DE2359625A1 - PROCESS FOR THE PREPARATION OF 1-HYDROXYALKYL-5-NITROIMIDAZOLE - Google Patents

Description

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'BASF Aktiengesellschaft ■ ·· ..-

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Process for the preparation of l-> hydroxyalkyl ~ 5-nitroimidazoleh

The invention relates to a process for the preparation of 1-hydroxyalkyl-5-nitroimidazoles by reacting 5-nitroimidazoles with 1,2-alkylene oxides in the presence of phosphoric acid and the mixed anhydride of formic acid and acetic acid ».

It is known from Belgian patent specification 64l 424 that one 5-Nitroimidazöle with A'thylenoxid in the presence of an organic Acid as a solvent, especially formic acid ^ to i ~ hydroxyalkyl-5-nitrile! nid.a2oien. A corresponding· Implementation in the presence of formic acid is described in the GDR patent 39 216, in the presence of phosphoric acid and acetic acid the Russian patent specification 201 416. The Russian patent specification uses acetic anhydride to remove the aqueous, 85 ~ weight percent phosphoric acid forms the water of acetic acid and thus a mixture for the> reaction from acetic acid and anhydrous phosphoric acid *

All these processes are unsatisfactory, especially on an industrial scale, in terms of yield, purity and easy work-up of the end product _o If the reaction is carried out in the presence of expensive tertiary amines that are more difficult to access in comparison to acids, as is also described in the aforementioned GDR patent So the uneconomical and cumbersome way of working with these bases in large-scale operations and the difficult, cumbersome and costly processing in order to obtain a pure end product are disadvantageous * -

It has now been found that l-Hydroxyalkyl-5-nitroimidazoles can be used the formula

117/73 / ■ - 2 -

S09823 / 091I

BATHROOM ORIGINAL ¹

r 2 Ι

I 1

Π-, Jn.

in which the individual radicals R ,, Rp, R ^ and R ₂ , can be identical or different and each represent an aliphatic, araliphatic, cyeloaliphatic or aromatic radical or "a hydrogen atom, by reacting 5-nitroimidazoles with alkylene oxides in the presence of phosphoric acid advantageously obtained when 5-nitroimidazoles of the formula

wherein Rp and R- have the aforementioned meaning with. 1,2-alkylene oxides the formula

wherein R, and R ^ have the meaning given above, in the presence of the mixed anhydride of formic acid and acetic acid implemented

It has also been found that the aforementioned reaction can be carried out advantageously when the acidic reaction mixture is used adjusts to a pH of 8 to 10 with potassium hydroxide solution and then separates the end product in a known manner *

The implementation can be used for the pail of. 2-methyl-5-nitroimidazole and ethylene oxide, represented by the following formulas:

5 0-9 P 2 3-- ·

W. NH + CH ₂ -O>

Ο, Ζ, 30

2359B25

CH,

Compared to the known processes, the process according to the invention provides l-hydroxyalkyl-5-nitroimidazoles in a simpler and more economical way and in better yield and purity Time-saving and more reliable "All these advantageous results are surprisingly _o - in view of the state of the art.

The starting materials used are 5-nitroimidazoles of the general formula II, which still have a substitutable hydrogen atom on a nitrogen atom. Because of the tautomerism of the imidazole, the substituent in the 5-position on the molecule can also be in the 4-position. Preferred starting materials IT and accordingly preferred end products I are see / in the formulas Rg and R, can be identical or different and each have a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms, a cyploalkyl radical with. 5 or 6 carbon atoms, an araikyl radical with 7 to 12 carbon atoms or a phenyl radical mean _a The radicals mentioned can also be substituted by groups which are inert under the reaction conditions, such as "ZoB, nitro groups, alkyl groups with 1 to 4 carbon atoms.

Thus, z, B _e In addition to 5-nitroimidazole itself the following substituted 5-nitroimidazoles are used as starting materials. II: 2-methyl-, 2-Ithyl-, 2-Cyclohexyl *, 2-rsopropyl-, 2-benzyl, 2- p-Nitrophenyl-, 2-m-nitrophenyl-, 2-o-nitrophenyl-, 2-phenyl-5-nitroimidazole and corresponding 5- (4) -nitroimidazolej 2,4-dimethyl- , S-Cyclopentyl- ^ - ^: ethyl-, 2-toluyl-4-phenyl-, 2,4-diethyl-, 2,4-dicyclohexyl-, 2,4-dibenzyl-, 2,4-diphenyl-5-nitroimidazole .

509823/0912

- 4 - O ₀ Z. pO 2 ^ 3

2359825

Other starting materials are 1,2-alkylene oxides III, which are in a stoichiometric amount or in excess, are preferably reacted in a molar ratio of 4 to 8 moles per mole of starting material II ₀ Preferred starting materials III and accordingly preferred end products I are those in which formulas R ₁ and R ₂ radicals can be identical or different and each represent an alkyl radical with 1 to 6 carbon atoms, an alkenyl radical with 2 to 6 carbon atoms, a cycloalkyl radical with 5 or 6 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical, a hydrogen atom, a carbalkoxy group with 2 to 6 carbon atoms, a carbonamido group. »The radicals mentioned can also be substituted by the inert groups indicated above.

It can be, for "B _o following alkylene oxides used as starting materials III: ethylene oxide, propylene oxide, 1,2-butylene oxide, 2,3-butylene oxide, styrene oxide, glycidamide, butadiene epoxide, ß-Methylglycidsäureäthylester _o

The reaction is carried out usually at a temperature of 20 ° C to 100 ⁰ C, preferably from 2J5 to! 55 ⁰ C, under atmospheric or superatmospheric pressure, continuously or discontinuously. Using the mixed anhydride of formic acid and acetic acid, generally in an amount of 100 to 300, preferably from 130 to 180 Gewo $, based on starting material II, The phosphoric acid may be wholly or partially as phosphorus pentoxide, orthophosphoric acid, metaphosphoric acid, pyrophosphoric acid or polyphosphoric Z ₀ B ₀ 72-88 wt _o $ P ₂ ° ^en 5 ^'vorlie S and is calculated here as HJ ³ O ₂ ^, regardless of the actual constitution of the phosphoric acid or _o of phosphoric anhydride "advantageously used 100 weight percent o-phosphoric acid or their 85 to 100 percent by weight aqueous solutions, if necessary, an excess of anhydride is selected in order to replace the proportion of anhydride converted into organic acid by the reaction with the water in the phosphoric acid solution. Quantities from 20 to 200, preferably from 40 to 140 GeW ₀ ^ H-PO ₂ ,, based on starting material II, are generally suitable.

- 5 -509823/0912

The reaction can be carried out as follows? A mixture the starting materials-II, III, phosphoric acid and anhydride is kept at the reaction temperature for 2 to 3 hours. The starting material III is expediently added with thorough mixing to the mixture of the other reactants. Then can from the reaction mixture in a known manner, e.g. by Addition of water, cooling and ■ filtration * ■ unreacted Separate starting material II and return it to the reaction. The end product can then be extracted from the piltrate in the usual way, e.g. through Addition of caustic soda or ammonia, cooling and filtration, be isolated »". .. '-'

In an advantageous embodiment of the process according to the invention, unreacted starting material II is advantageously separated off in the aforementioned manner and the acidic reaction mixture is then adjusted with potassium hydroxide: -to a pH> 7, preferably to a pH of 8 to 14, in particular 9-5 to 10.5 * a, cools the mixture and separates the end product In known catfish, ζ "B" by extraction with ethyl acetate or after a cooling time of 6 to 12 hours by filtration, "The use of potassium hydroxide solution instead of the bases usually used to separate the end product caustic soda or ammonia advantageously allows in a simpler, more economical and safer to form a purer end product to produce ₀

The compounds which can be prepared by the process of the invention are catalysts for polymerization and condensation reactions, especially for reactions with epoxides, the Aldol-v condensation, condensation reactions with malonic ester or acetoacetic ester and intermediates for the manufacture of Pharmaceutica, Dyes, textile auxiliaries and insecticides. Furthermore, they have chemotherapeutic properties, e.g. for the therapy of colpitids. Regarding the use, refer to the aforementioned patents, and drug research, Volume l6, Pages 2J ff (1966), referenced.

The parts mentioned in the examples are parts by weight.,

. SO 9-8-2 ^ 7 0.912.

- 6 - O, Z. 30 ^

example 1

100 parts of mixed anhydride of formic acid and acetic acid are placed in a stirred vessel and 105 parts of 85 percent by weight aqueous phosphoric acid are slowly added in portions, while cooling at 25 ° C. 6 "3.5 parts (99 percent by weight) of 2-methyl-5 -nitroimidazole and the mixture is stirred until everything is dissolved at 25 C. 120 parts of ethylene oxide are slowly added in portions to this viscous solution over the course of 2 hours. The temperature is kept at 25 ° C. to 30 ° C. by cooling. The mixture is stirred for 2 hours at 25 ° C., the reaction mixture is dissolved in 300 parts of cold water and the solution is cooled for 2 hours at 0 ° C., the unreacted 2-methyl-5-nitroimidazole crystallizing out. The precipitate is filtered off with suction and washed it twice with 20 parts of cold water each time, dries and receives 6 parts of starting material II, which are used in the next reaction without further purification. The piltrate is cooled with 290 parts len 50 percent by weight, aqueous potassium hydroxide solution was adjusted to pH 10 and ^{kept at 0} ° C. for 9 hours. The end product which has separated out is filtered off with suction, washed three times with 100 parts of ice water each time and dried in vacuo at 60.degree. The yield obtained is 65 parts of 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole with a melting point of 16 ° C. which, when titrated in an anhydrous medium with isopropanolic potassium hydroxide solution, show a purity of 99 * 6 % .

The yield is 84.5 % of theory, based on the converted 2-methyl-5-nitroimidazole, the conversion is 90.5 %

Example 2 (comparison)

Analogously to Example 1, 6j5.5 parts of 2-methyl-5-nitroimidazole are in The presence of 100 parts of the acids shown in the table below reacted. The indicated yields are obtained.

SÖ8C23 / Q912

Tab e 1 le

O.Z. 30th

Example solvents

- yield.
of theory % conversion

2a formic acid 2b acetic acid.

64.2.
63,. *

81, 80.5

Example 3. ■■:

In 100 parts of mixed anhydride of formic acid and acetic acid * 5 parts of 5-Natraimidazol introduced with stirring at 20 to 25 ° C, 150 parts of 85-gewiehtsprozentige, aqueous phosphoric acid and then 56 = Within '3' hours at 25 to 30 ⁰ G 180 parts of ethylene oxide slowly and portionwise added "The mixture is stirred for 2" hours, diluted with 500 parts of cold water and held for 2 hours at 0 ⁰ C. The off. divorced unreacted 5-nitroimidazole (25 parts) is sucked off, with Ice water washed and dried,, ■

To remove the polyglycols formed from the excess ethylene oxide, the filtrate is extracted with 100 parts of ethyl acetate and then adjusted to pH 10 with 50 percent strength by weight aqueous potassium hydroxide solution. By extraction with 300 parts Essigester is obtained 33 parts of l- (2-hydroxyethyl) -5-nitroimidazole with a melting point of 83 ⁰ C (75% of theory, based on "the converted 5-nitroimidazole)" The conversion is 55.8 %,

"-'_ ,. ■ _: _ Example 4

Analogously to Example 3, 70.5 parts of 2-ethyl-5-nitroimidazole are reacted with 110 parts of ethylene oxide in a solution of 100 parts of mixed anhydride of formic acid and acetic acid and 55 parts of phosphoric acid. 48 parts of 1- (2-hydroxyethyl) -2-ethyl-5-M-troimidazor with a melting point of 91 ° C. are obtained, corresponding to a yield of 53 * 6 % of theory at a conversion of 97.2%. '■■' ■ _ ''. ■>. .. ■■, - ■, ". ■" -

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509823/0912

- 8 - O. Z. 30 24j>

Example 5

Analogously to Example 3, 77 * 5 parts of 2-isopropyl-5-nitroimidazole are reacted and worked up in a mixture of 100 parts of mixed anhydride of formic acid and acetic acid and 55 parts of phosphoric acid with 110 parts of ethylene oxide. As yield is obtained 78 parts of l- (2 ~ hydroxyethyl) -2-isopropyl ~ 5-nitroimidazole with a melting point of 103 ⁰ C, corresponding to a yield of 78.4% of theory '

Example 6

Analogously to Example 3, 63.5 parts of 2-methyln5-nitroimidazole are dissolved in 100 parts of mixed anhydride of formic acid and acetic acid and 55 parts of phosphoric acid and 6 parts of propylene oxide are added slowly and in portions at 55 ° C. Then the temperature is increased during one hour to 90 ⁰ C, is clearly resolved until everything, then cooled for 2 hours at 20 ⁰ C, the mixture was dissolved in 3OO parts of cold water and cooled for 3 hours at ⁰ ° C. The unreacted starting material II (24 parts) is filtered off with suction, the filtrate is adjusted to pH 10 with 50 percent strength by weight aqueous potassium hydroxide solution and cooled in ice for 10 hours. 39 parts of 1- (1-methyl-2-hydroxyethyl) -2 are obtained methyl-5-nitroimidazole melting point of 69 ⁰ C ₀ corresponding to a yield of 68.8% of theory, based on the unreacted 2-methyl-5-nitroimidazole. The conversion is 62.2 % *

Example 7

Analogously to Example 3, 63.5 parts of 4-methyl-5-nitroimidazole are dissolved in 100 parts of mixed anhydride of formic acid and acetic acid and 55 parts of phosphoric acid; at 25 to 30 ⁰ C 110 parts of ethylene oxide are entered in the course of 3 hours. Then, the mixture is stirred for 2 hours at 30 ⁰ C, dissolved in ice water and extracted with 3OO parts 100 parts Essigester. This extract is discarded. * The acidic, aqueous phase is adjusted to pH 3 to 3 with 50 percent strength by weight potassium hydroxide solution and continuously extracted with ethyl acetate. After the ethyl acetate has evaporated, 80 parts remain

ζ η q Q 5 ς /! "'Οίο BATH ORIGINAL

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oily residue which crystallizes after cooling and is recrystallized from alcohol., 7 ¹ J parts of 1- (2-hydroxyethyl) -4-methyl-5-n-nitroimidazole with a melting point of. 89 to 9O ⁰ C (63 * 5% of theory, relate to the 4-methyl-5-nitroimidazole) ο

Example 8. %

To the mixture of 100 parts of mixed anhydride of formic acid and acetic acid, 6j5.5 parts of 4-methyl-5-nitroimidazole and. 55 parts of phosphoric acid over yon JO minutes 145 parts of propylene oxide added _o The temperature rises to 95 C and form a clear solution "is allowed to. Cool the temperature to 2J ⁰ C over the course of 4 hours and dissolve the mixture in 300 parts of cold water, adjust to pH 10 with 50 percent by weight potassium hydroxide solution and extract the mixture continuously with ethyl acetate for several hours. After the ethyl acetate has been distilled off, 87 parts of oily residue are obtained which is dissolved in 2,000 parts of ether. The ethereal solution is dried over sodium sulfate. In the filtered solution is introduced under cooling, hydrogen chloride gas ₅ wherein the hydrochloride of 1- (1-methyl = 2 = hydroxyethyl) "4-methyl ~ 5" nitroimidasiols deposited, is obtained 71 parts of the hydrochloride of melting point 150 to ⁰ C, corresponding to a yield of 68 * 7 % of theory,

BAD ÖRIGINAi.

Claims (1)

■ - 10 - O.Z. 30th Claims Iy Process for the preparation of 1-hydroxyalkyl-5-nitroimidazoles the formula 2
-CH-CHOH- in which the individual radicals R ,, Rp, R- * and R ₂ , can be identical or different and each represent an aliphatic, araliphatic, cycloaliphatic or aromatic radical or a hydrogen atom, by reacting 5-nitroimidazoles with alkylene oxides in the presence of Phosphoric acid, characterized in that 5-nitroimidazoles of the formula ⁰ 2 wherein R ₂ and R, have the aforementioned meaning, with 1,2-alkylene oxides of the formula R _n -CH CH-R ₁ . wherein R., and R ₁ , have the meaning given above, reacts in the presence of the mixed anhydride of formic acid and acetic acid. Process according to Claim 1, characterized in that the acidic reaction mixture is adjusted to a pH of 8 to 14 with potassium hydroxide solution and then the end product is adjusted in a known manner separates " BASF Aktiengesellschaft / J