DE2827796C2 - Process for the preparation of 1- (2-acylaminoethyl) -5-nitroimidazoles - Google Patents

Description

N-CH ₂ -CH ₂ -NH-CO-R ³

10

R ¹

15th

R ^{1 is} a hydrogen atom, a lower alkyl radical, a phenyl radical or a phenyl radical substituted by alkyl groups, nitro groups or halogen atoms,

R ^{2 represents} a hydrogen atom or a lower alkyl radical and

R ^{3 represents} a hydrogen atom, a lower alkyl radical, a benzyl-phenyl radical or a phenyl radical substituted by nitro groups or chlorine atoms

mean, characterized in that one nitroimidazoles of the formula

20th

technical practice of this process are opposed to considerable difficulties with the production of N- (2-chloroethyl) acetamide are connected in the it is necessary to chlorinate acetylaminoethanol, with disruptive by-products such as 2-methyloxazoline, arise that have to be separated. Also is in the known process it is necessary to use the more valuable component 2-methyl-4 {5) -nitroimidazole to use in a molar excess to the N- (2-chloroethyl) acetamide in order to obtain a larger amount of 5-nitro isomers and get less 4-nitro isomer. Basically always arise the 4- and 5-nitro isomers, which, as in Example 2 of DE-OS 22 18 201 must be separated by fractional crystallization of their picric acid salts.

It has now been found that l- (2-acylaminoethyl) -5-nitroimidazoles the formula

R ² NO ₂

N N-CH ₂ -CH ₂ -NH-CO-R ³

25th

R ¹

in the

R ²

NO,

NH

(Π)

R ¹

R ^{1 is} a hydrogen atom, a lower alkyl radical, a phenyl radical or a phenyl radical substituted by alkyl groups, nitro groups or halogen atoms,
R ^{2 represents} a hydrogen atom or a lower alkyl radical and

R ^{3 represents} a hydrogen atom, a lower alkyl radical, a benzyl-phenyl radical or a phenyl radical substituted by nitro groups or chlorine atoms

in which R ¹ and R ^{2 have} the abovementioned meaning ha-, can produce considerably more advantageously if

ben, in the presence of strong organic acids, 40 one nitroimidazoles of the formula

Mineral acids, boron trifluoride or sulfur trioxide

with N-acylaminoethanols of the formula R ² NO ₂

R ³ CO-NH-CH ₂ -CH ₂ OH
or oxazolines of the formula

-N

(ΓΠ)

45

NH

R ¹

-R ³

in which R ^{3 has} the abovementioned meaning, converts.

so in which R ¹ and R ^{2 have} the abovementioned meaning, in the presence of strong organic acids, mineral acids or boron trifluoride with N-acylaminoethanols of the formula

55 R ³ CO-NH-CH ₂ -CH ₂ OH

or oxazolines of the formula

The invention relates to a process for the preparation of 1- (2-acylaminoethyl) -5-nitroimidazoles by reaction of 4 (5) -nitroimidazoles with N-acylaminoethanols or oxazolines in the presence of acids. -

1 - (2-Acylaminoethyl) -5-nitroimidazoles are valuable intermediates, e.g. B. for the production of Pharmaceuticals. Connections of this type can be used, for. B. after that described in DE-OS 22 18 201 Process by reacting 2-methyl-4 (5) -nitroimidazole with N- (2-chloroethyl) acetamide. Of the

R ³

(ΠΙ)

αν)

in which R ^{3 has} the abovementioned meaning, converts The starting materials of the formula II are mononitro

imidazoles whose nitro group is in the A or 5 position.

R ¹ denotes a hydrogen atom, a lower one

Alkyl radical with preferably 1 to 3 carbon atoms, such as a methyl, ethyl, propyl or isopropyl radical or a phenyl radical which can contain alkyl groups, nitro groups or halogen atoms. R ² denotes a hydrogen atom or a lower alkyl radical, such as a methyl radical. For example, the following nitroimidazoles are suitable:

2-methyl-4 (5) nitroimidazole,

4 (5) -nitroimidazole,

2-ethyl-4 (5) -methyl-5 (4) -nitroimidazole,

2-phenyl-4 (5) -nitroimidazole,

2-isopropyl-4 (5) -nitroimidazole or

4 (5) -methyl-5 (4) -nitroimidazole.

In the acylaminoethanols of the formula III and the oxazolines of the formula IV, R ³ denotes a hydrogen atom, a lower alkyl radical such as a methyl, ethyl or propyl radical, a benzyl radical, a phenyl radical or a phenyl radical substituted by nitro groups or chlorine atoms Oxazolines under consideration:

N-acetylaminoethanol,

N-propionylaminoethanol,

N-formylaminoethanol,

N-isobutyrylaminoethanol,

Oxazoline,

2-methyloxazoline,

2-isopropyloxazoline,

2- (4-nitrophenyl) oxazoline,

2- (4-chlorophenyl) oxazoline and

2-ethyloxazoline.

The reaction of the starting materials is carried out in the presence of strong organic acids, mineral acids or boron trifluoride. For example, phosphoric acid, anhydrous hydrochloric acid, Sulfur trioxide and boron trifluoride. Of these acids, anhydrous phosphoric acid is preferred

The starting materials are expediently used in such a way that there are 1 to 2 moles of the compound of the formula IH or IV for 1 mole of the nitroimidazole of the formula II. The amount of acid used is advantageously 4 to 5 times the amount by weight, based on one mole of the compound of the formula III or IV. B. carried out at temperatures of 80 to 150 ⁰ C, preferably 90 to 110 ⁰ C, the advantageous procedure is that one submits phosphoric acid, which is ^{completely dehydrated at 80 0} C with acetic anhydride. Dissolve in the resulting anhydrous mixture of phosphoric acid and acetic acid the nitroimidazole. The solution is then heated with the starting material III or IV for several hours

The reaction mixture is worked up by optionally removing the acetic acid under vacuum distilled off the remaining syrupy residue dissolves in water and - when using phosphoric acid preferably with potassium hydroxide solution - for other acids with ammonia water first blunt to pH 1.8, and the unreacted nitroimidazole (starting material II) which precipitates out at this pH is separated off. The filtrate is adjusted to pH 10 with further alkali, whereby the end product crystallizes out or with a suitable solvent (e.g. cyclohexanol) is extracted. The partly oily extract residues are made to crystallize by adding a suitable solvent.

According to the process of the invention, the 1- (2-acylaminoethyl) -5-nitroimidazoles are smooth and in good condition Yield obtained.

The l- (2-acyl-aminoethyl) -5-nitroimidazoles can,

if necessary, in a manner known per se, e.g. B. by saponification with aqueous mineral acids, can be converted into the corresponding 1- {2-aminoethyl) -5-nitroim! Dazenes.

example 1

To 105 parts of 85% phosphoric acid are under

ίο Stirring 100 parts of acetic anhydride added dropwise so that the temperature of 80 ⁰ C is not exceeded. 63.5 parts of 2-methyl-4 (5) -nitroimidazole are then added and the mixture is stirred until everything has dissolved. 43 parts of this solution are added at 80 to 100.degree

2-Methyloxazoline is slowly added dropwise. The mixture is stirred for 16 hours at 100 ° C. It is then cooled, diluted with 400 parts of water and prepared with about 50 parts of 50% potassium hydroxide solution while cooling with ice pH 1.8. After cooling in ice for one hour, the unreacted 2-methyl-4 (5) -nitroimidazole (= 22 Parts, conversion = 65.4%) and washed with 100 parts of water. Filtrate and wash water are with 50% potassium hydroxide solution adjusted to pH 10 and 5 times with each 150 parts of cyclohexanol extracted. The organic phase is dried over sodium sulfate and the Solvent distilled off in vacuo. About 140 parts of oil remain as residue. 140 parts are given Add acetone and cool for a few hours in an ice bath. About 40 parts of 1- (2-acetylaminoethyl) -2-methyl-5-nitroimidazole crystallize with a melting point of 153 to 154 ° C, corresponding to a yield of 57.7% d. Th. Based on converted 2-methyl-4 (5) -nitroimidazole.

Example 2

In a mixture of 105 parts of 85% phosphoric acid and 100 parts of acetic anhydride, 56.5 parts of 4 (5) -nitroimidazole with 43 parts of 2-methyloxazoline 16 h to 100 ^c C heated After working up according to Example 1, 25 parts of 1 - (2 -Acetylaminoäthyl) -5-nitroimidazole from melting point 96 to 98 ^C C corresponding to a yield of 55% of theory. Th. Based on converted 4 (5) -nitroimidazole. The conversion is 45%.

Example 3

To 50 parts of 85% phosphoric acid at 9O ⁰ C was added dropwise 200 parts of acetic anhydride. Then 63.5 parts of 2-methyl-4 (5) -nitroimidazole are added

so registered. When everything is dissolved, 76 parts of N-acetylaminoethanol are added dropwise and the mixture is boiled 4 Hours at reflux. It is evaporated in vacuo, the residue is dissolved in 400 parts of water and placed under Ice cooling by adding ammonia water to pH 1.8. After 30 minutes of ice cooling, you don't vacuum that reacted 2-methyl-4 (5) -nitroimidazole (about 35 parts) and the filtrate is made by further addition of Ammonia water to pH 10. Extraction is carried out with cyclohexanol and the process is continued as in Example 1 described.

Yield: 32 parts of 1- (2-acetylaminoethyl) -2-methyl-5-nitroimidazole, Melting point 152 to 154 ° C accordingly 67.2% of theory based on converted 2-methyl-4 (5) -nitroimidazole.

Example4

In 50 parts of glacial acetic acid, 34 parts are obtained at 20 to 25 ° C Boron trifluoride dissolved. In the solution one carries under

Cooling at 20 to 25 ° C. 63.5 parts of 2-methyl-4-nitroimidazole. 64 parts of 2-methylolxazoline are added dropwise and the mixture is ^{heated to 100 to 110 °} C. for 3 hours. After about 30 minutes, a homogeneous solution has formed.

After cooling, the replication mixture becomes 500 Dissolved parts of water, adjusted to pH 1.8 with ammonia water at 0 to 10 ° C. and cooled in an ice bath for 1 hour Here 23 parts of unreacted 2-methyl-4-nitroimidazole separate out. You suck off, wash with after cold water, the filtrate is adjusted to pH 8 with ammonia water and evaporated in vacuo. Of the The residue is dissolved in 100 parts of water, of a little Undissolved matter is filtered off and cooled. A total of 43 parts are obtained (= 63.6% of the total converted 2-methyl-4-nitroimidazole) 1- (2-acetylaminoethyl) -2-methyl-5-nitroimidazole, which after repeated recrystallization from alcohol at 151 to 153 ° C melts

Example 5

80 parts of sulfur trioxide are then introduced into 60 parts of glacial acetic acid with cooling and stirring 63.5 parts of 2-methyl-4 (5) -nitroimidazole are added, and the mixture is heated to 100 ° C. At 52 parts of acetylaminoethanol are added dropwise to this temperature and the mixture is refluxed for 20 hours. Man cools, adds 50 parts of water and adjusts to pH 1.8 with approx. 75 parts of ammonia water. After an hour

10

15th

20th Ice cooling, the unreacted 2-methyl-4 {5) -nitroimidazole is suctioned off (approx. 35 TeOe) and the filtrate is provided by further addition of ammonia water to pH 8. 20.4 parts of 1- (2-acetyl aminoethyl) -2-methyl-5-nitroimidazole with a melting point of 150 to 153 ° C. are obtained corresponding to ice yield of 43.7% of theory. Th. Related on converted 2-methyl-4 (5) -nitroimidazol

Example 6

100 parts of concentrated sulfuric acid are mixed with 100 parts of glacial acetic acid with stirring. 127 parts of 2-methyl-4 (5) -nitroiniidazole are then added. 103 parts Acetylaminoäthanol first be subsequently added dropwise and then 102 parts of acetic anhydride at 80 ° C within 1 hour added dropwise mail boiled for 8 hours under reflux (120 ⁰ C), evaporated under vacuum and the residue is dissolved in 800 parts of water. With ice cooling, the pH is adjusted to 1.8 with ammonia water and the mixture is cooled in an ice bath for one hour. The unreacted 2-methyl-4 (5) -nitroimidazole is filtered off with suction (approx. 75 parts) and the filtrate is adjusted to pH 8 with ammonia water. It is extracted several times with cyclohexanol. The cyclohexanol layer is separated off, dried, filtered and evaporated in vacuo. 70 parts) are mixed with 70 parts of acetone, cooled, and the precipitated crystals are filtered off with suction and dried. 43 parts of 1 - {2- acetylaminoethyl) -2-methyl-5-nitroimidazole, corresponding to a yield of 49.5% d. Th.

Claims (1)

Claim: Process for the preparation of 1- (2-acylaminoethyl) -5-nitroimidazoles the formula R ² in the NO ₂