CA2117209C - 2-substituted-5-chlorimidazoles - Google Patents
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- 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
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Abstract
The 2-substituted-5-chlorimidazole of the general 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 2-substituted-5-chlorimidazole (I), wherein R1 is hydrogen, to a 2-substituted-5-chlorimidazole-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, 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 2-substituted-5-chlorimidazole (I), wherein R1 is hydrogen, to a 2-substituted-5-chlorimidazole-4-carbaldehyde of the general formula (II):
Description
2-Substituted-5=Chlorimidazoles Field of The Invention The present invention relates to novel 2 substituted-5-chlorimidazoles, a process of preparing the 2 substituted-5-chlorimidazoles, and a process of converting some of the 2-substituted-5-chlorimidazoles to the corres-ponding 2-substituted-5-chlorimidazole-4-carbaldehydes.
Background of The Invention Several methods for the production of 2-substituted-5-chlorimidazole-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 amidinehydrochloride 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, there is provided a 2-substituted-5-chlorimidazole of the general formula (Ia) N~~~CJ
N Ia R
N
wherein R represents n-butyl, 2-butenyl or 3-butenyl.
According to another aspect of the present invention, there is provided a process for the production of a 2-substituted-5-chlorimidazole of the general formula:
N
I
~.-- N~
2 0 R' H
wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched C 2 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 phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched Clto C6 alkyl groups, nitro, or amino groups, -C02R3 or - (CH2) n-C02R3, wherein n is from 1 to 4 and R
represents a straight-chain or branched Clto C6 alkyl group, comprising, in a first step, reacting a glycine ester hydrohalide of the general formula (III):
Background of The Invention Several methods for the production of 2-substituted-5-chlorimidazole-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 amidinehydrochloride 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, there is provided a 2-substituted-5-chlorimidazole of the general formula (Ia) N~~~CJ
N Ia R
N
wherein R represents n-butyl, 2-butenyl or 3-butenyl.
According to another aspect of the present invention, there is provided a process for the production of a 2-substituted-5-chlorimidazole of the general formula:
N
I
~.-- N~
2 0 R' H
wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched C 2 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 phenyl group optionally substituted with one or more of halogen atoms, straight-chain or branched Clto C6 alkyl groups, nitro, or amino groups, -C02R3 or - (CH2) n-C02R3, wherein n is from 1 to 4 and R
represents a straight-chain or branched Clto C6 alkyl group, comprising, in a first step, reacting a glycine ester hydrohalide of the general formula (III):
p NH2 HX III
CO~ii2 wherein R1 has the above-mentioned meaning, R2 represents a straight-chain or branched C1 to C6 alkyl group and X
represents a halogen atom, with an imidic acid ester of the general formula (IV) p ~; I V
l wherein R has the above-mentioned meaning and R~ represents a straight-chain or branched C1 to C6 alkyl group, in the presence of a base, to give the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
A
N ~ V
~-- N
R
H
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 production of a 2-substituted-5-chlorimidazole-4-carbaldehyde of the general formula (II) : O
/!
C-H
N ~ C' II
--N~
H
wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched Cz to Cs alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or 3a 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 . The process includes reacting a 2-substituted-5-chlorimidazole (Ia), wherein R is as defined immediately above, with phosphoroxy chloride or phosgene in the presence of N,N-dimethylformamide.
The 2-substituted-5-chlorimidazoles (I) and (Ia) and the 2-substituted-5-chlorimidazole-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 production of a 2-substituted-5-chlorimidazole of the general formula (I) according to the present invention, in a first step, a glycine ester hydrohalide of the general formula (III):
2117~~.
CO~ii2 wherein R1 has the above-mentioned meaning, R2 represents a straight-chain or branched C1 to C6 alkyl group and X
represents a halogen atom, with an imidic acid ester of the general formula (IV) p ~; I V
l wherein R has the above-mentioned meaning and R~ represents a straight-chain or branched C1 to C6 alkyl group, in the presence of a base, to give the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
A
N ~ V
~-- N
R
H
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 production of a 2-substituted-5-chlorimidazole-4-carbaldehyde of the general formula (II) : O
/!
C-H
N ~ C' II
--N~
H
wherein R represents hydrogen, a straight-chain or branched C1 to C6 alkyl group, a straight-chain or branched Cz to Cs alkenyl group, a cyclopropyl-, cyclobutyl-, cyclopentyl-, or 3a 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 . The process includes reacting a 2-substituted-5-chlorimidazole (Ia), wherein R is as defined immediately above, with phosphoroxy chloride or phosgene in the presence of N,N-dimethylformamide.
The 2-substituted-5-chlorimidazoles (I) and (Ia) and the 2-substituted-5-chlorimidazole-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 production of a 2-substituted-5-chlorimidazole of the general formula (I) according to the present invention, in a first step, a glycine ester hydrohalide of the general formula (III):
2117~~.
R~ NH2 HX
CO R III
wherein R~ 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 genEaral formula (IV) IV
NH
wherein R has ths: above-mentioned meaning and R4 is an alkyl group, in the presence of a base, to the corresponding 2-substituted-3,5-dihydroimidazol-4-one of the general formula (V) R
O
N
V
N
R ' H
wherein R and R~ have the above-mentioned meanings.
With reference to the substituents, namely R, R~, RZ, R3 and R4 it will be understood that the indicated groups have the following meanings.
An alkyl group is a straight-chain or branched C6-alkyl group, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tent-butyl, pentyl or hexyl groups. The preferred alkyl group is one of the mentioned C~-C4-alkyl groups. The n-butyl group is the preferred R alkyl group substituent.
An alkenyl group is a straight-chain or branched C~
C6-alkenyl group, such as, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-bute:nyl, pentenyl and its isomers, or hexenyl and its isomers. The preferred R alkenyl group substituents are 2-butenyl and 3-butenyl..
CO R III
wherein R~ 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 genEaral formula (IV) IV
NH
wherein R has ths: above-mentioned meaning and R4 is an alkyl group, in the presence of a base, to the corresponding 2-substituted-3,5-dihydroimidazol-4-one of the general formula (V) R
O
N
V
N
R ' H
wherein R and R~ have the above-mentioned meanings.
With reference to the substituents, namely R, R~, RZ, R3 and R4 it will be understood that the indicated groups have the following meanings.
An alkyl group is a straight-chain or branched C6-alkyl group, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tent-butyl, pentyl or hexyl groups. The preferred alkyl group is one of the mentioned C~-C4-alkyl groups. The n-butyl group is the preferred R alkyl group substituent.
An alkenyl group is a straight-chain or branched C~
C6-alkenyl group, such as, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-bute:nyl, 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 t:he 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 lhalogen is chlorine.
Suitably, the glycine ester hydrohalide (III) is reacted in the presence of a base, suitably at a pH of from ~.0 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, sucr~ as, sodium hydroxide or potassium hydroxide, or alkali alcoholates, such as, sodium or potassium ~.5 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, ~!0 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 stoichiom~etric ratio of 1:1:1. A suitable reaction a!5 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 2-:~ubstii~u.ted-3, 5-dihydroimidazol-4-one (V) can be isolated by a~ method known to those skilled in the art, a0 such as by sim~>le filtration, in yields greater than 95 percent.
Advantageously, the resulting reaction mixture is prepared without isolation of the 2-substituted-3,5-dihydroimidazol-.4-one (V) for further processing to the ,j5 corresponding 2-substituted-5-chlorimidazole (I) (one-reactor process).
The first step of the process according to the present invention represents a tremendous improvement over the ''-i-~'~''~)~
Both t:he 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 lhalogen is chlorine.
Suitably, the glycine ester hydrohalide (III) is reacted in the presence of a base, suitably at a pH of from ~.0 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, sucr~ as, sodium hydroxide or potassium hydroxide, or alkali alcoholates, such as, sodium or potassium ~.5 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, ~!0 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 stoichiom~etric ratio of 1:1:1. A suitable reaction a!5 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 2-:~ubstii~u.ted-3, 5-dihydroimidazol-4-one (V) can be isolated by a~ method known to those skilled in the art, a0 such as by sim~>le filtration, in yields greater than 95 percent.
Advantageously, the resulting reaction mixture is prepared without isolation of the 2-substituted-3,5-dihydroimidazol-.4-one (V) for further processing to the ,j5 corresponding 2-substituted-5-chlorimidazole (I) (one-reactor process).
The first step of the process according to the present invention represents a tremendous improvement over the ''-i-~'~''~)~
known process a<:cording 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 tlne second step, the 2-substituted-3,5-dihydroimidazol-4-one ('V) is chlorinated to the corresponding 2-substituted-5-~chlorimidazole (I). Suitably the chlorination takes place with thio~n,yl chloride or phosphoroxy chloride, advantageously with a:n 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, phosphoroxy chloride is used as the chlorinating agent. The resultant 2-substituted-5-chlorimidazole (I) can be isolated with a high purity from the reaction mixture in a manner known to those skilled in the a.rt, preferably by extraction.
Preferred 2-substituted-5-chlorimidazoles 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 2-substituted-5-chlorimidazole-4-carbaldehyde (II) is a 2-substituted-5-chlorimidazole (I), wherein R~ is hydrogen. The reaction to the desired 2-substituted-5-chlorimidazole-4-carbaldehyde (II) takes place according to the present invention with phosphoroxy chloride or phosgene in the presence of N,N-dimethylformamid~e. Suitably the molar ratio of the 2-substituted-5-chlorimidazole (I) to phosphoroxy chloride or phosgene to N,N-dimethylformamide is in the range of from about l:l:l to 1:5:5, preferably at about 1:3:3. The reaction temperature is :auitabl~, in the range of from about 50°C to 130°C. Optiona:Lly, in the presence of an additional inert c r c v: ,~~ ,J
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 tlne second step, the 2-substituted-3,5-dihydroimidazol-4-one ('V) is chlorinated to the corresponding 2-substituted-5-~chlorimidazole (I). Suitably the chlorination takes place with thio~n,yl chloride or phosphoroxy chloride, advantageously with a:n 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, phosphoroxy chloride is used as the chlorinating agent. The resultant 2-substituted-5-chlorimidazole (I) can be isolated with a high purity from the reaction mixture in a manner known to those skilled in the a.rt, preferably by extraction.
Preferred 2-substituted-5-chlorimidazoles 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 2-substituted-5-chlorimidazole-4-carbaldehyde (II) is a 2-substituted-5-chlorimidazole (I), wherein R~ is hydrogen. The reaction to the desired 2-substituted-5-chlorimidazole-4-carbaldehyde (II) takes place according to the present invention with phosphoroxy chloride or phosgene in the presence of N,N-dimethylformamid~e. Suitably the molar ratio of the 2-substituted-5-chlorimidazole (I) to phosphoroxy chloride or phosgene to N,N-dimethylformamide is in the range of from about l:l:l to 1:5:5, preferably at about 1:3:3. The reaction temperature is :auitabl~, in the range of from about 50°C to 130°C. Optiona:Lly, in the presence of an additional inert c r c v: ,~~ ,J
solvent, it is possible in the one-reactor process to conduct the reaction in the solvent of the first step.
The i:~olation of the resultant 2-substituted-5 chlorimidazole-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.
LO Production of 2-n-butv~l-3~5-dihydroimidazol-4-one 31.71 g (0.25 mol) of glycine methyl ester hydrochloride wa,s 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 :15 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 :ZO from 30 to 50 mbar. The resulting orange suspension was diluted with met.hylene chloride (100 ml) and then filtered.
After removal of the solvent from the filtrate, 34.08 g (97%) of 2-n-butyl-3.,5-dihydroimidazol-4-one (content >95%, according to GC and 1H-NMR) was obtained.
25 Production of 2-n-butv~l-5-chlor-iH-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 :30 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 MgS04, filtered and concentrated by evaporation with a rotary evaporator. After purification of the residue by column :35 chromatography,2-n-butyl-5-chlor-1H-imidazole (5.52 g, 34.7%) was obtained in a high yield (>98%, according to GC and ~H-NMR). The product had a melting point of from about 85° to 87°C. Other data regarding the product were 21~'~'?~'~
The i:~olation of the resultant 2-substituted-5 chlorimidazole-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.
LO Production of 2-n-butv~l-3~5-dihydroimidazol-4-one 31.71 g (0.25 mol) of glycine methyl ester hydrochloride wa,s 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 :15 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 :ZO from 30 to 50 mbar. The resulting orange suspension was diluted with met.hylene chloride (100 ml) and then filtered.
After removal of the solvent from the filtrate, 34.08 g (97%) of 2-n-butyl-3.,5-dihydroimidazol-4-one (content >95%, according to GC and 1H-NMR) was obtained.
25 Production of 2-n-butv~l-5-chlor-iH-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 :30 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 MgS04, filtered and concentrated by evaporation with a rotary evaporator. After purification of the residue by column :35 chromatography,2-n-butyl-5-chlor-1H-imidazole (5.52 g, 34.7%) was obtained in a high yield (>98%, according to GC and ~H-NMR). The product had a melting point of from about 85° to 87°C. Other data regarding the product were 21~'~'?~'~
~H-NMR (CDC13) 8 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 (iH, s) , 10.65 (iH, br. s).
Production of 2-n-butt'l-~5-chlorimidazole-4-carbaldehyde from 2-n-butyl-5-chlo:r-1H-imidazole 7_0 N,N-dimethylformamide (1.46 g, 20 mmol) was added to a solution of 2-n-butyl-5-chlor-1H-imidazole (1.60 g, 10 mmol) in POC13 (3.07 g, 20 mmol) and chlorabenzene (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-~_5 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 tlhree times with 100 ml aliquots of ethyl ~:0 acetate. The combined organic phases were dried over MgS04, filtered and concentrated by evaporation. 2-n-Butyl-5-chlorimidazole-4~-carbaldehyde was obtained in a yield of 1.3 g (70%) .
Production of 2-n-butt'l-~5-chlorimidazole-4-carbaldehyde from 2-n-butyl-5-chlo:r-1H-imidazole 7_0 N,N-dimethylformamide (1.46 g, 20 mmol) was added to a solution of 2-n-butyl-5-chlor-1H-imidazole (1.60 g, 10 mmol) in POC13 (3.07 g, 20 mmol) and chlorabenzene (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-~_5 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 tlhree times with 100 ml aliquots of ethyl ~:0 acetate. The combined organic phases were dried over MgS04, filtered and concentrated by evaporation. 2-n-Butyl-5-chlorimidazole-4~-carbaldehyde was obtained in a yield of 1.3 g (70%) .
Claims (8)
1. A 2-substituted-5-chlorimidazole of the general formula (Ia):
wherein R represents n-butyl, 2-butenyl or 3-butenyl.
wherein R represents n-butyl, 2-butenyl or 3-butenyl.
2. A process for the production of a 2-substituted-5-chlorimidazole of the general 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, comprising, in a first step, reacting a glycine ester hydrohalide of the general formula (III):
wherein R1 has the above-mentioned meaning, R2 represents a straight-chain or branched C1 to C6 alkyl group and X
represents a halogen atom, with an imidic acid ester of the general formula (IV):
wherein R has the above-mentioned meaning and R4 represents a straight-chain or branched C1 to C6 alkyl group, in the presence of a base, to give the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
wherein R and R1 have the above-mentioned meanings, and, in a second step, chlorinating the corresponding 3,5-dihydroimidazol-4-one (V).
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, comprising, in a first step, reacting a glycine ester hydrohalide of the general formula (III):
wherein R1 has the above-mentioned meaning, R2 represents a straight-chain or branched C1 to C6 alkyl group and X
represents a halogen atom, with an imidic acid ester of the general formula (IV):
wherein R has the above-mentioned meaning and R4 represents a straight-chain or branched C1 to C6 alkyl group, in the presence of a base, to give the corresponding 3,5-dihydroimidazol-4-one of the general formula (V):
wherein R and R1 have the above-mentioned meanings, and, in a second step, chlorinating the corresponding 3,5-dihydroimidazol-4-one (V).
3. A process according to claim 2, wherein the base is an alkali hydroxide or an alkali alcoholate.
4. A process according to claim 2 or 3, wherein the reaction in the first step is performed at a pH in the range of from about 7 to 12.
5. A process according to any one of claims 2 to 4, wherein the glycine ester hydrohalide (III), the imidic acid ester (IV) and the base are reacted in a stoichiometric molar ratio of 1:1:1.
6. A process according to any one of claims 2 to 5, wherein the reaction temperature in the first step is from about -20°C to 50°C.
7. A process according to any one of claims 2 to 6, wherein the chlorination in the second step is performed with thionyl chloride or phosphoroxy chloride.
8. A process according to claim 7, wherein the chlorination with phosphoroxy chloride is performed at a temperature of from about 20°C to 110°C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002473422A CA2473422C (en) | 1993-03-12 | 1994-03-14 | Preparation of 5-chlorimidazoles |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH748/93 | 1993-03-12 | ||
| CH74893 | 1993-03-12 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002473422A Division CA2473422C (en) | 1993-03-12 | 1994-03-14 | Preparation of 5-chlorimidazoles |
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| CA2117209A1 CA2117209A1 (en) | 1994-09-13 |
| CA2117209C true CA2117209C (en) | 2005-05-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA002117209A Expired - Fee Related CA2117209C (en) | 1993-03-12 | 1994-03-14 | 2-substituted-5-chlorimidazoles |
| CA002473422A Expired - Fee Related CA2473422C (en) | 1993-03-12 | 1994-03-14 | Preparation of 5-chlorimidazoles |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002473422A Expired - Fee Related CA2473422C (en) | 1993-03-12 | 1994-03-14 | Preparation of 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) | CA2117209C (en) |
| DE (2) | DE59403903D1 (en) |
| DK (2) | DK0614890T3 (en) |
| ES (2) | ES2108894T3 (en) |
| HU (2) | HU213387B (en) |
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| 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 DK DK94103636.0T patent/DK0614890T3/en active
- 1994-03-09 ES ES94103636T patent/ES2108894T3/en not_active Expired - Lifetime
- 1994-03-09 EP EP94103636A patent/EP0614890B1/en not_active Expired - Lifetime
- 1994-03-09 DE DE59403903T patent/DE59403903D1/en not_active Expired - Lifetime
- 1994-03-09 AT AT94103636T patent/ATE157655T1/en active
- 1994-03-10 EP EP94103714A patent/EP0614891B1/en not_active Expired - Lifetime
- 1994-03-10 ES ES94103714T patent/ES2127845T3/en not_active Expired - Lifetime
- 1994-03-10 AT AT94103714T patent/ATE175199T1/en active
- 1994-03-10 DK DK94103714T patent/DK0614891T3/en active
- 1994-03-10 DE DE59407547T patent/DE59407547D1/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 HU HU9701565A patent/HU219708B/en not_active IP Right Cessation
- 1994-03-11 KR KR1019940004757A patent/KR100362353B1/en not_active IP Right Cessation
- 1994-03-14 CA CA002117209A patent/CA2117209C/en not_active Expired - Fee Related
- 1994-03-14 CA CA002473422A patent/CA2473422C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH072789A (en) | 1995-01-06 |
| EP0614891A3 (en) | 1995-05-03 |
| DE59403903D1 (en) | 1997-10-09 |
| CA2473422C (en) | 2007-05-22 |
| CA2117209A1 (en) | 1994-09-13 |
| ATE175199T1 (en) | 1999-01-15 |
| HU9400736D0 (en) | 1994-06-28 |
| EP0614891A2 (en) | 1994-09-14 |
| HUT66633A (en) | 1994-12-28 |
| HU219708B (en) | 2001-06-28 |
| EP0614891B1 (en) | 1998-12-30 |
| DK0614891T3 (en) | 1999-08-30 |
| ES2127845T3 (en) | 1999-05-01 |
| EP0614890A3 (en) | 1995-01-11 |
| EP0614890A2 (en) | 1994-09-14 |
| HU9701565D0 (en) | 1997-11-28 |
| ES2108894T3 (en) | 1998-01-01 |
| DK0614890T3 (en) | 1997-10-13 |
| CA2473422A1 (en) | 1994-09-13 |
| JP3716434B2 (en) | 2005-11-16 |
| KR100362353B1 (en) | 2003-03-19 |
| DE59407547D1 (en) | 1999-02-11 |
| ATE157655T1 (en) | 1997-09-15 |
| HU213387B (en) | 1997-05-28 |
| EP0614890B1 (en) | 1997-09-03 |
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