Note: Descriptions are shown in the official language in which they were submitted.
3 ~ f.r
--2--
The present invention relates to an improved process
for producing substituted pyrrole diesters which are useful
in the preparation of anti-inflarnmatory agents.
Al]cyl, aroyl substituted pyrrole-2-acetates are useful
anti-inflammatory agents. Compounds of this type are
disclosed, for example, in Carson; U. S. Pat. 3,752,826;
issued Au~ust 14, 1973. Useful precursors of the
substituted pyrroles exhibiting anti-inflammatory activity
are the diesters of 3-carboxy-1,4-dialkylpyrrole-2-acetic
acid. Such compounds can be hydrolyzed to the
corresponding diacid pyrroles which can then be selectively
monoesterified at the acetic acid group and subsequently
aroylated to provide the desired pharmaceutically active
pyrrole compounds.
Substituted pyrrole diesters can be produced via a
cyclization reaction involving acetone dicarboxylate
esters, alkyl amine and a halo-substituted ketone such as
chloro-aceton. This reaction is described, for example, in
Carson, U. S. Pat. 3,752,826, issued ~ugust 14, 1973;
Carson, U. S. Pat. 3r865,840, issued February 11, 1~75; and
in Carson et al., Journa:l oE ~edicinal Chemistry, 1~73,
Vol. 16, ~o. 2, pp. 172~174. As reported in the Carson et
al. article, diethyl acetone dicarboxylate is added rapidly
to a 40 percent aqueous solution of monomethyl amine to
produce a white ~reci~itate intermediate which is then
reacted with chloroactone to produce a 70 percent yield of
ethyl 1,4-dimethyl-3-ethoxycarbonyl pyrrole-2-acetate. The
reaction reported was conducted on laboratory scale using a
relatively large excess of the monomethyl amine and the
chloroacetone vis-a-vis the acetone dicarboxylate.
When such procedures are to be utilized for commercial
scale production of substituted pyrrole diesters, several
problems can arise. In commercial production it is, of
course, necessary to maintain pyrrole diester yields as
hi~h as possible while minimiæing the amounts of the
relatively expensive reactants employed~~in the cyclization
reaction. Large excesses of reactants should be avoided if
economically feasible processes are to be realized.
. ~ .
: :
-3-
Furthermore, scale-up of the pyrrole ester cyclization
reaction process to commerical quantities of reactants
increases the difficulties of obtaining acceptable yields
of the desired pyrrole ester product. The longer reactant
addition and reaction times involved in controlling the
reaction exotherm of the cyclization reaction on the
commercial scale tends to significantly reduce throughput
of reactants and the yield of the product obtained.
Accordingly, it is an object of the present invention
to provide~an improved process for the synthesis of
substituted pyrrole diesters by reacting acetone
dicarboxylate, primary amine and a substituted carbonyl
compound such as chloroacetone.
It is a further object of the present invention to
provide an improved pyrrole ester synthesis process that
makes possible increased reactant throughput with
acceptable yields of pyrrole diester product and with
minimized utilization of excess reactant concentrations.
It is a further object of the present invention to
provide an improved pyrrole synthesis process that can be
economically utilized for production of commercial
quantities of the pyrrole diester product.
~ ccordingly, the present invention involves the
process Eor the production of substituted pyrrole esters of
the formula:
- N ~C~l2-1_OR2
Rl
wherein Rl is a hydrocarbyl group containing up to about 20
carbon atoms or more, R2 and R3 are each an alkyl or
allcaryl group~containin~ up to about 2~ carbon atoms or
more and R~ is hydrogen or a hydrocarbyl group containing
up to 20 carhon atoms or more. In accordance with such a
process, the substituted pyrrole esters are formed by
reacting a primary amine of the formula Rl~`~H2 with an
acetone carboxylic acid ester of the formula:
_4
CE~ OR
C=O
and a substituted carbonyl compound of the formula:
f~'
R -~-CH X
wherein Rl, R2~ R3, and R4 are as hereinbefore defined and
X is a leaving group such as halogen.
The first step in a first aspect of the process of the
present invention comprises the formation of a reaction
medium comprisiny a dispersion of an aqueous solution of
the primary amine and an inert organic solvent which is
immiscible with water. As a second process step, the
acetone dicarboxylic acid ester and the substituted
carbonyl compound are combined with the reaction medium
dispersion, preferably in a substantially simultaneous
manner as hereinafter described in a second aspect of the
Eirst invention. The combined reaction medium and
reactants are maintained at a temperature below about 45C
for a period of time sufficient to form the desired
su~stituted pyrrole ester product.
The cyclizatiorl reaction which is the subject of the
present invention is carried out when one mole of tne
primary amine, one mole of the acetone dicarboxylate ester
and one mole of the substituted carbonyl compound, e.g., a
substituted aldehyde or ketone, are reacted to form the
substituted ~yrrole ester product. The primary amine used
in the process of this inverltiorl and in the cyclization
reaction can be of the yeneral formula RlN~12 wherein Rl is
a hydrocarhyl group containing up to about 20 carbon atoms
or more. Rl can be aryl, e.g., R11~112 can be aniline, or R
can b~ alkaryl, e.~., R~ 12 can be benzylamine.
Pre~erably, Rl is alkyl and more preferabry is a lower
al~yl grouE), e.g., an alkyl group containing from 1 to
: ~ ,
.
.
': ` ' - ~ . , :'' ' ' ': ':
- . . ~ . . ~, . . ..
. : ,~ , : : : -
-5~ ¢~
about 5 carbon atoms. Such preferred primary amines
include, for example, monomethyl amine, monoethyl amine,
mono--isopropyl arnine, mono-n-propyl amine, mono-isobutyl
amine, mono-n-butyl amine, mono-tert-butyl amine, mono-n~
amyl amine and the like. The preferred primary amine for
use in the process is mono-methyl amine.
~ dvantageously, the primary amine is employed in the
form of an agueous solution. In this manner, the amine
reactant serves to provide all or part of the requisite
aqueous fraction essentially present in the two-phase
aqueous/or~anic reaction medium as hereinafter more fully
described. Aqueous amine solutions can contain various
amounts of amine up to the solubility limit of the
particular amine being utilized. Advantageously, when
monomethyl amine is employed, it can be combined with the
or~anic solvent in the form of an aclueous amine solution
containing abou-t 30-40 percent by weight of the monomethyl
amine so as to form the t~o phase reaction medium
dispersion. Alternatively the primary amine reactant can
also be combined with the aqueous/organic reaction medium
dispersion in the form of an anhydrous c~as or liquid~ The
a~ueous amine solution is formed in the reaction rnedium by
virtue of the preferential solubility of the amine in the
aqueous portion of the two-phase system.
The acetone clicarboxylic ac d ester used as a reactant
in the process of the present invention has the cJeneral
formula:
1l
(~=0
C~12-C-0~3 ~.
o
wherein R2 and R~ are each either alkyl or alkaryl
contai~ cJ up to about 20 carbon atoms or more. Preferably
R2 and R3 are both lower alkyl, i.e., aL~y~ of 1 to 5
carbon atoms or benzyl. R2 and R3 can be the same or
-6~ ¢~
different ~roups but are preferably t~e same in a yiven
molecule. ~xamples of acetone dicarboxylie esters which
ean be employed herein inelude dimethyl aeetone
dicarboxylate, diethyl acetone diearboxylate, di-isopro~yl
acetone dicarboxylate, di-n-propyl acetone dicarboxylate,
di-isobutyl acetone diearboxylate, di-n-pentyl aeetone
dicarboxylate, dibenzyl acetone dicarboxylate, methyl ethyl
acetone dicarboxylate and the like. Preferred acetone
dicarboxylic acid esters are diethyl acetone dicarboxylate
and di-isopropyl acetone dicarboxylate~
Acetone diearboxylie acid esters for use in the
process herein ean be synthesized, for example, by reacting
citric acid or esters thereof with an anhydrous aeid sueh
as chloro-sulfonic acid or oleum followed, if necessary, by
the esterification of the acetone dicarboxylic acid groups.
Proeedures of this nature are described more fully in
Gerner, German Pat. No. 1,160,841, published July 15, 196~;
anc7 llamilton et al., U. S. Pat. 2,~87,50~; issued May 19,
1959, both of whieh are ineorporated herein by reference.
~eetone dicarboxylie acid e.sters can be employec3 in the
process herein in their isolated essentially pure liquid
form. Advantageously, however, the acetone dicarboxylate
ester eomponenc can be eombined with the reaction medium
dispersion dissolved in the same organic solvent, such as
dichloroethane, whieh serves as the orc3anie raetion of the
two-~hase a~ueo~ls/oryanie reaction mec~ium.
The substituted earborlyl compound which comprises the
third reactant in the pyrrole-forminc3 cyclization reaction
has the yeneral formula:
R,~--C-CH2X
wherein l~ )I or a hydroearbyl group containing up to
abo~lt 20 carbol- atoms or more, and X is a "leaving" group,
i.e., any (3roup which does not become a substituerlt of the
pyrrole eompound formed by the eyelization reaction~ R4
canV for example, include aryl or alkyl, substituted alkyl,
or eycloalkyl ~ontaininy from 1 to about 10 or more carbon
.
--7~
atoms, R4 is preferably lower al]cyl, say of 1 to 4 earbon
atoms and is most preferably methyl. The "leaving" group X
substituent ean inelude, for example, tosyl or halide,
e.g., iodide, ehloride, bromide or fluoride. Chloride and
bromide leaving groups substituents are preferred. 0~ the
substituted earbonyl compounds, the most preferred are
chloroacetone and ~romoacetone.
In accordance ~ith the first aspeet of the present
invention, the pyrrole-forming cyclization reaction is
conducted in a two-phase reaction medium dispersion
eomprising water and a li~uid orc3anic solvent which is
immisci~le with water. ~he water-immiscible orc3anic
solvent should, o~ course, be inert, i.e., essentially
nonreaetive with the pyrrole-formincJ reactants under
eonditions of the eyclization reaction. Pre~erably, the
water~immiscible organic solvent is heavier than ~ater so
that separation of the reactant-containing oryanic phase
may be facilitated in processes of commereial scale.
Useful solvents will frequently have a boiling point
between 35C and 175C to faeilitate removal of the solvent
by ~istillation.
Suitable organie solvents for use in the two~phase
reaetion medium herein inelude, for example, water~
immiseible aliphatie hydroearbons, haloyenated aliphatie
hydroearbons and aromatie hydrocarbons as well as any other
water-irnmiseible organie liquid composed primarily of
carbon along with a minor weight percentage of hydroc3en
with or without a minor amount of one or more elelnents sueh
as oxygen, nitroc3en, halogen and the like. Examples of
sueh suitable organie solvents inelude hexane, ehloroform,
earbon tetraehloride, diehloromethane, 1,2-dichloroethane;
1,1 diehloroethane, triehloroethylene, benzene,
ehlorobenzene, p-diehloroberlzene, toluene, xylene, and
diethylether. Preferred organie solvents inelude the
haloc3enated alkanes sueh as the diehloroethanes, diehloro-
methane and ehloroform.
: : : : .
-8~
Generally, the two~phase reaction medium may comprise,
on a reactant free basis, about 50 percent to 90 percent,
more preferably about 65 pereent to 75 percent, by weiyht
of the water-irnmiscible organic solvent and from about 10
pereent to 50 pereent, more preferabl~ about 25 percent to
35 percent, by wei~ht of water. Enou~h of the two-phase
reaction medium is employed to dissolve reactants as they
are initially added. Preferably, the wei~ht ratio of
reaction medium to the total amount of pyrrole-forming
reactants ran~3es from about 5:1 to 1:1, more preferably
from about 1~6:1 to 1.3:1.
When the pyrrole-forming cyclization reaction is
conducted in a dispersion of the two-phase reaction medium
as hereinbefore deseribed, yields of the desired pyrrole
esters can be enhaneed over those yields aehieved when only
a single-phase reaetion medium is ernployed. ~ithout being
bound by any partieular theory, it is helieved that the
eycli~ation reaetion oecurs in the orc3anic phase of the
reaction meclium~ The relatively lower solubility of the
primary amine in the orc3anie phase, vis-a-vis its
solubility in the aqueous phase, possibly serves to limit
the availability of the amine in the organie reaetiv~
phase. Coneentrations of the reaetants and intermediates
in the orc3allie phase are thus believed to be such that the
enhanced yields of the desired pyrrole ester procluct ean be
realized in the two-phase system. The presence of the
orc3anie solvent is also help~ul in controllin~ th~
eyelizatiol1 reaction exotherm and thereby permits faster
reaetant addition than eould be used without the solvent in
the reaetion medium.
In a second aspect of the present process for carrying
out the pyrrole-forming cyclization reaetion, the three
essential reaetants are preferably eornbined in such a way
that the aeetone diearboxylate and substituted earbonyl
eompound are introduced to the amine-co~t~ininc3 reaction
IllediUm itl a substantially simultaneous fashion.
"Substantially simultaneous" addition as used herein refers
....~...
- - ,. - - : .
. . , .. .: . . . . :
. :. . . ~ :
- .:, . -. -
, : .
_9~ 3~
to reactant combination in such a manner that the molar
ratio of substituted carbonyl compound to acetone
dicarboxylate combined with the reaction medium ranges frorn
about 1.6:1 to 1~4:1 during the time period in which those
reactants are being cornbined with the reaction mixture.
Substantially simultaneous reactant addition, of course,
includes the situation wherein the acetone dicarboxylate
and substituted carbonyl compound are continuously ed to
the reaction vessel using feed rates such tha~ -the
requisite molar ratio o~ these two reactants is maintained
during reactant addition. Substantially simultaneous
reactant addition can also include the situation wherein
the acetone dicarboxylate and substituted carbonyl
reactants are added in pairs of discrete increments or
"shots," provided the molar ratio of the total amounts of
each reactant added c10es not fall outside the 1.6:1 to
104:1 range. At least some and preferably all o~ the
primary a~ine reactant i5 present in the reaction medium
before a substantially simultaneous addition of the other
two reactants is begun.
Upon addition of the acetone diearboxylate to the
reaction medium containing primary amine, a white
preeipitate intermediate cornpound is generally formed.
Such an intermediate eompound is possibly an amine salt of
the acetone dicarboxylate ester. Further reaetion of this
intermediate compound with the substituted carbonyl
compound such as chloroacetone eventually produees the
desired substituted pyrrole diester. Since the
interme~liate eompound appears to deeompose with time, the
substantially simultaneous addition oE aeetone
dicarboxylate and substituted carbonyl compound is believed
to enhance pyrrole diester production by promoting reaetion
of the intermediate hefore it deeomposes. The simultaneous
reaetion addition ~eature of the present invention is thus
espeeially effeetive in maintaining an aeeeptably high
product yield in large bateh, hicJh throucJhput, commercial
seale processes wherein control of the cyclization reaction
, ,, : , . . .
', '
.
exotherm necessitates extended reactant addition procedures
and lonc3er reaction times.
In a preferred embodiment of the present invention
both the process improvement involving the two-phase
aqueous/or~anic reaction medium and the improvernent
involvincJ the substantially simultaneous addition o~
reactants as hereinbeEore described are employed in the
same process. Processes wherein both of these features are
utilized are especially advantageous. LO ensure adequate
yields of ~he desired substituted pyrrole diester product,
the primary amine and substituted carbonyl compound can be
employed in stoichiometric excess vis-a-vis the acetone
dicarboxylate. Generally the molar ratio of primary amine
to acetone dicarboxylate may be at least about 3.5:1,
preferably at least about 4.3:1. Generally, the molar
ratio of substituted carbonyl compound to acetone
dicarboxylate can be at least about 1.2:1, preferably at
least about 1.5:1. It is, of course, desirable to minimi~e
the amounts of excess reactants employed in the process for
economic reasons. Advantageously, therefore, the molar
ratio o~ amine to acetone dicarboxylate ranges from about
3.5:1 to 10:1, and the molar ratio of substituted carbonyl
compound to acetone dicarboxylate ranyes from about 1.2:1
to 5:1. It has been surprisingly discovered that by
emplo~ing a two-phase reaction medium and/or by utilizing
substantially simultaneous reaction addition, hi~her
reactant throughput rates and smaller amounts of excess
reactants can be employed to obtain a yiven pyrrole ester
~ield than when these novel process features are not
employed .
The reaction medium employed in the ~resent invention
is ~enerally agitated and cooled throughout the reaction.
The preEerred two-phase reaction medium is maintained as a
dispersion at the desired reaction temperature throughout
the reaction by a~3itating and cooling th~ ~eaction medium~
~gitation should be sufficient to form a uniform dispersion
containinc3 the aqueous and organic liquid phases and
- . -, : . : :, : , . - : :,: , . :
- . :~,. . - . : . : : : - :
- . :, . ,: :'~ ' ' :: '
3~
whatever solid intermediate precipitate may be formed
during the reaction. I'he reaction medium may also be
cooled throughout most o~ the reaction such that reaction
medium temperature remains below about 45C, preferably
below about 40C, e.g., 20 to 40C. Reaction medium
temperatures in excess of about 45C tend to lower yields
of the desired pyrrole diester product and/or to promote
forrnation of undesirably excessive amounts of cyclization
reaction by-products. Both agitation and reaction medium
temperature control can be maintained until the pyrrole
ester-forming cyclization reaction is complete to the
extent desired. Generally reaction time of from about 1 to
8 hours after reactant addition is complete will be
satisfactory.
~ fter the reaction has been completed, various
procedures to recover, purify and/or further treat the
desired substituted pyrrole ester product can be
undertaken. After the pyrrole ester is ~ormed ~ut before
agitation is discontinued, for example, the reaction medium
can be acidified with concentrated IICl in order to
eliminate organic amine excess reactants and/or by-products
from the organic phase. ~gitation can then be
discontinued, and, when utilized, the two-phase reaction
medium can be allowed to separate into 1) an aqueous layer
containing water, various excess reactants and reaction by-
products and a small amount of the desired substituted
pyrrole diester and 2) an organic layer containing the
water-immiscible organic solvent and most of the pyrrole
diester product. The aqueous and organic layers can be
separated by conventional means, and, if desired, the
aqueous layer can be extracted with additional organic
solvent to remove the small amount of pyrrole ester product
remaininy in the aclueous phase. AEter this extraction, the
pyrrole ester-containing extract can be combined with the
organic phase originally separated. ~
If an essentially pure pyrrole diester product is
desired, the organic solvent can be stripped from the
, , . . . : -
~9
-12-
pyrrole ester-containin~ or~anic phase by conventional
distillation procedures. The pyrrole diester product can
also be hydrolyzed to the pyrrole diacid if desired without
isolating the diester product. This can be accomplished by
adding sodium hydroxide to the or~anic phase to form the
pyrrole disodium salt in an aqueous system, followed by
hydrolysis to form the pyrrole diacid by the addition of
strong acid.
The pyrrole diester synthesis process of the present
invention is illustrated by the following examples which
are not limiting of the invention herein.
EXAMPLE I
144 ml. of a 40 percent ~w/w) aqueous monomethylamine
solution and 140 ml. of dichloroethane are placed in a one-
liter round-bottom flask fitted with a mechanical stirrer
and a thermometer. While this mixture is agitated to
maintain a uniform dispersion and cooled to maintain a
reaction temperature between 25-35C, 77.6 gm. (0.384
mole; 76 ml.) of diethyl acetone dicarboxylate and 48 ml.
(0~576 mole) of chloroacetone are added in a substantially
sirnultaneous manner in pairs of "shots"~ A slight initial
molar excess of acetone dicarboxylate over the
chloroacetone is provided in the flask by adding the first
acetone dicarboxylate shot immediately before the first
chloroacetone shot. Acetone dicarboxylate and
chloroacetone are added in increments over a 95-minute
period in accordance with the following schedule:
Time Amount of ~cetone Amount of Chloro-
dicarbo~y~late added acetone added
about 1 min. 10 ml. 5 ml.
5 min. 16 ml. 10 ml.
24 lS
32 20
~0 25
58 35
~5 68 41
76 4~
: :
- : - . .. .. . .
' : ,, : . .
. . ' . '.
.' ' ',
.
-
After the reactant acldition is complete, the mixture
is stirred at ambient temperature for an hour, cooled in an
ice bath and acidified with concentrated IICl (about 60 ml.)
under 25C. After the acidification, the mixture is
stirred for about 20 minutes and checked with pH paper to
make sure it is acidic before being transferred to a
separatory funnel. The separation gives 207 ml. (245.1
gm.) of organic layer (bottom layer) and 234 ml. (249.5
~m.) of aqueous layer. (Extraction of this aqueous layer
with 25 ml. of dichloroethane produces less than 1.3 gm. of
the diester product.) The organic layer (207 ml.; 245.1
gm.) is washed with 60 ml. of city water~ and after a
separation, 203 ml. (139.2 gm.) of organic solution and 62
ml. (61 gm.) of aqueous wash are obtained.
~ fter the wash~ the organic solution (203 ml.; 239.2
~m.) is placed in a 500 ml. flask for distillation of
dicl-lloroethane under atmospheric pressure (vapor temp. 76-
83C; pot temp. 92-130C) and under vacuum at the end of
the distillation. Dichloroethane obtained (1~5 rnl~, 151.3
~m.; 89.3~ recovery) can be reused in the pyrrole ester
reaction synthesis reaction without further ~urification.
~ fter the distillation, 50 ml. of isopropanol (BP
82.4C) at 60-75C is added to the residue followed by
addition of 170 ml. of city water at 60 75C. On
completion of the addition, the stirrinc~ is continued at
water bath temperature for an hour ~e~ore filtration. The
filtered ca~e is washed thorouyhly with city water to
remove colored materials and sucked falrly dry on the
furlnel to ~3ive 8G.4 ym. of wet ethyl 3-carbethoxy-1,4-
dimethylpyrrole-2-acetate.
~ ir dryin~ of the wet cake at room temperature ~ives
~5.8 ~m. of dry diester product, representincJ a ~7.7
percellt yield.
When in the ~xample I procedure, the dlchloroethane
solvent is replaced with an equivalent arnount of dichloro-
Methane or chloroform, substantially similar production of
.
-14~
the ethyl 3-carbethoxy-1,4-dimethylpyrrole-2-acetate
product is realized.
EXAMPLE II
The Example I procedure is repeated on a one-liter
bench scale basis. 432 ml. of a 40 percent (w/w) aqueous
monomethylamine solution and 420 ml. of dichloromethane are
placed in a two-liter round-bottom flask fitted with a
mechanical stirrer and thermometer. While this mixture is
agitated to maintain a uniform dispersion and cooled to
maintain a temperature between 25C-35C, 232.8 gm. of
diethyl acetone dicarboxylate (1.15 mole; 228 ml.) and 144
ml. of chloroacetone t159.6 gm.; 1.73 mole) are added in a
substantially simultaneous manner such that the amount of
chloroacetone is maintained at a slight molar excess over
the acetone dicarboxylate added to the flask.
Ater the addition of the reactants, the mixture is
stirred at 25-35C for an hour, cooled in an ice bath ancl
acidified with concentrated llCl ~about 180 ml.) at 125C.
After the acidification, the mixture is stirred ~or about
30 minutes and checked with pEI paper to make sure it is
acidic before being transferred to a separatory furlnel.
The separation gives about 620 mlO of organic layer (bottom
layer) and about 700 ml. of aqueous layer. The aqueous
layer is extracted with 60 mlO of dichloroethane. The
dichloroethane solutions are combined (total volume is
about 685 ml.) and washed once with 180 ml. of city water.
The product. is ethyl 3-earhethoxy-1,4-dimethylpyrrole-2-
acetate which is in dichloroethane solution. An aliquot of
the dichloroethane product solution is withdrawn ~or assay,
anc3 a yield oE 63 percent is ound.
E MPLE III
The production of ethyl 3-carbethoxy-1,4-
dirnethylpyrrole-2-acetate is carried out in pilot plant
equipment to demonstrate the feasibility oE the instant
process for commercial scale production~ 482 kg. of
dichloroethane are charged to a reactor fitted with an
ayitator and a cooling system. 359 kg. of a 40 percent
, .
, .... , ' ' .' . ' '' . .
-15- ~
(w/w) aqueous monomethylamine solution are then char~ed to
the reaction vessel. While the agitator is running 27 k~.
of crude diethyl acetone dicar~oxylate are charyed to the
reaction mixture, followed immediately by a char~e of 18.5
ky. of chloroacetone. Temperature of the reaction mixture
is maintained below 35C. Seven more identical charges of
diethyl acetone dicarboxylate and chloro-~cetone are then
macle in succession, and the reaction is continued for an
additional one hour.
The reaction mixture is transferred to another similar
reaction vessel and cooled to 20C. 196 kg. of 37 percent
IICl are then added while the reaction mixture is ayitated,
and the temperature is maintained below 2~C. Tlle ayitator
is then turned off, and the reaction rnixture is allowed to
separate for one-half hour into an upper aqueous phase and
a lower ortJanic pllase. Tlle lower organic phase is
transferred to another reaction vessel, and the remaining
aqutous phase is extracted with an additional 69 l;y. of
dichloroethane. Again, the or~anic extract layer is
separated from tlle aqueous phase and is added to the
or~Jallic phase frorn the first separation.
44 t3allons of water are added to the combined organic
phase fraction, and the mixture is agitated for one-half
hour and then is allowed to separate for one~half hour.
The lower organic ~hase is then separated and transferred
to another reactiorl vessel. The orc~anic phase thus
separated is at neutral p~l and is sampled for pyrrole ester
assay. A pyrrole ester yield of about 54 percent based on
the initial char~e of diethyl acetone dicar~oxylate is
obtained USillCJ this procedure-
_ A~IL'LL IV
~ c3iisopropyl pyrrole diester is prepared inaccordance with the following ~rocedures. A three-neck 500
ml. rouncl-l)ottoril ~las}; is ecfulpped with coolin~J apparatus
and a mechallical stirrerl 144 ml. of 40--percent ~w/w)
atlueous monomethylamine and 140 ml. of c3ichloroetllane are
cllarged to tlle flask and agitated. 95.9 gm. (0.38 mole) of
,
;
:
-16-
92 percent pure cru~e diisopropyl acetone dicarboxylate are
char~ed to one addition funnel, and 48 ml. (0.6 mole) of
chloroacetone are added to a second addition funnel. While
the reaction mixture in the flask is being a~itated and
main~ained in temperature between 25-35C, the acetone
dicarboxylate and chloroacetone are simultaneously added to
the Elask over a 25-minute period, maintaining a slight
molar excess of the chloroacetone during the addition.
The reaction mixture is subsequently stirred for one
., .
hour at 30-35C and is then cooled to about 10C and
acidified with ~5 ml. of concentrated ~IC1. This mixture is
stirred for an additional 30 minutes and is transferred to
a separatory funnel. The mixture is allowed to separate
into an upper aqueous layer and a lower organic layer. The
aqueous layer is separated and extracted with an additional
25 ml- of dichloroethane which is separated and combined
with the original or~anic layer. The combined organic
fractions are washed with 60 ml. of water. The
dichloroethane solvent is then stripped froln tile organic
~raction, and tlle remaining product is weighed. The
product obtained is isopropyl 3-carbisopropoxy-1,4-
dimethylpyrrole-2-acetate, and a crude product yield of
about 85 percent (mole) based on the original diisopropyl
acetone dicarboxylate is realized.
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