Note: Descriptions are shown in the official language in which they were submitted.
~N-360/361
--1--
PRI~PARATION O~` 5- ( ~RYLCYANO~IYDROXYMEI'~IYL. ) -l-LOW~RALKYLPYR-
ROLI`.-2-ACEl`IC ACID D~RIVATIVES AND 5-AROYL-l-LOWERALKYL=
rrl c A I D__RIVATIVES
This invention relates to novel 5-(arylcyanohydroxy-
methyl)-l-loweralkylpyrrole-2-acetic acid derivatives
(III), a process for their preparation, and a process for
their conversion to known 5-aroyl-1-loweralkyl pyrrole-
2-acetic acids and derivatives thereof. They are prepared
by the reaction of aroylcyanides (I) with l-loweralkyl-
pyrrole-2-acetic acid derivatives (II). The reaction is
carried out in an inert, aprotic solvent in the presence
of a protic acid catalyst. Products of type III may be
utilized by their conversion by mild treatment with alkali
metal hydroxides or by heating to 5-aroyl-1-loweralkylpyr-
role-2-acetic acid derivatives (IV). Materials of formula
IV are known to be useful in the manufacture of 5-aroyl-
l-loweralkylpyrrole-2-acetic acids (V) and their alkali
metal salts which are useful as anti-inflammatory agents
(Carson, U.S. Patent No. 3,752,826). Alternatively,
products of type III may be directly converted to products
of type V by more strenuous treatment with alkali metal
hydroxide solutions. Also, it is not necessary to isolate
III to prepare IV or V, and such processes are also
included in the present invention.
Alternatively, 5-Aroyl-l-loweralkylpyrrole-2-acetic acid
derivatives (IV) are prepared by the following new process
desiynated as step e): the aroylcyanide (I) is caused to
react with the 1-alkylpyrrole-2-acetic acid derivative
(II) at temperatures above 100C to give, after the loss
of the elements of hydrogen cyanide, a 5-aroyl-1-lower-
alkylpyrrole-2-acetic acid derivative (IV).
_ 35 The reactions are as set forth in the following schematic
-~ diagram:
-
1 15~8S8
R
ArCOCN ~ ~
/ N H2 Z
I / II
/ step e) step a)
~/ R
3 10 / ~OH ~
/Ar-C N CH2 Z
/ CN R
~ ~ tep c)
15 1 ~:tep b) ~
_~ R~ Rl
ArCO ~ N ~ CH2 z step d)~ ArCO R CHaCO2M (H)
IV V
wherein:
Ar represents phenyl or phenyl substituted by a
member selected from the group consisting of
loweralkyl, halo; nitro, methylthio, trifluoromethyl,
and loweralkoxy;
R represents loweralkyl;
Rl represents hydrogen or loweralkyl;
Z represents -CN or -COO(loweralkyl);
1 155858
HX represcnts any moderately strong to strong acid
having a pK< about 2, for example, C13CC02H,
CF3C02H, H02CC02l1, HCl, HC104,
CH3S03H, _-tolyl S03H; and
M represents alkali metal, for example Na, K.
As used herein, "loweralkyl" and "loweralkoxy" may be
straight or branch chained saturated hydrocarbons having
from one to six carbon atoms, such as, for example,
methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and
the like alkyls, and respectively, the corresponding
alkoxys, such as methoxy, ethoxy, propoxy, isopropoxy,
etc.
_vantages
Several disadvantages are inherent in known processes for
the production of products of type IV. The Friedel-Crafts
aroylation of 1-loweralkylpyrrole-2-acetic acid deriva-
tives (II) produces a mixture of 4- and 5-aroyl-1-
loweralkylpyrrole-2-acetic acid derivatives. [J.R. Carson
and S. Wong, J. Med. _hem., 14, 647 (1971)]. Uncatalyzed
aroylation of l-loweralkylpyrrole-2-acetic acid
derivatives (Carson, U.S.~Patent No. 3,998,844) is carried
out at high temperatures and produces hydrogen chloride
which can induce polymerization of pyrroles [Advances in
Heterocyclic Chemistry, ed. Katritsky, Vol. 2, p. 287,
Academic Press, New York (1963)]. The present invention
produces no isomeric by-products. Steps a) through d) are
operated at moderate temperatures and only catalytic
quantities of acid are used. The process of step e) of
the present invention does not produce a strong acid, and
is preferably carried out without solvent. Thus, a high
ratio of product to reactor volume is obtained.
--` 1 155858
~tility
The final products ~V) made by the processes of the
present invention are known compounds disclosed in
U.S. Patent No. 3,752,826 and other literature which are
useful as anti-inflammatory agents and analgesics, and
include tolmetin sodium, i.e., sodium l-methyl-5-p-
toluoylpyrrole-2-acetate dihydrate and zomepirac sodium,
i.e., sodium 5-(4-chlorobenzoyl)-1,4-dimethyl-lH-pyrrole-
j 10 2-acetate dihydrate among the better known members of this
class of compounds.
",
Detailed_Description
The protic acid catalyzed reactioh of an aroylcyanide (I)
with a l-loweralkylpyrrole-2-acetic acid derivative (II)
to give a 5-(arylcyanohydroxymethyl)-1-loweralkylpyrrole-2
derivative (III) is carried out as follows.
Approximately equivalent quantities of reactants I and II
are employed. The reaction is carried in an inert aprotic
solvent such as diethylether, tetrahydrofuran, benzene,
toluene, acetonitrile, ethyl acetate, methylene chloride,
chloroform, or acetone. The reaction is carried out at a
relatively low temperature of about 0-40C., preferably
25C. An acid with a pK below about 2 is employed for
example: trichloroacetic acid, perchloric acid,
methanesulfonic acid, oxalic acid, p-toluenesulfonic acid.
The acid catalyst is used in about 1-5 molar percent
quantities. The 5-(arylcyanohydroxymethyl)-1-loweralkyl-
pyrrole-2-acetic acid derivative III may be isolated
directly from the reaction mixture, for example by
filtration. Alternatively, they may be employed without
purification as intermediate to IV and V.
i
1 155858
The conversion of a substance of type III to the
correspondirlg derivative, IV, can be carried by heating at
a temperature in excess of about 100. This conversion
may be carried in the presence of an inert solvent, for
example, xylene. Alternatively, the conversion is carried
out by mild treatment with a base, for example, by
dissolving III in an inert, aprotic solvent and shaking it
with a base such as NaOH or KOH.
The conversion of III to V is carried out by hydrolysis
with an alkali metal hydroxide, preferably sodium
hydroxide~ A precipitate of the V in the form of its
alkali metal salt is collected by filtration.
The process of step e) of the present invention is carried
out by heating an aroylcyanide (I) with a l-loweralkyl-
pyrrole-2-acetic derivative (II) at a temperature in the
100-250 range, preferably at L20-180. It is
preferably carried out in the absence of any solvent, but,
if desired, it can be carried out in the presence of a
high boiling aprotic inert solvent such as xylene,
p-cymeme or _-dichlorobenzene. The reaction preferably is
carried out while passing a stream of inert ~as, such as
nitrogen, through the mixture. The product IV may be
purified or used without jfurther purification in
conversion to V.
Preparation of Starting Materials
The aroylcyanides used as starting materials for the
prcsent invention are known compounds or classes of
cornpounds. Thus, those aroylcyanides (I) wherein Ar is
phenyl or phenyl substituted by loweralkyl, halo, and
loweralkoxy are disclosed in Koenig & Weber, Tet. Let.,
2275 (1974). While that article only teaches individual
compounds other members of the class may be made in the
~ 1 155858
same manner tllere described. Those aroylcyanide (I)
compounds wherein Ar is nitrophenyl are disclosed in
Normant & Piechucki, Bull. Soc. Chem. France, 2402 (1972).
The aroylcyanide compounds wherein Ar represent
trifluoromethylphenyl and methylthiophenyl are not known,
but can be made by the procedure taught by Normant &
Piechucki above, i.e., by reacting p-methylthiobenzoyl
chloride or m-trifluoromethylbenzoyl chloride, with copper
cyanide in the presence of methylcyanide, the desired
aroylcyanide products will be obtained.
The loweralkylpyrrole-2-acetic acid derivatives~(II)
wherein Z represents CO21Oweralkyl are known
compounds, as disclosed in U.S. Patent No. 3,752,826 in
.. ;.
Examples CXI and CXXI. Those compounds in (II), wherein Z
represents CN, are disclosed in U.S. Patent No.~3,957,818.
The following examples are intended to illustrate, but not
to limit the scope of the present invention. All
temperatures therein are in degrees Celsius (C.).
Example I
Methyl -(cyanohydroxyphenylmethyl)-l-methylpyrrole-
2-acetate: A solution of~6.7 9 t0.05 mole) of
benzoylcyanide, 7.6 g (0.05 mole) of methyl l-methyl-
pyrrole-2-acetate and 0.2 g of trichloroacetic acid in 20
ml. of ether was stirred for four days at 25C. under
argon. The solution was cooled to 0 and the solid methyl
5-(cyanohydroxyphenylmethyl~-1-methylpyrrole-2-acetate was
collected by filtration; mp 148-153, yield, 4.0 g (28 per
cent).
`` ~ 1 155858
--7--
_ample II(A)
Methyl 5-[cyanohydroxy(4-methylphenyl)methyl]-1-methyl-
~ . A solution of 1.45 g (0.01 mole) of
4-methylbenzoylcyanide, 1.5 g (0.01 mole) of methyl
l-methylpyrrole-2-acetate and 40 mg (0.25 mmoles) of
trichloroacetic acid in 4 ml of ether was stirred at 25
under nitrogen for 21 days. The precipitated solid was
collected by filtration and washed with cold ether, then
hexane. The combined iiltrates were evaporated in vacuo.
A second crop of crystals was taken from hexane. After
recrystallization from toluene.hexane was obtained, 0.46 g
(16 per cent yield) of methyl 5-[cyanohydroxy(4-methyl-
phenyl)-methyl]-l-methylpyrrole-2acetate mp 117-118.
Hl NMR CDC13 2.35 (s, 3H); 3.35 (s,3H); 3.55 (s,2H), 3.65
(s,3H); 5.90 (d,lH); 6.05 (d,lH)j*7.15 (d,2H); 7.35 (d,2H).
MS m/e 281, 280, 266, 212 IRnUjol 3425, 1700 cm~l.
Example II(B)
Following the procedure of Example II(A), but replacing
the 4-methylbenzoylcyanide with each of the following:
3-propylbenzoylcyanide;
4-methoxybenzoylcyanide;
4-chlorobenzoylcyanide;
4-nitrobenzoylcyanide;
4-methylthiobenzoylcyanide;
3-trifluoromethylbenzoylcyanide,
there can be obtained the following, respectively.
methyl 5-[cyanohydroxy(3-propylphenyl)methyl]-1-
methylpyrrole-2-acetate;
methyl 5-[cyanohydroxy(4-methoxyphenyl)methyl]-1-
methylpyrrole-2-acetate;
methyl 5-[(4-chlorophenyl)cyanohydroxymethyl]-1-
methylpyrrole-2-acetatej
methyl 5-[cyanohydroxy(4-nitrophenyl)methyll-1-
methylpyrrole-2-acetate;
,,
*Trademark
1155858
methyl 5~~cyanohydroxy(4-methylthiophenyl)methyl]-1-
methylpyrrole-2-acetate.
methyl 5-[cyanohydroxy(3-trifluoromethylphenyl)
methyl]-l-methylpyrrole-2-acetate.
Example III
_
Methyl l-methyl-5-(cyanohydroxyphenylmethyl)pyrrole-2-
acetate: Benzoyl cyanide, 0.67 g (.005 mole) and methyl
1-methylpyrrole-2-acetate, 0.76 g (.005 mole) were stirred
together in ether (2 ml) containing oxalic acid (.04 g).
The reaction was run in the dark at room temperature.
After six days, the reaction mixture was placed in the
freezer overnight, filtered, and w~ashed with cold ether to
yield 0.17 g (12 per cent) of methyl 1-methyl-5-(cyanohy-
droxyphenylmethyl)pyrrole-2-acetate, mp 137-148. The
solid state IR spectrum was identical to authentic
material.
Example IV(A)
_
l-Methyl-5-(4-methylbenzoyl)pyrrole-2-acetonitrile: A
solution of 0.16 g (1.1 mmole) of 4-methylbenzoylcyanide
0.13 g (1.1 mmole) of 1-methylpyrrole-2-acetonitrile and 4
mg of trichloroacetic acid in 0.4 ml of ether was allowed
to stand in the dark under nitrogen at 25. After three
days, a small amount of hydrogen chloride gas was admitted
to the vessel. The mixture was allowed to stand for 14
days. It was diluted with methylene chloride and the
solution washed with sodium hydroxide. The solution was
dried (MgSO4) and the solvent evaporated 1n vacuo. The
residue was chromatographed on 37 ml of silica gel. The
fractions eluted with a mixture of l,l,l-trichloro-
ethane:hexane, 1:1 were discarded. The fractions eluted
Witil l,l,l-trichloroethaneihexane 3:1 were collected. The
solvent was evaporated to give 0.80 g of dark solid
`` 1 155858
l-methyl-5-(4-metllylbe~llzoyl~pyrrole-2-acetonitrilc (30 per
cent yield). It was rccrystallized from l,l,l-trichloro-
ethaneihexane to give brown solid, mp 103-104,
undepressed by admixture with authentic material.
Example IV(B)
.... _
Following the procedure of Example IV(A), but replacing
the 4-methylbenzoylcyanide with each of the following.
3-propylbenzoylcyanide;
4-methoxybenzoylcyanide;
4-chlorobenzoylcyanide;
4-nitrobenzoylcyanide;
4-methylthiobenzoylcyanide;
3-trifluoromethylbenzoylcyanide,
there can be obtained the following, respectively.
l-methyl-5-(3-propylbenzoyl?pyrrole-2-acetonitrile;
l-methyl-5-(4-methoxybenzoyl)pyrrole-2-acetonitrile;
l-methyl-5-(4-chlorobenzoyl)pyrrole-2-acetonitrile;
1-methyl-5-(4-nitrobenzoyl)pyrrole-2-acetonitrile;
l-methyl-5-(4-methylthiobenzoyl)pyrrole-2-
acetonitrile;
l-methyl-5-(3-trifluoromethylbenzoyl)pyrrole-2-
acetonitrile.
Example V
Methyl l-methyl-5-(4-methylbenzoyl pyrrole-2-acetate.
Methyl 5-[cyanohydroxy(4-methylphenyl)methyl]-1-
metllylpyrrole-2-acetate (0.161 g, 0.540 mmoles) was
dissolved in 30 ml of ether and shaken with 10 per cent
NaOH, washed with brine and dried over MgSO4.
Evaporation of the ether yielded 0.130 g (86.1 per cent)
of methyl l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate,
mp 118-120. rrhe IR was identical to an authentic sample
of methyl l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate.
-
1155858
--10--
Example VI
5-Benzoyl-l-me~ lpyrrole-2-ace_ic a id: A suspension of
1~0 g of methyl 5-(cyanohydroxyphenylmethyl)-1-
methylpyrrole-2-acetate in 20 ml of 5 per cent sodium
hydroxide solution was heated under reflux for 30 minutes.
The solution was acidified with 3N hydrochloric acid
solution. The solid was collected and recrystallized from
acetonitrile to give 0.61 ~ (77 per cent yield) of white
crystalline 5-benzoyl-1-methylpyrrole-2-acetic acid, mp
145-6, undepressed by admixture with authentic product.
Example VII
1-Methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid: Methyl
5-[cyanohydroxy(4-methylphenyl)methyl]-1-methylpyrrole-
2-acetate, 55 mg (0.185 mmole) was heated on a steam bath
in 15 per cent NaOH (1.5 ml) for 3.5 hours. The reaction
was cooled in ice for one hour then filtered. The solid
was dissolved in distilled water, hot filtered, cooled, 3N
HCl was added to precipitate 0.48 g (100 per cent) of
l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid, mp
153-158~, undepressed by admixture with authentic
material.
Ex _ple VIII(A)
Sodium l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate
dih~drate. A mixture of 1.45 g (0.01 mole) of
4-methylbenzoylcyanide, 1.53 g (0.01 mole) of methyl
l-methylpyrrole-2-acetate, 0.04 g (0.25 mmole) of
trichloroacetic acid, and 0.5 ml of ether was stirred
under nitrogen for 22.5 hours at 25.
1 1S5858
A 17 ml portion of :L0 per cent sodium hydroxidc solution
was added and the mixture heated under reflux ~or three
hours. The solution was cooled and the precipitated solid
was collected by filtration and washed with cold 95 per
S cent ethanol. The solid was recrystallized from 95 per
cent ethanol to give 1.03 g (37 per cent yield) of sodium
l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate, mp
299-300. The solid state IR was identical to authentic
material.
Example VIII(B)
Following the procedure of Example VIII(A), but replacing
the 4-methylbenzoylcyanide with each of the following
aroylcyanides.
3-propylbenzoylcyanidej
4-methoxybenzoylcyanide;
4-bromobenzoylcyanide;
4-nitrobenzoylcyanide;
4-methylthiobenzoylcyanide;
3-trifluoromethylbenzoylcyanide,
there can be obtained the following, respectively:
sodium l-methyl-5-(3-propylbenzoyl)pyrrole-2-acetate
dihydrate;
sodium 1-methyl-5-~4-methoxybenzoyl)pyrrole-2-
acetate dihydrate;
sodium l-methyl-5-(4-bromobenzoyl)pyrrole-2-acetate
dihydrate;
sodium l-methyl-5-(4-nitrobenzoyl)pyrrole-2-acetate
dihydrate;
sodium l-methyl-5-(4-methylthiobenzoyl)pyrrole-2-
acetate dihydrate;
sodium l-methyl-5-(3-trifluoromethylbenzoyl)pyrrole-
2-acetate dihydrate.
~155858
Example IX
Methyl 5-benzoyl-1-methylpyrrole-2-acetate: A 0 25 g
__
sample of methyl 5-~cyanohydroxyphenylmethyl)-l-
methylpyrrole-2-acetate in 2 ml of xylene was heated at
140C. for 2 hours. The solution was cooled and
methylcyclohexane added. There was obtained 0.16 g (70
per cent yield) of a gray solid. It was recrystallized to
give white solid methyl 5-benzoyl-1-methylpyrrole-
2-acetate, mp 96-98C., undepressed by admixture with
authentic material.
Example X
. _
Ethyl 5-(4-chlorobenzoylj-1,4-dimethylpyr ole-2-acetate.
A solution of 1.65 g (0.01 mole) of p-chlorobenzoyl-
cyanide, 1.81 g (0.01 mole) of ethyl 1,4-dimethyl-
pyrrole-2-acetate and 0.08 g of anhydrous oxalia acid in 4
ml of ether was stored in the dark under nitrogen for four
days. The solution was diluted with CH2C12. The
organic solution was washed with 10 per cent NaQH solu-
tion, dried ~MgSO4), and the solvent evaporated~ -
in vacuo. The residue was recrystallized from l,l,l-tri-
chloroethane to give 1.04 g of ethyl 5-(4-chlorobenzoyl)-
1,4-dimethylpyrrole-2-ace~ate, mp 105-108C., undepressed
by admixture with authentic material.
Example XI(A)
Methyl l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate; A
_
mixture of 5.0 g (0.034 mole) of 4-methylbenzoylcyanide
and 0.8 g (0.005 mole) of methyl 1-methyl-pyrrole-2-
acetate was added over 4 hours from a heated addition
funnel to a sample of 3.8 g (0.025 mole) of methyl
1-methylpyrrole-2-acetate at 180 through which nitrogen
was bubbled. The mixture was heated for six more hours
after the addition was complete. l`he reaction was cooled
1 155858
-13-
and dissolved in methylene chloride-toluene. The organic
solution was washed with 10 per cent sodium hydroxide
solution and saturated brine and dried (MgSO4). The
solvent was evaporated in vacuo and the residue recrys-
tallized twice from methanol to give 5.41 g (69 per cent
yield) of white crystalline methyl l-methyl-5-(4-methyl-
benzoyl)-pyrrole-2-acetate, mp 118-120C. The solid
state IR spectrum was identical to authentic material.
_xample XI(B)
Following the procedure of Example I(A), but replacing the
4-methylbenzoylcyanide with each of the following:
3-propylbenzoylcyanide;
4-methoxybenzoylcyanide;
4-nitrobenzoylcyanide;
4-methylthiobenzoylcyanide;
3-trifluoromethylbenzoylcyanide
there can be obtained the following, respectively:
methyl 1-methyl-5-(3-propylbenzoyl)pyrrole-2-acetate;
methyl l-methyl-5-(4-methoxybenzoyl)pyrrole-2-acetate;
methyl l-methyl-5-(4-nitrobenzoyl)pyrrole-2-acetate;
methyl l-methyl-5-(4-methylthiobenzoyl)pyrrole-2-
acetate;
methyl 1-methyl-5-(31trifluoromethylbenzoyl)pyrrole-2
acetate.
Example XII(A)
Ethyl 5-(4-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate:
A 1.50 g (0.0090 mole) sample of 4-chlorobenzoylcyanide
was added over a one-hour period to 1.50 g (0.00~2 mole)
of ethyl 1,4-dilnethylpyrrole-2-acetate at 120-130
through which nitrogen was slowly bubbled. The mixture
was heated for 27 hours. The resulting oil was
chromatographed on silica gel with successive elution with
1 1~$858
-14-
hexane and l,l l-trichloroethane. The solvent was
evaporated in vacuo from com~,ound-bearing fractions. l'he
residue was chromatographed through a Waters Associates,
Prep LC, System 500 with ~lution with a 2:3 mixture of
hexane:l,l,l-trichloroethane. Evaporation of solvent from
the second compound-bearing fraction afforded solid which
was recrystallized from methanol to give 0.74 g (28 per
cent yield) of ethyl 5-(4-chlorobenzoyl)-1,4-dimethyl-
pyrrole-2-acetate, mp 108-109, undepressed by admixture
with authentic material.
Example XII(B)
Following the procedure of Example II(A), but replacing
the ethyl 1,4-dimethylpyrrole-2-acetate with each of the
following:
ethyl l,4-diethylpyrrole-2-acetate;
methyl l-methyl-4-ethylpyrrole-2-acetate,
there can be obtained the following, respectively:
ethyl
5-(4-chlorobenzoyl)-1,4-diethylpyrrole-2-acetate;
methyl
5-(4-chlorobenzoyl)-1-methyl-4-ethylpyrrole-2-
acetate.
Example XIII(A)
Sodium l-methyl-5-(4-methylbenzoyl)pyrrole-2-acetate
dihydrate: A mixture of 7.0 g (0.042 mole) or ethyl
1-methylpyrrole-2-acetate and 7.25 g (0.05 mole) of
4-methylbenzoylcyanide was heated at 180 for 24 hours.
The mixture was dissolved in ether. The solution was
washed with dilute sodium hydroxide solution and saturated
brine. The solution was dried (MgSO4). The solvent
was evaporated in vacuo.
1155858
-15-
The residue was heated under reElux with 100 ml of 25 per
cent sodium hydroxide ~or one hour. The mixture was
cooled and the precipitated solid was collected by
filtration and washed with cold ethanol. The solid was
recrystall zed from ethanol with removal of insoluble
material by hot filtration. Two crops of crystals were
taken totalling 8.23 g. This was recrystallized from
ethanol to give 6.11 g (46 per cent yield) of sodium 1-
methyl-5-(4-methylbenzoyl)pyrrole-2-acetate dihydrate, mp
298-300~. The solid state infrared spectrum was
identical to authentic material.
Example XIII(B)
Following the procedure of Example III(A), but replacing
the 4-methylbenzoylcyanide with each of the following
aroylcyanides:
3-propylbenzoylcyanide;
4-methoxybenzoylcyanide;
4-bromobenzoylcyanide;
4-nitrobenzoylcyanide;
4-methylthiobenzoylcyanide;
3-trifluoromethylbenzoylcyanide,
there can be obtained the following, respectively:
sodium 1-methyl-5-(3ipropylbenzoyl)pyrrole-2-acetate
dihydrate;
sodium l-methyl-5-(4-methoxybenzoyl)pyrrole-2-acetate
dihydrate;
sodium l-methyl-5-(4-bromobenzoyl)pyrrole-2-acetate
dihydrate;
sodium l-methyl-5-(4-nitrobenzoyl)pyrrole-2-acetate
dihydrate;
sodium l-methyl-5-(4-methylthiobenzoyl)pyrrole-2-
acetate dihydrate;
sodium 1-methyl-5-(3-trifluoromethylbenzoyl)pyrrole-
2-acetate dihydrate.
115S858
-16-
Example XIV
l-Methyl-5-(4-methylbenzoyl)yyrrole-2-acetonitrile: A
mixture of 2.1 g (0.018 mole) of 1-methylpyrrole-2-
acetonitrile and 5.0 g (0.035 mole) of 4-methylbenzoyl-
cyanide was added dropwise over six hours to a sample of
4.1 g (.034 mole) of 1-methylpyrrole-2-acetonitrile at
180 through which a stream of nitrogen was passed. The
mixture was heated a total of two days at 180. It was
cooled, dissolved in CHC13, washed with 10 per cent
NaOH solution, dried (MgSO4) and the solvent
evaporated ln vacuo to give 10.1 g of a black oil. The
oil was triturated with ether. The ether was decanted
from tarry material and charcoaled. The ether was
evaporated in vacuo to give 7.4 g of oil. The excess
l-methylpyrrole-2-acetonitrile was removed by distillation
in a Kugelrohr apparatus at 70C., 0.1 mm/Hg. The residue
(4.2 g) was chromatographed on a Waters Associate System
500 preparative hplc. using ethyl acetate:cyclohexane,
1:3 as eluant and two passes through the column. The
fractions corresponding on TLC to desired product were
evaporated in vacuo to give 1.1 g of an oil. The oil was
triturated with cyclohexane and the cyclohexane was
decanted and evaporated in vacuo. The residue was
recrystallized from metha~ol to give 30 mg of
l-methyl-5-(4-methylbenzoylpyrrole-2-acetonitrile),
m.p. 101-105C., undepressed upon admixture with
authentic material. The solid state IR was identical to
that from authentic material.
