CA1193608A - Process for preparing 1-alkyl-5-aroyl-pyrrol-2-acetic acid derivatives - Google Patents
Process for preparing 1-alkyl-5-aroyl-pyrrol-2-acetic acid derivativesInfo
- Publication number
- CA1193608A CA1193608A CA000426132A CA426132A CA1193608A CA 1193608 A CA1193608 A CA 1193608A CA 000426132 A CA000426132 A CA 000426132A CA 426132 A CA426132 A CA 426132A CA 1193608 A CA1193608 A CA 1193608A
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- general formula
- alkyl
- carbon atoms
- hydrogen
- acid
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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
- C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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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)
- Detergent Compositions (AREA)
Abstract
Abstract The invention relates to a process for the preparation of 1-alkyl-5-aroyl-1H-pyrrole-2-acetic acid.
derivatives of the general formula (I) (I) wherein Ar is phenyl optionally substituted with halogen, alkyl having one to 4 carbon atoms or alkoxy having one to 4 carbon atoms;
R is alkyl having one to 4 carbon atoms;
R1 is hydrogen or alkyl having one to 4 carbon atoms;
X is an imino group and R2 is hydrogen or an alkyl group having one to 4 carbon atoms, or X is oxygen and R2 is hydrogen, and acid addition salts (if X=imino) and alkali metal or alkali earth metal salts (if R2=H) thereof, The above compounds are prepared. by reacting a pyrrole derivative of the general formula (II) (II) wherein Y stands for a -COOR3 group and.
R3 is an alkyl group having one to 4 carbon atoms, with an aromatic nitrile of the general formula Ar-CN
wherein Ar is as defined above, in an organic solvent, preferably aromatic hydrocarbon, saturated with dry hydrochloric acid gas and, if desired, hydrolysing a ketimino ester obtained into a corresponding ketimino acid or keto acid or a salt thereof. The process affords the desired products with a good yield, selective-ly, and, if desired, can be carried out in one pot, with-out isolating the intermediates.
derivatives of the general formula (I) (I) wherein Ar is phenyl optionally substituted with halogen, alkyl having one to 4 carbon atoms or alkoxy having one to 4 carbon atoms;
R is alkyl having one to 4 carbon atoms;
R1 is hydrogen or alkyl having one to 4 carbon atoms;
X is an imino group and R2 is hydrogen or an alkyl group having one to 4 carbon atoms, or X is oxygen and R2 is hydrogen, and acid addition salts (if X=imino) and alkali metal or alkali earth metal salts (if R2=H) thereof, The above compounds are prepared. by reacting a pyrrole derivative of the general formula (II) (II) wherein Y stands for a -COOR3 group and.
R3 is an alkyl group having one to 4 carbon atoms, with an aromatic nitrile of the general formula Ar-CN
wherein Ar is as defined above, in an organic solvent, preferably aromatic hydrocarbon, saturated with dry hydrochloric acid gas and, if desired, hydrolysing a ketimino ester obtained into a corresponding ketimino acid or keto acid or a salt thereof. The process affords the desired products with a good yield, selective-ly, and, if desired, can be carried out in one pot, with-out isolating the intermediates.
Description
The invention relates to a new process for the prep-aration of l-alkyl- and 1,4-dialkyl-5-aroyl-lH-pyrrole-2-acetic acid derivatives of the general formula (I) ¦ (I) Ar-lC N CH2-COOR
X R
wherein Ar is phenyl optionally substituted with halogen, alkyl having one to 4 carbon atoms or alkoxy having one to 4 carbon atoms;
R is alkyl having one to 4 carbon atoms;
Rl is hydrogen or alkyl having one to 4 carbon atoms;
X is an imino group and R2 is hydrogen or an alkyl group having one to 4 carbon atoms, or X is oxygen and R is hydrogen, and- if Xrepresents an imino group - acid addition sal-ts and -if R =H - alkali me-tal or alkali earth me-tal salts thereof.
Compounds of the general formula (I) in which X
represents oxygen are generally known in the art; their cer-tain representatives, e.g. l-methyl-5-(4-methyl-benzoyl)--lH-pyrrole-2-acetic acid and 1,4-dimethyl-5-(4-chlorobenzoyl)-lH-pyrrole-2-ace-tic acid have been reported to show biologi-cal activity [J. Med. Chem. 1971, 646 and 1973, 172; J. Clin.
Pharmacol. 1980, 216] and are ,'i , ~
:~g3 . 3 empLoyed in the therapy as antiphLogistic agents.
For the preparation of the compounds of generaL
formuLa (I), in which X stands for oxygen there are more processes known in the art, which aLL start from the compounds of the generaL formuLa (II) RL (II) wherein R and. R have the same meaning as d.efined above, and Y is -CN or -CooR3, in which L~ R3 is aLkyL having one to ~ carbon atoms.
Accorcl.ing to the known processes starting compounds of the formuLa (II) are substituted. in the 5-position of -the pyrroLe ring by d.ifferent me-thod.s and., if d.esired., the group Y is converted. into ot.her acid. d.erivatives. For exampLe according to the PubLished. German Patent Specification No. 2,Lo2,746 the compounds of the generaL formuLa (II) are aroyLated. with aromatic acid. haLides in the presence of a Lewis acid. (Fried.eL-Crafts reaction) or wi-th a mixed.
anhydrid.e of an aromatic acid. and. trifLuoroacetic acid, into the d.esired. 5-aroyLd.erivatives of the generaL formuLa (I). The known methods, however, produce Low yieLds, and the FriedeL-Crafts process affords isomeric mixtures (aLph~- and beta-substituted derivatives), This Latter 36~
probLem can be avoided according to tlle U.S. Patent Specifi-cation No. 3,998,844 by carrying out the ~aroyLation o-f the pyrroLe ring with an aroyL chLoride in an aprotic soLvent, in t:he absence of a cataLyst. Though by this process the formation of the beta_isomer can successfuLLy be avoid.ed., the equivalent amount of hyd.rogen chLorid.e envoLved. in the reaction may cataLyse t.he poLymerization of the pyrroLe compound.s [see Ad.vances in ~eterocycLic Chemistry, VoL, 2., p. 287, Academic Press~ New York,L963~, L0 and. as a resuL-t, undesired. by-prod.ucts with a detrimentaL
effect on the ~uaLi-ty of the product are aLso formed., Accord.ing to the United. States Patent Specification No.
4,255,335 it was attempted to overcome this disadvantage by using benzoyL cyanide as an acyLating agent. m e L~ appLication of this process on ind.ustriaL scaLe is, however, cumbersome d.ue to the formation of hyd.rogen cyanid.e in the reaction. There are aLso severaL further methods known in -the art, ~hlch are not particuLarly suitable for practicaL appLication, partLy due to the expensive reactants required.~ partLy because of the extreme reaction conditions, such as aroyLation wit:h a 2-aryL-d.ithioLanium cation (United. States Patent Specification No. 4,LL9,639) and a muLti-step process in which organic magnesium and. cadmium compounds are empLoyed. (Dutch Pa-tent Specifi-cation No. 73,L0,3~9~.
The L-aLkyL- or L,4-d.iaLkyL-~-aroyL-LH--pyrroLe-2-ace-tic acid esters obtained by the above methods can be converted into the corresponding L-aLkyL- and 93~
L,4-diaLkyL-5-aroyL-l~I-pyrroLe-2-acetic acids, which are more potent pharmaceuticaL agents, as described in the PubLished German Patent Specification No,
X R
wherein Ar is phenyl optionally substituted with halogen, alkyl having one to 4 carbon atoms or alkoxy having one to 4 carbon atoms;
R is alkyl having one to 4 carbon atoms;
Rl is hydrogen or alkyl having one to 4 carbon atoms;
X is an imino group and R2 is hydrogen or an alkyl group having one to 4 carbon atoms, or X is oxygen and R is hydrogen, and- if Xrepresents an imino group - acid addition sal-ts and -if R =H - alkali me-tal or alkali earth me-tal salts thereof.
Compounds of the general formula (I) in which X
represents oxygen are generally known in the art; their cer-tain representatives, e.g. l-methyl-5-(4-methyl-benzoyl)--lH-pyrrole-2-acetic acid and 1,4-dimethyl-5-(4-chlorobenzoyl)-lH-pyrrole-2-ace-tic acid have been reported to show biologi-cal activity [J. Med. Chem. 1971, 646 and 1973, 172; J. Clin.
Pharmacol. 1980, 216] and are ,'i , ~
:~g3 . 3 empLoyed in the therapy as antiphLogistic agents.
For the preparation of the compounds of generaL
formuLa (I), in which X stands for oxygen there are more processes known in the art, which aLL start from the compounds of the generaL formuLa (II) RL (II) wherein R and. R have the same meaning as d.efined above, and Y is -CN or -CooR3, in which L~ R3 is aLkyL having one to ~ carbon atoms.
Accorcl.ing to the known processes starting compounds of the formuLa (II) are substituted. in the 5-position of -the pyrroLe ring by d.ifferent me-thod.s and., if d.esired., the group Y is converted. into ot.her acid. d.erivatives. For exampLe according to the PubLished. German Patent Specification No. 2,Lo2,746 the compounds of the generaL formuLa (II) are aroyLated. with aromatic acid. haLides in the presence of a Lewis acid. (Fried.eL-Crafts reaction) or wi-th a mixed.
anhydrid.e of an aromatic acid. and. trifLuoroacetic acid, into the d.esired. 5-aroyLd.erivatives of the generaL formuLa (I). The known methods, however, produce Low yieLds, and the FriedeL-Crafts process affords isomeric mixtures (aLph~- and beta-substituted derivatives), This Latter 36~
probLem can be avoided according to tlle U.S. Patent Specifi-cation No. 3,998,844 by carrying out the ~aroyLation o-f the pyrroLe ring with an aroyL chLoride in an aprotic soLvent, in t:he absence of a cataLyst. Though by this process the formation of the beta_isomer can successfuLLy be avoid.ed., the equivalent amount of hyd.rogen chLorid.e envoLved. in the reaction may cataLyse t.he poLymerization of the pyrroLe compound.s [see Ad.vances in ~eterocycLic Chemistry, VoL, 2., p. 287, Academic Press~ New York,L963~, L0 and. as a resuL-t, undesired. by-prod.ucts with a detrimentaL
effect on the ~uaLi-ty of the product are aLso formed., Accord.ing to the United. States Patent Specification No.
4,255,335 it was attempted to overcome this disadvantage by using benzoyL cyanide as an acyLating agent. m e L~ appLication of this process on ind.ustriaL scaLe is, however, cumbersome d.ue to the formation of hyd.rogen cyanid.e in the reaction. There are aLso severaL further methods known in -the art, ~hlch are not particuLarly suitable for practicaL appLication, partLy due to the expensive reactants required.~ partLy because of the extreme reaction conditions, such as aroyLation wit:h a 2-aryL-d.ithioLanium cation (United. States Patent Specification No. 4,LL9,639) and a muLti-step process in which organic magnesium and. cadmium compounds are empLoyed. (Dutch Pa-tent Specifi-cation No. 73,L0,3~9~.
The L-aLkyL- or L,4-d.iaLkyL-~-aroyL-LH--pyrroLe-2-ace-tic acid esters obtained by the above methods can be converted into the corresponding L-aLkyL- and 93~
L,4-diaLkyL-5-aroyL-l~I-pyrroLe-2-acetic acids, which are more potent pharmaceuticaL agents, as described in the PubLished German Patent Specification No,
2,Lo2,746, whiLe a simiLar conversion of the L-aLkyL-or L,4-diaLkyL-5-aroyL-L~-pyrroLe-2-acetonitriLes pre-pared. from the starting cornpound.s of -the formuLa (II), in which Y is -CN in an anaLogeous -way, can be carried.
out accord.ing to the muLti-step process discLosed.
in the United. States Pa-tent Specification No, 4,2L3,905.
L0 In view of the disadvantages of the syn-theses known in the art for the preparation o~ pharmaceuticaLLy active L-aLkyL- and. L,4-diaLkyL-5-aroyL-L~-pyrroLe-2--acetic acids, respectively, the object of -the inven-tion is to provide a new process which yieLds -the desired.
L5 compounds of the generaL formuLa (I), whereitl the sub-stituents are as defined. above, with an e~ceLlent yieLd., in good quaLity without a substantiaL amount of by--products.
It is known in the art that the reaction of various pyrroLe d.erivatives with aromatic nitriLes in ether-type solvents, saturated. with hyd.rochloric acid gas affords -the corresponding ketimine hydrochLorid.es [Liebigs Ann. Chem. 577, lL5 (1952); Ber. L922, 2396], which may then b0 converted into the corresponding ketones 2~ accord.ing to conventionaL method.s. UntiL now this type of reaction has not been empLoyed. for an anaLogous conversion of the aLkyL-substituted pyrroLe-2-acetic acid. es-ters of the generaL formuLa (II), wherein the ~36(~
`
substituents have the same rneaning as defined above. Our experiments sho~ed. that aLthough the reaction of the Latter compoun.ds with aromatic nitriLes in the conventionaL ether--type soLvents afford.ed the desired ketimine ester hydro-chLorid.es with a poor yieLd. and in an unsatisfactory quaLity,the progress of the reaction was strongly dependent on the solvent employed. While for example in chlorinated hydro-carbons or ether-type soLvents the above-mentioned unsatis-factory resuLts are obtained., in aromatic hydxocarbons, particularLy in toluene or benzene the ketimines are formed.
under mild. reaction conditions, under slight heating, selective-ly, wi-th a good. yield. and in a high purity. According to the physico-chemicaL anaLys:is of the product the pyrroLe-ring is substitu-ted excLusiveLy in the 5-position, and. the L5 product does not get tarry in spite of the Large quantity of hyd.rochLoric acid present, The L-aLkyL- and L,4-d.lalkyl-~-(aromatic ketimino)-LH-pyrroLe-2-acetic acid. esters of the generaL
formuLa (I), in which X represents an =NH group, are new and. can be convorted into the corresponding L-alkyL-and. L,4-diaLkyL-~-aroyL-LH-pyrroLe-2-acetic acids of the generaL formuLa (I), in which R is hyd.rogen and X stands for oxygen, by hyd.roLysis.
We have further found. that during the alkaline hydroLysis of the ketirnine esters of the generaL formuLa (I), in which X stands for an =NH group and R2 is aLkyL, the :hydroLysis of the ester group is subs-tantialLy quicker than that of the ketimine group
out accord.ing to the muLti-step process discLosed.
in the United. States Pa-tent Specification No, 4,2L3,905.
L0 In view of the disadvantages of the syn-theses known in the art for the preparation o~ pharmaceuticaLLy active L-aLkyL- and. L,4-diaLkyL-5-aroyL-L~-pyrroLe-2--acetic acids, respectively, the object of -the inven-tion is to provide a new process which yieLds -the desired.
L5 compounds of the generaL formuLa (I), whereitl the sub-stituents are as defined. above, with an e~ceLlent yieLd., in good quaLity without a substantiaL amount of by--products.
It is known in the art that the reaction of various pyrroLe d.erivatives with aromatic nitriLes in ether-type solvents, saturated. with hyd.rochloric acid gas affords -the corresponding ketimine hydrochLorid.es [Liebigs Ann. Chem. 577, lL5 (1952); Ber. L922, 2396], which may then b0 converted into the corresponding ketones 2~ accord.ing to conventionaL method.s. UntiL now this type of reaction has not been empLoyed. for an anaLogous conversion of the aLkyL-substituted pyrroLe-2-acetic acid. es-ters of the generaL formuLa (II), wherein the ~36(~
`
substituents have the same rneaning as defined above. Our experiments sho~ed. that aLthough the reaction of the Latter compoun.ds with aromatic nitriLes in the conventionaL ether--type soLvents afford.ed the desired ketimine ester hydro-chLorid.es with a poor yieLd. and in an unsatisfactory quaLity,the progress of the reaction was strongly dependent on the solvent employed. While for example in chlorinated hydro-carbons or ether-type soLvents the above-mentioned unsatis-factory resuLts are obtained., in aromatic hydxocarbons, particularLy in toluene or benzene the ketimines are formed.
under mild. reaction conditions, under slight heating, selective-ly, wi-th a good. yield. and in a high purity. According to the physico-chemicaL anaLys:is of the product the pyrroLe-ring is substitu-ted excLusiveLy in the 5-position, and. the L5 product does not get tarry in spite of the Large quantity of hyd.rochLoric acid present, The L-aLkyL- and L,4-d.lalkyl-~-(aromatic ketimino)-LH-pyrroLe-2-acetic acid. esters of the generaL
formuLa (I), in which X represents an =NH group, are new and. can be convorted into the corresponding L-alkyL-and. L,4-diaLkyL-~-aroyL-LH-pyrroLe-2-acetic acids of the generaL formuLa (I), in which R is hyd.rogen and X stands for oxygen, by hyd.roLysis.
We have further found. that during the alkaline hydroLysis of the ketirnine esters of the generaL formuLa (I), in which X stands for an =NH group and R2 is aLkyL, the :hydroLysis of the ester group is subs-tantialLy quicker than that of the ketimine group
3~0~3 . 7 K hydroL. ~ hydroL. L0~ L) ester ketimine =
Taking use of the different hydroLysis veLocities, by proper seLection of the reaction cond.itions, -the new ketimine acids of th0 generaL f ~nuLa (I), in which X stand,s for an =NH group and. R is hydrogen (~r, R
and, R have the same meaning as defined, abo~e), acid.
ad.dition saLts and. aLka~i metaL and aLkaLi ear-th metaL
saLts thereof can aLso be prepared. If desired, these compounds can be transformed into the correspond.ing L--alkyL- and, L,l~-d.iaLkyL-5-aroyL-LH-pyrroLe-2-acetic acids (furt:her on: keto acids) or the saLts t.hereof by hyd.roLysis under more drastic conditions. If the Latter compounds are to be prepared, it is not necessary tv isoLate the ketimine acids, the ketimine esters can be converted.
L~ into the corresponding keto acid.s în situ.
By the mod.ified. ~ouben-~Ioesch synthesis aocording to the invention the ketimine esters can be prepared. with such a good. yield. and. high purity -that the totaL (II) ~ ketimine ester --~ ketimine acicl. --~
keto acid. reactivn route can be reaLized in one pot,without the isoLation of the intermed.iates, which has a great technoLogicaL ad.vantage. In the processes known in the art for the preparation of keto acid.s of the generaL formuLa (I), in which compound.s of the generaL
2~ formuLa (II) acyLated, with aroyL haLid.es resuLted.
in the keto nitriLes or keto esters which were converted, into the correspond.ing keto acids, the reactions steps cannot be combinecl in an anaLogeous way since -the ' 3~
e~cess amount of aroyL haLide present and, the tarry by-prod,ucts formed. in the reaction make the purification of the intermed,iates unavoidabLe.
Accord.ingLy, the invention reLates to a new process for the preparation of l-aLkyl- and. L,~--d,iaLkyL-~-aroyL- or ~-(aromatic ketimino) LH~pyrroLe--2-acetic acid, d.eriva-ti.ves of the generaL formuLa (I), in which Ar, R, R , R and, X have t.he s~le meaning as defined, above, and if X stand.s for `.hyd.rogen, alkaLi L0 metaL or aL~aLi earth metaL saLts thereof, which comprises reacting a pyrroLe derivative of t:he generaL formuLa (II), wherein R and. R have the same meaning as d.efined. above, Y stands for a -CooR3 group and. R3 is an aLkyL group having one to 4 carbon atoms, with an aromatic nitriLe L~ vf the generaL formuLa (III) Ar-CN (III) in which Ar has t~e same meaning as d.efined, above, and, if d.esired., converting a ketimine ester of the generaL
formuLa (I), in which X stand.s for an imino group and.
R is aLkyL having one to 4 carbon atoms (Ar, R and. R
are as defined. above), obtained. as a hydrogen chLori.d,e, into a corresponding ketimine acid. of the generaL formuLa 2~ (I), in which R3 is hyd.rogen and. X is an imino group, or an aLkaLi metaL, aLkaLi earth metaL or acid. ad.dition saLt thereof, by hyd.roLysis, and./or into a ketc acid. of the generaL form~La (I), in which R3.is hydrogen and X
~L~
g is o~ygen, or an aLkaLi metaL or al.kaLi earth metaL
salt thereof, by further hydroLysis.
According to a preferred. embod.iment of the invention a starting pyrroLe derivative of the generaL
5 formuLa (II) and an at Least equimoLar amount but at most 20 moLar % excess of an aromatic nitriLe of the greneraL
formuLa (III) are dissoLved. in an aromatic soLvent, preferabLy toLuene or ben~ene, the soLution i9 saturated.
with dry hydrogen chLoride gas at room temperature, L0 aLLowed to s$and at L0 to 80 C, preferabLy 20 to 30 C
for 20 to 24 hours, and the soLvent is e~aporated. und.er reduced. pressure. The ketimine ester hydrochLoride obtained.
as a crystaLLine residue can be purified. by trituration with a soLvent in which said. compound. is poorLy soLubLe, L~ e,g. an ether, or an ester or ketone having a Low boiLing point, but if a further conversion is required, ït can be hydroLysed. into a correspond.ing ketimine acid. or an aLkaLi metaL or aLkaLi earth metaL saLt thereof withou-t purification. For this purpose the ketimine ester hydro-chLorid.e is dissoLved for e~ampLe in ethanoL and. stirred.with a O.L to L0 n aqueou~ aLkaLi metaL or aLkaLi earth metaL hyd.roxid.e soLution, at a temperature between 0 C and 60 C, preferabLy L~ C and. 40 C,for L0 to L~, minutes. In this manner an aLkali metaL or aLkaLi 2-, earth metaL saLt of the correspond.ing ketimine acid. is obtained which can be converted. into a correspond.ing acid addition saLt for exampLe by reacting with a mineraL
acid :;
~1936~
If the ketimine acids obtained as described above or -the saL-ts thereof are further hydrolysed under more drastic condit-ions, for exampLe in a L to 10 n aqueous alkaLi hydroxide soLution, at a tempera-ture between 60 C and 110 C, preferably 90 C and L00 C, the corresponding keto acid.s of the generaL formula (I), in whlch X stands for oxygen, are obtained as aLkaLi metal saLts which,if desired, can be con~erted into the correspondin~ keto acids of the general formula (I) by a caLcuLated amount of a mineral acid..
According to another embodiment of the process of the invention, the ketimine esters of the generaL
formula (I), in which R3 represents a lower aLkyL group, can be converted into the corresponding keto acids of the ~eneraL formuLa (I), in which X stands for oxygen, directLy, by :hydroLysis under the above-mentioned. more drastic cond.itions, In other words, in this case -the hydrolysis need. not be separated into two stages, more-over, the ketimine ester can be hydrolysed. in the same reaction mixture where it has been formed., i.e. the starting compounds of the generaL formula (II) can be converted into the keto acid. end products or -the salts thereof without isoLating the intermediates, directly, in one pot, The main advantages of the process accordin~
to the inven.tion are as folLows:
- the ketimine est~r saLt intermediates are obtained in such a high purity that~if d.esired, they - Ll -can be con~erted into the desired end product directLy, without isolation;
- d,uring the hydroLysis of the ketimine ester saLts the hydroLysis of the ester g~roup i5 essentiaLLy qulcker than that of the ketimine group, hence from -the same intermed,iate various compounds of the generaL form~l.a (I), incLud.ing some new compounds, e.g. ketimine acids, acid, ad.d.ition or aLkaLi rnetaL or aLkaLi earth metaL
saLts there~f,can be prepared;
L0 - from the ketimine acid.s or d.irectLy from the ketimine ester saLts, by a proper seLection of -the reac-; tion parameters, the keto acicls of the generaL formuLa (I) can be prepared, with an exceLLent yieLd,, in a quaLity suitabLe for pharmaceuticaL purposes;
L5 - unLike the processes known in the art for the preparation of keto acids of the generaL formuLa. (I) starting from compounds of the generaL f~rmuLa (II), t:he muLti-step process according to the invention can be performed. in one pot, without the isoLation or purification of the intermed.iates, and. affords the pharmaceuticaLLy active end prod.uct with a good yiel.d, and, in a quaLity which meets the internationaL stand,ard,s.
The fact that the process accord,ing to the invention can be carried, out in one reaction mixture 2~ from -the very beginning up to the isoLation of the end.
prod.uct is especiaLLy ad.vantageous in comparison with the state of art, since in this manner the losses d.ue to the isolation of the interrned.iates are eLiminated,, ~9~)8 the reacti~n time, the soLvent, equipment and L~bour requirements are essentiaLLy red.uced. and, accord.ingLy, the productivity is highly improved..
The invention wiLl now be iLLustrated. in greater d.etaiL in the foLlowing specific ExampLes, which are given for iLLustration and. not Limitation of our invention.
ExampLe L
L,4-Dimethyl-~-(4-chloro-benzimid.oyl)~
-pyrrole-2-ace-tic acid, ethyL ester hyd.ro-chLorid.e a) 36,2 g. (0,2 moles) of L,4-dimethyL-LH--pyrroLe-2-acetic acid. ethyL ester and. 30.4 g. (0.22 moLes) 1~ of 4-chLoro-benzonitriLe are d.issoLved. in L00 mL. of toLuene and. d.ry hyd.rochLoric aci.d. gas is bubbLed. through the reaction mixture for one hour. By ou-ter cooling with water care is tc~ken -that the temperature of the reaction mi~ture shouLd, not exceed. 30 C at the beginn-ing of the hyd.rochloric acid. absorption. The reactionmi~ture i9 then aLLowed. to stand, at room temperature for 20 hours and, is subsequently evaporated. to d.ryness under red.uced. pressure. The yelLow crystaLLine resid..le is taken up in ether and. washed, on a fiLter. ~4~0 g.
2~ (76 ~0) of the titLe compound are obtained., meLting at L93 t~ L94 C, with decomposition.
- 13 ~
AnaLysis for CL7H20CL2N202 (355.27):
caLcuLated.: C ~ 57,47-~0; H = 5,67 ~; N = 7.88 ~; Cl = L9.9~ ~
found.: C = 57~23 ~; H _ 5.46 %; N = 7.63 %; CL = L~i80 ~.
b) 18,L g. (O,L moLes) of L,4-d.imethyL-LH--pyrroLe-2-acetic acld. ethyL ester and. 15.2 g. (O.LL rnoLes) of 4-chLoro-benzonitrile are suspend.ed. in 150 mL. of diisopropyL ether and dry hydrvchLoric acid. gas is bubbl.ed.
through the suspensi.on at room temperature, for one hour.
After stand.ing for 24 hours, the mixture oonsisting of LO two Liquid. phases is evaporated. to dryness und.er reduced.
pressure, the semicrystaLLine resid.ue is treated. with a mixture of aceton.e and. e-ther, fiLtered. and. washed.
with ether. 2L.5 g (60.4 %) of the titLe compound. are obtained., meLting at L82 to L83 C, with d.ecomposition.
L~
ExampLe 2 .. ..
L,4-DimethyL-5-(4-chLoro-benzimidoyl)-LH--pyrroLe-2-acetic acid. hydrochLorid.e 3.55 g, (O.OL moLe) of L,4-d.imethyL-5--(4-chLoro-benzimid.oyL)-LH-pyrroLe-2-acetic acid ethyL
ester hyd.rochLorid.e are d.issoLved. in 40 mL. of ethanoL, whereupon a soLution of o.84 gG (0.02L moLe) of sod.ium hydroxid.e in 40 mL. of water are ad.d.ed. The reaction mixture is stirred at 40 C for LO minutes and. is evaporated to d.ryness und.er reduced. pressure. The soLid residue is dissoLved. in 40 mL. of a L:L mixture of hydrochloric acid. and water and. stirred at ro_m temperature.
The product precipitated after a few mlnutes is fiLtered.
c)ff and washed, with a smaLL amount of ice water and, ace-tone.
The crud,e reaction procluct obtained, can be further manufactured, in two aLternative ways:
a) The crude product is recrystaLLized, from a mi~ture of ethanoL and ether to yieLd 3.L g. (83 ~o) of the titLe compound, meLting at 256 to 267 C with d,ecomposition.
AnaLysi L7 22 2 2 3 ( Y
-ethanoL) (373.28):
L0 caLcuLated,: N = 7.30 %, CL = L9.00 %;
fcund: N = 7~70 %, CL = L9.20 ~0.
b) The crude produc-t is recrystaLLiæed from water to yieLd 2.26 g. (69 %) of -the titLe compound, meLting at 250 to 253 C with decomposition.
L5 AnaLysis for CL~EIL6CL2N202 (327.2L):
caLcuLatecl: N = 8.56 ~0, C1 = 2L.67 ~o;
found: N = 8.32 %, CL = 2L.54 %.
ExampLe 3 L,4-DimethyL-5-(4-chLoro-benzoyL)-LH-pyrroLe--2-acetic acid sod,ium saLt dihyd,rate a) L7.8 g. (0.05 moLe) of L,4-d,imethyL-5--(4-chLoro-'benzimidoyL)-LH_pyrroLe-2-acetie aeid ethyL
ester hydroehLvride are weighed, into a soLution of 2~ 4.2 g, (O.L05 moLe) of sod,ium hyd,roxide in 50 mL. of water. The reaction mixture is boiLed for 4 hours, with stirring. After cooLing 50 mL. of acetone are added,, and, the mi~ture i5 aLLowqd to stand -in a refrigerator ~9~
- L-) -overnight. The precipitate is fiLtered off and. washed.
with a smaLL amount of ice wa-ter and. subsequentLy with acetone. L5.9 g. (~L %) of the titLe compound. are obtain-ed, meLting at 30~ to 306 C, with d.ecomposi-tion.
b) L8.L g. (O.L moLe) of L,4-d.imethyl-LH--pyrroLe-2-acetic ~cid. ethyL ester and L3.8 g. (O.L mole) of 4-chloro-benzonitriLe are dissoLved in ~0 mL. of toLuene, and. the svLution is saturated. with dry hyd.rochLoric acid gas. The reaction mixture is aLLowed to stand. at room L0 temperature for 20 hours, then evaporated to dryness und.er red.uced. pressure. To -the resid.ue a soLution of 9 g.
(0.225 moLe) of sod.ium hyd.roxide in L00 mL. of water is ad.ded., and. the mixture is boiLed. for 4 hours, with stirring. The reaction mixture is aLLowed. to stand.
L~ in a refrigerator overnight., fiLtered. and washed. with a smalL amount of ice water and. subsequentLy wi.th acetone.
24.7 g, (70,3 ~0) of -the titLe oompound. are obtained, meLting at 30~ to 307 C, with deoomposition.
c) 3.27 g, (0.01 moLe) of L,4-d.imethyL-~--(4-chLoro-benzimid.oyL)-LH-pyrroLe~2-acetic acid. hyd.ro-chLorid.e are weighed into a soLution of 0.84 g. (0.02L
moLe~ of sod.i~ hyd.roxid.e in L0 mL. of water. The re-action mixture is boiLed. for 3 hours, wi-th stirring.
After cooLing the prod.uct is fiLtered. off and. washed.
2~ with a smaLL amount of coLd. water and. subsequentLy with acetone. 3.36 g (96 ~p) of the titLe compound. are obtained, meLting at 299 to 300 C, with d.ecomposition.
Taking use of the different hydroLysis veLocities, by proper seLection of the reaction cond.itions, -the new ketimine acids of th0 generaL f ~nuLa (I), in which X stand,s for an =NH group and. R is hydrogen (~r, R
and, R have the same meaning as defined, abo~e), acid.
ad.dition saLts and. aLka~i metaL and aLkaLi ear-th metaL
saLts thereof can aLso be prepared. If desired, these compounds can be transformed into the correspond.ing L--alkyL- and, L,l~-d.iaLkyL-5-aroyL-LH-pyrroLe-2-acetic acids (furt:her on: keto acids) or the saLts t.hereof by hyd.roLysis under more drastic conditions. If the Latter compounds are to be prepared, it is not necessary tv isoLate the ketimine acids, the ketimine esters can be converted.
L~ into the corresponding keto acid.s în situ.
By the mod.ified. ~ouben-~Ioesch synthesis aocording to the invention the ketimine esters can be prepared. with such a good. yield. and. high purity -that the totaL (II) ~ ketimine ester --~ ketimine acicl. --~
keto acid. reactivn route can be reaLized in one pot,without the isoLation of the intermed.iates, which has a great technoLogicaL ad.vantage. In the processes known in the art for the preparation of keto acid.s of the generaL formuLa (I), in which compound.s of the generaL
2~ formuLa (II) acyLated, with aroyL haLid.es resuLted.
in the keto nitriLes or keto esters which were converted, into the correspond.ing keto acids, the reactions steps cannot be combinecl in an anaLogeous way since -the ' 3~
e~cess amount of aroyL haLide present and, the tarry by-prod,ucts formed. in the reaction make the purification of the intermed,iates unavoidabLe.
Accord.ingLy, the invention reLates to a new process for the preparation of l-aLkyl- and. L,~--d,iaLkyL-~-aroyL- or ~-(aromatic ketimino) LH~pyrroLe--2-acetic acid, d.eriva-ti.ves of the generaL formuLa (I), in which Ar, R, R , R and, X have t.he s~le meaning as defined, above, and if X stand.s for `.hyd.rogen, alkaLi L0 metaL or aL~aLi earth metaL saLts thereof, which comprises reacting a pyrroLe derivative of t:he generaL formuLa (II), wherein R and. R have the same meaning as d.efined. above, Y stands for a -CooR3 group and. R3 is an aLkyL group having one to 4 carbon atoms, with an aromatic nitriLe L~ vf the generaL formuLa (III) Ar-CN (III) in which Ar has t~e same meaning as d.efined, above, and, if d.esired., converting a ketimine ester of the generaL
formuLa (I), in which X stand.s for an imino group and.
R is aLkyL having one to 4 carbon atoms (Ar, R and. R
are as defined. above), obtained. as a hydrogen chLori.d,e, into a corresponding ketimine acid. of the generaL formuLa 2~ (I), in which R3 is hyd.rogen and. X is an imino group, or an aLkaLi metaL, aLkaLi earth metaL or acid. ad.dition saLt thereof, by hyd.roLysis, and./or into a ketc acid. of the generaL form~La (I), in which R3.is hydrogen and X
~L~
g is o~ygen, or an aLkaLi metaL or al.kaLi earth metaL
salt thereof, by further hydroLysis.
According to a preferred. embod.iment of the invention a starting pyrroLe derivative of the generaL
5 formuLa (II) and an at Least equimoLar amount but at most 20 moLar % excess of an aromatic nitriLe of the greneraL
formuLa (III) are dissoLved. in an aromatic soLvent, preferabLy toLuene or ben~ene, the soLution i9 saturated.
with dry hydrogen chLoride gas at room temperature, L0 aLLowed to s$and at L0 to 80 C, preferabLy 20 to 30 C
for 20 to 24 hours, and the soLvent is e~aporated. und.er reduced. pressure. The ketimine ester hydrochLoride obtained.
as a crystaLLine residue can be purified. by trituration with a soLvent in which said. compound. is poorLy soLubLe, L~ e,g. an ether, or an ester or ketone having a Low boiLing point, but if a further conversion is required, ït can be hydroLysed. into a correspond.ing ketimine acid. or an aLkaLi metaL or aLkaLi earth metaL saLt thereof withou-t purification. For this purpose the ketimine ester hydro-chLorid.e is dissoLved for e~ampLe in ethanoL and. stirred.with a O.L to L0 n aqueou~ aLkaLi metaL or aLkaLi earth metaL hyd.roxid.e soLution, at a temperature between 0 C and 60 C, preferabLy L~ C and. 40 C,for L0 to L~, minutes. In this manner an aLkali metaL or aLkaLi 2-, earth metaL saLt of the correspond.ing ketimine acid. is obtained which can be converted. into a correspond.ing acid addition saLt for exampLe by reacting with a mineraL
acid :;
~1936~
If the ketimine acids obtained as described above or -the saL-ts thereof are further hydrolysed under more drastic condit-ions, for exampLe in a L to 10 n aqueous alkaLi hydroxide soLution, at a tempera-ture between 60 C and 110 C, preferably 90 C and L00 C, the corresponding keto acid.s of the generaL formula (I), in whlch X stands for oxygen, are obtained as aLkaLi metal saLts which,if desired, can be con~erted into the correspondin~ keto acids of the general formula (I) by a caLcuLated amount of a mineral acid..
According to another embodiment of the process of the invention, the ketimine esters of the generaL
formula (I), in which R3 represents a lower aLkyL group, can be converted into the corresponding keto acids of the ~eneraL formuLa (I), in which X stands for oxygen, directLy, by :hydroLysis under the above-mentioned. more drastic cond.itions, In other words, in this case -the hydrolysis need. not be separated into two stages, more-over, the ketimine ester can be hydrolysed. in the same reaction mixture where it has been formed., i.e. the starting compounds of the generaL formula (II) can be converted into the keto acid. end products or -the salts thereof without isoLating the intermediates, directly, in one pot, The main advantages of the process accordin~
to the inven.tion are as folLows:
- the ketimine est~r saLt intermediates are obtained in such a high purity that~if d.esired, they - Ll -can be con~erted into the desired end product directLy, without isolation;
- d,uring the hydroLysis of the ketimine ester saLts the hydroLysis of the ester g~roup i5 essentiaLLy qulcker than that of the ketimine group, hence from -the same intermed,iate various compounds of the generaL form~l.a (I), incLud.ing some new compounds, e.g. ketimine acids, acid, ad.d.ition or aLkaLi rnetaL or aLkaLi earth metaL
saLts there~f,can be prepared;
L0 - from the ketimine acid.s or d.irectLy from the ketimine ester saLts, by a proper seLection of -the reac-; tion parameters, the keto acicls of the generaL formuLa (I) can be prepared, with an exceLLent yieLd,, in a quaLity suitabLe for pharmaceuticaL purposes;
L5 - unLike the processes known in the art for the preparation of keto acids of the generaL formuLa. (I) starting from compounds of the generaL f~rmuLa (II), t:he muLti-step process according to the invention can be performed. in one pot, without the isoLation or purification of the intermed.iates, and. affords the pharmaceuticaLLy active end prod.uct with a good yiel.d, and, in a quaLity which meets the internationaL stand,ard,s.
The fact that the process accord,ing to the invention can be carried, out in one reaction mixture 2~ from -the very beginning up to the isoLation of the end.
prod.uct is especiaLLy ad.vantageous in comparison with the state of art, since in this manner the losses d.ue to the isolation of the interrned.iates are eLiminated,, ~9~)8 the reacti~n time, the soLvent, equipment and L~bour requirements are essentiaLLy red.uced. and, accord.ingLy, the productivity is highly improved..
The invention wiLl now be iLLustrated. in greater d.etaiL in the foLlowing specific ExampLes, which are given for iLLustration and. not Limitation of our invention.
ExampLe L
L,4-Dimethyl-~-(4-chloro-benzimid.oyl)~
-pyrrole-2-ace-tic acid, ethyL ester hyd.ro-chLorid.e a) 36,2 g. (0,2 moles) of L,4-dimethyL-LH--pyrroLe-2-acetic acid. ethyL ester and. 30.4 g. (0.22 moLes) 1~ of 4-chLoro-benzonitriLe are d.issoLved. in L00 mL. of toLuene and. d.ry hyd.rochLoric aci.d. gas is bubbLed. through the reaction mixture for one hour. By ou-ter cooling with water care is tc~ken -that the temperature of the reaction mi~ture shouLd, not exceed. 30 C at the beginn-ing of the hyd.rochloric acid. absorption. The reactionmi~ture i9 then aLLowed. to stand, at room temperature for 20 hours and, is subsequently evaporated. to d.ryness under red.uced. pressure. The yelLow crystaLLine resid..le is taken up in ether and. washed, on a fiLter. ~4~0 g.
2~ (76 ~0) of the titLe compound are obtained., meLting at L93 t~ L94 C, with decomposition.
- 13 ~
AnaLysis for CL7H20CL2N202 (355.27):
caLcuLated.: C ~ 57,47-~0; H = 5,67 ~; N = 7.88 ~; Cl = L9.9~ ~
found.: C = 57~23 ~; H _ 5.46 %; N = 7.63 %; CL = L~i80 ~.
b) 18,L g. (O,L moLes) of L,4-d.imethyL-LH--pyrroLe-2-acetic acld. ethyL ester and. 15.2 g. (O.LL rnoLes) of 4-chLoro-benzonitrile are suspend.ed. in 150 mL. of diisopropyL ether and dry hydrvchLoric acid. gas is bubbl.ed.
through the suspensi.on at room temperature, for one hour.
After stand.ing for 24 hours, the mixture oonsisting of LO two Liquid. phases is evaporated. to dryness und.er reduced.
pressure, the semicrystaLLine resid.ue is treated. with a mixture of aceton.e and. e-ther, fiLtered. and. washed.
with ether. 2L.5 g (60.4 %) of the titLe compound. are obtained., meLting at L82 to L83 C, with d.ecomposition.
L~
ExampLe 2 .. ..
L,4-DimethyL-5-(4-chLoro-benzimidoyl)-LH--pyrroLe-2-acetic acid. hydrochLorid.e 3.55 g, (O.OL moLe) of L,4-d.imethyL-5--(4-chLoro-benzimid.oyL)-LH-pyrroLe-2-acetic acid ethyL
ester hyd.rochLorid.e are d.issoLved. in 40 mL. of ethanoL, whereupon a soLution of o.84 gG (0.02L moLe) of sod.ium hydroxid.e in 40 mL. of water are ad.d.ed. The reaction mixture is stirred at 40 C for LO minutes and. is evaporated to d.ryness und.er reduced. pressure. The soLid residue is dissoLved. in 40 mL. of a L:L mixture of hydrochloric acid. and water and. stirred at ro_m temperature.
The product precipitated after a few mlnutes is fiLtered.
c)ff and washed, with a smaLL amount of ice water and, ace-tone.
The crud,e reaction procluct obtained, can be further manufactured, in two aLternative ways:
a) The crude product is recrystaLLized, from a mi~ture of ethanoL and ether to yieLd 3.L g. (83 ~o) of the titLe compound, meLting at 256 to 267 C with d,ecomposition.
AnaLysi L7 22 2 2 3 ( Y
-ethanoL) (373.28):
L0 caLcuLated,: N = 7.30 %, CL = L9.00 %;
fcund: N = 7~70 %, CL = L9.20 ~0.
b) The crude produc-t is recrystaLLiæed from water to yieLd 2.26 g. (69 %) of -the titLe compound, meLting at 250 to 253 C with decomposition.
L5 AnaLysis for CL~EIL6CL2N202 (327.2L):
caLcuLatecl: N = 8.56 ~0, C1 = 2L.67 ~o;
found: N = 8.32 %, CL = 2L.54 %.
ExampLe 3 L,4-DimethyL-5-(4-chLoro-benzoyL)-LH-pyrroLe--2-acetic acid sod,ium saLt dihyd,rate a) L7.8 g. (0.05 moLe) of L,4-d,imethyL-5--(4-chLoro-'benzimidoyL)-LH_pyrroLe-2-acetie aeid ethyL
ester hydroehLvride are weighed, into a soLution of 2~ 4.2 g, (O.L05 moLe) of sod,ium hyd,roxide in 50 mL. of water. The reaction mixture is boiLed for 4 hours, with stirring. After cooLing 50 mL. of acetone are added,, and, the mi~ture i5 aLLowqd to stand -in a refrigerator ~9~
- L-) -overnight. The precipitate is fiLtered off and. washed.
with a smaLL amount of ice wa-ter and. subsequentLy with acetone. L5.9 g. (~L %) of the titLe compound. are obtain-ed, meLting at 30~ to 306 C, with d.ecomposi-tion.
b) L8.L g. (O.L moLe) of L,4-d.imethyl-LH--pyrroLe-2-acetic ~cid. ethyL ester and L3.8 g. (O.L mole) of 4-chloro-benzonitriLe are dissoLved in ~0 mL. of toLuene, and. the svLution is saturated. with dry hyd.rochLoric acid gas. The reaction mixture is aLLowed to stand. at room L0 temperature for 20 hours, then evaporated to dryness und.er red.uced. pressure. To -the resid.ue a soLution of 9 g.
(0.225 moLe) of sod.ium hyd.roxide in L00 mL. of water is ad.ded., and. the mixture is boiLed. for 4 hours, with stirring. The reaction mixture is aLLowed. to stand.
L~ in a refrigerator overnight., fiLtered. and washed. with a smalL amount of ice water and. subsequentLy wi.th acetone.
24.7 g, (70,3 ~0) of -the titLe oompound. are obtained, meLting at 30~ to 307 C, with deoomposition.
c) 3.27 g, (0.01 moLe) of L,4-d.imethyL-~--(4-chLoro-benzimid.oyL)-LH-pyrroLe~2-acetic acid. hyd.ro-chLorid.e are weighed into a soLution of 0.84 g. (0.02L
moLe~ of sod.i~ hyd.roxid.e in L0 mL. of water. The re-action mixture is boiLed. for 3 hours, wi-th stirring.
After cooLing the prod.uct is fiLtered. off and. washed.
2~ with a smaLL amount of coLd. water and. subsequentLy with acetone. 3.36 g (96 ~p) of the titLe compound. are obtained, meLting at 299 to 300 C, with d.ecomposition.
Claims (4)
1. Process for the preparation of 1-alkyl-and 1,4-dialkyl-5-aroyl-1H-pyrrole-2-acetic acid derivatives of the general formula (I) (I) wherein Ar is phenyl optionally substituted with halogen, alkyl having one to 4 carbon atoms or alkoxy having one to 4 carbon atoms;
R is alkyl having one to 4 carbon atoms;
R1 is hydrogen or alkyl having one to 4 carbon atoms;
X is an imino group and. R2 is hydrogen or an alkyl group having one to 4 carbon atoms, or X is oxygen and R2 is hydrogen, and if X represents an imino group, acid addition salts, if R2 stands for hydrogen, alkali metal or alkali earth metal salts thereof, which comprises reacting a pyrrole derivative of the general formula (II) (II) wherein R and R1 have the same meaning as defined above, Y stands for a -COOR3 group and, R3 is an alkyl group having one to 4 carbon atoms, with an aromatic nitrile of the general formula (III) Ar-CN (III) wherein Ar has the same meaning as defined above, in an organic solvent, preferably aromatic hydrocarbon, saturated with dry hydrochloric acid gas and, if desired, converting the obtained hydrochloride of a ketimine ester of the general formula (I), in which X stands for an imino group and R2 is an alkyl group having one to 4 carbon atoms, Ar, R and R1 have the same meaning as defined above, by hydrolysis into the corresponding ketimine acid of the general formula (I), in which R3 is hydrogen and X stands for an imino group, or into an alkali metal or alkali earth metal salt thereof, and/or by further hydrolysis into a keto acid of the general formula (I), in which R3 is hydrogen and X stands for an oxygen atom, or into an alkali metal or alkali earth metal salt thereof.
R is alkyl having one to 4 carbon atoms;
R1 is hydrogen or alkyl having one to 4 carbon atoms;
X is an imino group and. R2 is hydrogen or an alkyl group having one to 4 carbon atoms, or X is oxygen and R2 is hydrogen, and if X represents an imino group, acid addition salts, if R2 stands for hydrogen, alkali metal or alkali earth metal salts thereof, which comprises reacting a pyrrole derivative of the general formula (II) (II) wherein R and R1 have the same meaning as defined above, Y stands for a -COOR3 group and, R3 is an alkyl group having one to 4 carbon atoms, with an aromatic nitrile of the general formula (III) Ar-CN (III) wherein Ar has the same meaning as defined above, in an organic solvent, preferably aromatic hydrocarbon, saturated with dry hydrochloric acid gas and, if desired, converting the obtained hydrochloride of a ketimine ester of the general formula (I), in which X stands for an imino group and R2 is an alkyl group having one to 4 carbon atoms, Ar, R and R1 have the same meaning as defined above, by hydrolysis into the corresponding ketimine acid of the general formula (I), in which R3 is hydrogen and X stands for an imino group, or into an alkali metal or alkali earth metal salt thereof, and/or by further hydrolysis into a keto acid of the general formula (I), in which R3 is hydrogen and X stands for an oxygen atom, or into an alkali metal or alkali earth metal salt thereof.
2. A process as claimed in claim 1, which comprises reacting a compound of the general formula (II) with an aromatic nitrile of the general formula (III) in toluene saturated with dry hydrochloric acid gas.
3. A process as claimed in claim 1 for the preparation of compounds of the general formula (I), in which X stands for an imino group and R2 is hydrogen, which comprises hydrolysing the ketimino ester obtained.
by reacting a corresponding pyrrole derivative of the general formula (II) with an aromatic nitrile of the general formula (III) in an alkaline aqueous medium, at a temperature between 0 °C and 60 °C.
by reacting a corresponding pyrrole derivative of the general formula (II) with an aromatic nitrile of the general formula (III) in an alkaline aqueous medium, at a temperature between 0 °C and 60 °C.
4. A process as claimed in claim 1 for the preparation of compounds of the general formula (I), in which X stands for oxygen and R2 represents hydrogen, which comprises hydrolysing the ketimino ester obtained by reacting a corresponding pyrrole derivative of the general formula (II) with an aromatic nitrile of the general formula (III) or the ketimino acid prepared according to claim 3 in an alkaline aqueous medium, at a temperature between 60 °C and 100 °C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1187/82 | 1982-04-19 | ||
| HU118782A HU187131B (en) | 1982-04-19 | 1982-04-19 | Process for producing 1-alkyl-5-aroyl-pyrrol-2-acetic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1193608A true CA1193608A (en) | 1985-09-17 |
Family
ID=10953241
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000426132A Expired CA1193608A (en) | 1982-04-19 | 1983-04-19 | Process for preparing 1-alkyl-5-aroyl-pyrrol-2-acetic acid derivatives |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS58213754A (en) |
| AT (1) | AT376205B (en) |
| BE (1) | BE896472A (en) |
| CA (1) | CA1193608A (en) |
| CH (1) | CH652711A5 (en) |
| DK (1) | DK153396C (en) |
| ES (1) | ES8501749A1 (en) |
| FI (1) | FI831310L (en) |
| HU (1) | HU187131B (en) |
| IN (1) | IN156527B (en) |
| NO (1) | NO161973C (en) |
| SE (1) | SE447105B (en) |
-
1982
- 1982-04-19 HU HU118782A patent/HU187131B/en not_active IP Right Cessation
-
1983
- 1983-04-15 CH CH203683A patent/CH652711A5/en not_active IP Right Cessation
- 1983-04-15 BE BE1/10761A patent/BE896472A/en not_active IP Right Cessation
- 1983-04-18 SE SE8302158A patent/SE447105B/en not_active IP Right Cessation
- 1983-04-19 AT AT140283A patent/AT376205B/en not_active IP Right Cessation
- 1983-04-19 ES ES521631A patent/ES8501749A1/en not_active Expired
- 1983-04-19 CA CA000426132A patent/CA1193608A/en not_active Expired
- 1983-04-19 NO NO831375A patent/NO161973C/en unknown
- 1983-04-19 FI FI831310A patent/FI831310L/en not_active Application Discontinuation
- 1983-04-19 IN IN456/CAL/83A patent/IN156527B/en unknown
- 1983-04-19 DK DK170583A patent/DK153396C/en not_active IP Right Cessation
- 1983-04-19 JP JP6789383A patent/JPS58213754A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NO831375L (en) | 1983-10-20 |
| FI831310L (en) | 1983-10-20 |
| DK170583A (en) | 1983-10-20 |
| ATA140283A (en) | 1984-03-15 |
| BE896472A (en) | 1983-10-17 |
| DK153396C (en) | 1988-11-28 |
| DK153396B (en) | 1988-07-11 |
| AT376205B (en) | 1984-10-25 |
| FI831310A0 (en) | 1983-04-19 |
| NO161973C (en) | 1989-10-18 |
| HU187131B (en) | 1985-11-28 |
| CH652711A5 (en) | 1985-11-29 |
| IN156527B (en) | 1985-08-24 |
| SE8302158L (en) | 1983-10-20 |
| DK170583D0 (en) | 1983-04-19 |
| ES521631A0 (en) | 1984-12-01 |
| NO161973B (en) | 1989-07-10 |
| JPS58213754A (en) | 1983-12-12 |
| SE447105B (en) | 1986-10-27 |
| SE8302158D0 (en) | 1983-04-18 |
| ES8501749A1 (en) | 1984-12-01 |
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