US3325507A - Process for the preparation of 5-nitroimidazole-2-carboxylic acids - Google Patents

Process for the preparation of 5-nitroimidazole-2-carboxylic acids Download PDF

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US3325507A
US3325507A US326392A US32639263A US3325507A US 3325507 A US3325507 A US 3325507A US 326392 A US326392 A US 326392A US 32639263 A US32639263 A US 32639263A US 3325507 A US3325507 A US 3325507A
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nitroimidazole
lower alkyl
methyl
acid
carboxylic acids
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US326392A
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Kollonitsch Janos
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Merck and Co Inc
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Merck and Co Inc
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Priority to BR164787/64A priority patent/BR6464787D0/en
Priority to FR996476A priority patent/FR1427762A/en
Priority to NL6413815A priority patent/NL6413815A/xx
Priority to CH1536464A priority patent/CH449630A/en
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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
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5

Definitions

  • l-lower alkyl-S-nitroimidazole-2-carboxylic acids are important compounds for the preparation of l-lower alkyl- S-nitroimidazole-2-carboxamides, which latter substances have a very high degree of activity against the parasitic diseases histomoniasis and T. vaginalis vaginitis.
  • These imidazole-Z-carboxylic acids are highly unstable compounds under many conditions. Heretofore, they have been prepared in alkaline media and isolated in the form of alkali metal salts in order to avoid or minimize decarboxylation of the free acid.
  • One method of producing such carboxylic acids is by oxidation of a 1lower alkyl-Z- hydroxymethyl-5-nitroimidazoles, as shown structurally below:
  • R represents lower alkyl and Y is hydrogen or an alkali metal.
  • l-lower alkyl-S-nitroimidazole-2-carboxylic acid is surprisingly stable under certain strongly acidic conditions and that the free acid can in fact be prepared in high yield by the oxidation under such acidic conditions of l-lower alkyl-Z-hydroxymethyl-S-nitroimidazole. It is therefore an object of this invention to provide a new synthesis of l-lower alkyl-S-nitroimidazole-Z-carboxylic acid. It is a further object to provide a synthesis which affords the free carboxylic acid in high yield. A still further object is provision of a synthesis in which the undesired oxidation of the imi-dazole ring and decarboxylation of the free acid is essentially eliminated. Further objects will become clear from the following description of the invention.
  • l-lower alkyl-S-nitroimidazole-Z-carboxylic acids are produced in high yield on treatment of the corresponding Z-hydroxymethyl imidazole with an acidic oxidizing agent in a sulfuric acid medium.
  • an acidic oxidizing agent there may be used oxidizing agents such as nitric acid, nitrogen tetroxide, chromic acid (i.e. chromium trioxide) or manganese dioxide.
  • the preferred oxidizing agent is nitric acid.
  • the amount of oxidant employed is not critical to the success of this process, although it is desirable to employ at least an equimolar quantity with respect to the nitroimidazole reactant.
  • the oxidizing agent should be present in excess, and I prefer to use from about 1-3 moles of oxidizing agent per mole of l-lower alkyl-Z-hydroxymethyl- 5-nitroimidazole.
  • a key feature of my invention is the carrying out of the oxidation in a sulfuric acid medium.
  • the reaction medium does not have to be anhydrous, but it should not contain more than about 25% by weight of water since the yield of l-lower alky-l-5-nitroimidazole-2-carboxylic acid is reduced considerably when more water is present. This loss of yield is apparently due to decarboxylation of the free acid. It is therefore preferred to keep the amount of water in the reaction medium to a minimum.
  • Concentrated sulfuric acid is preferably employed as the solvent, although fuming sulfuric acid can be used if desired.
  • Some water will, of course, be introduced with certain oxidizing agents, such as concentrated nitric acid, but this does not adversely affect the process as long as the total amount of water in the final medium is less than about 25% by weight.
  • the amount of sulfuric acid used as reaction solvent is not unduly critical except that sufficient should be present to dissolve the l-lower alkyl-Z-hydroxymethyl-S- nitroimid azole reactant and to provide a reaction mixture that is sufiiciently fluid to permit stirring or agitation during the course of the process.
  • Generally good results are achieved by employing from about 3-10 moles of concentrated sulfuric acid per mole of l-lower alkyl-2- hydroxymethyl-S-nitroimidazole.
  • the oxidation is conducted at elevated temperatures of at least about C., and preferably at 70-90 C. 'Even at these temperatures, the process is not a rapid one, and reaction times of at least about 10 hours are normally employed. For best results at temperatures of 7'090 C., it is preferred to continue the reaction for at least 15 hours; however, periods of up to 70 hours may be used without adverse effect.
  • the l-lower alkyl-5-nitroimidazole-Z-carboxylic acid may be isolated by quenching the highly acidic reaction mixture in ice or ice-water.
  • the water-insoluble free acid which is reasonably stable in the cold, precipitates and is recovered by filtration or centrifugation.
  • l-lower alkyl-S- nitr-oimidazole-Z-carboxylic acids examples of which are the 1-methyl, l-ethyl, l-propyl and l-butyl-5-nitroimidazole-2-carboxylic acid, from the corresponding l-lower alkyl-Z-hydroxymethyl-S-nitrioimidazole.
  • These acids may be converted to the corresponding antiparasitic amides via a lower alkyl ester, such as the methyl ester.
  • ester can be formed directly, without isolation of the free acid, by addition of methanol to the sulfuric acid reaction medium after removal of excess oxidizing agent.
  • the methyl ester of l-lower alkyl-S-nitroimidazole-Z- carboxylic acid is then precipitated on dilution of the sulfuric acid solution with Water.
  • the amide is obtained on treatment of the ester with ammonia.
  • Example 1 4.71 g. (0.03 M) of 1-methyl-2-hydroxymethyl5-nitroimidazole is added with stirring to 16.5 g. (0.17 M) of concentrated sulfuric acid. 6.66 g. of nitric acid (0.072 M) is then added to the sulfuric acid mixture. The resulting solution is heated for 60 hours at -80" C. At the end of this time the reaction mixture is added slowly to 30 g. of ice. l-methyl-5-nitroimidazole-2-carboxylic acid precipitates and is recovered by filtration. It is Washed with water and dried in vacuo at room temperature. 3.5 g. of product are obtained, M.P. 8485 C.
  • Example 4 The l-lower alkyl-Z-hydroxymethyl-S-nitroimidazoles employed as starting materials for this invention are obtained by the procedure exemplified below for making the l-methyl compound:
  • the process for preparing 1-methyl-5-nitroimidazole- Z-carboxylic acid that comprises treating 1-methyl-2-hydroxymethyl-S-nitroimidazole with nitric acid in a sulfuric acid reaction medium containing less than about 25 weight perccglt of water at a temperature of between 60 and 90 3.
  • the process for preparing 1-rnethyl-S-nitroimidazole- Z-carboxylic acid that comprises treating 1-rnethyl-2-hydroxymethyl-S-nitroirnidazole with nitric acid in concentrated sulfuric acid at a temperature of between 60 and 90 C.

Description

United States Patent 3,325,507 PROCESS FOR THE PREPARATION OF S-NITRO- IMIDAZOLE-Z-CARBQXYLIC ACIDS Janos Kollonitsch, Westfield, NJ, assignor to Merck & Co., Inc, Rahway, Ni, a corporation of New Jersey No Drawing. Filed Nov. 27, 1963, Ser. No. 326,392 3 Claims. (Cl. 260-309) This invention relates generally to the synthesis of imidazole-carboxylic acids. More particularly, it relates to the preparation of l-lower alkyl-S-nitroimidazole-Z-car- 'boxylic acids. Still more specifically, it is concerned with a new and novel method of obtaining l-lower alkyl-S- nitroimidazole-2-carboxylic acids from the corresponding Z-hydroxyrnethyl imidazoles.
l-lower alkyl-S-nitroimidazole-2-carboxylic acids are important compounds for the preparation of l-lower alkyl- S-nitroimidazole-2-carboxamides, which latter substances have a very high degree of activity against the parasitic diseases histomoniasis and T. vaginalis vaginitis. These imidazole-Z-carboxylic acids are highly unstable compounds under many conditions. Heretofore, they have been prepared in alkaline media and isolated in the form of alkali metal salts in order to avoid or minimize decarboxylation of the free acid. One method of producing such carboxylic acids is by oxidation of a 1lower alkyl-Z- hydroxymethyl-5-nitroimidazoles, as shown structurally below:
where R represents lower alkyl and Y is hydrogen or an alkali metal. Previous work has been limited to the use of alkaline oxidizing agents which lead to formation of salts. These methods are not feasible on a practical basis, and the yields thus obtained are not satisfactory. Many acidic oxidizing systems afforded no improvement due to destruction of the imidazole ring or spontaneous decarboxylation of the imidazole carboxylic acid.
In accordance with the present invention, it has now been found that l-lower alkyl-S-nitroimidazole-2-carboxylic acid is surprisingly stable under certain strongly acidic conditions and that the free acid can in fact be prepared in high yield by the oxidation under such acidic conditions of l-lower alkyl-Z-hydroxymethyl-S-nitroimidazole. It is therefore an object of this invention to provide a new synthesis of l-lower alkyl-S-nitroimidazole-Z-carboxylic acid. It is a further object to provide a synthesis which affords the free carboxylic acid in high yield. A still further object is provision of a synthesis in which the undesired oxidation of the imi-dazole ring and decarboxylation of the free acid is essentially eliminated. Further objects will become clear from the following description of the invention.
It has now been found that l-lower alkyl-S-nitroimidazole-Z-carboxylic acids (Formula II above, where Y is hydrogen) are produced in high yield on treatment of the corresponding Z-hydroxymethyl imidazole with an acidic oxidizing agent in a sulfuric acid medium. As the oxidant, there may be used oxidizing agents such as nitric acid, nitrogen tetroxide, chromic acid (i.e. chromium trioxide) or manganese dioxide. The preferred oxidizing agent is nitric acid. The amount of oxidant employed is not critical to the success of this process, although it is desirable to employ at least an equimolar quantity with respect to the nitroimidazole reactant. For best results, the oxidizing agent should be present in excess, and I prefer to use from about 1-3 moles of oxidizing agent per mole of l-lower alkyl-Z-hydroxymethyl- 5-nitroimidazole.
A key feature of my invention is the carrying out of the oxidation in a sulfuric acid medium. The reaction medium does not have to be anhydrous, but it should not contain more than about 25% by weight of water since the yield of l-lower alky-l-5-nitroimidazole-2-carboxylic acid is reduced considerably when more water is present. This loss of yield is apparently due to decarboxylation of the free acid. It is therefore preferred to keep the amount of water in the reaction medium to a minimum. Concentrated sulfuric acid is preferably employed as the solvent, although fuming sulfuric acid can be used if desired. Some water will, of course, be introduced with certain oxidizing agents, such as concentrated nitric acid, but this does not adversely affect the process as long as the total amount of water in the final medium is less than about 25% by weight.
The amount of sulfuric acid used as reaction solvent is not unduly critical except that sufficient should be present to dissolve the l-lower alkyl-Z-hydroxymethyl-S- nitroimid azole reactant and to provide a reaction mixture that is sufiiciently fluid to permit stirring or agitation during the course of the process. Generally good results are achieved by employing from about 3-10 moles of concentrated sulfuric acid per mole of l-lower alkyl-2- hydroxymethyl-S-nitroimidazole.
The oxidation is conducted at elevated temperatures of at least about C., and preferably at 70-90 C. 'Even at these temperatures, the process is not a rapid one, and reaction times of at least about 10 hours are normally employed. For best results at temperatures of 7'090 C., it is preferred to continue the reaction for at least 15 hours; however, periods of up to 70 hours may be used without adverse effect.
At the end of the oxidation, the l-lower alkyl-5-nitroimidazole-Z-carboxylic acid may be isolated by quenching the highly acidic reaction mixture in ice or ice-water. The water-insoluble free acid, which is reasonably stable in the cold, precipitates and is recovered by filtration or centrifugation.
Employing the acidic oxidant-sulfuric acid system of this invention, there may be obtained l-lower alkyl-S- nitr-oimidazole-Z-carboxylic acids, examples of which are the 1-methyl, l-ethyl, l-propyl and l-butyl-5-nitroimidazole-2-carboxylic acid, from the corresponding l-lower alkyl-Z-hydroxymethyl-S-nitrioimidazole. These acids may be converted to the corresponding antiparasitic amides via a lower alkyl ester, such as the methyl ester. If desired, such ester can be formed directly, without isolation of the free acid, by addition of methanol to the sulfuric acid reaction medium after removal of excess oxidizing agent. The methyl ester of l-lower alkyl-S-nitroimidazole-Z- carboxylic acid is then precipitated on dilution of the sulfuric acid solution with Water. The amide is obtained on treatment of the ester with ammonia.
The following examples are given for the purpose of illustration and not by way of limitation.
Example 1 4.71 g. (0.03 M) of 1-methyl-2-hydroxymethyl5-nitroimidazole is added with stirring to 16.5 g. (0.17 M) of concentrated sulfuric acid. 6.66 g. of nitric acid (0.072 M) is then added to the sulfuric acid mixture. The resulting solution is heated for 60 hours at -80" C. At the end of this time the reaction mixture is added slowly to 30 g. of ice. l-methyl-5-nitroimidazole-2-carboxylic acid precipitates and is recovered by filtration. It is Washed with water and dried in vacuo at room temperature. 3.5 g. of product are obtained, M.P. 8485 C.
a (dec.) The mother liquor is adjusted to pH 2 with sodium bicarbonate, whereupon an additional 0.7 g. of l-methyl- S-nitroimidazole-Z-ca1'boxylic acid precipitates.
Similar results are obtained when the above process is carried out by heating at 7580 C. for 15 hours instead of 60 hours.
' Example 2 The l-lower alkyl-S-nitroimidazole-2-carboxylic acids obtained by the method of this invention are converted to the corresponding imidazole-2-carboxamides as follows:
13.7 g. of 1-methyl-5-nitroimidazole-Z-carboxylic acid is suspended in 10 ml. of ice water in an ice bath. 57 ml. of 2.5 N sodium hydroxide is added in small portions with cooling and stirring. The resulting solution is poured into 800 ml. of isopropanol and the mixture cooled in an ice bath. Sodium 1-methyl-5-nitroimidazole-2-carboxylate precipitates, and is recovered by filtration.
9.70 g. of sodium 1-methyl-5nitroimidazole-2-carboxylate is suspended in benzene. 30 ml. of oxalyl chloride is added and the reaction mixture allowed to stand until the evolution of gas subsides. It is then warmed to reflux on a steam bath, then the benzene is evaporated in vacuo. The resulting crude solids are flushed with benzene to remove any traces of oxalyl chloride. The solid lmethyl- 5-nitroimidazole-2-carbonyl chloride which remains is extracted with warm benzene. The benzene extract is filtered to remove any solid, and concentrated to dryness in vacuo. The 1-methyl-S-nitr0i-midazole-2-carbonyl chloride crystallizes, M.P. 150-l53 C.
0.86 g. of 1-methyl-5-nitroimidazole-2-carbonyl chloride is suspended in 5 ml. of benzene. The resulting suspension is filtered to remove inorganic salts. An excess of anhydrous ammonia is bubbled into the benzene solution, with rapid stirring. The benzene is then removed in vacuo, and the residue of 1-methyl-S-nitroimidazole-Z-carboxamide is dissolved in a minimum amount of ethyl acetate. The ethyl acetate solution is filtered and the filtrate concentrated to dryness. The residual l-methyl-S-nitroimidazole-2-carboxamide is recrystallized from acetone to give substantially pure material, M.'P. 222-224 C. (subl).
This conversion of the carboxylic acids of this invention to the imidazole-2-carboxarnides is not a part of the present invention but is rather the invention of my colleague Dale R. Hoff, and is subject matter of his application No. 300,629, filed Aug. 7, 1963. Such l-lower alkyl- 5 -nitroimidazole-2-carboxamides are useful in treating turkey blackhea-d disease, and for this purpose are orally administered to turkeys via the feed or drinking water of the birds.
Example 4 The l-lower alkyl-Z-hydroxymethyl-S-nitroimidazoles employed as starting materials for this invention are obtained by the procedure exemplified below for making the l-methyl compound:
27.9 g. of 1-methyl-5-nitroimidazole and 30.1 g. of para formaldehyde are added to 154 ml. of dirnethylsulfoxide and the resulting solution is sealed into a glass-lined tube. The solution is then removed from the reaction vessel and the dimethylsulfoxide removed by distillation at 53- 56 C./2 mm. The residue is extracted with 3x150 ml. of hot benzene. The benzene extracts are combinedand cooled to room temperature. 1-methy1-2-hydroxymethyl- S-nitroimidazole crystallizes, and is recovered by filtration. 23 g. of product are obtained, M.P. 112114.5 C.
When this procedure is followed using 31 g. of 1-ethyl- S-nitroimidazole as starting material, 1-ethyl-2-hydroxymethyl-S-nitroimidazole is obtained.
This direct formylation method is not the subject of the present application, but is rather the invention of my co-pending application No. 326,379, filed Nov. 27, 1963, now abandoned.
Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.
What is claimed is:
1. The process for preparing l-lower alkyl-S-nitroimidazole-2-carboxylic acid that comprises treating a compound of the formula where R represents lower alkyl, with nitric acid in a sulfuric acid reaction medium containing less than about 25 weight percent of water at a temperature of between 60 C. and C.
2. The process for preparing 1-methyl-5-nitroimidazole- Z-carboxylic acid that comprises treating 1-methyl-2-hydroxymethyl-S-nitroimidazole with nitric acid in a sulfuric acid reaction medium containing less than about 25 weight perccglt of water at a temperature of between 60 and 90 3. The process for preparing 1-rnethyl-S-nitroimidazole- Z-carboxylic acid that comprises treating 1-rnethyl-2-hydroxymethyl-S-nitroirnidazole with nitric acid in concentrated sulfuric acid at a temperature of between 60 and 90 C.
References Cited UNITED STATES PATENTS 1,576,999 3/1926 Seydel 260-687 2,475,969 7/1949 Larrison 260687 2,673,216 3/1954 Goedkoop 260-687 2,694,070 11/1954 Martin 260-687 2,794,813 6/ 1957 Farinacci 260-687 WALTER A. MODANCE, Primary Examiner.
JOHN D. RANDOLPH, Examiner.
NATALIE TROUSOF, Assistant Examiner.

Claims (1)

1. THE PROCESS FOR PREPARING 1-LOWER ALKYL-5-NITROIMIDAZOLE 2-CARBOXYLIC ACID THAT COMPRISES TREATING A COMPOUND OF THE FORMULA
US326392A 1963-11-27 1963-11-27 Process for the preparation of 5-nitroimidazole-2-carboxylic acids Expired - Lifetime US3325507A (en)

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US326392A US3325507A (en) 1963-11-27 1963-11-27 Process for the preparation of 5-nitroimidazole-2-carboxylic acids
GB45944/64A GB1077693A (en) 1963-11-27 1964-11-11 Preparation of 1-alkyl-5-nitroimidazole-2-carboxylic acids
BR164787/64A BR6464787D0 (en) 1963-11-27 1964-11-25 IMIDAZAL MANUFACTURING PROCESS
FR996476A FR1427762A (en) 1963-11-27 1964-11-26 Manufacturing process of imidazole-carboxylic acids
NL6413815A NL6413815A (en) 1963-11-27 1964-11-27
CH1536464A CH449630A (en) 1963-11-27 1964-11-27 Process for the preparation of imidazolene carboxylic acids

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3761491A (en) * 1966-07-18 1973-09-25 Merck & Co Inc 1-substituted-5-nitroimidazol-2-ylalkyl-(n-substituted)-carbamates

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1576999A (en) * 1921-07-16 1926-03-16 Seydel Chemical Company Method of oxidizing aromatic side-chain compounds
US2475969A (en) * 1945-03-22 1949-07-12 Allied Chem & Dye Corp Oxidation of heterocyclic aromatic nitrogen compounds
US2673216A (en) * 1950-03-28 1954-03-23 Directie Staatsmijnen Nl Production of aromatic polycarboxylic acids
US2694070A (en) * 1952-03-26 1954-11-09 Allied Chem & Dye Corp Process for preparing pyridine carboxylic acids
US2794813A (en) * 1953-09-15 1957-06-04 Farinacci Nicholas Thomas Oxidation of organic compounds with a chromic oxidizing agent

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1576999A (en) * 1921-07-16 1926-03-16 Seydel Chemical Company Method of oxidizing aromatic side-chain compounds
US2475969A (en) * 1945-03-22 1949-07-12 Allied Chem & Dye Corp Oxidation of heterocyclic aromatic nitrogen compounds
US2673216A (en) * 1950-03-28 1954-03-23 Directie Staatsmijnen Nl Production of aromatic polycarboxylic acids
US2694070A (en) * 1952-03-26 1954-11-09 Allied Chem & Dye Corp Process for preparing pyridine carboxylic acids
US2794813A (en) * 1953-09-15 1957-06-04 Farinacci Nicholas Thomas Oxidation of organic compounds with a chromic oxidizing agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3761491A (en) * 1966-07-18 1973-09-25 Merck & Co Inc 1-substituted-5-nitroimidazol-2-ylalkyl-(n-substituted)-carbamates

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CH449630A (en) 1968-01-15
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