NO843074L - PROCESS OF PREPARING THE DIMETHYL ESTER OF 3 (1-METHYL-5-NITRO-2-IMIDAZOLYL) -2-ACETYLPROPENIC ACID - Google Patents

Description

The present invention relates to a compound of formula (I):

with a strong anti-protozoal and antimycotic activity, as well as the relevant manufacturing method.

When performing experiments on the molecule of (methyl-1-'nitro-5-1H-imidazolyl)-methylene-2-oxo-3-ethylbutyrate of the formula (II): (hereinafter referred to as propenidazole) described in Italian patent No. 605 812, the possibility was discovered for investigation of the compound of formula (I) according to the following reaction scheme:

Compound (I) was found to have, compared to propenidazole, a stronger anti-mycotic and anti-protozoal activity. The procedure for the preparation of compound (I) will now be described.

Step 1

60 g of intermediate alcohol (1-methyl-2-hydroxymethyl-5-nitroimidazole) (compound III) were introduced into a 2 liter flask, to which 1 liter of chloroform RP was added.

The solution was heated with stirring until complete dissolution, and 150 g of MnO 2 was added which had previously been activated at 120°C continuously for 1 week.

The whole was then refluxed for 10 hours with vigorous stirring and filtered hot on a celite panel.

Then the filtered product was dried and taken up, extracting the residue cold with ethyl ether for 4 hours using 150 ml of ethyl ether each time.

The filtered ether extracts were dried in a rotary evaporator whereby approx. 23 g of aldehyde with a yield of 33.3% and a purity of 90%.

It is possible to recover the alcohol that does not take part

in the reaction.

Step 2

The aldehyde thus obtained (20 g) was placed in a 500 ral flask, and the following was added, in this order: 200 ml of benzene (to dissolve the aldehyde), 14.25 g of RP dimethyl malonate, 1.8 ml of glacial acetic acid and 2.2 ml anhydrous base RP piperidine. It is then boiled under reflux for 90 minutes, and water is continuously separated.

The flask, with the compound obtained from reflux, is dried under vacuum until a thick, paste-like liquid is obtained. The residue is taken up in 100 ml of chloroform and dissolved again completely; 100 ml of RP ethyl ether is added. After stirring and cooling, the folding reaction is carried out by scraping the walls. The whole thing is kept in the fridge for 4 hours, and

then the residue is separated by filtration.

The mother liquor is dried, taken up in 30 ml chloroform and 30 ml ether and placed in a refrigerator. The precipitate is separated and mixed with the previously obtained precipitate. In this way, 27 g of crude product is obtained, and the yield is insignificantly below 80%.

Step 3

The 27 g of crude product obtained are dissolved in the smallest possible amount of chloroform to obtain a clear solution, and then an amount of ethyl ether equivalent to the chloroform is added.

The operations described above are carried out to obtain a white, yellowish precipitate.

This operation is repeated twice, and then the residue is purified by crystallizing it with 96% ethanol.

Thus, 20 g of pure product is obtained which is ground and has the following properties:

Molecular weight: 269.2.

Analysis:

C = 44.57%

H = 4.08%

N = 15.60%

0 = 35.66%

Appearance: yellow, crystalline powder

Smell: odorless

Melting point: 140.5 - 141.5°C

Moisture to K.F.: <0.5%

Solubility in water: none

UV spectrum: 100 mg in 100 ml methanol - by diluting 2 ml to 100 ml with HCl 0.1 N a characteristic spectrum is obtained with maximum adsorption at 334.5 µm and E* = 738 ;/ 1 cm; TLC: silica gel support 60 F 254, CHC13 eluent: CH3OH (saturated chamber) 90:2 ; deposited amount: 100; 15 cm test for 2 hours Rf single spot = 0.85 ; Reaction to light: the product tends to become weak brown. The compound according to the invention has been treated on AMI "Difco" medium inoculated with Bacillus Subtilis at a concentration of 25y - 50y - 100y. A strong antimycotic, antiprotozoal and antibacterial activity was found to be present, by both oral treatment and topical application. The product can be administered in the form of pastilles (100-250 mg active drug), gel capsules (200-500 mg active drug), vaginal suppositories (100-300 mg active drug), or by applying skin lotions, creams and gels, with concentrations from 0 .5 to 1.5%. *

Claims (5)

1. Dimethyl ester of 3-(1-methyl-5-nitro-2-imidazolyl)-2-acetylpropenoic acid with the formula: where R - R' can be H, COOH, C0CHo , COOCH- , C00Co Hc , CH_, j 6 Z d J C^ H^ 0<3 aromatic derivatives, with antiprotozoal, antimycotic and antibacterial activity. 2. Procedure for the preparation of compounds of formula (I), characterized in that R is H, COOH, COC <H>3 , COOCH3 , COOC2 H5 , CH3 , C2 H5 and aromatic derivatives thereof, characterized by the following reaction steps: 3. Process for the preparation of a compound of formula (I), characterized in that the compound of formula (III) is boiled under reflux with stirring while adding RP chloroform and, after addition of Mn02 activated at 120°C, again boiled under reflux, is filtered hot, dried and taken up, and the residue is extracted with ethyl ether to obtain the product IV after filtration. 4. Process according to claim 3, characterized in that the product IV, with the addition of benzene, RP dimethylmalonate, glacial acetic acid and anhydrous RP piperidine, is boiled under reflux while water is continuously separated, the residue is taken up in chloroform and, after addition of RP ethyl ether, is reacted to form the raw product. 5. Process according to claims 2 - 4, characterized in that the crude product is dissolved in chloroform and, after addition of ethyl ether, stirred and cooled, and then separated by filtration to obtain the pure product.