GB2033903A - Monoesterification of substituted pyrrole diacids - Google Patents

Abstract

A process for the production of a compound having the formula: <IMAGE> wherein R1 and R2 are each hydrogen or hydrocarbyl groups having up to 20 carbon atoms and R3 is an alkyl or alkaryl group of up to 20 carbon atoms, comprises reacting a compound of the formula: <IMAGE> with an anhydrous alkanol of the formula R3OH in the presence of a strong acid ion exchange resin esterification catalyst under esterfying reaction conditions.

Description

SPECIFICATION Monoesterification of substituted pyrrole diacids The present invention relates to methods for synthesizing selectively esterified, substituted pyrrole compounds. Such compounds are useful in the preparation of pyrrole-based, anti-inflammatory agents.

Alkyl, aroyl-substituted pyrrole -2- acetates are useful anti-inflammatory agents. Compounds of this type are disclosed as anti-inflammatory agents, for example, in Carson, U.S. Pat. 3,752,826, issued August 14, 1973. Useful precursors of the substituted pyrroles which exhibit anti-inflammatory activity include the monoesters of 3 - carboxy - 1,4 - dialkyl pyrrole-2-acetic acid having the acetic acid group selectively esterified. Such compounds can be decarboxylated and subsequently aroylated to provide the desired pharmaceutically active pyrrole materials.

Substituted pyrrole acid ester compounds can be prepared by esterifying the corresponding pyrrole diacid with an alcoholic esterifying agent in the presence of an acid catalyst. For example, esterification of 3 - carboxyl - 1,4 - - dimethyl pyrrole - 2 - acetic acid using an ethanol esterification agent and HCI as a catalyst is disclosed in Carson et al., Journal of Med icinal Chemistry 1973, Vol. 16, No. 2, pp. 172-174.

When employing such esterification procedures, it is, of course, desirable to maximize the amount of the acetate monoester formed and to minimize the amount of the pyrrole diester formed. This is because substituted pyrrole esters having antiinflammatory activity are decarboxylated at the 3-position of the pyrrole ring, and such decarboxylation is easierto accomplish when the acid group at the 3-position is unesterified. While treatment of substituted 3 - carboxy - pyrrole - 2 - acetic acids with alcohol and conventional esterification catalysts will yield a product which is predominantly the acetate monoester, a significant amount of the undesirable diester is also produced by such reaction.Esterification using conventional mineral acid catalysts also presents the problem of removing or separating the esterification catalyst from the reaction mixture after esterification is complete since strong acids should not be present during subsequent decarboxylation treatment of the pyrrole acid ester products. Given such conditions and difficulties involving preparation of substituted pyrrole acid ester compounds, there is a continuing need to develop improved procedures for the preparation of selectively esterified, substituted pyrrole precursors of pyrrole-based anti-inflammatory agents.

Accordingly, it is an object of the present invention to provide an improved process for the synthesis of the acetate monoesters of 3 - carboxy - 1,4 - disubstituted pyrrole - 2 - acetic acid.

It is a further object of the present invention to provide an esterification method for preparing these particular useful pyrrole monoesters in such a way that formation of less desirable pyrrole diesters is minimized.

It is a further object of the present invention to provide an esterification method for synthesizing such pyrrole monoesters using reactants and esterification catalysts that can be readily separated from the product monoesters after completion of the esterification reaction.

In accordance with the present invention, a substituted pyrrole diacid of the formula:

wherein R1 and R2 are each either hydrogen or a hydrocarbyl group of up to about 20 carbon atoms or more, is selectively esterified to a pyrrole monoester of the formula:

wherein R3 is alkyl or alkaryl of up to about 20 carbon atoms or more. Such selective esterification is car ried out by reacting the substituted pyrrole diacid with an anhydrous alkanol of the formula R3OH using conventional esterification reaction conditions in the presence of a strong acid, ion exchange resin catalyst.

The substituted pyrrole diacid starting materials for use in the method herein can be synthesized in known fashion from the corresponding substituted pyrrole diesters which in turn can be prepared by reacting primary amines, acetone dicarboxylate diesters and halomethyl lower alkyl ketones. Synthesis processes of this type are disclosed, for exam ple, in Carson, U.S. Pat 4,070,368, issued January24, 1978; Carson, U.S. Pat 3,865,840, issued February 11, 1975; Carson, U.S.Pat. 3,752,826, issued August 14, 1973; and Carson et al.,Journal of Medicinal Chemistry, 1973, Vol. 16, No.2, pp. 172-174. The substituents, R1 and R2, at the 4 and 1 positions, respectively, on the reactant pyrrole ring can be either hydrogen or an aliphatic or aromatic hydrocarbyl group containing up to about 20 carbon atoms or more. Preferably, such substituents are alkyl, and more preferably, lower alkyl containing from 1 to about 4 carbon atoms. The most preferred substituted pyrrole diacid reactant is that wherein the R, and R2 ring substituents are both methyl, i.e., 3 - carboxy - 1,4 - dimethylpyrrole - 2 - acetic acid.

When the pyrrole ring substituents are lower alkyl, the substituted pyrrole diacid starting material is generally employed in the form of a solid crystalline material which can be dissolved in the an hydros alkanol used to obtain the desired selective monoesterification.

The an hydros alkanol esterification agent employed in the method herein has the general formula R3OH wherein R3 is alkyl or alkaryl, e.g., benzyl, of up to about 20 carbon atoms or more. R3 is preferably lower alkyl, e.g., alkyl of from 1 to about 6 carbon atoms. Examples of suitable anhydrous alkanols include absolute alkanols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, n-pentanol, n-hexanol and the like. Preferred esterification agents are absolute methanol, abso lute ethanol and absolute isopropanol. The most preferred alkanol is absolute methanol.

The anhydrous alkanol esterification agent may also serve as the liquid reaction medium in which the selective pyrrole monoesterification ofthe present method is carried out. Accordingly, the anhydrous alkanol is usually employed in substantial excess over stoichiometric monoesterification concentration vis-a-vis the substituted pyrrole diacid starting material. Generally enough of the anhydrous alkanol is employed so that all reactants and reaction products are dissolved in the hot alkanoic reaction medium throughout the esterification procedure. Advantageously the weight ratio of alkanol to the substituted pyrrole diacid reactant ranges from about 3:1 to 20:1, more preferably from about 7:1 to 8:1.

The unexpectedly selective monoesterification reaction of the present method is effected by catalyzing the esterification reaction between pyrrole diester and alkanol with a solid, strong acid (cation), ion exchange resin catalyst. Ion exchange resins of this type are generally solid polymeric materials which contain -SO3H groups that can donate protons in a manner analogous to sulfuric acid. Typically, such resins utilize a divinyl benzene/styrene copolymer backbone or matrix which may be cross-linked to provide resins of varying degrees of porosity. Resins useful herein can be either micro- or macro-reticular (small or large pore) as determined by the extent of resin cross-linking. Advantageously the resin has from about 2 or3 to 15 percent cross-iinking.Percent cross-linking refers to the weight percentage of cross-linking monomer, e.g., divinyl benzene, in the resin copolymer.

Strong acid, ion exchange resins are commercially available in a variety of particle sizes and can have varying amounts of water associated with the resinous, porous material. Ion exchange resins having a particle size between about 16 and 50 mesh and water content values up to about 52 percent by weight, preferably between about 1 to 50 percent by weight can be advantageously employed herein.

Water content values of this type are generally determined by Loss-On-Drying (LOD) gravimetric analytical procedures.

In a particularly preferred embodiment of the present invention, the strong acid, ion exchange resins employed are pretreated by washing them with an excess of a lower alkanol, e.g., the alkanol to be used as esterification agent and reaction medium in the monoesterification process herein. Such pretreatment with alkanol in this manner serves to wash off at least some of the water normally associated with the ion exchange resin catalyst. Preferred alkanols for this pretreatment procedure include methanol and ethanol.

Strong acid, ion exchange resins are commercially available materials. Amberlite (Registered Trade Mark) IR-120-AR, Amberlite IR-120 (H) CP and Amberlyst (Registered Trade Mark) 15, all marketed by Mallinckrodt, Inc., are examples of such commercially-available materials which are suitable for use in the process herein. All of these materials have a styrene-divinyl copolymer matrix and -SO35 functional groups. Some ofthese commerciallyavailable materials are "hydrated" with a Loss-On Drying water content of about 48 to 49 percent. The Amberlite IR-120-AR and Amberlite IR-120 (H) CP resins are medium porosity ion exchange resins having a cross-linking percentage of about 8 percent.

The Amberlite 15 resin is a high porosity material especially useful in non-aqueous systems.

The strong acid, ion exchange resin catalyst used to promote the esterification in the method of the present invention is, of course, employed in the reaction mixture in an amount sufficient to effectively cataryze the monoesterification reaction. Advantageously, the weight ratio of the substituted pyrrole diacid reactant to ion exchange resin catalyst ranges from about 1:1 to about 35:1, more preferably from about 5:1 to about 10:1.

Utilization of the strong acid, ion exchange resin as an esterification catalyst for the preparation of the desired substituted pyrrole monoesters herein provide several unexpected advantages. Most importantly, the ion exchange resin catalyst promotes very selective monoesterification of the pyrrole diacid reactant in comparison with convention mineral acid esterification catalysts. When an ion exchange resin catalyst is employed, esterification occurs almost exclusively at the acetic acid group in the 2-position on the substituted pyrrole ring. Very little, if any, detectable diester or isomeric 3-monoester may be formed in the esterification reaction. The solid, ion exchange resin catalysts are also easily removed from the reaction mixture, for example, by filtration, after the esterification reaction is completed.Catalyst removal is often a necessary procedure since the substituted pyrrole monoesters formed by the process are generally subjected to furthertreatment wherein the presence of acid catalysts would be undesirable or unacceptable. Such further treatment, for example, frequently will involve thermal decarboxylation of the substituted acid ester pyrrole, and strong acid materials must not be present in the reaction mixture during such decarboxylation procedures. Since the ion exchange resin catalysts used herein are solid materials, they are more easily removed from the reaction mixture than are conventional liquid mineral acid catalysts.

The selective esterification method of the present invention is carried out under reaction conditions which serve to obtain the desired monoesterification reaction. Such conditions include conventional ones for esterification reactions of the type herein involved. Advantageously the esterification reaction mixture is maintained at a temperature between about 25"C and 150 C, more preferably from about 60"C to 650C. If desired, the requisite esterification temperature conditions can be advantageously maintained by refluxing the alkanol reaction medium solvent throughout the esterification reaction. Reaction mixture agitation may also be emp loyed, if desired.

The esterification reaction is continued until monoesterification of the substituted pyrrole diacid reactant has proceded to the extent desired, and preferably until substantially complete. Advantageously, reaction times of from about 0.5 hour to several days, more preferably from about 5 hours to 6 hours can be employed The reaction medium in which the monoesterification reaction is carried out is generally substantially anhydrous. However, a relatively small amount of water may be introduced to the reaction mixture in association with the ion exchange resin catalyst.

The substituted pyrrole monoester reaction product can be recovered from the reaction mixture and purified or treated further using conventional techniques. Advantageously, for example, the solid, ion exchange resin catalyst is simply filtered from the reaction mixture atthe conclusion of esterification, and the alkanol solvent reaction medium can then be stripped by distillation from the mixture in order to recover the substituted pyrrole monoester product.

As noted hereinbefore, the substituted pyrrole monoester product recovered can be decarboxylated and subsequently aroylated to provide various pharmaceutically active materials. Procedures of this type are more thoroughly described in Carson et al., Journal of Medicinal Chemistry, 1973, Vol, 16, No. 2, pp. 172-174, cited above.

The selective monoesterification method of the present invention is illustrated by the following examples which are not limiting of the invention herein.

EXAMPLE I A two-liter, three-necked flask is fitted with a thermometer, mechanical stirrer and condenser and is charged with 1156 ml. of absolute methanol. While the mixture is being stirred, 12.4 gm. of Am berlite IR-120-AR strong acid cation ion exchange resin catalyst is added to the flask, followed by 120 gm. of 3 - carboxy - 1,4 - dimethyl pyrrole - 2 - acetic acid.

Using a heating mantle, the reaction mixture is heated to reflux at an internal temperature of about 65"C. Within lotto 15 minutes, the reaction mixture is clear and dark brown in color. Reflux of the reaction mixture is continued for 6 hours with reaction mixture temperature of about 65-66"C and a vapor temperature of about 63-64"C.

After refluxing for 6 hours, the hot solution (60"C) is decanted to separate the ion exchange resin catalyst. Catalyst and flask are rinsed with 50 ml. of abso lute methanol, and the methanol rinse is combined with reaction mixture. Atotal volume of 1250 ml. of methanolic solution is obtained, and a sample is withdrawn for assay.

A yield of about 94 percent of the methyl 3 - car boxy - 1,4 - dimethyl pyrrole - 2 - acetate is obtained.

No diester or isomeric monoester can be detected in the mixture by Thin-Layer Chromotography techni ques.

Substantially similar production of methyl 3 - car boxy - 1,4 - dimethylpyrrole - 2 - acetate is realized when, in the Example I procedure, the Amberlite IR-120-AR ion exchange resin is replaced with an equivalent amount of Amberlyst 15 or Amberlite 120 (H) CP strong acid cation ion exchange resins.

Substantially similar production of ethyl 3 - carboxy - 1,4 - dimethylpyrrole - 2 - acetate is realized when, in the Example I procedure, the absolute methanol is replaced with an equivalent amount of absolute ethanol.

EXAMPLE II 718 kg. of anhydrous methyl alcohol are charged to a heated reaction vessel equipped with an agitator and refluxing apparatus. While the methyl alcohol is being agitated, 10 kg. of Amberlite IR-120 (H) CP strong acid cation ion exchange resin is charged to the reaction vessel. 97 kg. of 3 - carboxy - 1, 4 dimethyl pyrrole - 2 - acetic acid are then added to the agitated reaction mixture. The reaction mixture is refluxed at 65"C to 70"C for 6 hours.

After refluxing for 6 hours, the contents of the reaction vessel at 60"C are recirculated through a preheated Kynar-coated Niagara filter to remove the ion exchange resin catalyst. The reaction vessel contents are then transferred through the filter to a second reaction vessel equipped with heating apparatus. The reaction mixture in the second vessel is heated, starting at 65"C, to strip off methyl alcohol from the mixture. Methyl alcohol is removed from five batches of acid ester pyrrole in this manner. Five such batches will yield approximately 100 gallons of the semi-solid pasty methyl 3 - carboxy - 1,4 dimethyl pyrrole- 2- acetate reaction product.

EXA MPL E Ill 15 gm. of 3 - carboxy 1,4 - dimethyl pyrrole - 2 acetic acid, 0.4 gm. of Amberlite IR-120-AR strong acid ion exchange resin and 150 ml. of absolute methanol are stirred with reflux. After 1.5 hours, all the diacid is dissolved in the methanol. Samples of the reaction mixture are taken and qualitatively analyzed using Thin-Layer Chromotography (TLC) techniques in orderto detect the presence in the reaction mixture of the pyrrole diacid, the pyrrole monoester, and the pyrrole diester materials.

Since TLC indicates that after 3.5 hours, the esterification reaction is not complete, an additional 0.4 gm. of the Amberlite catalyst is added and the reaction mixture is allowed to reflux overnight with stirring. After overnight reaction, TLC indicates that the monoesterification reaction is complete with very little of the diester product formed.

Claims (12)

1. A method for selectively esterifying a substituted pyrrole diacid of the formula:

wherein R1 and R2 are independently selected from hydrogen atoms and hydrocarbyl groups of up to about 20 carbon atoms, said method comprising reacting said substituted pyrrole diacid with an anhydrous alkanol of the formula R3OH, wherein R3 is alkyl or alkaryl of up to about 20 carbon atoms, in the presence of a strong acid ion exchange resin esterification catalyst under esterifying reaction conditions to form a substituted acid monoester pyrrole of the formula:

wherein R1, R2 and R3 are as defined above.

2. A method according to claim 1 for the preparation of compounds of formula II wherein R1 and R2 are lower alkyl and R3 is a methyl or ethyl group, wherein the anhydrous alkanol is selected from methanol and ethanol and is used as a reaction medium for conducting the esterification reaction.

3. A method according to either of claims 1 and 2 wherein the strong acid ion exchange resin is a divinyl benzene/styrene copolymer having -SO3H functional groups associated therewith.

4. A method according to any one of the preceding claims wherein R1 and R2 are methyl.

5. A method according to any one of the preceding claims wherein.

A) The weight ratio of anhydrous alkanol to substituted pyrrole diacid ranges from about 3:1 to 20:1; and B) The weight ratio of substituted pyrrole diacid to esterification catalyst ranges from about 1:1 to 35:1.

6. A method according to any one of the preceding claims wherein the esterification reaction is conducted at a temperature of from about 25"C to 150"C.

7. A method according to any one of the preceding claims wherein the ion exchange resin catalyst is pretreated by washing said resin with an anhydrous alkanol selected from methanol and ethanol before said resin is introduced into the reaction medium.

8. A method according to any one of the preceding claims wherein the esterification reaction is car ried out at the reflux temperature of the anhydrous alkanol reaction medium.

9. A method according to claim 8 wherein the anhydrous alkanol is methanol.

10. A method according to any one of the preceding claims wherein, after formation of the substituted acid monoester pyrrole, esterification catalyst is removed by filtration from the anhydrous alkanol reaction medium, and the anhydrous alkanol reaction medium is subsequently separated by distillation from the substituted acid monoester pyrrole.

11. A method for selectively esterifying a substituted pyrrole diacid substantially as herein described in any one of the Examples.

12. A pyrrole diacid monoesterwhenever prepared by a method as claimed in any one of the preceding claims.