CA1043340A - Preparation of 5-aroyl-pyrrole compounds - Google Patents

Abstract

Abstract of the Disclosure A process for acylating pyrrole compounds comprising reacting an aroyl halide with the pyrrole compound in the presence of an alkyl aluminum halide. Such acylated pyrrole derivatives are useful as intermediates for the preparation of anti-inflammatory agents and as synthetic intermediates.

Description

Backqround of the Invention This invention relatec, to the production of 5-aroy~pyrrole compounds. Sucll coMpounds are known and described in U.S. 3,752,826 to Carson. According to the teaching of Carson, compounds such as 5-aroyl-pyrrole alkanoic acids and the corresponding salts, esters, nitriles, amides and substituted amides are prepared by Friedel-Crafts reaction between an appropriate aroyl halide (I), preferably chloride, and a pyrrole-2-acetic acid derivative (II), such as the cyano or lower alkoxy-carbonyl, in the presence of a Lewis acid, preferably a metallic halide, such as aluminum chloride to form 5-aroyl-pyrrole-2-acetic acid derivatives (III).
The reaction of Carson is shown in the following schematic diagram:

Ar-C-Cl + r ~ ~ 7H-R' ~ Ar-C ~ ~ _CRH-R' Rl 1 , I II III
in which Ar represents a member selected from the group consisting of phenyl, thienyl, 5-methylthienyl, mono-substituted phenyl and poly-substituted phenyl, each substituent of said substituted . , ~
' . ~ .. .. . .

- lV43340 phenyl~ being a member ~elected from the group con~lstlng o~
halo, lower alkyl, trl~luoromethyl, lower alkoxy, nltro, amlno, cyano and methylthio; R represent~ a member ~elected from the group conslstlng o~ hydrogen and lower alkyl; Rl repre~ents a member selected from the group con3i~ting Or hydrogen, lower ~lkyl ~nd benzyl, and R' ls cyano or lower alkoxy-carbonyl.
Sultable sol~ents are those typlcally employed in Friedel-Crafts react~on such as methylene chloride, 1,2-d~chloroethane, carbon dlsulrlde, nltrobenzene and the like. The 5-aroyl-pyrrole-2-acetlc acld derlvatlve (III) can then be converted to corres-pondlng 2-carboxyllc ~cld by conventional hydrolysi~. r`or oxample, by heatlng a ~olution o~ the 5-aroyl-pyrrole-2-acetlc ~cid derlvatlve wlth an alkall metal hydroxlde to form thc ~lkali metal ~alt o~ the acl~ and then acldifying the mixture.
A wld~ variety o~ 5-aroyl-pyrroles are produced a~cordlng to the process schemes ~hown ln C~rson. Such compound~ have useful pharmacologlcal propertles which make them sultable for ~ormu~at~on ln conventional pharmaceut~cal ~orm~ ~or admln~tratlon.
The 5-sroyl-pyrrole compounds described ln Carson have been found to poBsess antl-inflammatory activlty whlch has been demonstrated ~n stand~rd kaolin-lnduced rat pa~ edema and cotton pellet granuloma teats at do~es generally ranging ~rom 5-100 ~ ~g body wel~ht. Accordingly, improveC processes for acylsting the pyrrole-2-acetlc acld derl~atlves are desirable. mus, lt 1 an obJect Or the preaent ln~entlon to provlde a proces~ ror pre~arlng 5-aroyl-pyrrole-2-acetlc acld derlvatlve~, and partl-cularly 5-aroyl-pyrrole-2-aceton~trlle, ln hlgher ylelds, uslng a proce~ provldlng advantages over the prlor art. The rore-going and other obJects are ~ccompllshed by the process o~ the present lnventlon.

- 2 -1~343340 Summary o~ the Invention Accor~lng to the pre~ent lnvent~on, ther~ i~ provided a proces6 ~or selectlvely acylatlng a pyrrol~ compound in a po~ltlon alphs to the nltrogen atom and ~lthout alkylatin~ the pyrrole nucleus, comprislng react~ng an aroyl hallde and a pyrrole com-poun~ in the pre~ence ot an alkyl alumlnum hallde w~ile malntalnlng thc reaction mlxture at a temperature Or about 0 to about 40C.
Pre~erably, the pyrrole cQmpound i9 a pyrrole-2-acetlc acld derivatlve, ~or ex~mple, l-methylpyrrole-2-acetonltr$1e, ~urther, pre~erred aroyl hallde6 are toluoyl ~nd benzoyl halldes, for example, toluoyl chlorlde and ben~oyl chloride. Typically, the a~kyl alu~lnum halide compound can be dlalkyl alumlnum hallde, ~lkyl aluminwm dihallde ond alkyl alumlnum se~qulhallde compounds, ~uch as,.ethyl alumlnum dlchlorl~e, dlethyl alumlnum chlorlde, . 15 dim~t~yl alumlnum chloride and ethyl aluminum sesquichlorlde.

. .
escri~tlon Or Pre~erred Embodlments Accordlng to the present lnventlon there 18 provlded a proCe~ ror the preparatlon o~ 5-aroyl-1-methylpyrrole-2-aceto-nltrile compound9. Such cQ~pounds h~e ~ characteristic pyrrolc rlng ~tructure ln ~hlch varioufl substltuent~ are pl~ced on the pyrrole rlng according to the proces~ Or the present invention.
~scordlngly, a startlng materlsl whlch 18 necessary ~or the present lnventlon ls a pyrrole com~ound, such a~, a l-lower alkyl ~yrrole co~pound, ~re~e~ably a l-met~ylpyrrole compound ~nd, more pr~erably, a 1-methylpyrrole-2-acetlc acld ~erl~atlve as ~escribe~ hereinabove. The startlng pyrrole compound ~ay have ~arlous other sub~tltuents attsched to the pyrrole rlng structure, For example, in the 2-posltlon eroups selected rrOn CYanOJ carboxy, c~rboxyllc acld e~ter, ~mlde, substltuted amlde, sub~tltuted dla~lde and simllar groups can be attsched vla a methylene group.

11:34;~340 The pyrrole compound may also have substituted in the 3- and/
or 4-position a radical which is a member of the group con-sisting of cyano, carboxylic acid, lower alkyl esters of carboxylic acids, amides of carboxylic acids, lower alkyl and dilower alkyl substituted amides of carboxylic acids, lower alkyl amino alkylene amides of carboxylic acids and the like. In the 5-position, the present process can be used to attach an aroyl group, for example, toluoyl, benzoyl, -chlorobenzoyl, thienoyl or similar groups having an aromatic nucleus which may be mono- or poly-substituted with lower alkyl, halo, cyano, nitro, lower alkoxy, amino, methylthio, tri-fluoromethyl and similar groups.
As used herein, the term "lower alkoxy" and "lower alkyl" means a straight or branched chain saturated hydrocarbon group having from 1-6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and similar alkyls and, respectively, the corresponding alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, etc. Accordingly, preferred compounds produced by the process of this invention are 5-aroyl-1-methylpyrrole-2-acetic acid compounds. Most preferably, the compounds produced according to this process are 5-aroyl-1-methylpyrrole-2-acetonitrile compounds. A number of the 5-aroyl-pyrrole compounds are disclosed in the Carson patent as above-mentioned.
The starting material for the process of the present invention is a pyrrole compound, for example, a 1-lower alkyl pyrrole-2-acetonitrile, preferably l-methylpyrrole-2-acetonitrile. As indicated above, the pyrrole ring may be substituted in the 3- and/or 4-position as well. However, for purposes of the present invention, the simpler l-methylpyrrole-2-acetonitrile .

104;~340 wlll be used ~or tllu~trative purpo6es, m e l-methylpyrrole-2-ac~tonitrile 18 acylated with an aroyl hallde. Approprlate sroyl hslides can be the aroyl chlorlde, lodlde, bromlde and rluoride ~ith the aroyl chlorlde being illustratlve and pre~erred. ffl e aroyl group can be any Or those lndicated above. Accordln~ly, preferred aroyl group~ are toluoyl, ben~oyl, n~phthoyl, p-chlorobenzoyl, ~-toluoyl, ~-nitrobenzoyl, 4-nltronaphthoyl, 5-propylthlenoyl, m-lsopropyltoluoyl, ~-butyl-benzoyl, 5-pentylnaphthoyl, ~-hexylbenzoyl, ~-methoxyben~oyl, ~-ethoxybenzoyl, 4-propo~ynaphthoyl, ~-butoxybenzoyl, 5-pentyl-oxynaphthoyl, m-amlnotoluoyl, 5-cyanothlenoyl, p-tri~luoromethyl-ben oyl, ~-methylthloben~oyl, 5-chlorothlenoyl, 3-bromobenzoyl,

3-~luoro-4-methylbenzoyl and the ll~e.
8uch ~royl halides are generally known and may be obtalned - 15 by trans~ormatSon o~ the correspondln~ acld Or the acld chloride rormed accordlng to conventlonal procedures, such ~8 re~luxlng o~ the aryl ~cid wlth thlonyl chlorlde and distlllln6 of~ excess thionyl chloride under vacuum to produco the correspond~ng aroyl chlorlde product.
Accordlng to such procedure, aroyl chloride~ such ~8 3,4-dlmetho~ybenzoyl chlorlde, 3-bromo-4-chlorobenzoyl chlorlde, 2,~,5-tribromobenzoyl chlorlde, 3,4-dimethylbenzoyl chlorlde, ~-ethylbenzoyl chlorlde, p-ethoxybenzoyl chlorlde and ~-methyl-th~obenzoyl chlorlde m~y be produced. In the pro¢ess of t~e present tnventlon a pre~erred ~royl hallde la ~-toluoyl hallde ~nd ~ost pre~erred 1~ E~toluoyl chlorlde, The ~mount o~ aroyl cblorlde requlred i8 only that 6u~1cient to react wlth the pyrrole ~onpound, usually ~n equ~molar amount or up to about a 5 ~eight percent excess i8 all that i8 necea3ary.

i~4~340 m e aroyl hallde and pyrrole derlvatlve are reacted in the presence of an ~lkyl alumlnum hallde composltlon. Any sultable alkyl aluminum hallde compound ~hlch does not adversely ef~ect the product or reactanta and glvee a reasonable rate Or reactlon may be employed. Preferably, the alkyl group 19 a ~louer ~lkyl" as de~ined herelnabove. Typlcal alkyl alumlnum hallde compound~ are alkyl alumlnum dlhalldes, dlalkyl alumlnum ~alides, alkyl alumlnum se~quihalldes and mixtures or other rorms Or these. Some examples o~ 6ultable dlalkyl alumlnum halides are:
d~methyl alumlnum brom~de, dlethyl alumlnum broml~e, dlet~yl alumlnum chlorldc dl-n-propyl alumlnum chlorlde, dllsobutyl all~mlnum lodlde, dllsoamy~ alumlnum chlorlde, d~hexyl alum~num chlorldeJ
and the llke. Example~ o~ u89fUl alkyl ~lumlnu~ dl~aldes ` -1 ludes ~etkyl alumlnum dlchlorlde, . -- ~
cthyl ~lumlnum dlchlorlde, othgl alumlnum dlbromide, - - . n-propyl alumlnum dlchlorlde, lsobutyl slumlnum dlbroni~e, n-hexyl alumlnum dibrffm~de, and the llke. Both the dlalkyl alumlnum hallde~ and the alkyl aluminwm dihalides are belle~ed to e~lst ln the rorm o~ dlmers ~nd these, Or cour~e, are lncluded ~lthln the scope Or t~e present lnvention.

iO43340 Alkyl alumlnum 6esqulhalldes havlng the ~ormula R3Al2X~, ln whlch R represents an alkyl group, pre~erably R lcwer alkyl group, ~nd X represent~ a halogen atom, ~re U8e~Ul ln the pre~ent ln~entlon. Examples Or typlcal alkyl alumlnu~ 3esquihalldes ~nclude:
methy~ alumlnum sesqulchlorlde, ~ethyl alumlnum sesqulbromlde, ethyl alumlnum ~esQulchlorlde, ethyl alumlnum sesquibrom~de, thyl alumlnum sesqullodide, n-propyl alu~lnum ~esqulchlorlde, n-~ro~yl aluminum sesquibromlde, lsobutyl alumlnum se~qulchlorlde, lsobutyl alumlnum sesquliod~de, n-hexyl alumlnum ~esquilodlde, and the like.
The above sIkyl alumlnum halide compounds can be u~ed ~nd~ldu~lly or can be added as mixtures to the aroyl hallde or to the react~on mlxture wlth good result~. Frequently, due to the~r tendency to lgnlte on expo6ure to alr, the alkyl alumlnum halldes are used ln the torm ot solutlon~ ~n lnert solvent~ 8uch a~ hydrocarbon~ or ethers. Partlcularly u~e~ul solvent~ are the ~ rocarbons ~uch as hexane, heptane, 1BOOCtRne, benzeneJ toluene, xyleno and the ll~e. ~owever, ln the present process a solvent ~5 1~ not necessary.
ffl e u6e ot an alkyl slum~num ~alide h~s several advant~e8.
~ncreased yleld6, reaction at reasonable temperatures and rea~on-able reactlon rates and cleaner reactions ~re several proce~
ad~antage8 whlch can be ~entioned. Pyrrole co~pounds are known - 30 to polymerlze ln the presence Or acld~. ~'lthout llmltlng the ~nventlon to any partlcular theory o~ mech~nlsm o2 operation, ~, .
_ 7 _ -1~4;~340 it 18 believed th~t acld~ are produced on resctlon Or the aroyl hallde wlth the pyrrole compounds formlng a hydrogen hallde whlch 1~ reacted with an e~ulvalent of alkyl aluminum hallde to form an alumlnum hallde and evolve a hydrocarbon gas. fflu9, by re-moving the hydrogen hallde, polymerlzatlon o~ pyrrole 18 prevented,lncreaslng ylelds and preventlng formatlon of heaYy ends in the reactlon mlxture.
Alt~ouBh alkyl alumlnum halide~ are preferredJ the process can also be carried out u~lng aryl alumlnum hallde~ and, hence, the3e are consldered equlvalents. However, the alXyl alumlnum halide~ are more readlly available and are accordingly preferred.
U08t prererred are alkyl alumlnum hallde~ ln which the alkyl group~ are lower alkyl groups as deflned herelnabove. Also, most preferred are alkyl alumlnum hallde6 wherein halogen is chlorlne. Thus, most preferred alkyl alumlnum halldes are selected fro~ the group conslstlng Or dlethyl alumlnum chlorlde, ethyl alumlnum dlchlorlde and ethyl alumlnum se~ulchlortde.
Most hlghly pre~erred ls diethyl alum$num chlor$de. m e amount of Alkyl alumlnum halide, A8 indlcated AbOVe, 18 that sufflclent to give reasonable rate o~ reactlon. It ha~ been found that a stoichiometrlc amount o~ the alkyl alumlnum hallde compound ls preSerred and a sllght exce6s up to about lO welght percent can be advantageous to obtaln the best reactlon.
m e reactlon can be carrled out ln a l~uld, racllltating contact o~ the reactants which i8 substantlally lnert to the reactants and product and has sur~lclent solvent power for keep~ng reactants and products ln ~uspenslon or 301utlon. Such reactlon medium or ll~uld dlluent i8 preferably an oreanic compound rrom the group con31stlng of saturated parafflnlc hydrocarbons, halo-3~ genated hydrocarbons, ~speclally halogenated aliphatlc and aromatlc -- ô --~V43340 hydrocarbons. Typlcal examples are solvents ~hlch ~re sultable~or Frle~el-Crarts reactlons ~uch QB, ~or example, methylene chlorlde, 1,2-dlchloroethane, carbon disulflde, nltrobenzene and th~ e. Pre~erably, methylene chlorlde, dlchlorobenzene and monochlorobenzene are employed. m e umount o~ reactlon medlum reaulred 18 not crltical and an amount sufrlclent to malntaln 8 stlrrable reactlon mlxture can be employed. m e u~e o~ A ~olvent 18 noe crltlcal, however, it provldes proce~s adYantages ln allow1ng good heat trans~er wlthout locallzed hot 6pot~ ln the reaction and Sacllitatea contact o~ t~e reactants. Prererably the reactlon medlum 18 an alkyl or aryl hallde, mo~t prererably, lo~er alkyl ballde BUCh a8 methyl chloride, ethyl chlorlde, propyl chlorlde, lsopropyl chlorlde, butyl chlorlde> pentyl - c~loride! hexyl chloride and tha dl- and, ~here pos~lble, trl-chlorinated sl~yls, or a ~ono-, dl- or trlchlorobenzene, toluene or xylene or analog~, bromlde6 or mixed halide~ thereor. Mo~t pre~erably, the reaction ~edium 18 methylene chlorlde, 1,2-dl-c~loroe~hane or monochlorobenzene, with monochlorobenzene belng mo8t hlgbly prererred.
; 20 m e reactlon 18 carrSed out at a temperature suS~cient to obtaln a ~ood rate o~ reactlon and yleld wlthln practical - llmltatlon~ o~ capltal lnvestment and proce~s economlc~. Pre-- ~erably,the reactlon can be csrrled out at a temperature ranglng ~rom 0 to about 40C. Althougb temperature~ hlgher and lower than thls can be employed, the more pre~erred reactlon temper-~ture range 18 ~rom 5 to about 25C. InltSally, the reactlon ~xture ~ay be ~rozen by, ~or example, uslng dry lce to obtaln a reactant ~lush and t~e reactant mlxture 1~ then warmed up to reactlon temperature. In the alternatlve, the reactants can be a~ded to the reactor at the lower end o~ the reactlon temperature range and as reaction proceeds the reactants are heated to the hlgher end of the reactlon temperature range.
m e reactlon can be carried out for a time suf~iclent to obtaln a good yield st reasonable reactlon rates and ~ith regard to reasonable cycle tlmes. Practlcal conslderatlons wlth respect to the slze of equipment and capital lnvestment should be taken into account when reactlon times are determlned. The reactlon time 18 not crltlcal and depend~, for example, on the temper-ature o~ reactlon, reactlvlty o~ reactants and the degree Or 0 completeness of reactlon de~lred and mlnlmizatlon of s~de re-action~. Pre~erably, the reactants are fed to the reactor for a perlod suf~icient to obtaln the deslred conditlons. m e reactlon mixture can be held at low temper~ture~, ~or example, less than 0C ror an inde~inlte perlod without a ~lgnlflcant amount o~ reactlon. However, after allowlng the reactor contents to warm up to a temperature suf~icient for reactlon, lt proceeds ~or ~rom about 30 to about 210 minutes, pre~erably from 90 to about 180 minutes. Best results are obtalned when the reactlon 18 allowed to occur over a perlod ~rom about 90 to about 120 mlnute6 and such timesare more preferred.
As lndlcated above, the reactants can be mlxed together at low te~perature and then warmed to reactlon temperature.
Alternatlvely, a mixture of the aroyl chlorlde and pyrrole c -pound can be made and the alkyl aluminum halide added, either all at once or over 8 perlod Or tlme, to this mlxture at reaction temperature. Alternatlvely, a mixture of the aroyl hallde and alkyl all~m~num hallde catalyst ln a sultable reactlon medlum c~n be made and the pyrrole added thereto. Another alternatl~e 18 to mix the pyrrole compound and alkyl alumlnum hallde wlth the reactlon medlum and then add thereto the aroyl chlorlde. Thus, 1~4;~340 the method or order of sddltlon of reactants 18 not crltice~.
At reactlon temperature, an exce~s Or one reactant or another coule have effects on selectivlty and yleld of de~lred 5-&royl pyrrole compound. Moreover, the addltlon o~ reactant~ and/or alkyl alumlnum hallde can be made 811 at once or one or more of the reactants m~y be a~ded over a relatively short perlod Or time, for example, ~ro~ 15 to about 45 minute6, accordlng to one of the alternate modes described hereinabove. Best re~ult~ are obtalned when the aroyl hallde and pyrrole are mlxed ln a ~ultable reaction medium and the alkyl slumlnum hallde 18 added over a perlod of ~rom about ~0 to about 45 minutes.
After reaction has occurred, the 6t~rtlng alkyl alumlnum h~llde ha~ been converted to another alumlnum compound havlng one more hallde atom replaclng sn alkyl group, for example, diethyl aluminum chlorlde would be converted to ethyl aluminum dlchloride, ~nd a sllght amount o~ alkyl aluminum hallde may remaln becau~e Or lncomplete reactlon or excess sdded, Arter reactlon ~or a su~ricient period of tlm~ to be substantlally -`
complete, the remalning alkyl alumlnum hsllde 1B decomposed by a 6ultable decompoaitlon agent and then the deslred 5-scylated pyrrole compound can be recovered. Any suitable agent which ~ecomposes alkyl slumlnum h~ltdes can be u~ed, typlcal are water, slcohols, dllute aclds, ba6es and mi~tures o~ the~e, ~or exa~ple, water can be used or lower al~anols such a~ methanol, ethanol, lsopropanol and dllute lnorgsnic mineral acid such a~ hyaro-chloric acld and the llke. Pre~errea alkyl alumlnu~ halide aecQmpositlon a6ents are water, lsopropanol and dllute hydro-cblorlc acid.
Another advantageous functlon Or the alkyl aluminum ~0 hallde decomposltion agent 18 to rorm a separnte pha6e lnto whlch t~e by-product~ o~ alkyl alumlnum halide decomposltlon, e.g., aluminum hydroxlde and/or alumlnum chlorlde, wlll b~ removed ~rom the organic phase contalnlng the 5-~royl pyrrole product.
For this purpose, exceYs decompo~ltlon agent 1~ employed. Pre-5 ~erably, from about l to about 2 moles or greater Or decom-posltlon agent ba~ed on the amount Or ~lkyl alumlnum hallde may be u~ed. or cour~e, larger excesses of decomposlt~on agent may glve more convenlent decompo~ition rates And/or ~hase separatlons.
Generally, ~ typlcal procedure ~or conductlng the ~rocess o~ the preaent in~enelon includes the provi610n of a reactor ritted wlth temperature sens1ng meQns, stlrrer ~nd an overhead condenser. To the reactor ls added the reactlon medlum, aroyl hallde and the pyrrole compound m e mlxture 18 then stlrred and cooled to around 0C. m en a ~u~flclent amount of slkyl alumlnu~ hallde ~rom ~n addltion ~unnel 1~ added o~er about a 45 mlnute perlod. m e mlldly exothermlc react~on tQkes - - place and temperatures are controlled at o-400c during addltlon.
m e ga~ generated durlng reactlon iB vented. The reactlon m~xture 18 held wlth stlrrlng at 10-20C ror rrom l/2 to ~-l/2 hour~ ~ter addltlon. Yery llttle gafi 18 evolved durlng the la~t hour o~ holdlng. The color of the reactlon mixture i8 reddlsh-brown. m e last traces o~ alkyl aluminum ~alide are remo~ed by one of t~e ~e~eral method~ lndlcated herelnabove. In ~nother pre~erred embod~ment, for example, the reaction mixture it~el~ csn be poured into ~ater. The cataly~t decomposltlon reaction 18 Yery exothenmtc during the rir~t ~ddltlon Or reactlon ml~ture into ~ater. Cooling must be provided to control the temperature belo~ 30C. A~ter 810w addltion o~ the flrst l/4 o~
the reaction mixture the remalning amount o~ reactlon mlxture can be added at a ~aster rate. m e reaction mixture 1~ allowed .

to separate lnto two layers, the hottom dark brown laycr con-taining the product. The lower layer i.s removed and the solvent evaporated to give solid 5-aroyl substituted pyrrole.
According to the process of this invention, it is preferred to carry out the reaction in which the pyrrole compound is l-methyl-pyrrole-2-acetonitrile~ The preferred alkyl aluminum halide is diethyl aluminum chloride, and the preferred aroyl halide is _-toluoyl halide, most preferably _-toluoyl chloride.
During the reaction, the reaction mixture is maintained at a temperature of from about 5 to about 25 C and the reaction medium employed is methylene chloride. In a further preferred embodiment of the process of this invention includes the reaction for a period ranging from about 90 to about 120 minutes and then adding an amount of alkyl aluminum halide decomposition agent sufficieht to decompose the remaining alkyl aluminum halide catalyst, for example, water, an alkanol or dilute acid, and recovering the 5-substituted aroyl pyrrole-2-acetonitrile from the reaction mixture.
The following examples are illustrative of the process of this invention. After examples of this invention, there are given some comparative experiments in which a metallic halide, e.g., aluminum chloride is used. Finally, several examples showing typical procedures for the process of this invention are given.

.
In a serum capped vial was placed 1.2 g (10 mmoles) of a nitrile mixture containing 90.8 mole % 1-methylpyrrole-2-acetonitrile and 9.2 mole % of 1,2-dimethyl-5-cyanopyrrole and 1.55 g of ~-toluoyl chloride (10 mmoles) in 10 ml of methylene chloride 1(3433~0 ~hich had been dried over a molecular s~ev~. To thi6 mlxture wa~ added 2.5 ml Or a solutlon prep~red by taklng 6 g (11.8 mmoles) of ethyl alumlnum dlchlorlde and adding dry hexs,ne to make 10 ml of ~olution. The lnitial nitrile-~-toluoyl chlorlde ~olutlon was frozen ln a dry lce slush and then allowed to ~ust tha~ ~t which po~nt the ethyl ~luminu~ dichloride-hexane solutlon ~as added. me m~xture was then allowed t~ warm up to room temperature over a perlod o~ hour. As the temperature reached 15-~0C, evolution o~ ethane be~an and contlnued ror about 10 minutes. After a rurther 10 mlnutes elapsed, ? ml o~
methanol was added and the mlxture began to boll wlth the heat of reactlon ~nd/or ethane evolutlon, ffl e reactlon mixture was then treated wlth about 50 ml of dllute (about 5~) hydrochlorlc acld and the aqueou~ phase was extracted tw~ce wlth met~ylene chlorlde. The extract~ were comblned, follo~ed by drylng over eodlum sulfat~, and ga~e 2.2?6 g o~ product after evaporatlon or the methylene c~lorlde. This materlal was added to enough 1,2-dlchloroethane to msk~ a aolutlon of 50 ml and a 5 ml ~llquot was analyzed by vapor phase chromatography glvln~ the ~olloulng compo~tion~;
Unkno~n - o,36 1,2-Dimethyl-5-cyanopyrrole - 3.45 l-Methylpyrrole-2-acetonltrile - 0 Un~nown - 2.04 5-~-Toluoyl-l-met~ylpyrrole-2-scetonltrlle - 51,40 ~-~-Toluoyl-l-methylpyrrole-2-scetonltrlle - 38.90 Accountablllty - 96.15 Y~eld ba~ed on the startlng nltrlle content - 92.4 o~ whtch 52.6~ 1~ the 5-acylnltrlle ~nd 39.8 ~8 4-acylnltrlle _ 14 -10433~0 Recovery of starting amount of 1,2-dimethyl-5-cyanopyrrole - 69.2%
In a similar procedure as that of Example 1, sevcral other alkyl aluminum halides and solvents were employed. The results are shown in Table I:

, . , , . - ; .:~, 1(343340 0~
:~ h ~
~ CU0 ~
~ C U~N ~i ~ ~CU ~ .

c ~ Q`

SC r E~ J

O ID ~ b - ~ ; a5 I . ~ . .
5 ~ ~ * ;
'.

1~4;~340 The fo~lowing procedure elnploys ethyl aluminum dichloride as thc alkyl aluminum halide is addcd over a period of time instead of all in a single addition as in the previous example.

To a 1-liter, 4-necked flask reactor, fitted with thermometer, stirrer and overhead condenser, was added 150 g of methylene chloride, 39 g of _-toluoyl chloride (0.25 mole), 30 g of a mixture of pyrroles (93.3% 1-methylpyrrole-2-acetonitrile and 4.2% 1,2-dimethyl-5-cyanopyrrole, 0.25 mole total). The mixture was stirred and cooled to 10C, 32 g (0.25 mole) of ethyl aluminum dichloride was then added over a 30 minute period with an addition funnel. Ethane gas was generated and vented.
The reaction mixture was held with stirring at 10 for 30 minutes and then warmed to 21C and held for an additional 40 minutes. Then, approximately 250 g of water was added slowly with cooling to maintain the temperature below 30C. The bottom organic phase was separated. It weighed 152 g and was analyzed by vapor phase chromatography. The analysis indicated that the yield of 5-~-toluoyl-1-methylpyrrole-2-acetonitrile was 48.7~ based upon the starting nitrile and the ratio of the 5-~-toluoyl isomer to 4-p-toluoyl isomer was l.S.

To a 500-ml, 4-necked glass reactor fitted with thermometer, stirrer and overhead condenser was added lS0 g methylene chloride, 39 g p-toluoyl chloride (0.25 mole) and 40 g of a mixture of l-methylpyrrole nitriles (93.3% of 1-methylpyrrole-2-acetonitrile and 4.2% of 1,2-dimethyl-5-cyano-pyrrole, 0.243 moles total). The mixture was stirred and cooled to 7.5C, 30 g (0.25 mole) of diethyl aluminum chloride in an addition funnel .

1~4~340 ~ae then Added over a 45-mlnute per~od. A mildly exothermic reactlon was observed and tempersture tlas controlled at 10C
during additlon. Ethane gas was generated an~ vented. m e reactlon mlxture wa~ held with ~tlrrln~ at 10C for 3.5 hour~.
~ery llttle gas wa~ evolved dur~ng the last hour of holdlng. Th¢
color o~ the reactlon mixture wa~ reddlsh-brown~ Next, 220 g of water was adde~ to decompose the remaln~ng dlethyl alumlnum chlorlde~ m e reactlon wa~ very exothermlc during the ~ir~t ~ew drops o~ wat~r. ~oollng wa~ provided to control the temperature below 30~. Ar~er ~low sdditlon of the first 25 ml of water, the remalnlng water was &dded ~t a raster rAte, me mixture was BiphOned out and allowed to ~epar~te ln two layers, The bott~m dark brown layer conta~ned the product. It welg~ea 172~1 g of which 167 g ~ere e~aporated to ~v~ 57.1 g o~ brown ~olld.
~he crude product solutlon wa~ analyzed by ~apor phase chromatogr~phy to give th~ ~ollowln6 composltlon in welght percent:

Met~ylene chloride - 61.25 (65,8 by evaporatlon) 1,2-Dimethyl-5-cysnopyrrole - O,62 1-Methylpyrrole-2-acetonltrlle - 0.30 5-Cyano-1,2-dl~ethyl-3-~-toluoylpyrrole - 0.14 5-~-Toluoyl-l-met~ylpyrrole-2-acetonitrlle - 21.71

4-E~Toluoyl-l-methylpyrrole-2-~cetonltrlle - 9,32 -- -- Mlscellaneous unknowns - Approxlmately o.66 Total - 93.86 ~98.41 by evaporation) ~ aterlal balance calculatlons rro~ the Qbove analy8e8 lndicates that gO¢ Or the 1,2-dimethyl-5-cyanopyrrole was re-coYered but only 1.7~ Or startlng l-methylpyrrole-2-acetonltrlle ~a8 remalning in the crude product 601utlon, m e yleld o~

1~43340

5-~-toluoyl-1-methylpyrrole-2-acetonltrile wa~ 67.4~ and the ratlo Or 5-~-toluoyl lsome~ to 4-~-toluoyl lsomer ~as 2.3 m e efrect of vsriatlon of the reactlon tlme, temperature, additlon tlme and the method o~ decomposlng the remalning alkyl alumlnum hallde compound was 6tudled by 8 procedure slmllar to Example 6. Table II below shows that the reactlon temperature ha~ lmportant e~rects on yleld. m e e~fect o~ varylng the method of hydrolysl3 Or remalnlng alkyl aluminum hallde ha~ llttle effect on the results. Accor~ngly, the results Or several experlments are shown ln Tnble II here~nbelow:

1~43340 TABLE II
Acylatlon Or l-MethylPyrrole-2-acetonltrlle With Alkyl Aluminum Hallde Cataly~t Under Varled Reaction Condltlons Ex~mple number 7 8 9 10 11 ~urity o~ l-methylpyrrole-2-acetonitrllel93.~ 93.~ 93.3 93.3 93.
Alkyl alum~num ha~ldee D~AC. DEAC DEAC DEAC ~E~C
Temp~rature, C 10 10 10 ? 20 Tl~e, mlnute~
Addltlon 3 45 45 45 60 Holding 180 210 210 120 120 ~ethod Or Alkyl Aluminum ~alide Decomposltlon~ A A B a c Re~ults Ba8ed on VPC
% o~ or~g~nal l-methylpyrrole-2-scetonltrlle 5.0 1,0 2~2 2.7 orlglnal 1,2-di~ethyl- . :
5-cyanopyrrole o^O 41 88 71 9 Yleld o~ 5-~-toluoyl-1-mathylpyrrole-2-aceto-nltrlle 56 64 65 67 61 ~atlo Or 5-~-toluoyl l~omer . ----- -4-~-toluoyl l~omer 2.4 2.3 2.5- 2.5 2.2 . . .

14.2~ 1,2-dlmethyl-5-cyanopyrrole DEAC - dlethyl alumlnum ch~or~de ~ethod o~ decomposltlon:
A, Add ~ater to reaction mixture below ~4DC.
B. Add lsopropanol to the reactlon mixture belo~
~0 ~0C, then add water.
C. Add re~ctlon mixture to water below 20C.

_ ~0 --1~4;~340 j~
For comparatlve purpo~es, the procedure o~ Example 6 was repeated 11¦
ln which trlethyl aluminum was employed as a catalyst. However, !~
the reactlon mlxture became a solld mass on stlrrlng after the addltlon of the trlethyl aluminum could not be ~urth~r stlrred and the experlment was dl~contlnued.
In a further comparatlYe experlment followlng the procedures o~ Example 5, 30 g Or a mixture Or l-methylpyrrole nltrlles (90.7 l-methylpyrrole-2-acetonltrlle snd 9.3~ 1,2-d~methyl-5-cyanopyrrole ¦9 mlxture, 0.25 mole total~ was mlxed wlth 38.6 g (0.25 mole) of ~-toluoyl chlorlde in 250 ml of methylene chlorlde. A slurry 3~.~ g of alumlnum chloride and 250 ml of ethylene chlorlde wa~ ~
prepared and malntained suspended by stirrlng mechanlcally in a 1 dropping funnel. The pyrrole-acid chloride mlxture was cooled to -30 to -35C wlth dry lce slush and the slumlnum chlorlde slurry added steadlly over about 1/2 hour. The mlxture was stlrred magnetlcally becomlng homogeneous ln a ~hort tlme. m e mlxture wa~ then allowed to warm up to about 20C and a 8~mple taken showed a substantlal amount Or unreacted ~-toluoyl chlorlde by ~
NMR analysls. Although the pyrrole protons ~ere shlrted, probably ¦`
by a complexatlon wlth alumlnum chlorlde, no appreciable exotherm ~as noted during the warmln~ o~ the reaction mixture Or 20C.
ffl e reaction mlxture was allowed to react ~or a total o~ 17 hours at room temperature after whlc~ a sample taken appeared completely reacted. me mixture was hydrolyzed wlth di~tilled water, about 250 ml,and phases separated. The aqueous phase wa3 extracted twlce with methylene chloride. m e extracts were comblned with the organic phase o~ the reactlon mlxture and these were drted w~th anhydrous sodlun sulrate. m e methylene chlorlde was evaporated on a ~team bath leaving a resldue Or 70 g conta~nln6 16.67~ methylene chlorlde by VPC. m e crude product welght wa~

_ 21 -lV433~0 by difference 5B.33 g. Vapor pllaxe chroln;l~o~r~ph ana]ysis o the crude product showed 37.95% of 5-~-toluoyl-1-methylpyrrole-2-acetonitrile and 25.98~ -toluoyl-1-methylpyrrole-2-acetonitrile, which calculates to a yield of 49.2% of the 5-~-toluoyl isomer and 33.7~ yield of 4-_-toluoyl isomer. The ratio of 5-p-toluoyl isomer to 4-~-toluoyl isomer was 1.46 and a total yield of only 83~ of acylated pyrrole compared with isomer ratios of 2.2-2.5 and total yield of acylated pyrrole of 95 to 99~ using the alkyl aluminum halide, such as diethyl aluminum chloride.
Product accountability by VPC for this comparative experiment was 82.546, the remainder being apparently aluminum compounds or heavy ends. The selectivity of the reaction was low in com-parison to the reactions with alkyl aluminum chloride with respect to acylation of the 1,2-dimethyl-5-cyanopyrrole. Since only 11.2~ of this starting impurity remains compared to about 93~ with the alkyl aluminum halide reactions.
In another comparative experiment following as closely as possible Example XIII of Carson, U.S. 3,752,826, 26.6 g of anhydrous aluminum trichloride (0.20 mole) and 80 ml of 1,2-dichloroethane which had been dried over a molecular sieve were added to a reaction vessel and stirred together in a dry nitrogen atmosphere and then 30.9 g of ~-toluoyl chloride (0.2 mole) was added to give a soluble complex while maintaining a temperature of approximately 25C using an ice bath. The resulting solution was transferred to a dropping funnel and added to a solution of 24.2 g (0.20 mole) of a pyrrole mixture (90.7 weight percent l-methylpyrrole-2-acetonitrile and 9.3 weight percent 1,2-dimethyl-5-cyanopyrrole) in 80 ml of 1,2-dichloroethane over approximately 30 minutes while maintaining a temperature of 20 C. The resulting solution was stirred at room temperature for 20 minutes and then refluxed for ~ minute~. m e Eolution wa~ poured lnto ice acldi-~led with dllute HCl'and the mlxture allowed to ~ust melt. m e lower organlc layer was separated and combined wlth a chloroform extract of the upper aqueous phase and the mlxture was wa~hed 3uccesslvely wlth dllute 1,3-propanediamlne, dllute hydrochlorlc acld, 5 percent aqueous sodlum bicarbonate and saturated sodlum chlorlde. The or~anlc layer was then drled over anhydrous Na2SO~, flltered and the solvent strlpped off to yleld 56,45 g of strlpped product.
On analysls by vapor pba~e chromatograph, the product contalned 16.87 g of 5-~-toluoyl-1-methylpyrrole-~-acetonitrlle plu9 1, 2-dlmethyl-5-cyano-3-~-toluoyl pyrrole, 1~,80 g Or 4-~-toluoyl-l-methylpyrrole-2-acetonltrlle and 0.067 g of 1,2-dimethyl-5-cyano pyrrole. Because of the llmitatlonæ of the vapor phase chromatograph and the lnterference of 1,2-dimethyl-5-cyano-~-p-toluoyl pyrrole, the percentage o~ 5-p-toluoyl-1-methylpyrrole-2-acetonitrlle WaB determined to be 29.1-31.58 percent. m e y~eld o~ 4-~-toluoyl-1-methylpyrrole-2-acetonitrlle was 4~.5 per-cent. Yleld of total acylated pyrrole compound was 74.85 percent.
It 18 clear t~at more of the 4-~-toluoyl-1-methylpyrrole-2-acetonitrile specles was produced and the reactlon is much less selectlve than the proces~ of the present lnventlon. Thi8 experlment followed as closely a~ posslble Example XIII o~ Car~on patent, U S. ~,752,826, except ror the u3e of lmpure l-methyl-pyrrole-2-acetonltrlle and wa6hlng with 1,3-propanedlamlne. How-ever, 8uch mlnor varlatlons are not belleved slgnlflcant for comparlson of the result~ wlth results from the example6 of the pre~ent lnventlon. Accordlngly, lt can be æeen that the reactlon ln the presence of alumlnum alkyl hallde 18 more ~elective, produces hlgher ylelds and glves a better reactlon than wlth al~minum chlorlde accord~ng to the prlor art.

1¢~43340 A typlcally ~ployed procedure of thc ln~tant process can be lllustrated ln the followlng manner.

EXA,M,PI~E l?
A glas3-llned reactor fltted ~ith agitator, cooline water ~acket, temperature ~en~lng m~ansJ vent llne~, and reactant reed ~nd product dlscharge llnes was purged ~lth nltrogen for 15 minutes. ffl en 275 pound~ o~ methylene chloride was added to the reactor and the agltator and br~ne coolant flo~ ln the water Jacket were 6tarted. Then 71 pounda of ~-toluoyl chlorlde and ~Q 55 pounds Or a m~xture o~ l-methylpyrrole-2-acetonitrlles ~u6ually conta~nlng as an ~mpurlty 1,2-dlmethyl-5-cyano pyrrole) were successlvely Qdded to the reactor. me agltator 6peed wa3 increased, the reactor ccntents were cooled to 10C and, after purg~ng the reed line wlth nltrogen, 55 pounds o~ dlethyl alumlnum chlorlde was added at 8 rate of 0.1 gpm over a perlod of about 50 minutes wh~le malntainlng the reactlon mixture at about 20C.
Becauqe o~ gas evolutlon dur~ng the reactlon the dlethyl alumlnum chlorlde ~hould be added with the reactor vent llne open. me reactlon mixture was stlrred ~or 2 hours w U le the temperature 2~ ~a~ maintalned at 20C. m en a stalnles~ steel reactor al80 hsY~ng an agltator, coollng water Jacket, charge and dlschar6e llnes, Yent llne and temperature senslng means was rllled ~lth 385 pounds of deminerallzed ~ater. m e agltator was started ~nd coollng set at 10C. m en arter the react1on ~lxture ~rom the rlrst resctor reacted tor 2 hours at 20C lt was transrerred to ~he second reactor over a perlod o~ about 60 mlnutes. The additlon Or reaction mlxture ~rom the rlr6t reactor to water ln the second reactor generates a gas and the ~ent ln the second reactor must be open. Arter trans~er was completed, the ~gitator o~ the second rèactor wa~ ~topped and the resultlng two-phasc 1~433~0 ~ystem was allowed to separate for 30 mlnutes. m e bottom organic phase wa6 trans~erred rrom the ~econd reactor and product recovered or ~ent to rurther processlng. A ~ample ls taken for analysls by v~por phase chromatograph.
In accord wlth the above procedure 6everal runa were made and the results from Example 12 and the other runs are found ln the Table III whlch rollows.

. .

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Claims (17)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for selectively acylating a pyrrole derivative in a position alpha to the nitrogen atom, said process comprising reacting an aroyl halide and said pyrrole derivative in the presence of an alkyl aluminum halide while maintaining the reaction mixture at a temperature of about 0 to about 40°C.

2. The process of claim 1 wherein said pyrrole derivative is 1-methylpyrrole-2-acetonitrile.

3. The process of claim 1 wherein the alkyl groups of said alkyl aluminum halide are lower alkyl groups.

4. The process of claim 1 wherein the halogen of said alkyl aluminum halide is chlorine.

5. The process of claim 1 wherein said alkyl aluminum halide is diethyl aluminum chloride.

6. The process of claim 1 wherein said alkyl aluminum halide is ethyl aluminum dichloride.

7. The process of claim 1 wherein said alkyl aluminum halide is ethyl aiuminum sesquichloride.

8. The process of claim 1 wherein said aroyl halide is selected from toluoyl, benzoyl, naphthoyl, and thienoyl halide and such aroyl halides having the aromatic nucleus mono-, di- or tri-substituted with groups selected from lower alkyl, halo, cyano, nitro, amino, lower alkoxy, methylthio and trifluoromethyl groups.

9. The process of claim 1 further characterized in that said mixture contains a reaction medium which is an alkyl halide.

10. The process of claim 9 in which said reaction medium is methylene chloride.

11. The process of claim 9 in which said reaction medium is dichloroethane.

12. The process of claim 9 in which said reaction medium is monochlorobenzene.

13. The process of Claim 1 in which said pyrrole derivative is 1-methylpyrrole-2-acetonitrile, said alkyl aluminum halide is diethyl aluminum chloride, said aroyl halide is p-toluoyl halide, and said mixture is maintained at a temperature of from about 5 to about 25°C in a reaction medium which is methylene chloride.

14. The process of Claim 1 further characterized in that the acylation reaction is stopped after substantially all of the pyrrole derivative is reacted by adding an alkyl aluminum halide decomposition agent to the reaction mixture.

15. The process of Claim 14 wherein said decomposition agent is selected from the group consisting of water, alcohol and dilute acid.

16. The process of Claim 14 wherein said dcomposition agent is water.

17. The process of Claim 13 wherein the reaction is carried out for a period ranging from about 90 to about 120 minutes and then an amount of an alkyl aluminum halide decom-position agent sufficient to decompose the remaining diethyl aluminum chloride is added to the reaction mixture and the p-toluoyl-1-methylpyrrole-2-acetonitrile is recovered from the reaction mixture.