HU206089B - Process for producing hydroxyalkyl derivatives of nitroimidazole derivatives - Google Patents

Abstract

The present invention relates to hydroxyalkylation of 1-alkyl substituted nitroimidazole derivatives with 1-sulfonic compounds of the formula I in which R is alkyl, R 1 or -O-CCH 2 -O-CO-R. n 2 or 3 After condensation of the corresponding nitroimidazole derivative and the compound of formula I, hydrolysis or alcoholysis is also carried out to give a compound of formula (VI) wherein R 2 is hydrogen or C 1-4 alkyl and Y 2 C3-hydroxyalkyl group RC0-O- (CH2) n-O-SO2-R (D NX (IV) HU 206 089 B '1 Scope of description: 6 pages (including 1 sheet))

Description

The present invention relates to novel hydroxyalkylating agents for the preparation of hydroxyalkyl derivatives of nitroimidazole compounds.

1- (Hydroxyalkyl) -nitro-imidazole derivatives, such as 1- (hydroxyethyl) -2-methyl-5-nitroimidazole (metronidazole), 1- (2-hydroxypropyl) -2 -methyl-5-nitro-imidazole (secnidazole) and 1- (3-hydroxypropyl) -2-methyl-5-nitro-imidazole (temidazole) are pharmacologically valuable valuable compounds that can be used against protozoal and bacterial infections [ArzneimittelForschung, 16 (1) 23-29 (1966)].

A number of processes for hydroxyalkylation of the 1-position nitrogen atom of nitroimidazoles are disclosed in U.S. Patent Nos. 2,944,061 and 3,178,446, U.S. Patent Nos. 2,001,432 and 2,359,625, British Patent Nos. 939,681 and 1,301,225. descriptions). Average yield of processes

It is around 6-18%.

According to Spanish Patent No. 305,073, 2-methyl-4-nitroimidazole is reacted with 2-butoxyethyl p-toluenesulfonate to produce metronidazole and then hydrolyzed. The yield of the process is only 27.3%.

One known method of introducing a hydroxyalkyl group is based on the use of appropriate alkylene sulfate (U.S. Patent No. 3,743,653). However, the yield of the process and the degree of conversion are not satisfactory.

It has been found that the nitroimidazole derivatives of formula (VI), wherein R _{2 is} hydrogen or (C 1 -C 4) alkyl and Y (C 2 -C 4) hydroxyalkyl can be prepared in excellent yield and conversion from nitroimidazole compounds of formula (IV) wherein

R ₂ is hydrogen or C 1-4 alkyl and

X is hydrogen or (C 1 -C 4) -alkanoyloxymethyl with the new sulfone derivatives of formula (I)

R is C 1-4 alkyl,

R 1 is C 1 -C 4 alkyl or

-O- (CH ₂ ) _n -O-CO-R wherein R is as defined above and both R are the same and n is condensed by 2 or 3, followed by hydrolysis or alcoholysis of the resulting compound. When X in the starting compound is C 1-4 alkanoyloxymethyl, then Y is always attached to the opposite nitrogen atom.

The condensation with the compound of formula I is generally carried out at a temperature of from 60 to 100 ° C, preferably about 80 ° C, optionally in a solvent such as an ester such as methyl acetate, ethyl acetate or an ether such as methyl tert-butyl ether or in an ketone such as methyl isobutyl ketone, and in aromatic hydrocarbons such as toluene or xylene or mixtures thereof.

For example, the resulting compound can be hydrolyzed or alcoholized by heating at 60-100 ° C in water or an alcohol such as methanol or ethanol.

The resulting 1- (hydroxyalkyl) nitroimidazole can be isolated from the reaction mixture in a conventional manner at about pH 10.

The imidazole derivatives of formula (IV) may be prepared by the methods described in British Patent 1,026,631.

The sulfone derivatives of formula (I) may be prepared by reacting an acid of formula (II), wherein R 1 is C 1 -C 4 alkyl, with a diester of formula (III), or R 1 -O- (CH ₂ ) _n -O-CO-R by reacting methyl sulfate with a diester of formula III.

The diester of formula (III) may also be used in excess.

Both variants are generally carried out under reduced pressure (1.3-26.6 kPa) at 80-160 ° C. The RCOOH acid or alkyl ester formed and, optionally, the excess diester of formula (III) is removed by distillation.

In general, the resulting compound of formula (I) is used without further purification.

Particularly preferred hydroxyalkylating agents are di (2-acetoxyethyl) sulfate and 2-acetoxyethyl mesylate.

The following non-limiting examples illustrate the details of the process of the invention.

Example 1

292.3 g (2 mol) of glycol diacetate and 50.4 g (0.4 mol) of dimethyl sulphate are introduced into the distillation apparatus, the flask of which is immersed in an acetone-dry ice bath. The apparatus was pressurized to 200 mmHg (26.6 kPa) and the reaction mixture was heated at 150 ° C for 5 hours. While heating, 60 ml of methyl acetate are distilled off. The reaction mixture was then cooled to about 100 ° C and further distilled at 1 mm Hg (0.13 kPa) and 206 ml of glycol diacetate (water bath temperature 110 ° C and steam temperature 65 ° C).

The distillation flask afforded di (2-acetoxyethyl) sulfate, a light yellow oil.

The di (2-acetoxyethyl) sulphate characterized by the following: infrared spectrum characteristic absorption at ^cm-1 in 1740 (C = 0 acetate); 1395-1195 (CO-SO ₂ -OC) and 1245 (CO), proton magnetic resonance spectrum (360 MHz; CD ₃ CN chemical shift in ppm) = 4.45 (triplet), 4.31 (triplet) and 2 ( singlet).

Into a flask fitted with a magnetic stirrer was added 2.7 g (0.01 mol) of di (2-acetoxyethyl) sulfate and 1.99 g (0.01 mol) of 1- (acetoxymethyl) -2-methyl-4-nitro -imidazole. The reaction mixture was heated at 80 ° C for 5 hours. Water (5 ml) was added and heating continued at 80 ° C for 3 hours.

After cooling, it is determined by high performance liquid chromatography; 1.10 g of metronidazole and 0.288 g of 2-methyl-4- (or -5) -nitroimidazole are obtained.

HU 206 089 Β

The conversion of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was 77.3%.

The yield of metronidazole was 64.2% based on the 1- (acetoxymethyl) -2-methyl-4-nitroimidazole used and the converted 1- (acetoxymethyl) -2-methyl-4-nitroimidazole. %. The isolated metronidazole melts at 158-160 ° C.

Example 2 ^t flask Magnetic stirrer with introducing sulphate 10.8 g (0.04 mol) of di (2-acetoxyethyl), prepared as described in Example 1 and 7.96 g (0.04 mol) 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was passed. The reaction mixture was heated at 80 ° C for 4 hours. At this time, methanol (20 mL) was added and refluxed for 4 hours. The resulting solution was determined by high performance liquid chromatography (HPLC) using an external standard of 4.89 g of metronidazole and 0.95 g of 2-methyl-4- (or -5) -nitroimidazole.

The conversion of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was 81%.

The yield of metronidazole was 71.5% based on the 1- (acetoxymethyl) -2-methyl-4-nitroimidazole used and 88% on the converted 1- (acetoxymethyl) -2-methyl-4-nitroimidazole.

Example 3

7.96 g (0.04 mol) of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole and 10.8 g (0.04 mol) of di (2-acetoxyethyl) were placed in a magnetic stirrer flask. sulfate. The reaction mixture was heated at 80 ° C for 4 hours, then methanol (20 ml) was added and the mixture was heated under reflux for 4 hours. Cool to 20 ° C and adjust the pH to 11.7,

5.5 ml of concentrated sodium hydroxide solution (density = 1.33) were added. The resulting precipitate was collected by filtration and washed with methanol (2 x 3 mL).

After drying, 4.61 g of product is obtained which is a mixture of imidazole derivatives and 98.6% of metronidazole and 0.6% of 2-methyl-4- (or -5) -nitro-imidazole (as determined by high performance liquid chromatography). using an internal standard).

Analysis of the product by high performance liquid chromatography using an external standard shows that 2.85 g of metronidazole and 0.014 g of

Contains 2-methyl-4- (or -5) -nitro-imidazole.

HPLC analysis of the filtrate using an external standard indicated that μ contains 2.15 g of metronidazole and 0.93 g of 2-methyl-4- (or -5) -nitro-imidazole. The conversion of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was 81.4%.

¹ * The yield of metronidazole is 90% relative to the converted 1- (acetoxymethyl) -2-methyl-4-nitroimidazole.

Example 4

A distillation apparatus, the flask of which is immersed in an acetone-dry ice bath, is charged with 23.4 g (0.16 mol) of glycol diacetate and 7.84 g (0.08 mol) of concentrated sulfuric acid (density 1.83).

Hgmm (2 kPa) was maintained and the reaction mixture was heated at 100 ° C for 3 hours, during which time 8 g of acetic acid was distilled off.

The distillation flask afforded di (2-acetoxyethyl) sulfate as a yellow oil.

A magnetic stirrer flask was charged with 7 g of di (2-acetoxyethyl) sulfate prepared as described above and 5.1 g (0.026 mol) of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole. . The reaction mixture was stirred for 6 hours

Heat at 80 ° C. Water (13 ml) was added and the mixture was heated at 90 ° C for 4 hours.

The resulting solution was determined by high performance liquid chromatography using an external standard and contained 2.39 g of metronidazole and 1.03 g of 2-methyl-4- (or -5) -nitroimidazole.

The conversion of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was 68%.

The yield of metronidazole was 54.5% based on the 1- (acetoxymethyl) -2-methyl-4-nitroimidazole used and 79% based on the converted 1-acetoxymethyl-2-methyl-4-nitroimidazole.

Example 5

Into a flask equipped with a magnetic stirrer was charged 6 g of di (2-acetoxyethyl) sulfate prepared according to Example 4 25 and 4.38 g (0.022 mol) of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole. . The reaction mixture was heated at 80 ° C for 6 hours, then methanol (11 mL) was added and the mixture was refluxed.

4 hours.

The resulting solution was determined by high performance liquid chromatography using an external standard and the solution was 2.47 g metronidazole and 0.82 g

Contains 2-methyl-4- (or -5) -nitro-imidazole.

The conversion of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was 71%.

The yield of metronidazole was 65.6% based on the 1- (acetoxymethyl) -2-methyl-4-nitroimidazole used and the converted 1- (acetoxymethyl) -2-methyl-4-nitroimidazole40 93%.

Example 6

The distillation apparatus, the flask of which is immersed in an acetone-dry ice bath, is charged with 9 g (0.062 mol) of glycidol diacetate and 6 g (0.062 mol) of methanesulfonic acid. The apparatus was pressurized (15 mmHg, 2 kPa) and the reaction mixture was heated at 110 ° C for 4 hours. During heating, 2.81 g of acetic acid is distilled off.

The distillation flask recovered a pale yellow oil containing 80% by weight of acetoxyethylene glycol mesylate.

Acetoxyethylene glycol mesylate can be characterized as having a characteristic ab55 absorption spectrum in cm -1 at 1740 (C-0 acetate), 1360 (C-O) and 1180 (SO ₂ -O).

The protomágneses resonance spectrum (360 MHz; CD ₃ CN, chemical shift in ppm): 4.36 (triplet), 4.26 (triplet) 3.07 (singlet) and 2 (singlet).

Flask with magnetic stirrer as above

Acetoxyethylene glycol mesylate (2.5 g) and 1.427 g (0.072 mol) of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole were passed. The reaction mixture was heated at 90 ° C for 6 hours. Ethanol (20 ml) was added and refluxed for 1 hour.

The resulting solution was determined by HPLC using an external standard and contained 0.932 g of metronidazole and 0.120 g of 2-methyl-4- (or -5) -nitro-imidazole. The conversion of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole was 87%.

The yield of metronidazole was 77% based on the used 1- (acetoxymethyl) -2-methyl-4-nitroimidazole and 89% based on the converted 1- (acetoxymethyl) -2-methyl-4-nitroimidazole.

Example 7

A magnetic stirrer flask was charged with 2.5 g of the acetoxyethylene glycol mesylate prepared in Example 6 and 1.405 g (0.071 mol) of 1- (acetoxymethyl) -2-methyl-4-nitroimidazole. The reaction mixture was heated at 90 ° C for 6 hours. Water (20 ml) was added and the mixture was heated at 80 ° C for 1 hour.

The resulting solution was determined by HPLC using an external standard of 0.907 g of metronidazole and 0.112 g of 2-methyl-4- (or -5) -nitroimidazole.

The conversion of 1- (acetoxymethyl) -2-methyl-4-imidazole was 88%. The yield of metronidazole was 74% based on the 1- (acetoxymethyl) -2-methyl-4-nitroimidazole used and 85% based on the converted 2- (acetoxymethyl) 4-nitroimidazole.

Example 8

5.4 g of di (2-acetoxyethyl) sulfate and 1.85 g of 1- (acetoxymethyl) -4-nitroimidazole are introduced into a flask equipped with a magnetic stirrer. Xylene (30 ml) was added and heated at 80 ° C for 6 hours. Water (30 ml) was added and the reaction mixture was refluxed for 4 hours.

The organic phase was determined by HPLC using an external standard and had a conversion rate of 88% for 1- (acetoxymethyl) -4-nitroimidazole and 1-hydroxyethyl-5-nitroimidazole. which is identical to that described in British Patent No. 939,681, is 97% of the converted 1- (acetoxymethyl) -4-nitroimidazole.

Example 9

Placed -nitroimidazole and 1.66 g (4.10 ^"3 mol) of di (2-acetoxyethyl) sulphate flask equipped with stirrer, 0.264 g (2.10 ³ mol) of 2-methyl-4 (or 5). After heating under argon for 5 hours and a half at 80 ° C, 0.12 ml of concentrated sulfuric acid was added and the mixture was allowed to stand at 80 ° C for 30 minutes. Water (2 ml) was added and stirred at 80 ° C for 36 hours. After cooling and diluting the reaction mixture, high pressure liquid chromatography afforded 0.162 g of metronidazole and 59 mg of 2-methyl-4 (or 5) nitroimidazole. The conversion of 2-methyl-4 (or 5) -nitroimidazole is 77.6%. Metronidazole yields 61% of the converted 2-methyl-4 (or 5) -nitroimidazole and 47.4% of the starting 2-methyl-4 (or 5) -nitroimidazole.

Example 10 (known procedure)

A stirred flask was charged with 131 mg (0.001 mol) of 2-methyl-4- (or 5) -nitroimidazole, 130 mg (0.001 mol) of ethylene sulfate and 2 ml of xylene. The mixture was heated at 80 ° C for 4 hours, then ethanol (5 ml) was added and the mixture was refluxed for 4 hours. The resulting solution contains 25 mg of metronidazole and 100 mg of 2-methyl-4 (or 5) -nitro-imidazole by high performance liquid chromatography.

The conversion of 2-methyl-4 (or 5) -nitro-imidazole is 23%.

The yield of metronidazole is 14% relative to the starting 2-methyl-4 (or 5) -nitroimidazole and 60% relative to the converted 2-methyl-4- (or 5) -nitroimidazole.

Example 11 (known procedure)

A stirred flask was charged with 130 mg (0.001 mol) of 2-methyl-4 (or 5) -nitro-imidazole and 130 mg (0.001 mol) of ethylene sulfate and heated at 90 ° C for 4 hours. Ethanol (5 ml) was added and the mixture was refluxed for 4 hours.

After diluting the reaction mixture, 42.4 mg of metronidazole and 76.2 mg of 2-methyl-4 (or 5) -nitro-imidazole are identified by high performance liquid chromatography.

The conversion of 2-methyl-4 (or 5) -nitroimidazole is 42%.

The yield of metronidazole is 24% relative to the starting 2-methyl-4 (or 5) -nitroimidazole and 58% relative to the converted 2-methyl-4 (or 5) -nitroimidazole.

Claims (8)

A process for the preparation of nitroimidazole compounds of formula VI: wherein _R2 is hydrogen or C1-4 alkyl and Y is C2-3 hydroxyalkyl group which comprises, reacting a compound '(IV) wherein X is hydrogen or C1-4 alkanoyloxy-methyl group, R ₂ as defined above, with a sulfone derivative of the formula I in the formula R is C 1-4 alkyl, R 1 is C 1 -C 4 alkyl or -O (CH ₂ ) _n -O-CO-R in which R is as defined above and both R are the same and n is 2 or 3 condensed and the resulting compound is hydrolyzed or alcoholized. (Priority: January 13, 1989) 2. A process according to claim 1 wherein R _is -O- (CH ₂ ) ₂ -O-CO-R and R is as defined above. (Priority: January 13, 1989) HU 206 089 B 3. The process according to claim 1 or 2, wherein the compound of formula I is selected from the group consisting of R 1 -O- (CH ₂ ) ₂ -OCO-CH ₃ . (Priority: January 13, 1989) 4. Process according to any one of claims 1 to 3, characterized in that di (2-acetoxyethyl) sulfate is used as the compound of formula (I). * (Priority: January 13, 1989) A process according to claim 1 wherein R 1 is C 1 -C 4 alkyl. (Priority: 13/13/1989) 6. A process according to claim 1 or 5, wherein R is methyl and R 1 is a compound of formula (I). according to claim 5. (Priority: January 13, 1989) The process according to claim 1, 5 or 6, wherein (2-acetoxyethylene glycol) mesylate is used. (Priority: January 13, 1989) 8 8. In Figures 1-7. A process for the preparation of 1- (hydroxyethyl) -2-methyl-5-nitroimidazole according to any one of claims 1 to 3, characterized in that a compound of formula IV is used wherein R _{2 is} methyl and X is as defined above. 10 (Priority: Jan 15, 1988) 9. A process according to any one of claims 1 to 4, characterized in that it is condensed at 60-100 ° C. (Priority: January 13, 1989) 10. A method according to any one of claims 1 to 6 Characterized in that it is condensed in an organic solvent, preferably an ester, ether, ketone or aromatic hydrocarbon.