Process for preparing 5-aroyl 1,2-dihydro-3-H pyrrolo[1,2-a]pyrrole-1-carboxylic acids and novel intermediates therein

5-Substituted-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids of the formula ##STR1## wherein: X is hydrogen or lower alkyl; Ar is a moiety selected from the group consisting of ##STR2## in which: Y is oxygen or sulfur; PA0 R is hydrogen, methyl, chloro, or bromo, the R substitution being at the 3, 4 or 5 position of the ring; PA0 R.sup.1 is hydrogen, lower alkyl, lower alkoxyl, lower alkoxycarbonyl, lower alkylcarbonyl, fluoro, chloro or bromo, the R.sup.1 substitution being at any available position in the ring; PA0 R.sup.2 is hydrogen or lower alkyl; are prepared by .beta.-decarboxylation of the corresponding dialkyl-1,1-dicarboxylates. Certain substituted pyrroles are useful as intermediates for preparing the compounds of formula I.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a process for preparing 
5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acids of the 
formula 
##STR3## 
by decarboxylation of the corresponding 1,1-dicarboxylates. This invention 
also related to a process for the preparation of the 1,1-dicarboxylates 
and novel intermediates therein. 
2. Prior Art 
The "end-products" of Formula (I) with the exception of those wherein 
R.sup.1 is carboxyl, lower alkoxycarbonyl or lower alkylcarbonyl, have 
been previously described. The Ar moiety, as will be described herein 
below, is shown as 
##STR4## 
in U.S. Pat. No. 4,087,539, as 
##STR5## 
in U.S. Pat. No. 4,089,969, and as 
##STR6## 
and U.S. Pat. No. 4,097,579. The preparation of the above is disclosed by 
methods other than those disclosed herein. 
The compounds of Formula (I) are useful as anti-inflammatory agents, 
analgesic agents, platelet aggregation inhibitors, fibrinolytic agents, 
and as smooth muscle relaxants. They can be used both prophylactically and 
therapeutically, as disclosed in U.S. Pat. Nos. 4,087,539, 4,089,969, and 
4,097,579 which are incorporated herein by reference. 
SUMMARY OF THE INVENTION 
One aspect of the invention herein relates to preparation of the compounds 
of Formula (I) by decarboxylating the corresponding dialkyl 
5-substituted-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylates of 
the formula 
##STR7## 
wherein: 
X is hydrogen or lower alkyl; Ar is a moiety selected from the group 
consistig of 
##STR8## 
in which: 
Y is oxygen or sulfur; 
R is hydrogen, methyl, chloro, or bromo, the R substitution being at the 3, 
4 or 5 position of the ring; 
R.sup.1 is hydrogen, lower alkyl, lower alkoxycarboxyl, lower 
alkoxycarbonyl, lower alkylcarbonyl, fluoro, chloro or bromo, the R.sup.1 
substitution being at any available position in the ring; 
R.sup.2 is hydrogen or lower alkyl; 
and R.sup.3 is hydrogen or lower alkyl, to compounds of Formula I, by 
treating them with acid or preferably by treating with base and 
subsequently treating with acid. Said conversion may be represented 
schematically: 
##STR9## 
Another aspect of this invention relates to overall synthesis of compounds 
of formula I and preparation of compounds of formula II. 
The intermediate compounds in said overall process are new. Therefore, in 
another aspect, the present invention relates to these novel compounds, 
which are useful as intermediates in the process herein and are set forth 
below. 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
As used herein, "lower alkyl" means a branched or unbranched saturated 
hydrocarbon chain containing from one to four carbon atoms; 
"lower alkoxyl" means --OR wherein R is lower alkyl as herein defined; 
"lower alkoxycarbonyl" means 
##STR10## 
wherein R is lower alkyl as herein defined; 
"lower alkylcarbonyl" means 
##STR11## 
wherein R is lower alkyl as herein defined; 
"strong mineral acid" means an inorganic water soluble, easily dissociable 
Bronsted Lowry acid, such as hydrochloric, sulfuric, phosphoric and the 
like; 
"strong mineral base" means an inorganic water soluble, base with a 
pk.sub.b less than about 5, such as sodium hydroxide, sodium carbonate, 
potassium bicarbonate and the like. 
"optionally substituted phenyl" means a phenyl group which may or may not 
be substituted with a moiety selected from the group consisting of halo 
and lower alkyl. 
PREATION OF COMPOUNDS OF FORMULA II 
A schematic of the conversion of compounds of Formula A, i.e. pyrrole or 
the 3-lower alkyl or 3-halo pyrroles to compounds of Formula II is shown 
in Reaction Scheme I 
##STR12## 
The intermediates B through H may be isolated, if desired, using 
conventional techniques, including but not limited to, filtration, 
distillation, crystallization, chromatography and the like as stated 
hereinabove. Such intermediates may be characterized using conventional 
means, including physical constants and spectral characteristics. 
As seen from Reaction Scheme I, the process is congruent in Steps 1 and 2, 
but diverges at compounds of Formula C into 3 alternative pathways, a, b 
and c (which, at times overlap) and then converges to a common 
intermediate at compounds of Formula H. Step 6 is then congruent with 
respect to these alternatives. 
Preparation of compounds of Formula B, accomplished herein in Step 1, has 
been described elsewhere: Matteson et al, J. Org. Chem. 22:1500 (1957); 
Japanese Pat. No. 53/025,559. 
However, in the present invention, improved yields were obtained by a new 
process which comprises treating the appropriate pyrrole or 3-alkyl 
pyrrole with a reagent formed from dimethylsulfide and an 
N-halosucinimide. 
(Other dialkyl sulfides may also be used, but there is no advantage to 
doing so, as the alkyl sulfide group will be lost during the subsequent 
steps in the process.) 
In this conversion, an N-halosuccinimide, preferably N-chlorosuccinimide, 
dissolved in a non-polar aprotic solvent, preferably dichloromethane, is 
treated with an approximately equimolar amount of dimethylsulfide, also so 
dissolved. The treatment is accomplished slowly, preferably dropwise, and 
the reaction mixture thereby maintained at low temperature (about 
-10.degree. to +5.degree., preferably 0.degree. to +5.degree.). 
When the reagent preparation described above is complete, the solution is 
cooled to about -50.degree. to -20.degree., preferably to -35.degree. to 
-25.degree., allowed to stand for 10 minutes to 3 hours, preferably about 
1 hour, and then an approximately equimolar amount of the pyrrole starting 
material of formula A also dissolved in the above solvent is slowly added. 
The reaction mixture may be allowed to stand at this low temperature for 
about 10 minutes to 3 hours, preferably about 1 hour, and the temperature 
is then allowed to rise to room temperature, preferably 20.degree.. 
Solvent is removed by evaporation, and product is formed by either heating 
in vacuo and collecting product as distillation occurs, or by heating in 
the presence of solvent and collecting the product by subsequent 
distillation. 
In Step 2, the process used is substantially that described in U.S. Pat. 
Nos. 4,087,539; 4,089,969 and 4,097,579, which are incorporated herein by 
reference. The procedures as described therein may be modified by using 
other dialkylamines, such as methyl ethyl amine, ethyl n-propyl amine and 
the like to form the aroylamides. The resulting aroylamides may then be 
substituted for the aroyldimethylamides in the same procedures. 
Additionally, aroyl halides may be used directly, obviating the need for 
phosphorous oxychloride or other analogous halogenating agent. However, 
the resulting compounds of Formula C are new. 
Steps 3a, 3b and 4c are each effected in the same manner as each other. The 
subject pyrrole derivative is treated with an excess of an alkali metal 
hydride or other strong base, preferably sodium hydride under an inert 
atmosphere e.g. nitrogen, neon or argon, preferably argon, until reaction 
is complete. This time may range from 10 minutes to 10 hours, but is 
ordinarily in the range of 1-2 hours. The reaction takes place at about 
0.degree.-40.degree., but preferably at room temperature i.e. 
15.degree.-25.degree.. Operable solvents include any aprotic organic polar 
solvent, e.g., DME, diglyme, DMF and the like; preferably DMF. 
After the treatment with the hydride, compound J, i.e. 
spiro[2,5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione, prepared according to 
Singh et al, J. Org. Chem. 40: 2969 (1975) is added in slight excess and 
the temperature is raised to about 40.degree.-80.degree., preferably 
50.degree.-60.degree., and the mixture is allowed to react for about 1-10 
hours or to completion. The product, a compound of Formula D (Steps 3a or 
3b) or Formula G (Step 4c) may be isolated, preferably as the salt. 
Analogous spiro cyclopropyl compounds, with the general formula 
##STR13## 
wherein each R may independently be lower alkyl, may also be used. These 
compounds may be prepared in a manner similar to that for 
spiro[2,5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione by substituting other 
ketones for acetone to form the dioxyketal ring. Thus, for example, 
spiro[2,5]-5,7-dioxa-6,6-diethyl-octane-4,8-dione; 
spiro[2,5]-5,7-dioxa-6-methyl-6-ethyl-octane-4,8-dione, and 
2-spiro[2,5]-5,7-dioxa-6-methyl-6-propyl-octane-4,8-dione, may be prepared 
using 3-pentanone, methyl ethyl ketone (2-butanone) and 2-pentanone 
respectively. However, there is no particular advantage in varying the 
6,6-substitution, since subsequent steps in the overall process remove 
these groups, and ease of removal is not enhanced by such variation. 
Therefore, the preferred method is to employ 
spiro[2,5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione. 
Steps 4a, 5b and 5c are carried out similarly to each other. In each case 
the cyclic diester dissolved in a suitable solvent, e.g. an alcohol, is 
converted to the corresponding dialkyl dicarboxylate or dicarboxylic acid 
by treatment with a suitable alcohol in the presence of acid. In a 
preferred embodiment the subject compound is dissolved in methanol and 
treated with methanol previously saturated with HCl at about 
25.degree.-80.degree., preferably 60.degree.-70.degree. for about 5 
minutes to 5 hours, preferably 10 minutes to 40 minutes. The dimethyl or 
other dialkyl ester may then be recovered by suitable conventional 
techniques. 
Steps 5a, 3c, and 4b all represent the oxidation of the methyl thiopyrrole 
to the methyl sulfonylpyrrole. An excess of oxidizing agent, e.g. 
peroxide, permanganate, or peracid preferably m-chloroperbenzoic acid in 
excess, and preferably in an approximately 2:1 molar ratio to the subject 
compound is used. The reaction can be done at low temperature, about 
-10.degree. to +15.degree., preferably 0.degree. C. in a non-polar, 
aprotic organic solvent, e.g. chloroform, dichloromethane or 
dichloroethane, preferably dichloromethane. The reaction time may vary 
from about 15 minutes to 10 hours; usually it is in the range of 2-3 
hours. The product is then recovered using techniques familiar to those 
skilled in the art. 
The sequences 3a, 4a, 5a; 3b, 4b, 5b; and 3c, 4c, 5c all converge at 
compounds of formula H, the 1-(2-ethylmalonate) derivative of the 5-aroyl 
pyrrole. Cyclization to the corresponding pyrrolo[1,2-a]pyrrole compound 
of Formula II takes place in step 6. 
To carry out step 6, the subject compound is dissolved in an aprotic 
organic polar solvent, preferably dimethylformamide and treated with a 
slight excess of an alkali metal hydride, preferably sodium hydride in 
mineral oil. The reaction mixture may be heated to about 
50.degree.-150.degree. for about 10 minutes to 10 hours, preferably to 
100.degree.-110.degree. for 4-6 hours. All of these operations are carried 
out in an inert atmosphere, preferably under nitrogen. The mixture is then 
cooled to about 5.degree.-40.degree., preferably room temperature 
(15.degree.-25.degree.) and the solution made acidic, preferably by 
addition of 10% hydrochloric acid. The product of Formula II may then be 
recovered. 
The compounds of Formula II are then converted to the corresponding 
5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids as 
described hereinbelow. 
THE CONVERSION OF COMPOUNDS OF FORMULA II TO COMPOUNDS OF FORMULA I 
The conversion herein consists of treatment with base to accelerate ester 
hydrolysis, followed by treatment with acid to effect decarboxylation. 
In the special case where R.sup.3 is hydrogen, treatment with base is 
unnecessary, and the conversion can be carried out in the presence of acid 
only. Where R.sup.3 is lower alkyl, it is possible, but not particularly 
desirable to carry out the entire conversion under acid conditions; the 
preferred method is to hydrolyze the esters first by treatment with base, 
and then decarboxylate in acid. 
The conditions of treatment with base and acid to effect hydrolysis and 
decarboxylation are familiar to those skilled in the art for 
decarboxylation of .beta.-dicarboxylic acid esters. For hydrolysis under 
basic conditions, the use of a strong base, preferably a mineral base, 
e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, and the 
like, in the presence of water is preferred. Advantageously, water 
miscible organic solvents, e.g., 2-methoxyethanol, methanol, ethanol, 
ethylene glycol, dimethylsulfoxide, and the like are used to facilitate 
solution of the reactants. The reaction is peferably carried out under an 
inert atmosphere, e.g., nitrogen, argon, and the like, with nitrogen being 
the most preferred. The reaction times and temperatures are not critical 
and depend, as will be apparent to those skilled in the art, on the 
reactants (and other ingredients of the reaction mixture) employed. Thus 
the reaction time can be from about 5 minutes to about 2 hours, with 30 
minutes to 1 hour being preferred; and the reaction temperature from about 
60.degree. C. to reflux temperature with 70.degree. C. to reflux 
temperature being preferred. 
Subsequent treatment with acid is effected preferrably with a strong 
mineral acid, e.g., phosphoric acid, sulfuric acid, hydrochloric acid, 
hydrobromic acid, and the like in the presence of water, with or without 
the presence of an organic acid, e.g., acetic acid, formic acid, propionic 
acid, and the like. If desired other organic solvents miscible with the 
mineral acid (and the water and the organic acid, if the latter is used) 
can be used. Suitable organic solvents are ethyl acetate, methanol, 
ethanol, ethylene glycol, dimethylsulfoxide, dioxane, tetrahydrofuran, 
ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether 
(diglyme), and the like. The reaction may be carried out under an inert 
atmosphere, e.g., nitrogen, argon, and the like, with nitrogen being the 
most preferred. The reaction times and temperatures are not critical and 
depend, as will be apparent to those skilled in the art, on the reactants 
and other ingredients of the reaction mixture) employed. Thus, the 
reaction time can be from instanteous to about 10 hours with one minute to 
5 minutes being preferred; and the reaction temperature from about 
10.degree. C.-100.degree. C., preferably 15.degree.-30.degree. C. 
Isolation, separation, and purification of the desired compound of Formula 
(I) from the reaction mixture containing it can be effected by any 
suitable separation or purification procedure, such as, for example, 
extraction, filtration, evaporation, distillation, crystallization, 
thin-layer chromatography, or column chromatography, high pressure liquid 
chromatography, and the like, or a combination of these procedures. 
Illustrations of suitable isolation, separation and purification 
procedures can be had by reference to the Examples herein below. However, 
other isolation, separation and isolation procedures, could of course, 
also be used. 
NOVEL INTERMEDIATES 
The compounds of formula C, D, E, F, G, H and II are novel, and are useful 
as intermediates in preparing compounds of formula (I) which are 
therapeutically useful as discussed hereinbefore. 
PREFERRED EMBODIMENTS 
A set of preferred embodiments of the present invention is composed of 
those wherein the decarboxylation of the compounds of formula II is 
effected by treating said compounds with acid, especially strong mineral 
acid, or more preferably by treating said compounds with base, followed by 
acid, and most preferably with strong mineral base followed by strong 
mineral acid. 
The sequences 1, 2, 3a, 4a, 5a, 6 and 1, 2, 3b, 4b, 5b, 6 in the 
preparation of the compound of formula II appear slightly superior to the 
sequence 1, 2, 3c, 4c, 5c, 6. However, the latter sequence is certainly 
perfectly practicable. 
Another set of preferred embodiments is that wherein X is hydrogen or 
methyl and Ar is thien-2-yl, furan-2-yl, pyrrol-2-yl or optionally 
substituted phenyl. 
The conversion of step 6 is best carried out by treating a compound of 
formula H with an alkali metal hydride in an aprotic solvent. 
The conversions of steps 5a, 4b, and 3c are best carried out by treating 
compounds of formulas, F, D and C, respectively, with a perbenzoic acid. 
The following examples illustrate the embodiment of the present invention, 
and should not be construed to limit it.