Note: Descriptions are shown in the official language in which they were submitted.
1043340
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
- 4 -
.
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
1043340
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,
-- 10 -
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
1043340
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
.
1043340
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.
EXAMPLE 1
.
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
- 13 -
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 ~ ~ * ;
'.
- 16 --
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.
EXAMPLE 5
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.
EXAMPLE 6
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
- 17 -
.
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:
- 19 -
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
- 24 -
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.
. .
' _ 25 -
1~43;~0
I ~ a
o~
o ~ ,~
o
o
~ o~
_I ~ ~ O ~ G~ CO U~
.,~ o~ ~ a
,
~P o
s~
a o E~ E~ ~ u~
0 ~ ~ I O ~D ~ ~ ~ r~
~1 1 ~ u~
I H ~ CO 1
~0
~`J
O ~-~
~ R S~ O
_I U~
Q .,1 ~ rl
O a~
~ ~ O E~
X ~ a~ ~ I O o r-
W .0~ ~ ~u~ . . . _.
I ~') I H ~r ~D 11') U) ~D
1 I
o
H O
H h
. ~ ~
~ Q 0'0 ~
o ~ ~
.,1 ~ ~ ~ U~
O ~ c~
O ~ _I ~ co o a~ o
3 ~ ~. ~ ~ ~ ~
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O _I a~
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X Z ~ ~ ~ ~ ~D
~1 _I _I ~1 ~1
-- 26 --
.... , .. .. , ,_, . .. . . . . . . . . .
