CA1105039A - Process for producing substituted pyrrole diesters - Google Patents
Process for producing substituted pyrrole diestersInfo
- Publication number
- CA1105039A CA1105039A CA336,509A CA336509A CA1105039A CA 1105039 A CA1105039 A CA 1105039A CA 336509 A CA336509 A CA 336509A CA 1105039 A CA1105039 A CA 1105039A
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- CA
- Canada
- Prior art keywords
- diester
- reaction medium
- acetone dicarboxylate
- carbonyl compound
- amine
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
PROCESS FOR PRODUCING SUBSTITUTED PYRROLE DIESTERS ABSTRACT OF THE DISCLOSURE An improved process for producing substituted pyrrole diesters by reacting a primary amine with an acetone dicarboxylic acid diester and a substituted carbonyl compound such as chloroacetone. The pyrrole ester-forming reaction is conducted in an amine-containing, two-phase, aqueous/organic reaction medium dispersion with which the aceonte dicarboxylic acid ester and substituted carbonyl compound are combined and/or in an amine-containing reaction medium to which the acetone dicarboxylic acid ester and substituted carbonyl compounds are added in a substantially simultaneous manner.
Description
3 ~ f.r The present invention relates to an improved process for producing substituted pyrrole diesters which are useful in the preparation of anti-inflarnmatory agents.
Al]cyl, 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 Au~ust 14, 1973. Useful precursors of the substituted pyrroles exhibiting anti-inflammatory activity are the diesters of 3-carboxy-1,4-dialkylpyrrole-2-acetic 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 halo-substituted ketone such as chloro-aceton. This reaction is described, for example, in Carson, U. S. Pat. 3,752,826, issued ~ugust 14, 1973;
Carson, U. S. Pat. 3r865,840, issued February 11, 1~75; and in Carson et al., Journa:l oE ~edicinal Chemistry, 1~73, Vol. 16, ~o. 2, pp. 172~174. 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 ~reci~itate 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 hi~h as possible while minimiæing 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.
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Furthermore, scale-up of the pyrrole ester cyclization reaction process to commerical 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.
~ ccordingly, the present invention involves the process Eor the production of substituted pyrrole esters of the formula:
- N ~C~l2-1_OR2 Rl wherein Rl is a hydrocarbyl group containing up to about 20 carbon atoms or more, R2 and R3 are each an alkyl or allcaryl group~containin~ up to about 2~ carbon atoms or more and R~ is hydrogen or a hydrocarbyl group containing up to 20 carhon atoms or more. In accordance with such a process, the substituted pyrrole esters are formed by reacting a primary amine of the formula Rl~`~H2 with an acetone carboxylic acid ester of the formula:
_4 CE~ OR
C=O
and a substituted carbonyl compound of the formula:
f~' R -~-CH X
wherein Rl, 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 comprisiny 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 Eirst invention. The combined reaction medium and reactants are maintained at a temperature below about 45C
for a period of time sufficient to form the desired su~stituted pyrrole ester product.
The cyclizatiorl reaction which is the subject of the present invention is carried out when one mole of tne 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 ~yrrole ester product. The primary amine used in the process of this inverltiorl and in the cyclization reaction can be of the yeneral formula RlN~12 wherein Rl is a hydrocarhyl group containing up to about 20 carbon atoms or more. Rl can be aryl, e.g., R11~112 can be aniline, or R
can b~ alkaryl, e.~., R~ 12 can be benzylamine.
Pre~erably, Rl is alkyl and more preferabry is a lower al~yl grouE), e.g., an alkyl group containing from 1 to : ~ , .
.
': ` ' - ~ . , :'' ' ' ': ':
- . . ~ . . ~, . . ..
. : ,~ , : : : --5~ ¢~
about 5 carbon atoms. Such preferred primary amines include, for example, monomethyl amine, monoethyl amine, mono--isopropyl arnine, 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 mono-methyl amine.
~ dvantageously, the primary amine is employed in the form of an agueous 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/or~anic 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 or~anic solvent in the form of an aclueous amine solution containing abou-t 30-40 percent by weight of the monomethyl amine so as to form the t~o 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 c~as or liquid~ The a~ueous amine solution is formed in the reaction rnedium by virtue of the preferential solubility of the amine in the aqueous portion of the two-phase system.
The acetone clicarboxylic ac d ester used as a reactant in the process of the present invention has the cJeneral formula:
1l (~=0 C~12-C-0~3 ~.
o wherein R2 and R~ are each either alkyl or alkaryl contai~ cJ up to about 20 carbon atoms or more. Preferably R2 and R3 are both lower alkyl, i.e., aL~y~ of 1 to 5 carbon atoms or benzyl. R2 and R3 can be the same or -6~ ¢~
different ~roups but are preferably t~e same in a yiven molecule. ~xamples of acetone dicarboxylie esters which ean be employed herein inelude dimethyl aeetone dicarboxylate, diethyl acetone diearboxylate, di-isopro~yl acetone dicarboxylate, di-n-propyl acetone dicarboxylate, di-isobutyl acetone diearboxylate, di-n-pentyl aeetone dicarboxylate, dibenzyl acetone dicarboxylate, methyl ethyl acetone dicarboxylate and the like. Preferred acetone dicarboxylic acid esters are diethyl acetone dicarboxylate and di-isopropyl acetone dicarboxylate~
Acetone diearboxylie acid esters for use in the process herein ean be synthesized, for example, by reacting citric acid or esters thereof with an anhydrous aeid sueh as chloro-sulfonic acid or oleum followed, if necessary, by the esterification of the acetone dicarboxylic acid groups.
Proeedures of this nature are described more fully in Gerner, German Pat. No. 1,160,841, published July 15, 196~;
anc7 llamilton et al., U. S. Pat. 2,~87,50~; issued May 19, 1959, both of whieh are ineorporated herein by reference.
~eetone dicarboxylie acid e.sters can be employec3 in the process herein in their isolated essentially pure liquid form. Advantageously, however, the acetone dicarboxylate ester eomponenc can be eombined with the reaction medium dispersion dissolved in the same organic solvent, such as dichloroethane, whieh serves as the orc3anie raetion of the two-~hase a~ueo~ls/oryanie reaction mec~ium.
The substituted earborlyl compound which comprises the third reactant in the pyrrole-forminc3 cyclization reaction has the yeneral formula:
R,~--C-CH2X
wherein l~ )I or a hydroearbyl group containing up to abo~lt 20 carbol- atoms or more, and X is a "leaving" group, i.e., any (3roup which does not become a substituerlt of the pyrrole eompound formed by the eyelization reaction~ R4 canV for example, include aryl or alkyl, substituted alkyl, or eycloalkyl ~ontaininy from 1 to about 10 or more carbon .
--7~
atoms, R4 is preferably lower al]cyl, say of 1 to 4 earbon atoms and is most preferably methyl. The "leaving" group X
substituent ean inelude, for example, tosyl or halide, e.g., iodide, ehloride, bromide or fluoride. Chloride and bromide leaving groups substituents are preferred. 0~ the substituted earbonyl compounds, the most preferred are chloroacetone and ~romoacetone.
In accordance ~ith the first aspeet of the present invention, the pyrrole-forming cyclization reaction is conducted in a two-phase reaction medium dispersion eomprising water and a li~uid orc3anic solvent which is immisci~le with water. ~he water-immiscible orc3anic solvent should, o~ course, be inert, i.e., essentially nonreaetive with the pyrrole-formincJ reactants under eonditions of the eyclization reaction. Pre~erably, the water~immiscible organic solvent is heavier than ~ater so that separation of the reactant-containing oryanic phase may be facilitated in processes of commereial scale.
Useful solvents will frequently have a boiling point between 35C and 175C to faeilitate removal of the solvent by ~istillation.
Suitable organie solvents for use in the two~phase reaetion medium herein inelude, for example, water~
immiseible aliphatie hydroearbons, haloyenated aliphatie hydroearbons and aromatie hydrocarbons as well as any other water-irnmiseible organie liquid composed primarily of carbon along with a minor weight percentage of hydroc3en with or without a minor amount of one or more elelnents sueh as oxygen, nitroc3en, halogen and the like. Examples of sueh suitable organie solvents inelude hexane, ehloroform, earbon tetraehloride, diehloromethane, 1,2-dichloroethane;
1,1 diehloroethane, triehloroethylene, benzene, ehlorobenzene, p-diehloroberlzene, toluene, xylene, and diethylether. Preferred organie solvents inelude the haloc3enated alkanes sueh as the diehloroethanes, diehloro-methane and ehloroform.
: : : : .
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Generally, the two~phase reaction medium may comprise, on a reactant free basis, about 50 percent to 90 percent, more preferably about 65 pereent to 75 percent, by weiyht of the water-irnmiscible organic solvent and from about 10 pereent to 50 pereent, more preferabl~ about 25 percent to 35 percent, by wei~ht of water. Enou~h of the two-phase reaction medium is employed to dissolve reactants as they are initially added. Preferably, the wei~ht ratio of reaction medium to the total amount of pyrrole-forming reactants ran~3es 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 deseribed, yields of the desired pyrrole esters can be enhaneed over those yields aehieved when only a single-phase reaetion medium is ernployed. ~ithout being bound by any partieular theory, it is helieved that the eycli~ation reaetion oecurs in the orc3anic phase of the reaction meclium~ The relatively lower solubility of the primary amine in the orc3anie phase, vis-a-vis its solubility in the aqueous phase, possibly serves to limit the availability of the amine in the organie reaetiv~
phase. Coneentrations of the reaetants and intermediates in the orc3allie phase are thus believed to be such that the enhanced yields of the desired pyrrole ester procluct ean be realized in the two-phase system. The presence of the orc3anie solvent is also help~ul in controllin~ th~
eyelizatiol1 reaction exotherm and thereby permits faster reaetant addition than eould be used without the solvent in the reaetion medium.
In a second aspect of the present process for carrying out the pyrrole-forming cyclization reaetion, the three essential reaetants are preferably eornbined in such a way that the aeetone diearboxylate and substituted earbonyl eompound are introduced to the amine-co~t~ininc3 reaction IllediUm itl a substantially simultaneous fashion.
"Substantially simultaneous" addition as used herein refers ....~...
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- .:, . -. -, : .
_9~ 3~
to reactant combination in such a manner that the molar ratio of substituted carbonyl compound to acetone dicarboxylate combined with the reaction medium ranges frorn about 1.6:1 to 1~4:1 during the time period in which those reactants are being cornbined with the reaction mixture.
Substantially simultaneous reactant addition, of course, includes the situation wherein the acetone dicarboxylate and substituted carbonyl compound are continuously ed to the reaction vessel using feed rates such tha~ -the requisite molar ratio o~ 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 c10es not fall outside the 1.6:1 to 104:1 range. At least some and preferably all o~ the primary a~ine reactant i5 present in the reaction medium before a substantially simultaneous addition of the other two reactants is begun.
Upon addition of the acetone diearboxylate to the reaction medium containing primary amine, a white preeipitate intermediate cornpound is generally formed.
Such an intermediate eompound is possibly an amine salt of the acetone dicarboxylate ester. Further reaetion of this intermediate compound with the substituted carbonyl compound such as chloroacetone eventually produees the desired substituted pyrrole diester. Since the interme~liate eompound appears to deeompose with time, the substantially simultaneous addition oE aeetone dicarboxylate and substituted carbonyl compound is believed to enhance pyrrole diester production by promoting reaetion of the intermediate hefore it deeomposes. The simultaneous reaetion addition ~eature of the present invention is thus espeeially effeetive in maintaining an aeeeptably high product yield in large bateh, hicJh throucJhput, commercial seale processes wherein control of the cyclization reaction , ,, : , . . .
', ' .
exotherm necessitates extended reactant addition procedures and lonc3er reaction times.
In a preferred embodiment of the present invention both the process improvement involving the two-phase aqueous/or~anic reaction medium and the improvernent involvincJ the substantially simultaneous addition o~
reactants as hereinbeEore described are employed in the same process. Processes wherein both of these features are utilized are especially advantageous. LO ensure adequate yields of ~he 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 minimi~e the amounts of excess reactants employed in the process for economic reasons. Advantageously, therefore, the molar ratio o~ amine to acetone dicarboxylate ranges from about 3.5:1 to 10:1, and the molar ratio of substituted carbonyl compound to acetone dicarboxylate ranyes from about 1.2:1 to 5:1. It has been surprisingly discovered that by emplo~ing a two-phase reaction medium and/or by utilizing substantially simultaneous reaction addition, hi~her reactant throughput rates and smaller amounts of excess reactants can be employed to obtain a yiven pyrrole ester ~ield than when these novel process features are not employed .
The reaction medium employed in the ~resent invention is ~enerally agitated and cooled throughout the reaction.
The preEerred two-phase reaction medium is maintained as a dispersion at the desired reaction temperature throughout the reaction by a~3itating and cooling th~ ~eaction medium~
~gitation should be sufficient to form a uniform dispersion containinc3 the aqueous and organic liquid phases and - . -, : . : :, : , . - : :,: , . :
- . :~,. . - . : . : : : - :
- . :, . ,: :'~ ' ' :: ' 3~
whatever solid intermediate precipitate may be formed during the reaction. I'he reaction medium may also be cooled throughout most o~ the reaction such that reaction medium temperature remains below about 45C, preferably below about 40C, e.g., 20 to 40C. Reaction medium temperatures in excess of about 45C tend to lower yields of the desired pyrrole diester product and/or to promote forrnation 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.
~ fter 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 ~ormed ~ut before agitation is discontinued, for example, the reaction medium can be acidified with concentrated IICl in order to eliminate organic amine excess reactants and/or by-products from the organic phase. ~gitation 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 small amount of the desired substituted pyrrole diester and 2) an organic layer containing the water-immiscible 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 remaininy in the aclueous phase. AEter 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 , , . . . : -~9 pyrrole ester-containin~ or~anic 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 or~anic 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 round-bottom 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 25-35C, 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 sirnultaneous 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 dicarboxylate shot immediately before the first chloroacetone shot. Acetone dicarboxylate and chloroacetone are added in increments over a 95-minute period in accordance with the following schedule:
Time Amount of ~cetone Amount of Chloro-dicarbo~y~late added acetone added about 1 min. 10 ml. 5 ml.
5 min. 16 ml. 10 ml.
24 lS
~0 25 ~5 68 41 76 4~
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- : - . .. .. . .
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. . ' . '.
.' ' ', .
-After the reactant acldition is complete, the mixture is stirred at ambient temperature for an hour, cooled in an ice bath and acidified with concentrated IICl (about 60 ml.) under 25C. 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 ~m.) 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.
~ fter the wash~ the organic solution (203 ml.; 239.2 ~m.) is placed in a 500 ml. flask for distillation of dicl-lloroethane under atmospheric pressure (vapor temp. 76-83C; pot temp. 92-130C) and under vacuum at the end of the distillation. Dichloroethane obtained (1~5 rnl~, 151.3 ~m.; 89.3~ recovery) can be reused in the pyrrole ester reaction synthesis reaction without further ~urification.
~ fter the distillation, 50 ml. of isopropanol (BP
82.4C) at 60-75C is added to the residue followed by addition of 170 ml. of city water at 60 75C. On completion of the addition, the stirrinc~ is continued at water bath temperature for an hour ~e~ore filtration. The filtered ca~e is washed thorouyhly with city water to remove colored materials and sucked falrly dry on the furlnel to ~3ive 8G.4 ym. of wet ethyl 3-carbethoxy-1,4-dimethylpyrrole-2-acetate.
~ ir dryin~ of the wet cake at room temperature ~ives ~5.8 ~m. of dry diester product, representincJ a ~7.7 percellt yield.
When in the ~xample I procedure, the dlchloroethane solvent is replaced with an equivalent arnount of dichloro-Methane or chloroform, substantially similar production of .
-14~
the ethyl 3-carbethoxy-1,4-dimethylpyrrole-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 25C-35C, 232.8 gm. of diethyl acetone dicarboxylate (1.15 mole; 228 ml.) and 144 ml. of chloroacetone t159.6 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.
Ater the addition of the reactants, the mixture is stirred at 25-35C for an hour, cooled in an ice bath ancl acidified with concentrated llCl ~about 180 ml.) at 125C.
After the acidification, the mixture is stirred ~or about 30 minutes and checked with pEI paper to make sure it is acidic before being transferred to a separatory furlnel.
The separation gives about 620 mlO of organic layer (bottom layer) and about 700 ml. of aqueous layer. The aqueous layer is extracted with 60 mlO 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-earhethoxy-1,4-dimethylpyrrole-2-acetate which is in dichloroethane solution. An aliquot of the dichloroethane product solution is withdrawn ~or assay, anc3 a yield oE 63 percent is ound.
E MPLE III
The production of ethyl 3-carbethoxy-1,4-dirnethylpyrrole-2-acetate is carried out in pilot plant equipment to demonstrate the feasibility oE the instant process for commercial scale production~ 482 kg. of dichloroethane are charged to a reactor fitted with an ayitator and a cooling system. 359 kg. of a 40 percent , .
, .... , ' ' .' . ' '' . .
-15- ~
(w/w) aqueous monomethylamine solution are then char~ed to the reaction vessel. While the agitator is running 27 k~.
of crude diethyl acetone dicar~oxylate are charyed to the reaction mixture, followed immediately by a char~e of 18.5 ky. of chloroacetone. Temperature of the reaction mixture is maintained below 35C. Seven more identical charges of diethyl acetone dicarboxylate and chloro-~cetone are then macle 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 20C. 196 kg. of 37 percent IICl are then added while the reaction mixture is ayitated, and the temperature is maintained below 2~C. Tlle ayitator is then turned off, and the reaction rnixture is allowed to separate for one-half hour into an upper aqueous phase and a lower ortJanic pllase. Tlle lower organic phase is transferred to another reaction vessel, and the remaining aqutous phase is extracted with an additional 69 l;y. of dichloroethane. Again, the or~anic extract layer is separated from tlle aqueous phase and is added to the or~Jallic phase frorn the first separation.
44 t3allons 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 ~hase is then separated and transferred to another reactiorl vessel. The orc~anic phase thus separated is at neutral p~l and is sampled for pyrrole ester assay. A pyrrole ester yield of about 54 percent based on the initial char~e of diethyl acetone dicar~oxylate is obtained USillCJ this procedure-_ A~IL'LL IV
~ c3iisopropyl pyrrole diester is prepared inaccordance with the following ~rocedures. A three-neck 500 ml. rouncl-l)ottoril ~las}; is ecfulpped with coolin~J apparatus and a mechallical stirrerl 144 ml. of 40--percent ~w/w) atlueous monomethylamine and 140 ml. of c3ichloroetllane are cllarged to tlle flask and agitated. 95.9 gm. (0.38 mole) of , ;
:
92 percent pure cru~e diisopropyl acetone dicarboxylate are char~ed 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 a~itated and main~ained in temperature between 25-35C, the acetone dicarboxylate and chloroacetone are simultaneously added to the Elask over a 25-minute period, maintaining a slight molar excess of the chloroacetone during the addition.
The reaction mixture is subsequently stirred for one ., .
hour at 30-35C and is then cooled to about 10C and acidified with ~5 ml. of concentrated ~IC1. 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 or~anic layer. The combined organic fractions are washed with 60 ml. of water. The dichloroethane solvent is then stripped froln tile organic ~raction, and tlle 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.
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. ' .~ ' ' " ' . : '': . ' ' . ' .
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Al]cyl, 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 Au~ust 14, 1973. Useful precursors of the substituted pyrroles exhibiting anti-inflammatory activity are the diesters of 3-carboxy-1,4-dialkylpyrrole-2-acetic 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 halo-substituted ketone such as chloro-aceton. This reaction is described, for example, in Carson, U. S. Pat. 3,752,826, issued ~ugust 14, 1973;
Carson, U. S. Pat. 3r865,840, issued February 11, 1~75; and in Carson et al., Journa:l oE ~edicinal Chemistry, 1~73, Vol. 16, ~o. 2, pp. 172~174. 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 ~reci~itate 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 hi~h as possible while minimiæing 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, scale-up of the pyrrole ester cyclization reaction process to commerical 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.
~ ccordingly, the present invention involves the process Eor the production of substituted pyrrole esters of the formula:
- N ~C~l2-1_OR2 Rl wherein Rl is a hydrocarbyl group containing up to about 20 carbon atoms or more, R2 and R3 are each an alkyl or allcaryl group~containin~ up to about 2~ carbon atoms or more and R~ is hydrogen or a hydrocarbyl group containing up to 20 carhon atoms or more. In accordance with such a process, the substituted pyrrole esters are formed by reacting a primary amine of the formula Rl~`~H2 with an acetone carboxylic acid ester of the formula:
_4 CE~ OR
C=O
and a substituted carbonyl compound of the formula:
f~' R -~-CH X
wherein Rl, 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 comprisiny 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 Eirst invention. The combined reaction medium and reactants are maintained at a temperature below about 45C
for a period of time sufficient to form the desired su~stituted pyrrole ester product.
The cyclizatiorl reaction which is the subject of the present invention is carried out when one mole of tne 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 ~yrrole ester product. The primary amine used in the process of this inverltiorl and in the cyclization reaction can be of the yeneral formula RlN~12 wherein Rl is a hydrocarhyl group containing up to about 20 carbon atoms or more. Rl can be aryl, e.g., R11~112 can be aniline, or R
can b~ alkaryl, e.~., R~ 12 can be benzylamine.
Pre~erably, Rl is alkyl and more preferabry is a lower al~yl grouE), e.g., an alkyl group containing from 1 to : ~ , .
.
': ` ' - ~ . , :'' ' ' ': ':
- . . ~ . . ~, . . ..
. : ,~ , : : : --5~ ¢~
about 5 carbon atoms. Such preferred primary amines include, for example, monomethyl amine, monoethyl amine, mono--isopropyl arnine, 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 mono-methyl amine.
~ dvantageously, the primary amine is employed in the form of an agueous 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/or~anic 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 or~anic solvent in the form of an aclueous amine solution containing abou-t 30-40 percent by weight of the monomethyl amine so as to form the t~o 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 c~as or liquid~ The a~ueous amine solution is formed in the reaction rnedium by virtue of the preferential solubility of the amine in the aqueous portion of the two-phase system.
The acetone clicarboxylic ac d ester used as a reactant in the process of the present invention has the cJeneral formula:
1l (~=0 C~12-C-0~3 ~.
o wherein R2 and R~ are each either alkyl or alkaryl contai~ cJ up to about 20 carbon atoms or more. Preferably R2 and R3 are both lower alkyl, i.e., aL~y~ of 1 to 5 carbon atoms or benzyl. R2 and R3 can be the same or -6~ ¢~
different ~roups but are preferably t~e same in a yiven molecule. ~xamples of acetone dicarboxylie esters which ean be employed herein inelude dimethyl aeetone dicarboxylate, diethyl acetone diearboxylate, di-isopro~yl acetone dicarboxylate, di-n-propyl acetone dicarboxylate, di-isobutyl acetone diearboxylate, di-n-pentyl aeetone dicarboxylate, dibenzyl acetone dicarboxylate, methyl ethyl acetone dicarboxylate and the like. Preferred acetone dicarboxylic acid esters are diethyl acetone dicarboxylate and di-isopropyl acetone dicarboxylate~
Acetone diearboxylie acid esters for use in the process herein ean be synthesized, for example, by reacting citric acid or esters thereof with an anhydrous aeid sueh as chloro-sulfonic acid or oleum followed, if necessary, by the esterification of the acetone dicarboxylic acid groups.
Proeedures of this nature are described more fully in Gerner, German Pat. No. 1,160,841, published July 15, 196~;
anc7 llamilton et al., U. S. Pat. 2,~87,50~; issued May 19, 1959, both of whieh are ineorporated herein by reference.
~eetone dicarboxylie acid e.sters can be employec3 in the process herein in their isolated essentially pure liquid form. Advantageously, however, the acetone dicarboxylate ester eomponenc can be eombined with the reaction medium dispersion dissolved in the same organic solvent, such as dichloroethane, whieh serves as the orc3anie raetion of the two-~hase a~ueo~ls/oryanie reaction mec~ium.
The substituted earborlyl compound which comprises the third reactant in the pyrrole-forminc3 cyclization reaction has the yeneral formula:
R,~--C-CH2X
wherein l~ )I or a hydroearbyl group containing up to abo~lt 20 carbol- atoms or more, and X is a "leaving" group, i.e., any (3roup which does not become a substituerlt of the pyrrole eompound formed by the eyelization reaction~ R4 canV for example, include aryl or alkyl, substituted alkyl, or eycloalkyl ~ontaininy from 1 to about 10 or more carbon .
--7~
atoms, R4 is preferably lower al]cyl, say of 1 to 4 earbon atoms and is most preferably methyl. The "leaving" group X
substituent ean inelude, for example, tosyl or halide, e.g., iodide, ehloride, bromide or fluoride. Chloride and bromide leaving groups substituents are preferred. 0~ the substituted earbonyl compounds, the most preferred are chloroacetone and ~romoacetone.
In accordance ~ith the first aspeet of the present invention, the pyrrole-forming cyclization reaction is conducted in a two-phase reaction medium dispersion eomprising water and a li~uid orc3anic solvent which is immisci~le with water. ~he water-immiscible orc3anic solvent should, o~ course, be inert, i.e., essentially nonreaetive with the pyrrole-formincJ reactants under eonditions of the eyclization reaction. Pre~erably, the water~immiscible organic solvent is heavier than ~ater so that separation of the reactant-containing oryanic phase may be facilitated in processes of commereial scale.
Useful solvents will frequently have a boiling point between 35C and 175C to faeilitate removal of the solvent by ~istillation.
Suitable organie solvents for use in the two~phase reaetion medium herein inelude, for example, water~
immiseible aliphatie hydroearbons, haloyenated aliphatie hydroearbons and aromatie hydrocarbons as well as any other water-irnmiseible organie liquid composed primarily of carbon along with a minor weight percentage of hydroc3en with or without a minor amount of one or more elelnents sueh as oxygen, nitroc3en, halogen and the like. Examples of sueh suitable organie solvents inelude hexane, ehloroform, earbon tetraehloride, diehloromethane, 1,2-dichloroethane;
1,1 diehloroethane, triehloroethylene, benzene, ehlorobenzene, p-diehloroberlzene, toluene, xylene, and diethylether. Preferred organie solvents inelude the haloc3enated alkanes sueh as the diehloroethanes, diehloro-methane and ehloroform.
: : : : .
-8~
Generally, the two~phase reaction medium may comprise, on a reactant free basis, about 50 percent to 90 percent, more preferably about 65 pereent to 75 percent, by weiyht of the water-irnmiscible organic solvent and from about 10 pereent to 50 pereent, more preferabl~ about 25 percent to 35 percent, by wei~ht of water. Enou~h of the two-phase reaction medium is employed to dissolve reactants as they are initially added. Preferably, the wei~ht ratio of reaction medium to the total amount of pyrrole-forming reactants ran~3es 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 deseribed, yields of the desired pyrrole esters can be enhaneed over those yields aehieved when only a single-phase reaetion medium is ernployed. ~ithout being bound by any partieular theory, it is helieved that the eycli~ation reaetion oecurs in the orc3anic phase of the reaction meclium~ The relatively lower solubility of the primary amine in the orc3anie phase, vis-a-vis its solubility in the aqueous phase, possibly serves to limit the availability of the amine in the organie reaetiv~
phase. Coneentrations of the reaetants and intermediates in the orc3allie phase are thus believed to be such that the enhanced yields of the desired pyrrole ester procluct ean be realized in the two-phase system. The presence of the orc3anie solvent is also help~ul in controllin~ th~
eyelizatiol1 reaction exotherm and thereby permits faster reaetant addition than eould be used without the solvent in the reaetion medium.
In a second aspect of the present process for carrying out the pyrrole-forming cyclization reaetion, the three essential reaetants are preferably eornbined in such a way that the aeetone diearboxylate and substituted earbonyl eompound are introduced to the amine-co~t~ininc3 reaction IllediUm itl a substantially simultaneous fashion.
"Substantially simultaneous" addition as used herein refers ....~...
- - ,. - - : .
. . , .. .: . . . . :
. :. . . ~ :
- .:, . -. -, : .
_9~ 3~
to reactant combination in such a manner that the molar ratio of substituted carbonyl compound to acetone dicarboxylate combined with the reaction medium ranges frorn about 1.6:1 to 1~4:1 during the time period in which those reactants are being cornbined with the reaction mixture.
Substantially simultaneous reactant addition, of course, includes the situation wherein the acetone dicarboxylate and substituted carbonyl compound are continuously ed to the reaction vessel using feed rates such tha~ -the requisite molar ratio o~ 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 c10es not fall outside the 1.6:1 to 104:1 range. At least some and preferably all o~ the primary a~ine reactant i5 present in the reaction medium before a substantially simultaneous addition of the other two reactants is begun.
Upon addition of the acetone diearboxylate to the reaction medium containing primary amine, a white preeipitate intermediate cornpound is generally formed.
Such an intermediate eompound is possibly an amine salt of the acetone dicarboxylate ester. Further reaetion of this intermediate compound with the substituted carbonyl compound such as chloroacetone eventually produees the desired substituted pyrrole diester. Since the interme~liate eompound appears to deeompose with time, the substantially simultaneous addition oE aeetone dicarboxylate and substituted carbonyl compound is believed to enhance pyrrole diester production by promoting reaetion of the intermediate hefore it deeomposes. The simultaneous reaetion addition ~eature of the present invention is thus espeeially effeetive in maintaining an aeeeptably high product yield in large bateh, hicJh throucJhput, commercial seale processes wherein control of the cyclization reaction , ,, : , . . .
', ' .
exotherm necessitates extended reactant addition procedures and lonc3er reaction times.
In a preferred embodiment of the present invention both the process improvement involving the two-phase aqueous/or~anic reaction medium and the improvernent involvincJ the substantially simultaneous addition o~
reactants as hereinbeEore described are employed in the same process. Processes wherein both of these features are utilized are especially advantageous. LO ensure adequate yields of ~he 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 minimi~e the amounts of excess reactants employed in the process for economic reasons. Advantageously, therefore, the molar ratio o~ amine to acetone dicarboxylate ranges from about 3.5:1 to 10:1, and the molar ratio of substituted carbonyl compound to acetone dicarboxylate ranyes from about 1.2:1 to 5:1. It has been surprisingly discovered that by emplo~ing a two-phase reaction medium and/or by utilizing substantially simultaneous reaction addition, hi~her reactant throughput rates and smaller amounts of excess reactants can be employed to obtain a yiven pyrrole ester ~ield than when these novel process features are not employed .
The reaction medium employed in the ~resent invention is ~enerally agitated and cooled throughout the reaction.
The preEerred two-phase reaction medium is maintained as a dispersion at the desired reaction temperature throughout the reaction by a~3itating and cooling th~ ~eaction medium~
~gitation should be sufficient to form a uniform dispersion containinc3 the aqueous and organic liquid phases and - . -, : . : :, : , . - : :,: , . :
- . :~,. . - . : . : : : - :
- . :, . ,: :'~ ' ' :: ' 3~
whatever solid intermediate precipitate may be formed during the reaction. I'he reaction medium may also be cooled throughout most o~ the reaction such that reaction medium temperature remains below about 45C, preferably below about 40C, e.g., 20 to 40C. Reaction medium temperatures in excess of about 45C tend to lower yields of the desired pyrrole diester product and/or to promote forrnation 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.
~ fter 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 ~ormed ~ut before agitation is discontinued, for example, the reaction medium can be acidified with concentrated IICl in order to eliminate organic amine excess reactants and/or by-products from the organic phase. ~gitation 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 small amount of the desired substituted pyrrole diester and 2) an organic layer containing the water-immiscible 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 remaininy in the aclueous phase. AEter 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 , , . . . : -~9 pyrrole ester-containin~ or~anic 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 or~anic 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 round-bottom 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 25-35C, 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 sirnultaneous 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 dicarboxylate shot immediately before the first chloroacetone shot. Acetone dicarboxylate and chloroacetone are added in increments over a 95-minute period in accordance with the following schedule:
Time Amount of ~cetone Amount of Chloro-dicarbo~y~late added acetone added about 1 min. 10 ml. 5 ml.
5 min. 16 ml. 10 ml.
24 lS
~0 25 ~5 68 41 76 4~
: :
- : - . .. .. . .
' : ,, : . .
. . ' . '.
.' ' ', .
-After the reactant acldition is complete, the mixture is stirred at ambient temperature for an hour, cooled in an ice bath and acidified with concentrated IICl (about 60 ml.) under 25C. 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 ~m.) 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.
~ fter the wash~ the organic solution (203 ml.; 239.2 ~m.) is placed in a 500 ml. flask for distillation of dicl-lloroethane under atmospheric pressure (vapor temp. 76-83C; pot temp. 92-130C) and under vacuum at the end of the distillation. Dichloroethane obtained (1~5 rnl~, 151.3 ~m.; 89.3~ recovery) can be reused in the pyrrole ester reaction synthesis reaction without further ~urification.
~ fter the distillation, 50 ml. of isopropanol (BP
82.4C) at 60-75C is added to the residue followed by addition of 170 ml. of city water at 60 75C. On completion of the addition, the stirrinc~ is continued at water bath temperature for an hour ~e~ore filtration. The filtered ca~e is washed thorouyhly with city water to remove colored materials and sucked falrly dry on the furlnel to ~3ive 8G.4 ym. of wet ethyl 3-carbethoxy-1,4-dimethylpyrrole-2-acetate.
~ ir dryin~ of the wet cake at room temperature ~ives ~5.8 ~m. of dry diester product, representincJ a ~7.7 percellt yield.
When in the ~xample I procedure, the dlchloroethane solvent is replaced with an equivalent arnount of dichloro-Methane or chloroform, substantially similar production of .
-14~
the ethyl 3-carbethoxy-1,4-dimethylpyrrole-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 25C-35C, 232.8 gm. of diethyl acetone dicarboxylate (1.15 mole; 228 ml.) and 144 ml. of chloroacetone t159.6 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.
Ater the addition of the reactants, the mixture is stirred at 25-35C for an hour, cooled in an ice bath ancl acidified with concentrated llCl ~about 180 ml.) at 125C.
After the acidification, the mixture is stirred ~or about 30 minutes and checked with pEI paper to make sure it is acidic before being transferred to a separatory furlnel.
The separation gives about 620 mlO of organic layer (bottom layer) and about 700 ml. of aqueous layer. The aqueous layer is extracted with 60 mlO 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-earhethoxy-1,4-dimethylpyrrole-2-acetate which is in dichloroethane solution. An aliquot of the dichloroethane product solution is withdrawn ~or assay, anc3 a yield oE 63 percent is ound.
E MPLE III
The production of ethyl 3-carbethoxy-1,4-dirnethylpyrrole-2-acetate is carried out in pilot plant equipment to demonstrate the feasibility oE the instant process for commercial scale production~ 482 kg. of dichloroethane are charged to a reactor fitted with an ayitator and a cooling system. 359 kg. of a 40 percent , .
, .... , ' ' .' . ' '' . .
-15- ~
(w/w) aqueous monomethylamine solution are then char~ed to the reaction vessel. While the agitator is running 27 k~.
of crude diethyl acetone dicar~oxylate are charyed to the reaction mixture, followed immediately by a char~e of 18.5 ky. of chloroacetone. Temperature of the reaction mixture is maintained below 35C. Seven more identical charges of diethyl acetone dicarboxylate and chloro-~cetone are then macle 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 20C. 196 kg. of 37 percent IICl are then added while the reaction mixture is ayitated, and the temperature is maintained below 2~C. Tlle ayitator is then turned off, and the reaction rnixture is allowed to separate for one-half hour into an upper aqueous phase and a lower ortJanic pllase. Tlle lower organic phase is transferred to another reaction vessel, and the remaining aqutous phase is extracted with an additional 69 l;y. of dichloroethane. Again, the or~anic extract layer is separated from tlle aqueous phase and is added to the or~Jallic phase frorn the first separation.
44 t3allons 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 ~hase is then separated and transferred to another reactiorl vessel. The orc~anic phase thus separated is at neutral p~l and is sampled for pyrrole ester assay. A pyrrole ester yield of about 54 percent based on the initial char~e of diethyl acetone dicar~oxylate is obtained USillCJ this procedure-_ A~IL'LL IV
~ c3iisopropyl pyrrole diester is prepared inaccordance with the following ~rocedures. A three-neck 500 ml. rouncl-l)ottoril ~las}; is ecfulpped with coolin~J apparatus and a mechallical stirrerl 144 ml. of 40--percent ~w/w) atlueous monomethylamine and 140 ml. of c3ichloroetllane are cllarged to tlle flask and agitated. 95.9 gm. (0.38 mole) of , ;
:
92 percent pure cru~e diisopropyl acetone dicarboxylate are char~ed 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 a~itated and main~ained in temperature between 25-35C, the acetone dicarboxylate and chloroacetone are simultaneously added to the Elask over a 25-minute period, maintaining a slight molar excess of the chloroacetone during the addition.
The reaction mixture is subsequently stirred for one ., .
hour at 30-35C and is then cooled to about 10C and acidified with ~5 ml. of concentrated ~IC1. 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 or~anic layer. The combined organic fractions are washed with 60 ml. of water. The dichloroethane solvent is then stripped froln tile organic ~raction, and tlle 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 (55)
1. The process for producing a substituted pyrrole ester of the formula:
wherein R1 is a hydrocarbyl group of up to about 20 carbon atoms; R2 and R3 are each alkyl or alkaryl 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 each alkyl or alkaryl 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 R1NH2 wherein R1 is hydrocarbyl of up to about 20 carbon atoms; said reaction medium being maintained at a temperature below about 45°C for a period of time sufficient to form said substituted pyrrole ester; said process characterized in that said reactants are combined utilizing an improvement selected from the group consisting of:
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 reaction medium dispersion 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 is a substantially simultaneous manner such that the molar ratio of said substituted carbonyl compound reactant to said acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1 during the time period in which said reactants are added to said reaction medium; and C) carrying out said reaction by combining said acetone dicarboxylate and substituted carbonyl compound reactants in said substantially simultaneous manner with said amine-containing, two-phase reaction medium dispersion.
wherein R1 is a hydrocarbyl group of up to about 20 carbon atoms; R2 and R3 are each alkyl or alkaryl 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 each alkyl or alkaryl 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 R1NH2 wherein R1 is hydrocarbyl of up to about 20 carbon atoms; said reaction medium being maintained at a temperature below about 45°C for a period of time sufficient to form said substituted pyrrole ester; said process characterized in that said reactants are combined utilizing an improvement selected from the group consisting of:
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 reaction medium dispersion 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 is a substantially simultaneous manner such that the molar ratio of said substituted carbonyl compound reactant to said acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1 during the time period in which said reactants are added to said reaction medium; and C) carrying out said reaction by combining said acetone dicarboxylate and substituted carbonyl compound reactants in said substantially simultaneous manner with said amine-containing, two-phase reaction medium dispersion.
2. An improved process for producing a substituted pyrrole ester of the formula:
wherein R1 is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are each lower alkyl 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 inert, water-immiscible organic solvent;
B) combining said reaction medium dispersion with 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:
R4-?-CH2X
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 45°C for a period of time sufficient to form said substituted pyrrole ester.
wherein R1 is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are each lower alkyl 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 inert, water-immiscible organic solvent;
B) combining said reaction medium dispersion with 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:
R4-?-CH2X
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 45°C for a period of time sufficient to form said substituted pyrrole ester.
3. An improved process for producing a substituted pyrrole ester of the formula:
wherein R1 is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are each lower alkyl 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 R1NH2 wherein R1 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 each alkyl of about 1 to 5 carbon atoms; and a substituted carbonyl compound of the formula:
R4-?-CH2X
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 the molar ratio of said substituted carbonyl compound reactant to said acetone dicarboxylate reactant ranges from about 1.6-1 to 1.4:1 during the time period in which said reactants are added to said reaction medium; and C) maintaining said reaction medium at a temperature below about 45°C for a period of time sufficient to form said substituted pyrrole ester.
wherein R1 is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are each lower alkyl 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 R1NH2 wherein R1 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 each alkyl of about 1 to 5 carbon atoms; and a substituted carbonyl compound of the formula:
R4-?-CH2X
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 the molar ratio of said substituted carbonyl compound reactant to said acetone dicarboxylate reactant ranges from about 1.6-1 to 1.4:1 during the time period in which said reactants are added to said reaction medium; and C) maintaining said reaction medium at a temperature below about 45°C for a period of time sufficient to form said substituted pyrrole ester.
4. An improved process for synthesizing a substituted pyrrole ester of the formula:
wherein R1 is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are each lower alkyl 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) 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:
R4-?-CH2X
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 the molar ratio of said substituted carbonyl compound reactant to said acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1 during the time period in which said reactants are added to said reaction medium dispersion; and C) maintaining said reaction medium dispersion at temperature below about 45°C for a period of time sufficient to form said substituted pyrrole ester.
wherein R1 is a lower alkyl group of about 1 to 5 carbon atoms;
R2 and R3 are each lower alkyl 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) 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:
R4-?-CH2X
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 the molar ratio of said substituted carbonyl compound reactant to said acetone dicarboxylate reactant ranges from about 1.6:1 to 1.4:1 during the time period in which said reactants are added to said reaction medium dispersion; and C) maintaining said reaction medium dispersion at temperature below about 45°C for a period of time sufficient to form said substituted pyrrole ester.
5. A process according to claim 1 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 claim 2 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.
7. A process according to claim 3 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.
8. A process according to claim 4 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.
9. A process according to claim 5 wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
10. A process according to claim 6 wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
11. A process according to claim 7 wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
12. A process according to claim 8 wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
13. A process according to claim 9 wherein A) the primary amine is monomethylamine; and B) the substituted carbonyl compound is chloro-acetone.
14. A process according to claim 10 wherein A) the primary amine is monomethylamine; and B) the substituted carbonyl compound is chloro-acetone.
15. A process according to claim 11 wherein A) the primary amine is monomethylamine; and B) the substituted carbonyl compound is chloro-acetone.
16. A process according to claim 12 wherein A) the primary amine is monomethylamine; and B) the substituted carbonyl compound is chloro-acetone.
17. A process in accordance with claim 13 wherein the acetone dicarboxylate diester is the diethyl diester.
18. A process in accordance with claim 14 wherein the acetone dicarboxylate diester is the diethyl diester.
19. A process in accordance with claim 15 wherein the acetone dicarboxylate diester is the diethyl diester.
20. A process in accordance with claim 16 wherein the acetone dicarboxylate diester is the diethyl diester.
21. A process in accordance with claim 13 wherein the acetone dicarboxylate diester is the diisopropyl diester.
22. A process in accordance with claim 14 wherein the acetone dicarboxylate diester is the diisopropyl diester.
23. A process in accordance with claim 15 wherein the acetone dicarboxylate diester is the diisopropyl diester.
24. A process in accordance with claim 16 wherein the acetone dicarboxylate diester is the diisopropyl diester.
25. A process according to claim 1 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 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 substi-tuted 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.
B) the weight ratio of reaction medium to the total amount of amine, acetone dicarboxylate diester and substi-tuted 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.
26. A process according to claim 2 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 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.
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.
27. A process according to claim 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 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.
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.
28. A process according to claim 25 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 haloace-tone.
B) the acetone dicarboxylate diester is selected from diethyl diesters and diisopropyl diesters; and C) the substituted carbonyl compound is a haloace-tone.
29. A process according to claim 26 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 haloace-tone.
B) the acetone dicarboxylate diester is selected from diethyl diesters and diisopropyl diesters; and C) the substituted carbonyl compound is a haloace-tone.
30. A process according to claim 27 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 haloace-tone.
B) the acetone dicarboxylate diester is selected from diethyl diesters and diisopropyl diesters; and C) the substituted carbonyl compound is a haloace-tone.
31. A process according to claim 28 wherein the water-immiscible organic solvent is selected from aliphatic hydrocarbons, halogenated aliphatic hydro-carbons, and aromatic hydrocarbons.
32. A process according to claim 29 wherein the water-immiscible organic solvent is selected from aliphatic hydrocarbons, halogenated aliphatic hydro-carbons, and aromatic hydrocarbons.
33. A process according to claim 30 wherein the water-immiscible organic solvent is selected from aliphatic hydrocarbons, halogenated aliphatic hydro-carbons, and aromatic hydrocarbons.
34. A process according to claim 31, wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
35. A process according to claim 32, wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
36. A process according to claim 33 wherein the temperature of the reaction medium is maintained between about 20°C and 40°C throughout the pyrrole-forming reaction.
37. A process according to claim 31 wherein A) the primary amine is monomethylamine B) the substituted carbonyl compound is selected from chloroacetone and bromoacetone; and C) the water immiscible organic solvent is selected from dichloroethane, dichloromethane and chloroform.
38. A process according to claim 32 wherein A) the primary amine is monomethylamine B) the substituted carbonyl compound is selected from chloroacetone and bromoacetone; and C) the water-immiscible organic solvent is selected from dichloroethane, dichloromethane and chloroform.
39. A process according to claim 33 wherein A) the primary amine is monomethylamine B) the substituted carbonyl compound is selected from chloroacetone and bromoacetone; and C) the water-immiscible organic solvent is selected from dichloroethane, dichloromethane and chloroform.
40. A process in accordance with claim 37 wherein the substituted carbonyl compound is chloroacetone.
41. A process in accordance with claim 38 wherein the substituted carbonyl compound is chloroacetone.
42. A process in accordance with claim 39 wherein the substituted carbonyl compound is chloroacetone.
43. A process in accordance with claim 40 wherein the water-immiscible organic solvent is dichloroethane.
44. A process in accordance with claim 41 wherein the water-immiscible organic solvent is dichloroethane.
45. A process in accordance with claim 42 wherein the water-immiscible organic solvent is dichloroethane.
46. A process in accordance with claim 43 wherein the acetone dicarboxylate diester is the diethyl diester.
47. A process in accordance with claim 44 wherein the acetone dicarboxylate diester is the diethyl diester.
48. A process in accordance with claim 45 wherein the acetone dicarboxylate diester is the diethyl diester.
49. A process in accordance with claim 43 wherein the acetone dicarboxylate diester is the diisopropyl diester.
50. A process in accordance with claim 44 wherein the acetone dicarboxylate diester is the diisopropyl diester.
51. A process in accordance with claim 45 wherein the acetone dicarboxylate diester is the diisopropyl diester.
52. A process according to claim 1 wherein the organic solvent employed is heavier than water.
53. A process according to claim 2 wherein the organic solvent employed is heavier than water.
54. A process according to claim 4 wherein the organic solvent employed is heavier than water.
55. A process in accordance with claim 52, 53 or 54 wherein a solution of substituted pyrrole ester product in organic solvent is recovered by discontinuing reaction medium agitation after formation of the sub-stituted pyrrole ester product to thereby allow the reaction medium to separate into an organic layer and an aqueous layer, and subsequently separating the resulting product-containing organic layer from the aqueous layer.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95271178A | 1978-10-19 | 1978-10-19 | |
| US95268278A | 1978-10-19 | 1978-10-19 | |
| US952,682 | 1978-10-19 | ||
| US952,711 | 1978-10-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105039A true CA1105039A (en) | 1981-07-14 |
Family
ID=27130329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA336,509A Expired CA1105039A (en) | 1978-10-19 | 1979-09-27 | 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) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4565879A (en) * | 1980-04-04 | 1986-01-21 | Ethyl Corporation | Process for producing substituted pyrroles |
| US4388468A (en) * | 1980-04-04 | 1983-06-14 | Ethyl Corporation | Process for producing substituted pyrroles |
| US4455433A (en) * | 1981-11-02 | 1984-06-19 | Ethyl Corporation | Process for producing substituted pyrroles |
| US4383117A (en) | 1981-11-02 | 1983-05-10 | Ethyl Corporation | Process for producing substituted pyrroles |
| IT1151731B (en) * | 1982-04-21 | 1986-12-24 | Montedison Spa | PROCESS FOR THE PREPARATION OF 3-CARBOXY-1,4-DIMETHYLPIRROL-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 |
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 FI FI793221A patent/FI793221A/en not_active Application Discontinuation
- 1979-10-17 SE SE7908596A patent/SE7908596L/en not_active Application Discontinuation
- 1979-10-18 GB GB7936183A patent/GB2034304A/en not_active Withdrawn
- 1979-10-18 DE DE19792942140 patent/DE2942140A1/en not_active Withdrawn
- 1979-10-19 NL NL7907735A patent/NL7907735A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI793221A (en) | 1980-04-20 |
| NL7907735A (en) | 1980-04-22 |
| GB2034304A (en) | 1980-06-04 |
| SE7908596L (en) | 1980-04-20 |
| FR2439185A1 (en) | 1980-05-16 |
| DE2942140A1 (en) | 1980-04-30 |
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| MKEX | Expiry | ||
| MKEX | Expiry |
Effective date: 19980714 |