Process for producing substituted pyrroles

A process for the preparation of alkyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate compounds by reacting in a solvent in diloweralkyl acetone dicarboxylate, a chloromethyl lower alkyl ketone and an aqueous loweralkylamine in the presence of solids formation inhibiting amount of a lower alkanol having from 1 to about 6 carbon atoms.

BACKGROUND OF THE INVENTION 
This invention relates to a process for producing substituted pyrroles, 
especially pyrrole-2-acetic acids and derivative compounds thereof. More 
particularly, the process of this invention is concerned with processes 
which produce 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate 
which is a useful intermediate for analgesic and anti-inflammatory 
pharmaceutical compounds. 
It has been found difficult in the past to substitute pyrrole rings, which 
already contain substituents at other positions on the ring, at the 
4-position because of steric hindrance and ring deactivation. Thus, 
Carson, U.S. Pat. No. 3,752,826 and U.S. Pat. No. 3,865,840, teach the 
preparation of certain 4-substituted 5-aroylpyrrole alkanoic acids and the 
corresponding salts, esters, nitriles, amides and substituted amides 
thereof represented by the formulas: 
##STR1## 
wherein: 
Ar represents a member selected from the group consisting of phenyl, 
monosubstituted phenyl and polysubstituted phenyl, each substituent of 
said substituted phenyls being a member selected from the group consisting 
of halo, lower alkyl and lower alkoxy; 
Ar.sub.1 represents a member selected from the group consisting of phenyl, 
thienyl, 5-methylthienyl, monosubstituted phenyl and polysubstituted 
phenyl, each substituent of said substituted phenyls being a member 
selected from the group consisting of halo, lower alkyl, trifluoromethyl, 
lower alkoxy, nitro, amino, cyano, and methylthio; 
R represents a member selected from the group consisting of COOH, 
COO-(lower alkyl), CONH.sub.2, CONH-(lower alkyl) and CON-(lower 
alkyl).sub.2 ; 
R.sub.1 represents lower alkyl; 
R.sub.2 represents a member selected from the group consisting of hydrogen 
and lower alkyl, provided that when said Ar, is a member of the group 
consisting of nitrosubstituted phenyl, then, with regard to Formula III, 
R.sub.2 is hydrogen; 
Me is methyl; 
and the non-toxic, therapeutically acceptable salts of such acids, such as 
are obtained from the appropriate organic and inorganic bases. According 
to Carson, supra, the 4-substituted 5-aroyl-pyrrole alkanoic acids must be 
obtained by condensation of the appropriate 
1-aryl-1,2,3-butanetrione-2-oxime and an appropriate dialkyl 
acetonedicarboxylate as starting materials to provide the corresponding 
ring closed pyrrole, alkyl 5-aroyl-3-alkoxy 
carbonyl-4-methylpyrrole-2-acetate; or by condensation of an appropriate 
chloromethyl lower alkyl ketone added to a mixture of an appropriate 
di-loweralkyl acetonedicarboxylate, preferably the diethyl ester and a 
loweralkyl amine to provide the ring-closed pyrrole, alkyl 
1,4-diloweralkyl-3-alkoxy-carbonyl pyrrole-2-acetate. These pyrrole 
intermediates are then treated as disclosed in U.S. Pat. Nos. 3,752,826 
and 3,865,840 to obtain the desired 5-aroyl-4-lower 
alkyl-pyrrole-2-alkanoic acids and acid derivatives thereof useful as 
anti-inflammatory agents. 
The condensation of chloromethylketone, ammonia and hydroxy crotonic acid 
alkylester through an anticrotonic acid ester is taught by Fischer and 
Orth, Die Chemie Des Pyrroles, pp. 5-6 and 233-234, Edward Brothers, Inc., 
Ann Arbor, Mich., 1943. However, neither the 4-alkyl-substituent nor the 
diester functionality are disclosed in this reference. 
Another pyrrole ring-closure synthesis, known as the Hantzsch pyrrole 
synthesis, teaches the interaction of alphachloro-aldehydes or ketones 
with beta-ketoesters and ammonia or amines to give pyrroles, Gowan and 
Wheeler, Name Index of Organic Reactions, p. 116, Longmans, Green and Co., 
Ltd., New York, N.Y., 1960. 
In a similar manner, there is taught the reaction of chloroacetone with a 
salt produced from reaction of methyl amine and diethyl acetone 
dicarboxylate to give a 4-methylpyrrole, Jones and Bean, The Chemistry of 
Pyrroles, p. 59, 104, Academic Press Inc., New York, 1977. Also, the 
pyrrole synthesis from chloromethyl ketones and beta-ketocarboxylic esters 
with ammonia or amines is known, Krauch and Kunz, Organic Name Reactions, 
p. 211, John Wiley and Sons, Inc., New York, 1964. However, such teachings 
either fail to suggest the possibility of the pyrrole diester compounds or 
teach no more than Carson, supra, and are based thereon. 
Specifically pertinent to the improved process of this invention, U.S. Pat. 
Nos. 3,752,826 and 3,865,840 teach that after reaction of, for example, 
aqueous methylamine with diethyl acetone-dicarboxylate and then adding 
chloroacetone at a temperature just below 60.degree. C. for a period of 
two hours, the resultant reaction mixture is poured into ice-hydrochloric 
acid. The acidification acts to dehydrate the intermediate dihydroxy 
pyrrolidine to the desired pyrrole. However, the reaction forms solid 
intermediates which are difficult to agitate and conversion of the 
intermediate to the desired product results in an exothermic reaction 
which is difficult to control on a large scale. In an attempt to overcome 
the solids formation problem the reaction of diethyl acetone dicarboxylate 
with chloroacetone and aqueous methylamine was carried out in the presence 
of an added co-solvent, e.g., a halogenated hydrocarbon, such as methylene 
chloride, or an aromatic hydrocarbyl compound, such as toluene, at 
temperatures from 25.degree. to 40.degree. C. by Messrs. Dagani and Kao, 
respectively, as described in patent applications Ser. Nos. 137,231 and 
137,250 now pending, filed on Apr. 4, 1980. Accordingly, the reaction 
could be improved to control the formation of solids and moderate the 
exothermic reaction. 
THE INVENTION 
In a search for improved processes for the reaction of a loweralkyl amine 
in aqueous solution with a diloweralkyl acetone dicarboxylate, it was 
discovered that when conducting the reaction at even lower temperatures, 
say from 0.degree. to about 15.degree. C., that even in the presence of an 
added co-solvent such as methylene chloride, solids formation with its 
attendant lower contacting and mixing problems will occur. It has, 
however, been discovered that the addition to the reaction mixture of a 
lower alkanol having from 1 to about 6 carbon atoms serves to aid the 
dissolution of solids formed in the reaction mixture at temperatures down 
to about 0.degree. C. Accordingly, the present invention provides in a 
process for the preparation of a loweralkyl 
1,4-dilower-alkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate of the formula: 
##STR2## 
by reacting a chloromethyl loweralkyl ketone of the formula: Cl--CH.sub.2 
--CO--R.sub.4, with a diloweralkyl acetone dicarboxylate of the formula: 
##STR3## 
and an aqueous solution of a loweralkylamine of the formula: R.sub.3 
NH.sub.2, wherein the foregoing formulas said R.sub.3 and said R.sub.4 
represent loweralkyl, the improvement comprising carrying out the reaction 
in the presence of a solids formation inhibiting amount of a lower alkanol 
having from 1 to about 6 carbon atoms. 
As used in this invention, "loweralkyl" and "loweralkoxy" may be straight 
or branch chained saturated hydrocarbons having from 1 to 6 carbon atoms, 
such as, for example, methyl, ethyl, propyl, isobutyl, isopropyl, butyl, 
pentyl, hexyl and the like alkyls and, respectively, the corresponding 
alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, and the like. 
The loweralkoxy 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate of 
the present invention is preferably produced when the chloromethyl 
loweralkyl ketone is a chloroacetone. Chloroacetone is a readily available 
and relatively inexpensive ketone. The dicarboxylate is preferably 
dimethyl or diethyl acetone dicarboxylate which can be prepared according 
to known procedures. The other reactant is a loweralkylamine, preferably 
methylamine in order to have a 1-methylpyrrole compound produced. Should 
other 1-substituted pyrroles be desired, then other amines such as aryl 
amines or other alkyl amines, are also suitable reactants in the process 
of this invention. However, preferably, in order to produce the 
1,4-diloweralkyl pyrrole compound, methylamine is used. Preferably, a 40% 
solution of methylamine is employed since this is conveniently available. 
More preferably, the solution is a 40% aqueous solution of methylamine. 
As indicated hereinabove, it has been found that the use of an added amount 
of a lower alkanol has additional advantages. For one, the reaction can be 
carried out at lower temperature than heretofore practiced while obtaining 
comparable yields with prior art processes. Another advantage is that the 
inhibition of solids formation during the addition of methylamine allows 
more efficient agitation which is conducive to good reactant contact, 
better heat distribution, more effective process control and requires less 
power for agitation. 
The alkanols useful in the present invention are those which have the 
ability to reduce or inhibit the formation of solids during the reaction. 
It has been found that such solids formation inhibiting alkanols are lower 
alkanols, such as those having from 1 to about 6 carbon atoms; for 
example, methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, 
isobutanol, pentanol, hexanol and the like are suitably employed. Of 
course, substituted alkanols are within the scope of the present invention 
so long as the substituents are inert to the reactants and products of the 
reaction and do not adversely affect the power of the alkanol to dissolve 
the solids which would otherwise form. The preferred alkanol is ethanol. 
The alkanols are employed in amounts sufficient to inhibit the formation 
of solids during the first portion of the reaction. Because the useful 
alkanols have varying abilities to inhibit solids formation, it is to be 
expected that the alkanols are employed in varying amounts. Preferably, 
the lower alkanols useful in this invention are employed in a solids 
formation inhibiting amount which falls within the range of about 0.1 to 
about 18 moles of the alkanol per mole of the dilower alkyl acetone 
dicarboxylate. More preferably, the alkanol is employed within the range 
of about 0.5 to about 6 moles per mole of the dilower alkyl acetone 
dicarboxylate. 
When desired, the co-solvent employed in the process of this invention is 
an inert, water-immiscible organic solvent with a high degree of 
solubility for the dialkyl acetone dicarboxylate and the cyclized, 
substituted pyrrole product. Additionally, the added co-solvent must be 
relatively water-immiscible and capable of extracting the loweralkylamine 
from the aqueous solution thereof for reaction in the organic phase. 
It has been found that several types of organic solvents have utility in 
the present process. Typically, organic solvents which are aromatic 
hydrocarbon compounds, aliphatic hydrocarbon compounds, halogenated 
aromatic and aliphatic hydrocarbon compounds and the like which have 
boiling points from about 30.degree. to about 200.degree. C. at normal 
pressures are particularly suitable because such solvents in addition to 
preventing solids formation by solubilizing reactants and products also 
provide a method of convenient heat removal by operation at reflux. 
Specifically, chlorinated and brominated hydrocarbon solvents such as 
carbontetrachloride, carbontetrabromide, chloroform, bromoform, methylene 
chloride, methylene bromide, tetrachloroethane, ethylenedichloride, 
ethylene dibromide, chlorobenzene, bromobenzene, o-dichlorobenzene and the 
like are examples of useful solvents. Further, simple aromatic 
hydrocarbons, such as benzene, xylene and toluene are likewise useful and 
practical added co-solvents in the process of the present invention. Of 
particular preference, methylene chloride provides the combined properties 
of solubility, heat removal, water-immiscibility, sufficient inertness to 
the reactants and products and low cost for best results in the present 
process. Although methylene chloride is preferred, any solvent having 
similarly advantageous properties can be used. It is only necessary to 
maintain the diloweralkyl acetone dicarboxylate and the substituted 
pyrrole in solution while extracting the lower alkyl amine from aqueous 
solution to be usefully employed in the present process. 
The reaction of, for example, diethyl acetone dicarboxylate, methylamine 
and chloroacetone is carried out by adding an aqueous solution of 
methylamine to a solution of the other reactants in, for example, 
methylene chloride. Although not preferred, the addition may also be 
carried out inversely, i.e., adding a solution of diethylacetone 
dicarboxylate and chloroacetone to a solution of aqueous methylamine. 
Temperatures can be kept in the range initially from about 0.degree. C. up 
to about 15.degree. C. The reaction is conducted for a period of time 
sufficient to complete the reaction and then the resultant solution is 
acidified or thermally cyclized to finish the product. 
Although the most preferred and advantageous results occur with the process 
of this invention at reaction temperatures in the range of 
0.degree.-15.degree. C., the reaction can be carried out at temperatures 
both higher and lower than the preferred range. At lower temperatures the 
reaction slows considerably, however, and is less practical. In contrast, 
at reaction temperatures greater than about 15.degree. C., and up to about 
35.degree. C., there is less need for the additional dissolution effects 
of the added presence of the alkanol. Thus, as the reaction temperature 
increases the reaction mixture is more fluid and there is less tendency 
for the reaction products or intermediates to form separable solids. At 
the same time, it is not possible to say with certainty at what point the 
additional lower alkanol has lost its beneficial solids formation 
inhibiting purpose because not only the reaction temperature, but the 
nature of the lower alkanol, reaction solvent, reactants and other 
reaction conditions must be taken into account.

The process of the present invention can be illustrated, but not limited, 
more fully by the following Examples. 
EXAMPLE 1 
To a suitable reactor fitted with condensation/distillation head was added 
with agitation 411.8 grams of methylene chloride, 984.4 grams of a 20.52 
weight percent solution of diethyl acetone dicarboxylate in methylene 
chloride, 23.4 grams of ethanol (as 2B-ethanol) and 128 grams of 
chloroacetone. The reactor contents were chilled to 5.degree. C. and 620.5 
grams of methylamine as a 40 weight percent aqueous solution was added 
over a period of about 1 minute. The temperature rose to 13.5.degree. C. 
After addition of the methylamine there were very little solids formed at 
the top of the reactor and good agitation was observed. The temperature 
reached 24.6.degree. C. while the brine bath remained at 2.degree. C. 
Then heating started on the brine bath and the reactor contents reached 
37.8.degree. C. and began refluxing for about 30 minutes. The brine bath 
was then heated to about 100.degree. C. over a period of 2 hours and the 
reactor contents reached 90.degree. C. The heating was then stopped and 
the condensate phases separated while hot. Analysis by VPC and NMR 
indicates a 64.69 percent yield of ethyl 
1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate. 
In a similar manner, several other experiments were carried out varying the 
amount of ethanol and other reactants to study their effect on the yield 
of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate with the results 
being given in the following table. 
TABLE I 
______________________________________ 
Preparation of Ethyl 1,4-Dimethyl-3-ethoxycarbonylpyrrole- 
2-acetate (PDE) by Reaction of Diethyl Acetone Dicarboxylate 
(ADC), Chloroacetone (CA) and Aqueous Methylamine (MA) in 
Methylene Chloride (MeCl.sub.2) and Ethanol (EtOH) 
Ex- Percent 
ample Molar Ratio of Yield 
No. EtOH : MeCl.sub.2 : 
CA : MA : ADC of PDE 
______________________________________ 
2 0 16.3 1.36 8.06 1 60.8 
3 0 16.3 1.36 8.06 1 52.1, 54.6 
4 0 16.3 1.36 8.06 1 65.2 
5 0 16.3 1.36 8.06 1 52.7 
6 5.52 16.2 1.36 8.06 1 51.1 
7 0 16.3 1.36 8.06 1 51.9 
8 1.5 14 1.38 8.0 1 55.8 
9 6.0 22.2 1.38 8.0 1 55.2 
10 14 14 1.38 8.0 1 38.2 
11 18 10 1.38 8.0 1 39.6 
12 1.4 12.6 1.11 6.7 1.2 58.9 
______________________________________ 
It should be noted that when ethanol was employed in the above examples 
very few or no solids were observed. Moreover, other lower alkanols, as 
hereinabove described, can be used with similar results in the process of 
the present invention. Further, it is preferred that the alkyl groups on 
the dilower alkyl acetone dicarboxylate be the same as the alkyl portion 
of the lower alkanol added. This is because during the reaction it is 
believed that some transalkylation may occur leading to the formation of 
mixed pyrrole diesters. Although technically feasible, production of 
pyrrole diesters with mixed ester groups is impractical because of 
complications encountered in subsequent processing, recovery and recycle 
steps. 
The Carson patents, U.S. Pat. Nos. 3,752,826 and 3,765,840, are hereby 
incorporated by reference as if fully set forth. 
Having disclosed the process of the present invention, one skilled in the 
art can readily envision variations, modifications and changes within the 
scope and spirit of this invention. Therefore, it is desired that the 
present invention be limited only by the lawful scope of the following 
claims.