GB2034304A - Process for producing substituted pyrrole diesters - Google Patents
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
A process for producing a substituted pyrrole of the formula <IMAGE> wherein R1 is a hydrocarbyl group of up to about 20 carbon atoms, R2 and R3 are independently alkyl or aralkyl of up to about 20 carbon atoms and R4 is H or a hydrocarbyl of up to about 20 carbon atoms comprises reacting a primary amine R1NH2 with an acetone dicarboxylic acid diester R3OOCCH2COCH2COR2 and a substituted carbonyl compound R4COCH2X where X is a leaving group. The pyrrole forming reaction is conducted in a two-phase, aqueous/organic reaction medium dispersion containing R1NH2 with which the acetone dicarboxylic acid ester and substituted carbonyl compound are combined and/or in a reaction medium containing R1NH2 to which the acetone dicarboxylic acid ester and substituted carbonyl compounds are added in a substantially simultaneous manner.
Description
SPECIFICATION
Process for producing substituted pyrrole diesters
The present invention relates to an improved process for producing substituted pyrrole diesters which are useful in the preparation of antiinflammatory agents.
Alkyl, aroyl substituted pyrrole-2-acetates are useful anti-inflammatory agents. Compounds of this type are disclosed, for example, in Carson;
U.S. Pat. 3,752,826; issued August 14, 1973.
Useful precursors of the substituted pyrroles exhibiting anti-inflammatory activity are the diesters of 3-ca rboxy- 1 ,4-d ia I kylpyrrole-2-a cetic acid. Such compounds can be hydrolyzed to the corresponding diacid pyrroles which can then be selectively monoesterified at the acetic acid group and subsequently aroylated to provide the desired pharmaceutically active pyrrole compounds.
Substituted pyrrole diesters can be produced via a cyclization reaction involving acetone dicarboxylate esters, alkyl amine and a halosubstituted ketone such as chloroacetone. This reaction is described, for example, in Carson, U.S.
Pat. 3,752,826, issued August 14, 1973; Carson,
U.S. Pat. 3,865,840, issued February 11, 1975; and in Carson et al., Journal of Medicinal
Chemistry, 1 973, Vol. 1 6, No. 2, pp. 1 72-1 74.
As reported in the Carson et al. article, diethyl acetone dicarboxylate is added rapidly to a 40 percent aqueous solution of monomethyl amine to produce a white precipitate intermediate which is then reacted with chloroactone to produce a 70 percent yield of ethyl 1 ,4-dimethyl-3- ethoxycarbonyl pyrrole-2-acetate. The reaction reported was conducted on laboratory scale using a relatively large excess of the monomethyl amine and the chloroacetone vis-a-vis the acetone dicarboxylate.
When such procedures are to be utilized for commercial scale production of substituted pyrrole diesters, several problems can arise. In commercial production it is, of course, necessary to maintain pyrrole diester yields as high as possible while minimizing the amounts of the relatively expensive reactants employed in the cyclization reaction. Large excesses of reactants should be avoided if economically feasible processes are to be realized. Furthermore, scaleup of the pyrrole ester cyclization reaction process to commercial quantities of reactants increases the difficulties of obtaining acceptable yields of the desired pyrrole ester product. The longer reactant addition and reaction times involved in controlling the reaction exotherm of the cyclization reaction on the commercial scale tends to significantly reduce throughput of reactants and the yield of the product obtained.
Accordingly, it is an object of the present invention to provide an improved process for the synthesis of substituted pyrrole diesters by
reacting acetone dicarboxylate, primary amine and a substituted carbonyl compound such as chloroacetone.
It is a further object of the present invention to provide an improved pyrrole ester synthesis process that makes possible increased reactant throughput with acceptable yields of pyrrole diester product and with minimized utilization of excess reactant concentrations.
It is a further object of the present invention to provide an improved pyrrole synthesis process that can be economically utilized for production of commercial quantities of the pyrrole diester product.
Accordingly, the present invention involves the process for the production of substituted pyrrole esters of the formula:
wherein R1 is a hydrocarbyl group containing up to about 20 carbon atoms or more, R2 and R3 are each an alkyl or alkaryl group containing up to about 20 carbon atoms or more and R4 is hydrogen or a hydrocarbyl group containing up to 20 carbon atoms or more. In accordance with such a process, the substituted pyrrole esters are formed by reacting a primary amine of the formula
R1NH2 with an acetone carboxylic acid ester of the formula:
and a substituted carbonyl compound of the formula:
wherein R,, R2, R3, and R4 are as hereinbefore defined and X is a leaving group such as halogen.
The first step in a first aspect of the process of the present invention comprises the formation of a reaction medium comprising a dispersion of an aqueous solution of the primary amine and an inert organic solvent which is immiscible with water. As a second process step, the acetone dicarboxylic acid ester and the substituted carbonyl compound are combined with the reaction medium dispersion, preferably in a substantially simultaneous manner as hereinafter described in a second aspect of the first invention.
The combined reaction medium and reactants are maintained at a temperature below about 450C for a period of time sufficient to form the desired substituted pyrrole ester product.
The cyclization reaction which is the subject of the present invention is carried out when one mole of the primary amine, one mole of the acetone dicarboxylate ester and one mole of the substituted carbonyl compound, e.g., a substituted aldehyde or ketone, are reacted to form the substituted pyrrole ester product. The primary amine used in the process of this invention and in the cyclization reaction can be of the general formula RgNH2 wherein R is a hydrocarbyl group containing up to about 20 carbon atoms or more.
R1 can be aryl, e.g., R,NH2 can be aniline, or R, can be alkaryl, e.g., R,NH2 can be benzylamine.
Preferably, R, is alkyl and more preferably is a lower alkyl group, e.g., an alkyl group containing from 1 to about 5 carbon atoms. Such preferred primary amines include, for example, monomethyl amine, monoethyl amine, mono-isopropyl amine, mono-n-propyl amine, mono-isobutyl amine, mono-n-butyl amine, mono-tert-butyl amine, mono-n-amyl amine and the like. The preferred primary amine for use in the process is monomethyl amine.
Advantageously, the primary amine is employed in the form of an aqueous solution. In this manner, the amine reactant serves to provide all or part of the requisite aqueous fraction essentially present in the two-phase aqueous/organic reaction medium as hereinafter more fully described. Aqueous amine solutions can contain various amounts of amine up to the solubility limit of the particular amine being utilized. Advantageously, when monomethyl amine is employed, it can be combined with the organic solvent in the form of an aqueous amine solution containing about 30-40 percent by weight of the monomethyl amine so as to form the two-phase reaction medium dispersion.
Alternatively the primary amine reactant can also be combined with the aqueous/organic reaction
medium dispersion in the form of an anhydrous
gas or liquid. The aqueous amine solution is formed in the reaction medium by virtue of the
preferential solubility of the amine in the aqueous
portion of the two-phase system.
The acetone dicarboxylic acid ester used as a 3
reactant in the process of the present invention
has the general formula:
wherein R2 and R3 are each either alkyl or alkaryl containing up to about 20 carbon atoms or more.
Preferably R2 and R3 are both lower alkyl, i.e., alkyl of 1 to 5 carbon atoms or benzyl. R2 and R3 can be the same or different groups but are preferably the same in a given molecule. Examples of acetone dicarboxylic esters which can be employed herein include dimethyl acetone dicarboxylate, diethyl acetone dicarboxylate, di-isopropyl acetone dicarboxylate, di-n-propyl acetone dicarboxylate, di-isobutyl acetone dicarboxylate, di-n-pentyl acetone dicarboxylate, dibenzyl acetone dicarboxylate, methyl ethyl acetone dicarboxylate and the like. Preferred acetone dicarboxylic acid esters are diethyl acetone dicarboxylate and diisopropyl acetone dicarboxylate.
Acetone dicarboxylic acid esters for use in the process herein can be synthesized, for example, by reacting citric acid or esters thereof with an anhydrous acid such as chloro-sulfonic acid vr oleum followed, if necessary, by the esterification of the acetone dicarboxylic acid groups.
Procedures of this nature are described more fully in Gerner, German Pat. No. 1 ,1 60,841, published July 15, 1964: and Hamilton et al., U.S. Pat.
2,887,508; issued May 19, 1 959, both of which are incorporated herein by reference. Acetone dicarboxylic acid esters can be employed in the process herein in their isolated essentially pure liquid form. Advantageously, however, the acetone dicarboxylate ester component can be combined with the reaction medium dispersion dissolved in the same organic solvent, such as dichloroethane, which serves as the organic fraction of the two-phase aqueous/organic reaction medium.
The substituted carbonyl compound which comprises the third reactant in the pyrrole-forming cyclization reaction has the general formula:
wherein R4 is H or a hydrocarbyl group containing up to about 20 carbon atoms or more, and X is a "leaving" group, i.e., any group which does not become a substituent of the pyrrole compound formed by the cyclization reaction. R4 can, for example, include aryl or alkyl, substituted alkyl, or cycloalkyl containing from 1 to about 10 or more carbon atoms. R4 is preferably lower alkyl, say of 1 to 4 carbon atoms and is most preferably methyl.
The "leaving" group X substituent can include, for example, tosyl or halide, e.g., iodide, chloride, bromide or fluoride. Chloride and bromide leaving groups substituents are preferred. Of the substituted carbonyl compounds, the most preferred are chloroacetone and bromoacetone.
In accordance with the first aspect of the present invention, the pyrrole-forming cyclization reaction is conducted in a two-phase reaction medium dispersion comprising water and a liquid organic solvent which is immiscible with water.
The water-immiscible organic solvent should, of course, be inert, i.e., essentially nonreactive with the pyrrole-forming reactants under conditions of the cyclization reaction. Preferably, the waterimmiscible organic solvent is heavier than water so that separation of the reactant-containing organic phase may be facilitated in processes of commercial scale. Useful solvents will frequently have a boiling point between 35"C and 1 75CC to facilitate removal of the solvent by distillation.
Suitable organic solvents for use in the two
phase reaction medium herein include, for example, water-immiscible aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons as well as any other water-immiscible organic liquid composed primarily of carbon along with a minor weight percentage of hydrogen with or without a minor amount of one or more elements such as oxygen, nitrogen, halogen and the like. Examples of such suitable organic solvents include hexane, chloroform, carbon tetrachloride, dichloromethane, 1 ,2-dichloroethane; 1,1 dichloroethane, trich loroethylene, benzene, chlorobenzene, p-dichlorobenzene, toluene, xylene, and diethylether.Preferred organic solvents include the halogenated alkanes such as the dichloroethanes, dichloromethane and chloroform.
Generally, the two-phase reaction medium may comprise, on a reactant free basis, about 50 percent to 90 percent, more preferably about 65 percent to 75 percent, by weight of the waterimmiscible organic solvent and from about 10 percent to 50 percent, more preferably about 25 percent to 35 percent, by weight of water. Enough of the two-phase reaction medium is employed to dissolve reactants as they are initially added.
Preferably, the weight ratio of reaction medium to the total amount of pyrrole-forming reactants ranges from about 5:1 to 1:1, more preferably from about 1.6:1 to 1.3:1.
When the pyrrole-forming cyclization reaction is conducted in a dispersion of the two-phase reaction medium as hereinbefore described, yields of the desired pyrrole esters can beenhanced over those yields achieved when only a single-phase reaction medium is employed. Without being bound by any particular theory, it is believed that the cyclization reaction occurs in the organic phase of the reaction medium. The relatively lower solubility of the primary amine in the organic phase, vis-a-vis its solubility in the aqueous phase, possibly serves to limit the availability of the amine in the organic reactive phase.
Concentrations of the reactants and intermediates in the organic phase are thus believed to be such that the enhanced yields of the desired pyrrole ester product can be realized in the two-phase system. The presence of the organic solvent is also helpful in controlling the cyclization reaction exotherm and thereby permits faster reactant addition than could be used without the solvent in the reaction medium.
In a second aspect of the present process for carrying out the pyrrole-forming cyclization reaction, the three essential reactants are preferably combined in such a way that the acetone dicarboxylate and substituted carbonyl compound are introduced to the amine-containing reaction medium in a substantially simultaneous fashion. "Substantially simultaneous" addition as used herein refers to reactant combination in such a manner that the molar ratio of substituted carbonyl compound to acetone dicarboxylate combined with the reaction medium ranges from about 1.6:1 to 1.4:1 during the time period in which those reactants are being combined with the reaction mixture.Substantially simultaneous reactant addition, of course, includes the situation wherein the acetone dicarboxylate and substituted carbonyl compound are continuously fed to the reaction vessel using feed rates such that the requisite molar ratio of these two reactants is maintained during reactant addition. Substantially simultaneous reactant addition can also include the situation wherein the acetone dicarboxylate and substituted carbonyl reactants are added in pairs of discrete increments or "shots," provided the molar ratio of the total amounts of each reactant added does not fall outside the 1.6:1 to 1.4:1 range. At least some and preferably all of the primary amine reactant is present in the reaction medium before a substantially simultaneous addition of the other two reactants is begun.
Upon addition of the acetone dicarboxylate to the reaction medium containing primary amine, a white precipitate intermediate compound is generally formed. Such an intermediate compound is possibly an amine salt of the acetone dicarboxylate ester. Further reaction of this intermediate compound with the substituted carbonyl compound such as chloroacetone eventually produces the desired substituted pyrrole diester. Since the intermediate compound appears to decompose with time, the substantially simultaneous addition of acetone dicarboxylate and substituted carbonyl compound is believed to enhance pyrrole diester production by promoting reaction of the intermediate before it decomposes.
The simultaneous reaction addition feature of the present invention is thus especially effective in maintaining an acceptably high product yield in large batch, high throughput, commercial scale processes wherein control of the cyclization reaction exotherm necessitates extended reactant addition procedures and longer reaction times.
In a preferred embodiment of the present invention both the process improvement involving the two-phase aqueous/organic reaction medium and the improvement involving the substantially simultaneous addition of reactants as hereinbefore described are employed in the same process.
Processes wherein both of these features are utilized are especially advantageous. To ensure adequate yields of the desired substituted pyrrole diester product, the primary amine and substituted carbonyl compound can be employed in stoichiometric excess vis-a-vis the acetone dicarboxylate. Generally the molar ratio of primary amine to acetone dicarboxylate may be at least about 3.5:1, preferably at least about 4.3:1.
Generally, the molar ratio of substituted carbonyl compound to acetone dicarboxylate can be at least about 1.2:1, preferably at least about 1.5:1.
It is, of course, desirable to minimize the amounts of excess reactants employed in the process for economic reasons. Advantageously, therefore, the molar ratio of amine to acetone dicarboxylate ranges from about 3.5:1 to 10:1, and the molar ratio of substituted carbonyl compound to acetone dicarboxylate ranges from about 1.2:1 to 5:1. It has been surprisingly discovered that by employing a two-phase reaction medium and/or by utilizing substantially simultaneous reaction addition, higher reactant throughput rates and smaller amounts of excess reactants can be employed to obtain a given pyrrole ester yield than when these novel process features are not employed.
The reaction medium employed in the present invention is generally agitated and cooled throughout the reaction. The preferred two-phase reaction medium is maintained as a dispersion at the desired reaction temperature throughout the reaction by agitating and cooling the reaction medium. Agitation should be sufficient to form a uniform dispersion containing the aqueous and organic liquid phases and whatever solid intermediate precipitate may be formed during the reaction. The reaction medium may also be cooled throughout most of the reaction such that reaction medium temperature remains below about 450 C, preferably below about 40"C, e.g., 200 to 40oC.
Reaction medium temperatures in excess of about 450C tend to lower yields of the desired pyrrole diester product and/or to promote formation of undesirably excessive amounts of cyclization reaction by-products. Both agitation and reaction medium temperature control can be maintained until the pyrrole ester-forming cyclization reaction is complete to the extent desired. Generally reaction time of from about 1 to 8 hours after reactant addition is complete will be satisfactory.
After the reaction has been completed, various procedures to recover, purify and/or further treat the desired substituted pyrrole ester product can be undertaken. After the pyrrole ester is formed but before agitation is discontinued, for example, the reaction medium can be acidified with concentrated HCI in order to eliminate organic amine excess reactants and/or by-products from the organic phase.Agitation can then be discontinued, and, when utilized, the two-phase reaction medium can be allowed to separate into
1) an aqueous layer containing water, various excess reactants and reaction by-products and a smail amount of the desired substituted pyrroie diester and 2) an organic layer containing the water-immiscibie organic solvent and most of the pyrrole diester product The aqueous and organic layers can be separated by conventional means, and, if desired, the aqueous layer can be extracted with additional organic solvent to remove the small amount of pyrrole ester product remaining in the aqueous phase. After this extraction, the pyrrole ester-containing extract can be combined with the organic phase originally separated.
If an essentially pure pyrrole diester product is desired, the organic solvent can be stripped from the pyrrole ester-containing organic phase by conventional distillation procedures The pyrrole diester product can also be hydrolyzed to the pyrrole diacid if desired without isolating the diester product. This can be accomplished by adding sodium hydroxide to the organic phase to form the pyrrole disodium salt in an aqueous system, followed by hydrolysis to form the pyrrole diacid by the addition of strong acid.
The pyrrole diester synthesis process of the present invention is illustrated by the following examples which are not limiting of the invention herein.
EXAMPLE I
144 ml. of a 40 percent (w/w) aqueous monomethylamine solution and 140 ml. of dichloroethane are placed in a one-liter roundbottom flask fitted with a mechanical stirrer and a thermometer. While this mixture is agitated to maintain a uniform dispersion and cooled to maintain a reaction temperature between 250-350C, 77.6 gm. (0.384 mole; 76 ml.) of diethyl acetone dicarboxylate and 48 ml. (0.576 mole) of chloroacetone are added in a substantially simultaneous manner in pairs of "shots". A slight initial molar excess of acetone dicarboxylate over the chloroacetone is provided in the flask by adding the first acetone dica rboxylate shot im mediately before the first chloroacetone shot.Acetone dicarboxylate and chloroacetone are added in increments over a 95minute period in accordance with the following schedulel Amount of
Acetone Amount of
dicarboxylate Chloroacetone
Time added added
about 1 min. 10 ml. 5 ml.
5 mien. 16 ml. 10 ml.
20 24 15
35 32 20
50 40 25
65 50 30
75 58 35
85 68 41
95 76 48
After the reactant addition is complete, the mixture is stirred at ambient temperature for an hour, cooled in an ice bath and acidified with concentrated HCI (about 60 ml.) under 250C.
After the acidification, the mixture is stirred for about 20 minutes and checked with pH paper to make sure it is acidic before being transferred to a separatory funnel. The separation gives 207 ml.
(245.1 gm.) of organic layer (bottom layer) and 234 ml. (249.5 gm.) of aqueous layer. (Extraction of this aqueous layer with 25 ml. of dichloroethane produces less than 1.3 gm. of the diester product.) The organic layer (207 ml.; 245.1 gm.) is washed with 60 ml. of city water, and after a separation, 203 ml. (139.2 gm.) of organic solution and 62 ml. (61 gm.) of aqueous wash are obtained.
After the wash, the organic solution (203 ml.; 239.2 gm.) is placed in a 500 ml. flask for distillation of dichloroethane under atmospheric pressure (vapor temp. 76-830C; pot temp.
92-1300C) and under vacuum at the end of the distillation. Dichloroethane obtained (125 ml., 151.3 gm.; 89.3% recovery) can be reused in the pyrrole ester reaction synthesis reaction without further purification.
After the distillation, 50 ml. of isopropanol (BP 82.4aC) at 6O-750C is added to the residue followed by addition of 170 ml. of city water at 60--7 5 OC. On completion of the addition, the stirring is continued at water bath temperature for an hour before filtration. The filtered cake is washed thoroughly with city water to remove colored materials and sucked fairly dry on the funnel to give 86.4 gm. of wet ethyl 3-carbethoxy
1,4-dimethylpyrrole-2-acetate.
Air drying of the wet cake at room temperature gives 65.8 gm. of dry diester product, representing
a 67.7 percent yield.
When in the Example I procedure, the
dichloroethane solvent is replaced with an
equivalent amount of dichloromethane or
chloroform, substantially similar production of the ethyl 3 -carbethoxy-1 ,4-d imethylpyrrole-2 -acetate product is realized.
EXAMPLE II
The Example I procedure is repeated on a one
liter bench scale basis. 432 ml. of a 40 percent
(w/w) aqueous monomethylamine solution and
420 ml. of dichloromethane are placed in a two
liter round-bottom flask fitted with a mechanical
stirrer and thermometer. While this mixture is
agitated to maintain a uniform dispersion and
cooled to maintain a temperature between 250C-350C, 232.8 gm. of diethyl acetone
dicarboxylate (1.15 mole; 228 ml.) and 144 ml. of
chloroacetone (159.6 gm.; 1.73 mole) are added
in a substantially simultaneous manner such that
the amount of chloroacetone is maintained at a
slight molar excess over the acetone dicarboxylate
added to the flask.
After the addition of the reactants, the mixture
is stirred at 2535 C for an hour, cooled in an
ice bath and acidified with concentrated HCI
(about 180 ml.) at 1 250C. After the acidification,
the mixture is stirred for about 30 minutes and
checked with pH paper to make sure it is acidic
before being transferred to a separatory funnel.
The separation gives about 620 ml. of organic
layer (bottom layer) and about 700 ml. of aqueous
layer. The aqueous layer is extracted with 60 ml.
of dichloroethane. The dichloroethane solutions
are combined (total volume is about 685 ml.) and
washed once with 180 ml. of city water. The
product is ethyl 3-carbethoxy-1 ,4- dimethylpyrrole-2-acetate which is in dichloroethane solution. An aliquot of the dichloroethane product solution is withdrawn for assay, and a yield of 63 percent is found.
EXAMPLE Ill
The production of ethyl 3-carbethoxy-1,4dimethylpyrrole-2-acetate is carried out in pilot plant equipment to demonstrate the feasibility of the instant process for commercial scale production. 482 kg. of dichloroethane are charged to a reactor fitted with an agitator and a cooling system. 359 kg. of a 40 percent (w/w) aqueous monomethylamine solution are then charged to the reaction vessel. While the agitator is running, 27 kg. of crude diethyl acetone dicarboxylate are charged to the reaction mixture, followed immediately by a charge of 1 8.5 kg. of chloroacetone. Temperature of the reaction mixture is maintained below 350C. Seven more identical charges of diethyl acetone dicarboxylate and chloro-acetone are then made in succession, and the reaction is continued for an additional one hour.
The reaction mixture is transferred to another similar reaction vessel and cooled to 200C. 196 kg. of 37 percent HCl are then added while the reaction mixture is agitated, and the temperature is maintained below 250C. The agitator is then turned off, and the reaction mixture is allowed to separate for one-half hour into an upper aqueous phase and a lower organic phase. The lower organic phase is transferred to another reaction vessel, and the remaining aqueous phase is extracted with an additional 69 kg. of dichloroethane. Again, the organic extract layer is separated from the aqueous phase and is added to the organic phase from the first separation.
44 gallons of water are added to the combined organic phase fraction, and the mixture is agitated for one-half hour and then is allowed to separate for one-half hour. The lower organic phase is then separated and transferred to another reaction vessel. The organic phase thus separated is at neutral pH and is sampled for pyrrole ester assay.
A pyrrole ester yield of about 54 percent based on the initial charge of diethyl acetone dicarboxylate is obtained using this procedure.
EXAMPLE IV
A diisopropyl pyrrole diester is prepared in accordance with the following procedures. A three-neck 500 ml. round-bottom flask is equipped with cooling apparatus and a mechanical stirrer. 144 mi. of 40 percent (w/w) aqueous monomethylamine and 140 ml. of dichloroethane are charged to the flask and agitated. 95.9 gm. (0.38 mole) of 92 percent pure crude diisopropyl acetone dicarboxylate are charged to one addition funnel, and 48 ml. (0.6 mole) of chloroacetone are added to a second addition funnel.While the reaction mixture in the flask is being agitated and maintained in temperature between 25-350C, the acetone dica rboxylate and ch loroacetone are simultaneously added to the flask over a 25minute period, maintaining a slight molar excess of the chloroacetone during the addition.
The reaction mixture is subsequently stirred for one hour at 30--3 5 OC and is then cooled to about 1 00C and acidified with 85 ml. of concentrated
HCI. This mixture is stirred for an additional 30 minutes and is transferred to a separatory funnel.
The mixture is allowed to separate into an upper aqueous layer and a lower organic layer. The aqueous layer is separated and extracted with an additional 25 ml. of dichloroethane which is separated and combined with the original organic layer. The combined organic fractions are washed with 60 ml. of water. The dichloroethane solvent is then stripped from the organic fraction, and the remaining product is weighed. The product obtained is isopropyl 3-carbisopropoxy-1 ,4- dimethylpyrrole-2-acetate, and a crude product yield of about 85 percent (mole) based on the original diisopropyl acetone dicarboxylate is realized.
Claims (22)
1. The process for producing a substituted pyrrole ester of the formula:
wherein Rr is a hydrocarbyl group of up to about 20 carbon atoms' R2and R3 are independently selected from alkyl and alkaryl groups of up to about 20 carbon atoms; and R4 is H or a hydrocarbyl group of up to about 20 carbon atoms; whereby an acetone dicarboxylate ester of the formula:
wherein R2 and R3 are independently selected from alkyl and alkaryi groups of up to about 20 carbon atoms; and a substituted carbonyl compound of the formula:
wherein R4 is H or hydrocarbyl of up to about 20 carbon atoms and X is a leaving group; are combined with a reaction medium containing a primary amine of the formula RrNH2 wherein R1 is hydrocarbyl of up to about 20 carbon atoms: said reaction medium being maintained at a temperature below about 450C for a period of time sufficient to form the desired substituted pyrrole ester; wherein the process comprises one of the following steps;
A) forming a two-phase reaction medium comprising a dispersion of an aqueous solution of said primary amine and an inert, water-immiscible organic solvent, with which two phase reaction medium the acetone dicarboxylate ester and substituted carbonyl compounds are combined;
B) adding said acetone dicarboxylate and substituted carbonyl compound reactants to said primary amine-containing reaction medium in a substantially simultaneous manner such that at any time during substantially the whole time period in which said reactants are combined with said reaction medium, the molar ratio of total combined substituted carbonyl compound reactant to total combined acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1; or
C) carrying out said process by combining said acetone dicarboxylate and substituted carbonyl compound reactants in the substantially simultaneous manner of B) with the aminecontaining, two phase reaction medium dispersion of A).
2. A process for producing a substituted pyrrole ester of the formula:
wherein R, is a lower alkyl group of about 1 to 5
carbon atoms;
R2 and R3 are independently selected from
lower alkyl groups of about 1 to 5 carbon atoms; and
R4 is H or a lower alkyl group of about 1 to 4 carbon atoms; which process comprises:
A) forming by agitation a reaction medium consisting essentially of a dispersion of an aqueous solution of a primary amine of the formula R1NH2 wherein R1 is lower alkyl of about 1 to 5 carbon atoms, and an inert, water-immiscible organic solvent;
B) combining said reaction medium dispersion with an acetone dicarboxylate diester of the formula:
wherein R2 and R3 are independently selected from lower alkyl groups of about 1 to 5 carbon atoms; and a substituted carbonyl compound of the formula:
wherein R4 is H or lower alkyl of about 1 to 4 carbon atoms and X is a leaving group selected from tosyl, chloride and bromide; and
C) maintaining said reaction medium dispersion at a temperature below about 450C for a period of time sufficient to form the desired substituted pyrrole ester.
3. A process for producing a substituted pyrrole ester of the formula:
wherein R, is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are independently selected from lower alkyl groups of about 1 to 5 carbon atoms; and
R4 is H or a lower alkyl group of about 1 to 4 carbon atoms; which process comprises:
A) forming a reaction medium consisting essentially of an aqueous solution of a primary amine of the formula R,NH2 wherein R, is lower alkyl of about 1 to 5 carbon atoms;
B) adding to said reaction medium in a substantially simultaneous manner an acetone dicarboxylate diester of the formula:
wherein R2 and R3 are independently selected from alkyl groups of about 1 to 5 carbon atoms; and a substituted carbonyl compound of the formula:
wherein R4 is H or lower alkyl of about 1 to 4 carbon atoms and X is a leaving group selected from tosyl, chloride and bromide, said substantially simultaneous addition being carried out such that at any time during substantially the whole of the time period in which said reactants are combined with said reaction medium, the molar ratio of total combined substituted carbonyl compound reactant to total combined acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1; and
C) maintaining said reaction medium at a temperature below about 45"C for a period of time sufficient to form the desired substituted pyrrole ester.
4. A process for synthesizing a substituted pyrrole ester of the formula:
wherein R, is a lower alkyl group of about 1 to 5 carbon atoms:
R2 and R3 are independently selected from lower alkyl groups of about 1 to 5 carbon atoms; and
R4 is H or a lower alkyl group of about 1 to 4 carbon atoms; which process comprises:
A) forming by agitation a reaction medium consisting essentially of a dispersion of an aqueous solution of a primary amine of the formula R,NH2 wherein R1 is lower alkyl of about 1 to 5 carbon atoms, and an inert, water-immiscible organic solvent;
B) adding to said reaction medium dispersion in a substantially simultaneous manner an acetone dicarboxylate diester of the formula:
wherein R2 and R3 are each lower alkyl of about 1 to 5 carbon atoms, and a substituted carbonyl compound of the formula::
wherein R4 is H or lower alkyl of 1 to about 5 carbon atoms and X is a leaving group selected from tosyl, chloride and bromide, said substantially simultaneous addition being carried out such that at any time during substantially the whole of the time period in which said reactants are combined with said reaction medium, the molar ratio of total combined substituted carbonyl compound reactant to total combined acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1 ; and C) maintaining said reaction medium dispersion at temperature below about 450C for a period of time sufficient to form the desired substituted pyrrole ester.
5. A process according to any one of the preceding claims wherein
A) the molar ratio of amine to acetone dicarboxylate is at least about 3.5:1; and
B) the molar ratio of substituted carbonyl compound to acetone dicarboxylate is at least about 1.2:1.
6. A process according to any one of the preceding claims wherein the temperature of the reaction medium is maintained between about 200C and 400C throughout the pyrrole-forming reaction.
7. A process according to any one of the preceding claims wherein
A) the primary amine is monomethylamine; and
B) the substituted carbonyl compound is chloroacetone.
8. A process in accordance with any one of the preceding claims wherein the acetone dicarboxylate diester is the diethyl diester.
9. A process in accordance with any one of claims 1 to 7 wherein the acetone dicarboxylate diester is the di-isopropyl diester.
10. A process according to claims 1, 2 or 4 wherein
A) the reaction medium dispersion of amine solution and organic solvent is formed by agitation and comprises from about 50 percent to 90 percent by weight organic solvent and from about 10 O percent to 50 percent by weight water on a reactant free basis;
B) the weight ratio of reaction medium to the total amount of amine, acetone dicarboxylate diester and substituted carbonyl compound ranges from about 5:1 to 1:1; C) the molar ratio of amine to acetone dicarboxylate is at least about 3.5:1; and
D) the molar ratio of substituted carbonyl compound to acetone dicarboxylate is at least about 1.2:1.
11. A process according to claim 10 wherein
A) the aqueous amine solution comprises from about 30 percent to 40 percent by weight of a primary lower alkyl amine;
B) the acetone dicarboxylate diester is selected from diethyl diesters and diisopropyl diesters; and
C) the substituted carbonyl compound is a haloacetone.
12. A process according to claim 11 wherein the water-immiscible organic solvent is selected from aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons.
13. A process according to claim 12 wherein the temperature of the reaction medium is maintained between about 200C and 400C throughout the pyrrole-forming reaction.
14. A process according to claim 12 wherein
A) the primary amine is monomethylamine
B) the substituted carbonyl compound is selected from chloroacetone and bromoacetune; and
C) the water-immiscible organic solvent is selected from dichloroethane, dichloromethane and chloroform.
1 5. A process in accordance with claim 14 wherein the substituted carbonyl compound is chloroacetone.
1 6. A process in accordance with claim 1 5 wherein the water-immiscible organic solvent is dichloroethane.
1 7. A process in accordance with claim 1 6 wherein the acetone dicarboxylate diester is the diethyl diester.
1 8. A process in accordance with claim 1 6 wherein the acetone dicarboxylate diester is the diisopropyl diester.
1 9. A process according to claim 1, 2 or 4 wherein the organic solvent employed is heavier than water.
20. A process in accordance with claim 1 9 wherein a solution of substituted pyrrole ester product in organic solvent is recovered by discontinuing reaction medium agitation after formation of the substituted pyrrole ester product to thereby allow the reaction medium to separate into an organic layer and an aqueous layer, and subsequently separating the resulting productcontaining organic layer from the aqueous layer.
21. A process as claimed in any one of the preceding claims substantially as herein described in any one of the Examples.
22. A substituted pyrrole ester whenever prepared by a process as claimed in any one of the preceding claims.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95268278A | 1978-10-19 | 1978-10-19 | |
| US95271178A | 1978-10-19 | 1978-10-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2034304A true GB2034304A (en) | 1980-06-04 |
Family
ID=27130329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7936183A Withdrawn GB2034304A (en) | 1978-10-19 | 1979-10-18 | Process for producing substituted pyrrole diesters |
Country Status (7)
| Country | Link |
|---|---|
| CA (1) | CA1105039A (en) |
| DE (1) | DE2942140A1 (en) |
| FI (1) | FI793221A (en) |
| FR (1) | FR2439185A1 (en) |
| GB (1) | GB2034304A (en) |
| NL (1) | NL7907735A (en) |
| SE (1) | SE7908596L (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4383117A (en) | 1981-11-02 | 1983-05-10 | Ethyl Corporation | Process for producing substituted pyrroles |
| EP0092487A1 (en) * | 1982-04-21 | 1983-10-26 | Montedison S.p.A. | Process for the preparation of 3-carboxy-1,4-dimethylpyrrol-2-acetic acid |
| US4455433A (en) * | 1981-11-02 | 1984-06-19 | Ethyl Corporation | Process for producing substituted pyrroles |
| US4835288A (en) * | 1987-01-14 | 1989-05-30 | Syntex Inc. | Process for preparing (+)-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates |
| US4874872A (en) * | 1987-01-14 | 1989-10-17 | Syntex (U.S.A.) Inc. | Process for preparing (+)-2,3-dihydro-1H-pyrrolo[1,2-A]pyrrole-1,7-dicarboxylates |
| US4937368A (en) * | 1987-01-14 | 1990-06-26 | Syntex (U.S.A.) Inc. | Process for preparing (+)-2,3-dihydro-1H-pyrrolo[1,2-A]pyrrole-1,7-dicarboxylates |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4388468A (en) * | 1980-04-04 | 1983-06-14 | Ethyl Corporation | Process for producing substituted pyrroles |
| US4565879A (en) * | 1980-04-04 | 1986-01-21 | Ethyl Corporation | Process for producing substituted pyrroles |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3752826A (en) * | 1970-01-26 | 1973-08-14 | Mcneilab Inc | Aroyl substituted pyrroles |
-
1979
- 1979-09-27 CA CA336,509A patent/CA1105039A/en not_active Expired
- 1979-10-17 FR FR7925757A patent/FR2439185A1/en active Pending
- 1979-10-17 SE SE7908596A patent/SE7908596L/en not_active Application Discontinuation
- 1979-10-17 FI FI793221A patent/FI793221A/en not_active Application Discontinuation
- 1979-10-18 DE DE19792942140 patent/DE2942140A1/en not_active Withdrawn
- 1979-10-18 GB GB7936183A patent/GB2034304A/en not_active Withdrawn
- 1979-10-19 NL NL7907735A patent/NL7907735A/en not_active Application Discontinuation
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4383117A (en) | 1981-11-02 | 1983-05-10 | Ethyl Corporation | Process for producing substituted pyrroles |
| US4455433A (en) * | 1981-11-02 | 1984-06-19 | Ethyl Corporation | Process for producing substituted pyrroles |
| EP0092487A1 (en) * | 1982-04-21 | 1983-10-26 | Montedison S.p.A. | Process for the preparation of 3-carboxy-1,4-dimethylpyrrol-2-acetic acid |
| US4835288A (en) * | 1987-01-14 | 1989-05-30 | Syntex Inc. | Process for preparing (+)-2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates |
| US4874872A (en) * | 1987-01-14 | 1989-10-17 | Syntex (U.S.A.) Inc. | Process for preparing (+)-2,3-dihydro-1H-pyrrolo[1,2-A]pyrrole-1,7-dicarboxylates |
| US4937368A (en) * | 1987-01-14 | 1990-06-26 | Syntex (U.S.A.) Inc. | Process for preparing (+)-2,3-dihydro-1H-pyrrolo[1,2-A]pyrrole-1,7-dicarboxylates |
Also Published As
| Publication number | Publication date |
|---|---|
| SE7908596L (en) | 1980-04-20 |
| DE2942140A1 (en) | 1980-04-30 |
| CA1105039A (en) | 1981-07-14 |
| FI793221A (en) | 1980-04-20 |
| NL7907735A (en) | 1980-04-22 |
| FR2439185A1 (en) | 1980-05-16 |
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Legal Events
| Date | Code | Title | Description |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |