externally with is cooled in an ice bath. The suspension obtained is stirred for 15 hours at room temperature. The received white solid, ethyl 5- (p-chlorobenzoyl) -4-methyl-2-trichloromethyl-pyrrole-3-acetate is filtered off and washed twice Purified recrystallization from methylcyclohexane. Fp 13? up to 137 ° C.

B The perchlorination of the 2-methyl group in Example 76 B obtained ester is carried out according to the method described in Example 77A.

Example 78

A. ^ - (p-Chlprbenzoyl) -4-methyl-2-carboxypyrrole- ^ ~ e8aigsaure A solution of 1.0 g (0.0026 mol) of ethyl-5- (p-chlorobenzoyl) -4-methyl-2- triohlomethylpyrrole-3-acetate in 10 ml of dioxane and 3 ml of water is refluxed for three hours. The resulting solution is cooled and extracted with chloroform. The organic fraction is extracted with a saturated solution of sodium bicarbonate. The aqueous phase

is acidified with dilute hydrochloric acid and the resulting precipitate of 5- (p-chlorobenzoyl-4-methyl-2-carboxypyrrole-3-acetic acid is filtered off and dried. Pp 240 ^° C.

B Using the procedure described in Example 78 A equivalent amounts of the 2-trichloromethyl ester obtained in Example 77 B are repeated. The corresponding 5-aroyl-4-methyl-2-carboxypyrrole-3-acetic acids were obtained.

Example 79

A 5- (p-chlorobenzoyl) -4-methylpyrrole-3-acetic acid A solution of 1.4 g (0.004 mol) 5- (p-chlorobenzoyl) -4-methyl-2-carboxypyrrole-3-acetic acid in 25 ml quinoline is heated to 160 ° C. overnight in a nitrogen atmosphere. The reaction mixture is poured onto ice acidified with hydrochloric acid. The mixture is extracted with chloroform and the organic phase is extracted with a saturated solution of sodium bicarbonate. The basic solution is acidified with dilute hydrochloric acid and thereby resultrierende solid, 5- (p-Chlorbenzoy]) - ^{4-methylpyrrole-3-essigsä>} acid is filtered off and purified by recrystallization from isopropyl alcohol. M.p. 145-147 ° C.

B The decarboxylation procedure described in Example 79 A is repeated with the modification that an equivalent amount of the 2-carboxypyrrole-3-acetic acids obtained in Example 78 B can be used as starting acids. In this way, the corresponding 5-aroyl-4-methylpyrrole-3-acetic acids obtain.

C Lower alkyl esters according to paragraphs A and B of this Acids obtained for example, such as the ethyl,

20981 5/1737

Isopropyl and n-butyl esters are used according to the usual esterification processes prepared using the corresponding lower alkenols.

D Primary and secondary and tertiary amides of the acids obtained in paragraphs A and B of this example are prepared according to customary Process produced, for example, the following amides are obtained:

5- (p-chlorobenzoyl) -4-methylpyrrole-5-acetamide _J 5-benzoyl-N-ethyl-4-methylpyrrole-3-acetamide, 5- (p-methoxybenzoylJ-Nn-propyl ^ -methylpyrrole-J-acetamide, 5- (2 ^f , 4 ^l -dichlorobenzoyl) -N, N-diethyl-4-methylpyrrole-3-acetamine

Example 80 A 2-dimethylaminomethyl-1-benzylpyrrole

A solution of 8.2 g (0.1 mol) / n of dimethylamine hydrochloride 8 m ^ ormaline is added dropwise to 17 * 12 g (0.1 mol) of 1-benzylpyrrole. The mixture is stirred at room temperature until solution occurs (about 4 hours). The solution is poured into a 10 # solution of sodium hydroxide and the mixture is then extracted three times with ether. The United organic fractions are washed with a saturated sodium chloride solution and dried over magnesium sulfate and the solvent evaporated in vacuo. The product obtained, 2-dimethylaminomethyl-1-benzylpyrrole, is at reduced Distilled under pressure (boiling point 73 ° C., 0.025 mm Hg).

B 2-Dimethylaminomethyl-1-benzylpyrrole methyl iodide A solution of 100 g (0.47 mol) of 2-dimethylaminomethyl-1-benzylpyrrole in 200 ml of absolute ethanol is cooled to 5 ° C. 29.4 ml (0.47 mol) of methyl iodide are added dropwise. A white solid precipitates out. The suspension is stirred until the precipitate is so thick that further stirring is impossible. The solid, 2-dimethylamlnomethyl-1-benzyl-

209815/1737

pyrrole methyl iodide is filtered off and dried in vacuo.

C1-Benzylpyrrole-2-aoetonitrile

A suspension of 88.9 g (0.25 mol) of 2-dimethylaminomethyl-1-benzylpyrrole-methyliodite is added to a suspension of 12.8 g (0.26 mol) of sodium yanide in 40 ml of dimethyl sulfoxide. The mixture is refluxed for 3 hours and stirred at room temperature overnight. The reaction mixture is poured into water and extracted three times with ether. The combined ethereal extracts are washed with brine and dried over anhydrous magnesium sulfate. The ether is evaporated in vacuo, leaving 41 g of an oily residue which crystallizes on standing. Recrystallization from methylcyclohexane gives the compound l-benzylpyrrole-2-acetonitrile, melting point 62-6J ⁰ C.

Example 8l

A 3 ~ chloro-4-methylbenzoyl chloride is obtained by refluxing a mixture of 30 g (0.175 mol) 3-chloro-4-methylbenzoic acid and 85 ml thionyl chloride for about 2.5 hours, after which the excess thionyl chloride is distilled off in vacuo. The obtained aroyl chloride, 3-chloro-4-methylbenzoyl chloride distilled at 70 to 74 ⁰ C under about 10.25 mm Hg.

B The process described in Example 71 A provides a method for converting benzoic acid derivatives into the corresponding ones Acid chlorides. According to this procedure, with the modification that an equivalent amount of a corresponding substituted benzoic acid was used as the starting material, the following aroyl chlorides were obtained:

3,4-dimethoxybenzoyl chloride,

3-bromo-4-chlorobenzoyl chloride,

2,3> 5-tribromobenzoyl chloride,

209815/1737

" ⁵⁹ " 177098A

J5i 4-dimethylbenzoyl chloride,
p-ethylbenzoyl chloride,
p-ethoxybenzoyl chloride and
p-methylthiobenzoyl chloride.

Example 82

Primary, secondary and tertiary amides of the acids obtained in Examples 68, 69, 70 B and 70 D are by customary Reaction with ammonia or with a corresponding alkylamine or dialkylamine produced. In this way, for example, the following amides are obtained:

5- (p-chlorobenzoyl) -l-methylpyrrole-2-propionamide, 5- (p-chlorobenzoyl) -ln-butylpyrrole-2-propionamide, 5- (p-chlorobenzoyl) -isoamylpyrrole-2-propionamide, 5- (p -Methylbenzoyl) -N-ethyl-l-methylpyrrole-2-propionamide, 5- (3 ', 4' , 5'-trimethoxybenzoyl) -N, N-diethyl-l-methylpyrrole-2-

propionamide,

5- (p-nitrobenzoyl) -l-methylpyrrole-2-propionamide and 5- (p-aminobenzoyl) -N-n-propyl-1-methylpyrrole-2-propionamide.

Example 83

A l-Benzyl-5- (p-chlorobenzoyl) -pyrrole-2-acetonitrile A solution of 8.43 ml (0.067 mol) p-chlorobenzoylechloride and 88.8 g (0.067 mol) aluminum chloride in 100 ml 1,2-dichloroethane are added at a temperature of 5 ° C. over a period of 5 minutes to a solution of 13 * 0 g (0.067 mol) of 1-benzylpyrrole-2-acetonitrile in 50 ml of 1,2-dichloroethane. The reaction mixture is stirred for 15 minutes and then rapidly refluxed for 3 minutes. The mixture is poured into an ice-hydrochloric acid mixture and then filtered. The aqueous layer is separated and washed with chloroform. The Ver-

209815/1737

- 6ο -

Some organic fractions are successively diluted with N, N-dimethylaminopropylamine hydrochloric acid and brine, and then dried over anhydrous magnesium sulfate. Naoh vaporizing an oily residue remains from the solvent which the desired compound by column chromatography on neutral aluminum oxide with a benzene-ether mixture is isolated in a ratio of 50:50 as eluent. Evaporation of the eluates gives l-benzyl-5- (p-chlorobenzoyl) pyrrole-2-acetonitrile as a yellow pest that is recrystallized from methanol and then has a melting point from 106 to 108 ° 0.

B l-Benzyl-4- (p-chlorobenzoyl) -pyrrole-2-acetonitrile Continued running of the chromatography column from Example 8j5 A with ethyl acetate and evaporation of the eluate obtained results in a yellow oil. Recrystallization from benzene-methylcyclohexane gives l-benzyl-4- (p-chlorobenzoyl) -pyrrole-2-acetonitrile as a white solid with a melting point of 102 to 104 ° C.

20981 B / 1 737

Claims (1)

PATENT CLAIMS 1. 5-aroylpyrrole-2-carboxylic acids and carboxylic acid derivatives of the formulas S fi j? cJ ^ ilc Ar-C- ^> -CH-R _o Ar-CMl JJ- \ ι R. (lower alkyl) CH, H ^Η (l-o) (1-d) and therapeutically useful salts of the corresponding carboxylic acids in which Ar is a phenyl radical or one with one or more of the radicals: Halogen, lower alkyl, lower alkoxy groups, nitro, amino, methylthio and cyano groups, substituted phenyl groups, \ Ar, a phenyl radical, one with one or more of the radicals: Halogen, lower alkyl and lower alkoxy radicals, substituted phenyl radical, R is a hydrogen atom or a lower alkyl radical, R is a hydrogen atom, a lower alkyl radical or a benzyl radical, R _{2 is} a -CN-, -COOH -, - COO- (lower alkyl) -, -CONH ₂ -, -CONH- (lower alkyl) - or a -CON- (lower alkyl) ₂ radical and R, one of the radicals: -COOH, -COO- (lower alkyl), -CONH ₂ , -CONH-low alkyl) and -CON- (lower alkyl) ₂ , with the proviso that R _{1 is} a lower alkyl radical and R _{2 is} a -CON-, -COOH- or a -COO- (lower alkyl) radical, 209815/1737 when Ar stands for a nitrophenyl or aminophenyl _{radical, that R 1 is} a lower alkyl radical and Rp is a -CÖOH or -COO- (lower alkyl) radical, when Ar stands for a cyanophenyl or methylthiophenyl radical and that R _{1 is} a hydrogen atom , if R also stands for a hydrogen atom. 2. 5- (p-Chloro-benzoyl) -l-methylpyrrole-2-acetic acid. 3. 5- (m-Chlorobenzoyl) -l-methylpyrrole-2-acetic acid. 4. 5- (o-Chlorobenzoyl) -l-methylpyrrole-2-acetic acid. 5 x 5- (2 ', 4'-dichlorobenzoyl) -l-methylpyrrole-2-acetic acid. 6. 5- (p-Bromobenzoyl) -l-methylpyrrole-2-acetic acid. 7. 5- (p-Fluorobenzoyl) -l-methylpyrrole-2-acetic acid. 8. 5- (p-Methoxybenzoyl) -l-methylpyrrole-2-acetic acid. 9 x 5- (p-methylbenzoyl) -l-methylpyrrole-2-acetic acid. 10. 5- (p-Nitrobenzoyl) -l-methylpyrrole-2-acetic acid. 11. 5- (p-Amlnobenzoyl) -l-methylpyrrole-2-acetic acid. 12. 5- (p-Cyanobenzoyl) -l-methylyprr-ol-2-acetic acid. 15. 5-Benzoyl-1-methylpyrrole-2-acetic acid. 14. 5- (p-Chlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid. 15. 5- (p-Chlorobenzoyl) -a-ethyl-1-methylpyrrole-2-acetic acid. 16. 5- (p-Chlorobenzoyl) -l-ethylpyrrole-2-acetic acid. 17 · l-Benzyl-5- (p-chlorobenzoyl) -pyrrole-2-acetic acid. 18. Ethyl 5- (p -chlorobenzoyl) -l-methylpyrrole-2-acetate. 19. Methyl 5- (p -chlorobenzoyl) -l-methylpyrrole-2-acetate. 20. 5- (p-Chlorobenzoyl) -1-methylpyrrole-2-acetamide. 21. 5- (p-Chlorobenzoyl) pyrrole-2-acetic acid. 22. 5- (p-Chlorobenzoyl) -N-ethyl-1-methylpyrrole-2-acetamide. 2 ^. 5- (p-Chlorobenzoyl) -N, N-diethyl-1-methylpyrrole-2-acetamide. 20981 5/1 737 if: JIf: ¹ '" ν ----- I -' ■ · Λ ■ .'- - ■■■■■■ "., '..' ϊίίίί 24. 5- (p-Chlorobenzoyl) -1-methylpyrrole-2-propionic acid. 25 x 5- (p-chlorobenzoyl) -4-methylpyrrole-5-acetic acid. 26. S-Benzoyl - ^ - methylpyrrole ^ -acetic acid. 27 • 5- (p-Chlorobenzoyl) -l-methylpyrrole-2-aoetonitrll. 28. Process for the preparation of 5-aroylpyrrole-2-carbon- acids and carboxylic acid derivatives of the formula Ia according to Claim 1, characterized in that a carboxylic acid halide of the formula 0
dd Ar -C halogen II with a pyrrole derivative of the formula V III ^R i reacts in the presence of a Lewis acid and a solvent, where R 'stands for a cyano or lower alkoxycarbonyl radical and Ar, R and R _{1 have} the meanings mentioned and optionally the product obtained by hydrolysis in f transfers the free carboxylic acid, that for the preparation of compounds of the formula Ia in which R is a lower alkyl radical and Rp is a -CN radical, -COO- (lower alkyl) - or -COOH radical means a compound of the formula Ar ' ⁸ π -C _ü R " 20981 5/1737 in which R 'has the meaning mentioned, R "is a lower alkyl or benzyl radical and Ar' is a phenyl radical or phenyl radical substituted by halogen, lower alkyl, lower alkoxy or cyano radicals, with a lower alkyl halide in the presence of a strong base C-alkylated and the product obtained is converted into the free carboxylic acid, if necessary by hydrolysis,
that for the preparation of compounds in which R is a lower alkyl radical, Ar the same radical as Ar ^! , a R denotes a lower alkyl radical and RpT-CN or -COOH radical, a compound of the formula Ar ¹ -C H
with the aid of a lower alkyl halide in the presence of a strong base as the alkylating agent, is subjected to N-alkylation and then to C-alkylation and the product obtained is optionally converted into the free carboxylic acid by hydrolysis, that to produce a compound in which Ar is an aminophenyl radical, the corresponding compound in which Ar is a nitrophenyl radical and Rp is the same as R ¹ , catalytically hydrogenated and the product obtained is optionally converted into the free carboxylic acid Preparation of a compound in which Rp denotes a lower alkyl _{ester group, the corresponding compound in which R 2} denotes a carboxyl group is esterified with a lower alkanol, that to prepare an acid amide in which Rp is a -CONHp radical, the corresponding compound in which R _{2 is} a -CN radical is partially hydrolyzed and that · to prepare an acid amide in which R _{2 is} a -CONH - means (lower alkyl) or -CON (lower alkyl) p radical, converts the free carboxylic acid into the corresponding acid chloride and reacts this with a lower alkylamine or a lower dialkylamine, 209815/1737 and that if necessary therapeutically useful salts of the free acids are prepared. 29. Process for the preparation of 5-aroylpyrrole ~ 2-carboxylic acids and carboxylic acid derivatives of the formula Ib according to claim 1, characterized in that a carboxylic acid halide the formula ti ArC — halogen in the Ar the given meaning with the exception of an aminophenyl radical, possesses, with a pyrrole derivative of the formula CH ₂ CH -C00- (normal alkyl) \ (lower alkyl)
reacts in the presence of a Lewis acid and a solvent and hydrolyzes the ester obtained, if necessary, to the free carboxylic acid, that compounds in which Ar denotes a nitrophenyl radical and R denotes a -COO- (lower alkyl) radical. by katalytlsche hydrogenation into the corresponding compound in which Ar is an aminophenyl group is transferred and the product obtained, if necessary, to the free carboxylic acid hydrolyzed \ Siert and the free acid, if necessary, by reaction with ammonia, a lower alkylamine or lower dialkyl amine converted to the acid amide or that the free carboxylic acid is converted into a therapeutically useful salt, if necessary by treatment with a base. 30. Process for the preparation of 5-aroylpyrrole-2-carboxylic acids and carboxylic acid derivatives of the formulas Ic and Id according to claim 1, characterized in that a compound the formula 1 COOH CH ₂ COO- (lower alkyl) 20 9815/1737 177098A or the formula CH ₂ COOH COOH (XXII) in which Ar has the stated meaning, by heating in a basic organic solvent to form compounds the formula ILcH ₂ COO- (lower alkyl) (XXI) and CH ₂ COOH (XXIII) decarboxylated, the compound XXII obtained through, if necessary Hydrolysis converted into the corresponding acid, the free acid obtained or the free acid of the formula XXIII optionally esterified with a lower alcohol or by reaction with ammonia or a lower alkylamine or lower alkyl diamine into the corresponding amides or by treatment with a base into a therapeutically useful one Salt transferred. 31. Process for the preparation of 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetic acid, characterized in that ethyl N-methylpyrrole-2-acetate with p-chlorobenzoyl chloride and the product obtained is converted into the free acid by hydrolysis. 2 0 9 815/1737 32. Process for the preparation of 5- (ro-chlorobenzoyl) -lmethylpyrrole-2-acetic acid, characterized in that l-methylpyrrole-2-acetonitrile with m-chlorobenzoyl chloride and the product obtained is converted into the free acid by hydrolysis. 33 Process for the preparation of 5- (o-chlorobenzoyl) -lmethylpyrrole-2-acetic acid, characterized in that one l-methylpyrrole-2-acetonitrile with o-chlorobenzoyl chloride and the product obtained is converted into the free acid by hydrolysis. 3 &. Process for the preparation of 5- (2 ', 4'-dichlorobenzoyl) -l-methylpyrrole-2-acetic acid, characterized in that 5- (2 ^!, 4'-dichlorobenzoyl) -l-methylpyrrole-2-acetonitrile is hydrolyzed. 35 Process for the preparation of 5- (p-bromobenzoyl) -lmethylpyrrole-2-acetic acid, characterized in that the corresponding nitrile is hydrolyzed to the free acid. 36. Process for the preparation of 5- (p-fluorobenzoyl) -l- methylpyrrole-2-acetic acid, characterized in that one the corresponding nitrile is hydrolyzed to the free acid. ™ 37 Process for the preparation of 5- (p-methoxybenzoyl) -lmethylpyrrole-2-acetic acid, characterized in that methyl (p-methoxybenzoyl) -l-methylpyrrole-2-acetate saponified, 38. Process for the preparation of 5- (p-methylbenzoyl) -lmethylpyrrole-2-acetic acid, characterized in that 5- (p-methylbenzoyl) -l-methylpyrrole-2-acetonitrile hydrolyzed. 209815/1737 39 · Process for the preparation of 5- (p-nitrobenzoyl) -lmethylpyrrole-2-acetic acid , characterized in that ethyl 5- (p-nitrobenzoyl) -l-methylpyrrole-2-acetate saponified. 40. Process for the preparation of 5- (p-aminobenzoyl) -lmethylpyrrole-2-acetic acid , characterized in that the corresponding ethyl ester is saponified. 41. Process for the preparation of 5- (p-cyanobenzoyl) -lmethylpyrrole-2-acetic acid, characterized in that the corresponding ethyl ester is saponified. 42. Process for the preparation of 5-benzoyl-1-methylpyrrole-2-acetic acid, gekennzeicanet by the fact that 1-methylpyrrole-2-acetonitrile reacted with benzoyl chloride and hydrolyzed the product obtained to the free acid. 43. Process for the preparation of 5- (p-chlorobenzoyl) -a-methyl-1-methylpyrrole-2-acetic acid, characterized in that the corresponding ethyl ester is saponified to the free acid. 44. Refining for the preparation of 5- (p-chlorobenzoyl) -aethyl-1-methylpyrrole-2-acetic acid, characterized in that the corresponding ethyl ester is saponified to form the free acid. 45. Process for the preparation of 5- (p-chlorobenzoyi) -lethylpyrrole-2-acetic acid, characterized in that the corresponding nitrile is converted to the free acid hydrolyzed. 46. Process for the preparation of l-benzyl-5- (p-chlorobenzoyl) -pyrrole-2-acetic acid, characterized in that the corresponding nitrile is converted to the free acid saponified. 209815/1737 47. Process for the preparation of ethyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetate, characterized in that one kthyl-N-methylpyrrole-2-acetate with p-chlorobenzoyl chloride implements. 48. Process for the preparation of methyl 5- (p-chlorobenzoyl) -l-methylpyrrole-2 ~ acetate, characterized in that methyl l-methylpyrrole-2-acetate is used with p-chlorobenzoyl chloride implements. 49. Process for the preparation of 5- (p-chlorobenzoyl) -lmethylpyrrole-2-acetamide, characterized in that f | the corresponding 2-acetonitrile is partially hydrolyzed. 50. Process for the preparation of 5- (p-chlorobenzoyl) -pyrrole-2-acetic acid, characterized in that 5- (p-chlorobenzoyl) pyrrole-2-acetonitrile to the free Hydrolyzed acid. 51. Process for the preparation of 5- (p-chlorobenzoyl) -N-ethyl-1-methylpyrrole-2-acetamide , characterized in that 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetic acid with oxalyl chloride and the product obtained is reacted with ethylamine. 52. Process for the preparation of 5- (p-chlorobenzoyl) -N, N-diethyl-1-methylpyrrole-2-acetamide, characterized that you have 5- (p-chlorobenzoyl) -l-methylpyrrole-2-acetic acid with thionyl chloride and the product obtained is reacted with diethylamine. 53 · Process for the preparation of 5- (p-chlorobenzoyl) -lmethylpyrrole-2-propionic acid , characterized in that the corresponding ethyl propionate is saponified to the free acid. 209815/1737 54. A process for the preparation of 5- (p-chlorobenzoyl) -4-methylpyrrole-3-acetic acid, characterized in that S-fp-chlorobenzoyl ^^ - methyl-a-carboxypyrrole-3-acetic acid is decarboxylated by heating in quinoline. 55 · Process for the preparation of 5-benzoyl-4-methylpyrrole- 2-acetic acid, characterized in that the corresponding ethyl ester is saponified to give the free carboxylic acid. 56. A process for the preparation of 5- (p-chlorobenzoyl) -lfc methylpyrrole-2-acetonitrile, characterized in that that one reacts l-methylpyrrole-2-acetonitrile with p-chloro benzoyl chloride. 57. Anti-inflammatory agent containing a compound of the formulas Ia, Ib, Ic or Id, and a customary pharmaceutical carrier material. 209815/1737