CA2473422C - Preparation of 5-chlorimidazoles - Google Patents
Preparation of 5-chlorimidazoles Download PDFInfo
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- CA2473422C CA2473422C CA002473422A CA2473422A CA2473422C CA 2473422 C CA2473422 C CA 2473422C CA 002473422 A CA002473422 A CA 002473422A CA 2473422 A CA2473422 A CA 2473422A CA 2473422 C CA2473422 C CA 2473422C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/68—Halogen atoms
Abstract
The 5-chloroimidazole of the general formula (I): (see formula I) wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched C2 to C6 alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched C1 to C6 alkyl groups, nitro, or amino groups, and R1 represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched C1 to C6 alkyl groups, nitro, or amino groups, -CO2R3 or -(CH2) n-CO2R3, wherein n is from 1 to 4 and R3 represents a straight-chain or branched C1 to C6 alkyl group, is a novel intermediate for the production of anti--hypertensive pharmaceutical agents and herbicidal compounds. There is disclosed a process for the production of these intermediates as well as a novel process for the further reaction of a 5-chloroimidazole (I), wherein R1 is hydrogen, to a 5-chloroimidazole-4-carbaldehyde of the general formula (II) : (see formula II)
Description
PREPAR.ATION OF 5-CHLOROIMIDAZOLES
This application is a division of Canadian Patent Application Serial No. 2,117,209. The claims of the present application are directed to a process for the production of 5-chloroimidazole-4-carbaldehydes. However, for a ready understanding of the overall invention, including all features which are inextricably bound up in one and the same inventive concept, the teachings of those features claimed in Canadian Patent Application Serial No. 2,117,209 are all retained herein.
Field of The Invention The present invention relates to novel 5-chloroimidazoles, a process of preparing the 5-chloroimidazoles, and a process of converting some of the 5-chloroimidazoles to the corresponding 5-chloroimidazole-4-carbaldehydes.
Backaround of The Invention Several methods for the production of 5-chloroimidazole-4-carbaldehydes are known.
U.S. Patent No. 4,355,040 describes a process according to which 2-amino-3,3-dichloroacrylonitrile is reacted with an aldehyde to the corresponding azomethine intermediate product and further with a hydrogen halide and water to the corresponding 2-substituted-5-haloimidazole-4-carbaldehyde. Experimental data is lacking in the patent. A
great drawback of the synthesis is that the starting material, 2-amino-3,3-dichloroacrylonitrile, has to be produced from dichloroacetonitrile by its reaction with hydrogen cyanide/sodium cyanide. The extremely toxic reactants and the safety measures associated therewith that are required just for the preparation of the starting material, make the entire process unsuitable for industrial-scale production.
In another embodiment, U.S. Patent No. 4,355,040 discloses a 3-stage process wherein, an amidine hydrochloride is cyclized under high NH3 pressure with dihydroxyacetone, the imidazole alcohol is halogenated and finally oxidized to aldehyde.
It has now been revealed that pressures of over 20 bars are necessary for the cyclization reaction.
The oxidation of the alcohol is achieved according to U.S. Patent No. 4,355,040 in the presence of chromium oxide. It will be appreciated by those skilled in the art that oxidation with heavy metal oxides, that are not generally recyclable, is no longer justifiable in view of current ecological concerns and requirements.
Summary of The Invention According to one aspect of the present invention, which is claimed in Canadian Patent Application Serial No.
2,117,209, there is provided a 2-substituted-5-chloroimidazole of the general formula (Ia):
~Cl Ia H
wherein R represents n-butyl, 2-butenyl or 3-butenyl.
According to another aspect of the present invention, which is claimed in Canadian Patent Application Serial No. 2,117,209, there is provided a process for the production of a 5-chloroimidazole of the general formula (I):
q I
;0-N A ' N
M
This application is a division of Canadian Patent Application Serial No. 2,117,209. The claims of the present application are directed to a process for the production of 5-chloroimidazole-4-carbaldehydes. However, for a ready understanding of the overall invention, including all features which are inextricably bound up in one and the same inventive concept, the teachings of those features claimed in Canadian Patent Application Serial No. 2,117,209 are all retained herein.
Field of The Invention The present invention relates to novel 5-chloroimidazoles, a process of preparing the 5-chloroimidazoles, and a process of converting some of the 5-chloroimidazoles to the corresponding 5-chloroimidazole-4-carbaldehydes.
Backaround of The Invention Several methods for the production of 5-chloroimidazole-4-carbaldehydes are known.
U.S. Patent No. 4,355,040 describes a process according to which 2-amino-3,3-dichloroacrylonitrile is reacted with an aldehyde to the corresponding azomethine intermediate product and further with a hydrogen halide and water to the corresponding 2-substituted-5-haloimidazole-4-carbaldehyde. Experimental data is lacking in the patent. A
great drawback of the synthesis is that the starting material, 2-amino-3,3-dichloroacrylonitrile, has to be produced from dichloroacetonitrile by its reaction with hydrogen cyanide/sodium cyanide. The extremely toxic reactants and the safety measures associated therewith that are required just for the preparation of the starting material, make the entire process unsuitable for industrial-scale production.
In another embodiment, U.S. Patent No. 4,355,040 discloses a 3-stage process wherein, an amidine hydrochloride is cyclized under high NH3 pressure with dihydroxyacetone, the imidazole alcohol is halogenated and finally oxidized to aldehyde.
It has now been revealed that pressures of over 20 bars are necessary for the cyclization reaction.
The oxidation of the alcohol is achieved according to U.S. Patent No. 4,355,040 in the presence of chromium oxide. It will be appreciated by those skilled in the art that oxidation with heavy metal oxides, that are not generally recyclable, is no longer justifiable in view of current ecological concerns and requirements.
Summary of The Invention According to one aspect of the present invention, which is claimed in Canadian Patent Application Serial No.
2,117,209, there is provided a 2-substituted-5-chloroimidazole of the general formula (Ia):
~Cl Ia H
wherein R represents n-butyl, 2-butenyl or 3-butenyl.
According to another aspect of the present invention, which is claimed in Canadian Patent Application Serial No. 2,117,209, there is provided a process for the production of a 5-chloroimidazole of the general formula (I):
q I
;0-N A ' N
M
wherein R represents hydrogen, a straight-chain or branched Cl to C. alkyl group, a straight-chain or branched C2 to C6 alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched Clto C6 alkyl groups, nitro, or amino groups, and R1 represents hydrogen, a straight-chain or branched Clto C6 alkyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or pheny:L group optionally substituted with one or more of halogen atoms, straight-chain or branched Clto C. alkyl groups, nitro, or amino groups, -C02R3 or -(CHz) -CO2R3, wherein n is from 1 to 4 and R3 represents a straight-chain or branched Clto C. alkyl group, comprising, in a first step, reacting a glycine ester hydrohalide of the general formula (III):
R' NHa HX
wherein R1 has the above-mentioned meaning, R2 represents a straight-chain or branched Clto C6 alkyl group and X
represents a halogen atom, with an imidic acid ester of the general formula (IV):
R OR
R' NHa HX
wherein R1 has the above-mentioned meaning, R2 represents a straight-chain or branched Clto C6 alkyl group and X
represents a halogen atom, with an imidic acid ester of the general formula (IV):
R OR
NH
IV
wherein R has the above-mentioned meaning and R4 represents a straight-chain or branched Clto C6 alkyl group, in the presence of a base, to give the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
O
N V
R~SI-N
wherein R and R1 have the above-mentioned meanings, and, in a second step, chlorinating the corresponding 3,5-dihydroimidazol-4-one (V).
According to a further aspect of the present invention, there is provided a process for the preparation of a 5-chloroimidazole-4-carbaldehyde of the general formula (II) :
C--H
II
N Ar p A~N
H
wherein R represents hydrogen, a straight-chain or branched Clto C6 alkyl group, a straight-chain or branched C2 to C6 alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched Clto C6 alkyl groups, nitro, or amino groups.
The process includes reacting a 5-chloroimidazole of formula (Ia), wherein R is as defined immediately above, with phosphorus oxychloride or phosgene in the presence of N,N-dimethylformamide.
The 5-chloroimidazoles (I) and (Ia) and the 5-chloroimidazole-4-carbaldehydes (II) are important starting materials for the production of anti-hypertensive pharmaceutical agents (U.S. Patent No. 4,355,040) and herbicidal compounds (German OS 2804435).
IV
wherein R has the above-mentioned meaning and R4 represents a straight-chain or branched Clto C6 alkyl group, in the presence of a base, to give the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
O
N V
R~SI-N
wherein R and R1 have the above-mentioned meanings, and, in a second step, chlorinating the corresponding 3,5-dihydroimidazol-4-one (V).
According to a further aspect of the present invention, there is provided a process for the preparation of a 5-chloroimidazole-4-carbaldehyde of the general formula (II) :
C--H
II
N Ar p A~N
H
wherein R represents hydrogen, a straight-chain or branched Clto C6 alkyl group, a straight-chain or branched C2 to C6 alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched Clto C6 alkyl groups, nitro, or amino groups.
The process includes reacting a 5-chloroimidazole of formula (Ia), wherein R is as defined immediately above, with phosphorus oxychloride or phosgene in the presence of N,N-dimethylformamide.
The 5-chloroimidazoles (I) and (Ia) and the 5-chloroimidazole-4-carbaldehydes (II) are important starting materials for the production of anti-hypertensive pharmaceutical agents (U.S. Patent No. 4,355,040) and herbicidal compounds (German OS 2804435).
Detailed Description of The Invention For the preparation of a 5-chloroimidazole of the general formula (I) according to the present invention, in a first step, a glycine ester hydrohalide of the general formula (III) :
R~ NH~ NX
COZ RZ I I I
wherein R1 has the above-mentioned meaning, R2 is an alkyl group and X is a halogen atom, is reacted with an imidic acid ester of the general formula (IV):
on IV
NH
wherein R has the above-mentioned meaning and R4 is an alkyl group, in the presence of a base, to the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
R
O
N
~'\"_N%
R
wherein R and R1 have the above-mentioned meanings.
With reference to the substituents, namely R, R1, R2, R3 and R4 it will be understood that the indicated groups have the following meanings.
An alkyl group is a straight-chain or branched C1-C6 alkyl group, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl groups. The preferred alkyl group is one of the mentioned C1-C4-alkyl groups. The n-butyl group is the preferred R alkyl group substituent.
An alkenyl group is a straight-chain or branched C1-C6-alkenyl group, such as, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl and its isomers, or hexenyl and its isomers. The preferred R alkenyl group substituents are 2-butenyl and 3-butenyl.
Suitable representatives of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
Both the benzyl group and the phenyl group can contain substituents, such as, the above-mentioned alkyl groups, halogen atoms, nitro groups or amino groups.
Suitable halogens are chlorine, bromine or iodine. Preferably, the halogen is chlorine.
Suitably, the glycine ester hydrohalide (III) is reacted in the presence of a base, suitably at a pH of from about 7 to 12, preferably from about 9 to 11, with the imidic acid ester (IV). The glycine ester hydrohalides (III) are commercially available stable compounds. Suitable bases are alkali hydroxides, such as, sodium hydroxide or potassium hydroxide, or alkali alcoholates, such as, sodium or potassium methylate, ethylate or tert-butylate.
Advantageously, the base is dissolved in a suitable solvent.
Especially suitable solvents are aliphatic alcohols, such as methanol or ethanol. The imidic acid ester (IV) is suitably added in the form of a solution in an inert solvent, such as, aromatic solvents, including toluene and chlorobenzene, or the above-mentioned aliphatic alcohols.
Advantageously, the reaction of the glycine ester hydrohalide (III), imidic acid ester (IV) and base takes place in the stoichiometric ratio of 1:1:1. A suitable reaction temperature is in the range of from about -20 C to 50 C, preferably from about 0 C to 25 C.
R~ NH~ NX
COZ RZ I I I
wherein R1 has the above-mentioned meaning, R2 is an alkyl group and X is a halogen atom, is reacted with an imidic acid ester of the general formula (IV):
on IV
NH
wherein R has the above-mentioned meaning and R4 is an alkyl group, in the presence of a base, to the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
R
O
N
~'\"_N%
R
wherein R and R1 have the above-mentioned meanings.
With reference to the substituents, namely R, R1, R2, R3 and R4 it will be understood that the indicated groups have the following meanings.
An alkyl group is a straight-chain or branched C1-C6 alkyl group, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl groups. The preferred alkyl group is one of the mentioned C1-C4-alkyl groups. The n-butyl group is the preferred R alkyl group substituent.
An alkenyl group is a straight-chain or branched C1-C6-alkenyl group, such as, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl and its isomers, or hexenyl and its isomers. The preferred R alkenyl group substituents are 2-butenyl and 3-butenyl.
Suitable representatives of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
Both the benzyl group and the phenyl group can contain substituents, such as, the above-mentioned alkyl groups, halogen atoms, nitro groups or amino groups.
Suitable halogens are chlorine, bromine or iodine. Preferably, the halogen is chlorine.
Suitably, the glycine ester hydrohalide (III) is reacted in the presence of a base, suitably at a pH of from about 7 to 12, preferably from about 9 to 11, with the imidic acid ester (IV). The glycine ester hydrohalides (III) are commercially available stable compounds. Suitable bases are alkali hydroxides, such as, sodium hydroxide or potassium hydroxide, or alkali alcoholates, such as, sodium or potassium methylate, ethylate or tert-butylate.
Advantageously, the base is dissolved in a suitable solvent.
Especially suitable solvents are aliphatic alcohols, such as methanol or ethanol. The imidic acid ester (IV) is suitably added in the form of a solution in an inert solvent, such as, aromatic solvents, including toluene and chlorobenzene, or the above-mentioned aliphatic alcohols.
Advantageously, the reaction of the glycine ester hydrohalide (III), imidic acid ester (IV) and base takes place in the stoichiometric ratio of 1:1:1. A suitable reaction temperature is in the range of from about -20 C to 50 C, preferably from about 0 C to 25 C.
After a reaction time of a few hours, the corresponding 3,5-dihydroimidazol-4-one (V) can be isolated by a method known to those skilled in the art, such as by simple filtration, in yields greater than 95 percent.
Advantageously, the resulting reaction mixture is prepared without isolation of the 3,5-dihydroimidazol-4-one (V) for further processing to the corresponding 5-chloroimidazole (I) (one-reactor process).
The first step of the process according to the present invention represents a tremendous improvement over the known process according to R. Jacquier et al Bull. Soc.
Chim. France, 1040; 1971, wherein the free glycine ester is reacted with an imidic acid ethyl ester in the absence of a solvent to the corresponding 3,5-dihydroimidazol-4-one. A
disadvantage of the known process is the fact that the free glycine ester is very unstable and, therefore, must be newly synthesized and isolated for every reaction. According to the known process, after a reaction time of 24 hours and more, yields of only 30 to 48% could be obtained.
In the second step, the 3,5-dihydroimidazol-4-one (V) is chlorinated to the corresponding 5-chloroimidazole (I). Suitably the chlorination takes place with thionyl chloride or phosphorus oxychloride, advantageously with an excess of the chlorinating agent of from about 10 to 300%, at a reaction temperature in the range of from about 20 C to 110 C. In this step, the chlorinating agent can also serve as the solvent so that, generally, an additional solvent is not necessary. Preferably, phosphorus oxychloride is used as the chlorinating agent. The resultant 5-chloroimidazole (I) can be isolated with a high purity from the reaction mixture in a manner known to those skilled in the art, preferably by extraction.
Preferred 5-chloroimidazoles of the general formula (I) are those wherein R represents n-butyl, 2-butenyl or 3-butenyl.
Advantageously, the resulting reaction mixture is prepared without isolation of the 3,5-dihydroimidazol-4-one (V) for further processing to the corresponding 5-chloroimidazole (I) (one-reactor process).
The first step of the process according to the present invention represents a tremendous improvement over the known process according to R. Jacquier et al Bull. Soc.
Chim. France, 1040; 1971, wherein the free glycine ester is reacted with an imidic acid ethyl ester in the absence of a solvent to the corresponding 3,5-dihydroimidazol-4-one. A
disadvantage of the known process is the fact that the free glycine ester is very unstable and, therefore, must be newly synthesized and isolated for every reaction. According to the known process, after a reaction time of 24 hours and more, yields of only 30 to 48% could be obtained.
In the second step, the 3,5-dihydroimidazol-4-one (V) is chlorinated to the corresponding 5-chloroimidazole (I). Suitably the chlorination takes place with thionyl chloride or phosphorus oxychloride, advantageously with an excess of the chlorinating agent of from about 10 to 300%, at a reaction temperature in the range of from about 20 C to 110 C. In this step, the chlorinating agent can also serve as the solvent so that, generally, an additional solvent is not necessary. Preferably, phosphorus oxychloride is used as the chlorinating agent. The resultant 5-chloroimidazole (I) can be isolated with a high purity from the reaction mixture in a manner known to those skilled in the art, preferably by extraction.
Preferred 5-chloroimidazoles of the general formula (I) are those wherein R represents n-butyl, 2-butenyl or 3-butenyl.
The starting material for the further reaction according to the present invention to a 5-chloroimidazole-4-carbaldehyde (II) is a 5-chloroimidazole (I), wherein R1 is hydrogen. The reaction to the desired 5-chloroimidazole-4-carbaldehyde (II) takes place according to the present invention with phosphorus oxychloride or phosgene in the presence of N,N-dimethylformamide. Suitably the molar ratio of the 5-chloroimidazole (I) to phosphorus oxychloride or phosgene to N,N-dimethylformamide is in the range of from about 1:1:1 to 1:5:5, preferably at about 1:3:3. The reaction temperature is suitably in the range of from about 50 C to 130 C. Optionally, in the presence of an additional inert solvent, it is possible in the one-reactor process to conduct the reaction in the solvent of the first step.
The isolation of the resultant 5-chloroimidazole-4-carbaldehyde (II) from the reaction mixture takes place advantageously in a manner known to those skilled in the art by extraction with a suitable solvent.
The following Examples illustrate the present invention.
Production of 2-n-butyl-3,5-dihydroimidazol-4-one 31.71 g (0.25 mol) of glycine methyl ester hydrochloride was added to a solution of 10.1 g (0.25 mol) sodium hydroxide in methanol at 0 C. After 15 minutes, 126.5 g of a 22.8 % solution of pentanimidic acid methyl ester in chlorobenzene was added over a period of 5 minutes, dropwise, to the resulting white suspension. The light yellow suspension was stirred for 4 hours at room temperature and diluted with chlorobenzene (100 ml). The methanol was distilled off at a temperature of 26 C and at a pressure of from 30 to 50 mbar. The resulting orange suspension was diluted with methylene chloride (100 ml) and then filtered.
After removal of the solvent from the filtrate, 34.08 g(97 a) of 2-n-butyl-3,5-dihydroimidazol-4-one (content >95%, according to GC and 1H-NMR) was obtained.
Production of 2-n-butyl-5-chloro-lH-imidazole 2-n-Butyl-3,5-dihydroimidazol-4-one (14.02 g, 0.1 mol) was added in portions over a period of 15 minutes to POC13 (50 ml) at 95 C. The solution was heated for 2 hours at 100 C, cooled and poured over 400 g of ice. The mixture was adjusted to pH 7 with 255 ml of 30% sodium hydroxide solution and extracted three times with 500 ml aliquots of ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated by evaporation with a rotary evaporator. After purification of the residue by column chromatography, 2-n-butyl-5-chloro-lH-imidazole (5.52 g, 34.7%) was obtained in a high yield (>98%, according to GC
and 1H-NMR). The product had a melting point of from about 85 to 87 C. Other data regarding the product were:
1H-NMR (CDC13) b 0.91 (3H, t, J = 7.5 Hz), 1.36 (2H, sextet, J = 7.5 Hz), 1.68 (2H, q, J = 7.5 Hz), 2.70 (2H, t, J = 7.5 Hz), 6.83 (1H, s), 10.65 (1H, br. s).
Production of 2-n-butyl-5-chloroimidazole-4-carbaldehyde from 2-n-butyl-5-chloro-lH-imidazole N,N-dimethylformamide (1.46 g, 20 mmol) was added to a solution of 2-n-butyl-5-chloro-lH-imidazole (1.60 g, 10 mmol) in POC13 (3.07 g, 20 mmol) and chlorobenzene (20 ml) heated to 95 C. The mixture was stirred for 3.5 hours at 98 C. Further portions of POC13 (1.53 g, 10 mmol) and N,N-dimethylformamide (0.73 g, 10 mmol) were added thereafter.
After another 2.5 hours at 98 C the mixture was cooled and poured over ice (40 g). After 15 minutes, the mixture was adjusted to pH 7 with 11 ml of 30% sodium hydroxide solution and extracted three times with 100 ml aliquots of ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated by evaporation. 2-n-Butyl-5-chloroimidazole-4-carbaldehyde was obtained in a yield of 1.3 g (70%).
The isolation of the resultant 5-chloroimidazole-4-carbaldehyde (II) from the reaction mixture takes place advantageously in a manner known to those skilled in the art by extraction with a suitable solvent.
The following Examples illustrate the present invention.
Production of 2-n-butyl-3,5-dihydroimidazol-4-one 31.71 g (0.25 mol) of glycine methyl ester hydrochloride was added to a solution of 10.1 g (0.25 mol) sodium hydroxide in methanol at 0 C. After 15 minutes, 126.5 g of a 22.8 % solution of pentanimidic acid methyl ester in chlorobenzene was added over a period of 5 minutes, dropwise, to the resulting white suspension. The light yellow suspension was stirred for 4 hours at room temperature and diluted with chlorobenzene (100 ml). The methanol was distilled off at a temperature of 26 C and at a pressure of from 30 to 50 mbar. The resulting orange suspension was diluted with methylene chloride (100 ml) and then filtered.
After removal of the solvent from the filtrate, 34.08 g(97 a) of 2-n-butyl-3,5-dihydroimidazol-4-one (content >95%, according to GC and 1H-NMR) was obtained.
Production of 2-n-butyl-5-chloro-lH-imidazole 2-n-Butyl-3,5-dihydroimidazol-4-one (14.02 g, 0.1 mol) was added in portions over a period of 15 minutes to POC13 (50 ml) at 95 C. The solution was heated for 2 hours at 100 C, cooled and poured over 400 g of ice. The mixture was adjusted to pH 7 with 255 ml of 30% sodium hydroxide solution and extracted three times with 500 ml aliquots of ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated by evaporation with a rotary evaporator. After purification of the residue by column chromatography, 2-n-butyl-5-chloro-lH-imidazole (5.52 g, 34.7%) was obtained in a high yield (>98%, according to GC
and 1H-NMR). The product had a melting point of from about 85 to 87 C. Other data regarding the product were:
1H-NMR (CDC13) b 0.91 (3H, t, J = 7.5 Hz), 1.36 (2H, sextet, J = 7.5 Hz), 1.68 (2H, q, J = 7.5 Hz), 2.70 (2H, t, J = 7.5 Hz), 6.83 (1H, s), 10.65 (1H, br. s).
Production of 2-n-butyl-5-chloroimidazole-4-carbaldehyde from 2-n-butyl-5-chloro-lH-imidazole N,N-dimethylformamide (1.46 g, 20 mmol) was added to a solution of 2-n-butyl-5-chloro-lH-imidazole (1.60 g, 10 mmol) in POC13 (3.07 g, 20 mmol) and chlorobenzene (20 ml) heated to 95 C. The mixture was stirred for 3.5 hours at 98 C. Further portions of POC13 (1.53 g, 10 mmol) and N,N-dimethylformamide (0.73 g, 10 mmol) were added thereafter.
After another 2.5 hours at 98 C the mixture was cooled and poured over ice (40 g). After 15 minutes, the mixture was adjusted to pH 7 with 11 ml of 30% sodium hydroxide solution and extracted three times with 100 ml aliquots of ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated by evaporation. 2-n-Butyl-5-chloroimidazole-4-carbaldehyde was obtained in a yield of 1.3 g (70%).
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 5-chloroimidazole-4-carbaldehyde of the general formula (II):
wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched C2 to C6 alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched C1 to C6 alkyl groups, nitro, or amino groups, comprising reacting a 5-chloroimidazole of the general formula (Ia) :
wherein R is as defined above, with phosphorus oxychloride or phosgene in the presence of N,N-dimethylformamide.
wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched C2 to C6 alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or cyclohexyl- group, or a benzyl or phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched C1 to C6 alkyl groups, nitro, or amino groups, comprising reacting a 5-chloroimidazole of the general formula (Ia) :
wherein R is as defined above, with phosphorus oxychloride or phosgene in the presence of N,N-dimethylformamide.
2. A process according to claim 1, wherein the 5-chloroimidazole of general formula (Ia), the phosphorus oxychloride or phosgene and the N,N-dimethylformamide are reacted in a molar ratio of from about 1:1:1 to 1:5:5.
3. A process according to claim 1, wherein the 5-chloroimidazole of general formula (Ia), the phosphorus oxychloride or phosgene and the N,N-dimethylformamide are reached in a molar ratio of about 1:3:3.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH74893 | 1993-03-12 | ||
| CHGES.748/93 | 1993-03-12 | ||
| CA002117209A CA2117209C (en) | 1993-03-12 | 1994-03-14 | 2-substituted-5-chlorimidazoles |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002117209A Division CA2117209C (en) | 1993-03-12 | 1994-03-14 | 2-substituted-5-chlorimidazoles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2473422A1 CA2473422A1 (en) | 1994-09-13 |
| CA2473422C true CA2473422C (en) | 2007-05-22 |
Family
ID=4194282
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002473422A Expired - Fee Related CA2473422C (en) | 1993-03-12 | 1994-03-14 | Preparation of 5-chlorimidazoles |
| CA002117209A Expired - Fee Related CA2117209C (en) | 1993-03-12 | 1994-03-14 | 2-substituted-5-chlorimidazoles |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002117209A Expired - Fee Related CA2117209C (en) | 1993-03-12 | 1994-03-14 | 2-substituted-5-chlorimidazoles |
Country Status (9)
| Country | Link |
|---|---|
| EP (2) | EP0614890B1 (en) |
| JP (1) | JP3716434B2 (en) |
| KR (1) | KR100362353B1 (en) |
| AT (2) | ATE157655T1 (en) |
| CA (2) | CA2473422C (en) |
| DE (2) | DE59403903D1 (en) |
| DK (2) | DK0614890T3 (en) |
| ES (2) | ES2108894T3 (en) |
| HU (2) | HU213387B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2175420C (en) * | 1995-05-17 | 2007-04-10 | Gareth Griffiths | Process for the preparation of optionally 2-substituted 5-chloroimidazole-4-carbaldehydes |
| JP4103149B2 (en) * | 1996-01-05 | 2008-06-18 | ロンザ リミテッド | Process for producing 2-substituted 5-chloroimidazole-4-carbaldehyde |
| KR101035559B1 (en) * | 2009-06-02 | 2011-05-19 | 한국화학연구원 | Pharmaceutical composition for the prevention or treatment of osteoporosis or obesity comprising a chloroimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3409606A (en) * | 1965-12-30 | 1968-11-05 | American Cyanamid Co | Halogenated chloroimidazole compounds |
| IL53783A (en) * | 1977-02-03 | 1982-08-31 | American Cyanamid Co | Imidazo(1,5-d)-as-triazine-4 (3h)-(thi)one derivatives,their preparation and pharmaceutical compositions containing them |
| JPS5671074A (en) * | 1979-11-12 | 1981-06-13 | Takeda Chem Ind Ltd | 1,2-disubstituted-4-halogenoimidazole-5-acetic acid derivative |
| DE3145927A1 (en) * | 1981-11-20 | 1983-06-01 | Basf Ag, 6700 Ludwigshafen | 4(5)-Methyl-5(4)-chloroimidazole and process for its preparation |
| DE3330192A1 (en) * | 1983-08-20 | 1985-03-07 | Basf Ag, 6700 Ludwigshafen | 4-ALKYLIMIDAZOLE DERIVATIVES, THEIR PRODUCTION AND USE |
| JPS62238383A (en) * | 1986-04-07 | 1987-10-19 | Chiyoda Kagaku Kenkyusho:Kk | Anticorrosive |
| CA1334092C (en) * | 1986-07-11 | 1995-01-24 | David John Carini | Angiotensin ii receptor blocking imidazoles |
| JPH02262562A (en) * | 1988-10-20 | 1990-10-25 | Ishihara Sangyo Kaisha Ltd | Imidazole compound |
| PT95899A (en) * | 1989-11-17 | 1991-09-13 | Glaxo Group Ltd | PROCESS FOR THE PREPARATION OF INDOLE DERIVATIVES |
| JPH0426678A (en) * | 1990-05-18 | 1992-01-29 | Nippon Synthetic Chem Ind Co Ltd:The | Production of imidazole-4-chloro-5-carbaldehyde derivative |
| US5126342A (en) * | 1990-10-01 | 1992-06-30 | Merck & Co., Inc. | Imidazole angiotensin ii antagonists incorporating acidic functional groups |
| EP0505098A1 (en) * | 1991-03-19 | 1992-09-23 | Merck & Co. Inc. | Imidazole derivatives bearing acidic functional groups as angiotensin II antagonists |
| RU2103262C1 (en) * | 1992-07-16 | 1998-01-27 | Лонца АГ Гампель/Валлис | Method for production of 2-substituted 5-chloroimidazole-4-carbaldehydes |
-
1994
- 1994-03-09 ES ES94103636T patent/ES2108894T3/en not_active Expired - Lifetime
- 1994-03-09 AT AT94103636T patent/ATE157655T1/en active
- 1994-03-09 DK DK94103636.0T patent/DK0614890T3/en active
- 1994-03-09 EP EP94103636A patent/EP0614890B1/en not_active Expired - Lifetime
- 1994-03-09 DE DE59403903T patent/DE59403903D1/en not_active Expired - Lifetime
- 1994-03-10 AT AT94103714T patent/ATE175199T1/en active
- 1994-03-10 EP EP94103714A patent/EP0614891B1/en not_active Expired - Lifetime
- 1994-03-10 DK DK94103714T patent/DK0614891T3/en active
- 1994-03-10 DE DE59407547T patent/DE59407547D1/en not_active Expired - Lifetime
- 1994-03-10 ES ES94103714T patent/ES2127845T3/en not_active Expired - Lifetime
- 1994-03-11 JP JP04081394A patent/JP3716434B2/en not_active Expired - Fee Related
- 1994-03-11 HU HU9400736A patent/HU213387B/en not_active IP Right Cessation
- 1994-03-11 KR KR1019940004757A patent/KR100362353B1/en not_active IP Right Cessation
- 1994-03-11 HU HU9701565A patent/HU219708B/en not_active IP Right Cessation
- 1994-03-14 CA CA002473422A patent/CA2473422C/en not_active Expired - Fee Related
- 1994-03-14 CA CA002117209A patent/CA2117209C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0614890B1 (en) | 1997-09-03 |
| CA2473422A1 (en) | 1994-09-13 |
| EP0614890A3 (en) | 1995-01-11 |
| JPH072789A (en) | 1995-01-06 |
| ATE157655T1 (en) | 1997-09-15 |
| HUT66633A (en) | 1994-12-28 |
| EP0614891A3 (en) | 1995-05-03 |
| DE59407547D1 (en) | 1999-02-11 |
| CA2117209A1 (en) | 1994-09-13 |
| ATE175199T1 (en) | 1999-01-15 |
| JP3716434B2 (en) | 2005-11-16 |
| HU219708B (en) | 2001-06-28 |
| EP0614891B1 (en) | 1998-12-30 |
| EP0614891A2 (en) | 1994-09-14 |
| HU9400736D0 (en) | 1994-06-28 |
| HU213387B (en) | 1997-05-28 |
| KR100362353B1 (en) | 2003-03-19 |
| DE59403903D1 (en) | 1997-10-09 |
| DK0614890T3 (en) | 1997-10-13 |
| ES2108894T3 (en) | 1998-01-01 |
| HU9701565D0 (en) | 1997-11-28 |
| EP0614890A2 (en) | 1994-09-14 |
| ES2127845T3 (en) | 1999-05-01 |
| CA2117209C (en) | 2005-05-31 |
| DK0614891T3 (en) | 1999-08-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20140314 |