CA1155858A - Preparation of 5-(arylcyanohydroxymethyl)-1- loweralkylpyrrole-2-acetic acid derivatives and 5- aroyl-1-loweralkylpyrrole-2-acetic acid derivatives - Google Patents
Preparation of 5-(arylcyanohydroxymethyl)-1- loweralkylpyrrole-2-acetic acid derivatives and 5- aroyl-1-loweralkylpyrrole-2-acetic acid derivativesInfo
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Abstract
PREPARATION OF 5-(ARYLCYANOHYDROXY)METHYL-1-LOWERALKYL-Abstract 5-(Arylcyanohydroxy)methyl-1-loweralkylpyrrole-2-acetic acid derivatives are prepared by the protic acid catalyzed reaction of aroylcyanides with 1-loweralkylpyrrole-2-acetic acid derivatives, which is then converted by treatment with alkali metal hydroxides or heat to form 5-aroyl-1-loweralkylpyrrole-2-acetic acid or derivatives thereof. In addition, 5-aroyl-1-loweralkylpyrrole-2-acetic acid derivatives are prepared by the reaction at above 100°C of an aroylcyanide with a 1-alkylpyrrole-2-acetic acid derivative.
Description
~N-360/361 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-
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 ~ ~
I / II
/ step e) step a) ~/ R
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 ~ ~
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);
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 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 _ample II(A) Methyl 5-[cyanohydroxy(4-methylphenyl)methyl]-1-methyl-~ . A solution of 1.45 g (0.01 mole) of
/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);
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 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 _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 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.
-Example VI
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 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.
-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.
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 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 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.
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.
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.
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.
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 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 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.
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.
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.
Claims (10)
1. The process of preparing 5-(arylcyanohydroxymethyl)-1-loweralkylpyrrole-2-acetic acid derivatives of formula:
which comprises reacting an aroylcyanide of formula:
ArCOCN
with a 1-loweralkylpyrrole-2-acetic acid derivative of formula:
in the presence of an acid of pK below about 2, in an inert aprotic solvent at a temperature between 0° and 40°C., wherein in the foregoing formulae:
R is loweralkyl;
R1 is hydrogen or loweralkyl;
Z is CN or COO(loweralkyl);
Ar is phenyl or phenyl substituted with a substituent selected from the group consisting of loweralkyl, halo, nitro, methylthio, trifluoromethyl and loweralkoxy.
which comprises reacting an aroylcyanide of formula:
ArCOCN
with a 1-loweralkylpyrrole-2-acetic acid derivative of formula:
in the presence of an acid of pK below about 2, in an inert aprotic solvent at a temperature between 0° and 40°C., wherein in the foregoing formulae:
R is loweralkyl;
R1 is hydrogen or loweralkyl;
Z is CN or COO(loweralkyl);
Ar is phenyl or phenyl substituted with a substituent selected from the group consisting of loweralkyl, halo, nitro, methylthio, trifluoromethyl and loweralkoxy.
2. A process for preparing methyl 5-(cyano-hydroxyphenylmethyl)-1-methylpyrrole-2-acetate which comprises reacting benzoylcyanide with methyl-1-methyl-pyrrole-2-acetate in the presence of trichloroacetic acid in ether at about room temperature and subsequently cooling.
3. A process for preparing methyl 5-[cyano-hydroxy(4-methylphenyl)methyl]-1-methylpyrrole-2-acetate which comprises reacting 4-methylbenzoyl-cyanide with methyl-1-methylpyrrole-2-acetate in the presence of trichloroacetic acid in ether at about room temperature.
4. A process for preparing ethyl 5-[(4-chloro-phenyl)cyanohydroxymethyl]-1,4-dimethylpyrrole-2-acetate which comprises reacting p-chlorobenzoyl-cyanide with ethyl 1,4-dimethylpyrrole-2-acetate in the presence of trichloroacetic acid in ether at about room temperature.
5. A process for preparing 1-methyl-5-[cyano-hydroxy(4-methylphenyl)methyl]pyrrole-2-aceto-nitrile which comprises reacting 4-methylbenzoyl-cyanide with methyl-1-methylpyrrole-2-acetonitrile in the presence of trichloroacetic acid in ether at about room temperature.
6. A 5-(arylcyanohydroxymethyl)-1-loweralkylpyrrole-2-acetic acid derivative of the formula.
wherein:
R is loweralkyl;
R1 is hydrogen or loweralkyl;
Z is CN or COO(loweralkyl), and Ar is phenyl or phenyl substituted with a substituent selected from the group consisting of loweralkyl, halo, nitro, methylthio, trifluoromethyl, and loweralkoxy whenever prepared or produced by the process of claim 1 or by any obvious chemical equivalent thereof.
wherein:
R is loweralkyl;
R1 is hydrogen or loweralkyl;
Z is CN or COO(loweralkyl), and Ar is phenyl or phenyl substituted with a substituent selected from the group consisting of loweralkyl, halo, nitro, methylthio, trifluoromethyl, and loweralkoxy whenever prepared or produced by the process of claim 1 or by any obvious chemical equivalent thereof.
7. Methyl 5-(cyanohydroxyphenylmethyl)-1-methylpyrrole-2-acetate whenever prepared or produced by the process of claim 2 or by any obvious chemical equivalent thereof.
8. Methyl 5-[cyanohydroxy(4-methylphenyl)methyl]-1-methylpyrrole-2-acetate whenever prepared or produced by the process of claim 3 or by any obvious chemical equivalent thereof.
9. Ethyl 5-[(4-chlorophenyl)cyanohydroxymethyl]-1,4-dimethylpyrrole-2-acetate whenever prepared or produced by the process of claim 4 or by any obvious chemical equivalent thereof.
10. 1-Methyl-5-[cyanohydroxy(4-methylphenyl)methyl]
pyrrole-2-acetonitrile whenever prepared or produced by the process of claim 5 or by any obvious chemical equivalent thereof.
pyrrole-2-acetonitrile whenever prepared or produced by the process of claim 5 or by any obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000415135A CA1157029A (en) | 1980-04-03 | 1982-11-08 | Preparation of 5-(arylcyanohydroxymethyl)-1- loweralkylpyrrole-2-acetic acid derivatives and 5- aroyl-1-loweralkylpyrrole-2-acetic acid derivatives |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US137,046 | 1980-04-03 | ||
| US06/137,046 US4255335A (en) | 1980-04-03 | 1980-04-03 | Preparation of 5-aroyl-1-loweralkylpyrrole-2-acetic acid derivatives |
| US06/141,438 US4294760A (en) | 1980-04-17 | 1980-04-17 | Preparation of 5-(arylcyanohydroxymethyl)-1-loweralkylpyrrole-2-acetic acid derivatives |
| US141,438 | 1980-04-17 |
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| Publication Number | Publication Date |
|---|---|
| CA1155858A true CA1155858A (en) | 1983-10-25 |
Family
ID=26834868
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| CA000373216A Expired CA1155858A (en) | 1980-04-03 | 1981-03-17 | Preparation of 5-(arylcyanohydroxymethyl)-1- loweralkylpyrrole-2-acetic acid derivatives and 5- aroyl-1-loweralkylpyrrole-2-acetic acid derivatives |
Country Status (1)
| Country | Link |
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-
1981
- 1981-03-17 CA CA000373216A patent/CA1155858A/en not_active Expired
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