IE45393B1 - Tetrazole-5-thiols - Google Patents

Description

This invention relates to tetrazole-5-thiols which are intermediates useful for the production of antibacterial agents, and to processes for preparing these intermediates.

The compounds of this invention are tetrazole-5-thiols of the structural formula (CH2)nNHS02R Formula I in which, n is from 2-to-5 and R is alkyl,of from 1 to 4 carbon atoms.

Preferably n is 2. A particularly valuable compound is l-(2-methanesulfonami doethyl)-tetrazole-5-thi ol.

A process of the invention is one for preparing a tetrazole-5-thiol of Formula I, in which a corresponding l-aminoalkyl-5-(2,4-dinitrophenylthio)tetrazole is reacted with an alkanesulfonyl halide, for instance methanesulfonyl chloride, - 2 '313303 and the 2,4-dinitrophenyl group is subsequently cleaved.

The l-aminoa1ky1-5-(2,4-dinitrophenylthio)tetrazole starting material can be prepared from an N-amino-alkyl acetamide, for instance N-(2-aminoethyl) acetamide, by reaction with carbon disulfide and an alkyl halide, for instance methyl iodide, in the presence of a base, for instance triethylamine, to give an alkyl N-acetamidoal kyldi thiocarbamate, which is reacted with an azide, for instance sodium azide, to give a l-acetamidoalkyl-tetrazole-5-thiol; this is then reacted with 2,4dinitrcfluorobenzene, followed by acid hydrolysis co give tne l-aminoalky1-5-{2,4di ni tropheny1 thio)tetrazole.

The tetrazc'ie-5-chiols of the invention are useful for the production of antibacterial agents, for example the 7-acylaminocepnalosporins with a l-(alkanesulfonamidoa1kyl)tetrazol-5-ylthiomethyl group at the 3-position of the cephem nucleus described and claimed in Patent Application .No. 45332 and 7-amino intermediates for such cephalosporins described and claimed in Patent Application No. 45394.

The following Example illustrates the invention: temperatures are in °C. EXAMPLE To a solution of 20.4 g (0.20 mol) of N-(2-aminoethyl)acetamide in 200 ml Of 93% ethanol was adder! 27.9 ml (0.20 mol) of triethylamine and 12.0 ml (0.20 mol) of carbon disulfide. The exothermic reaction reached reflux and then cooled to ambient temperature over a 1.5 hour period, Methyl iodide (28.4 g, 0.20 mol) was then added whicn again produced an exothermic reaction. After an additional 1.75 hours the reaction mixture was evaporated to dryness and the solid residue was dissolved in 200 ml of water. The aqueous solution was extracted twice with 250 ml portions of ethyl acetate. The extracts were combined, shaken with solid sodium thiosulfate dried (MgSO^) and evaporated to dryness to give methyl-N-(2acetami doethyi)dithiocarbamate.

To a solution of 38.4 g (0.198 mol) of methyl N-(2-acetamidoethyl)dithioca^bamate in 100 ml of 95% ethanol was added to a solution of 13.5 g (0.208 mol) of sodium azide in 100 ml of water. The reaction mixture was refluxed for 24 hours, - 3 45393 then cooled and concentrated under reduced pressure to about half volume. The solution was cooled to 15° and 50 ml of 6N sulfuric acid was added. The acidic solution was filtered and the filtrate was concentrated to about 100 ml and chilled at 5° to induce crystallization of l-(2-acetamidoethyl)tetrazole-5-thiol which was collected by filtration, mp 139-139.5°. Additional amounts of the product were obtained by continuous extraction of the filtrate with ethyl acetate.

A solution of 9.3 g (0.050 mol) of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 9.35 g (0.050 mol) of l-(2-acetamidoethyl)tetrazole-5-thiol and 6.85 ml (0.050 mol) of triethylamine in 100 ml of acetone and the reaction mixture was stirred for 1 hour. The solid material was collected by filtration and recrystallized from acetonitrile to give l-(2-acetamidoethyl)-5-(2,4dinitrophenylthio)tetrazole, mp 197-198°.

A mixture of 6.5 g (0.02 mol) of l-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, 100 ml of 12W hydrochloric acid and 100 ml of 95% ethanol was refluxed for 4.5 hours. The mixture was evaporated to dryness to give a gummy residue v/hich crystallized upon addition of ethanol to give 1-(2-arainoethyl )-5(2,4-dinitropheny1thio)tetrazo1e hydrochloride, mp 217-219° (d).

To a suspension of 4.9 g (14,1 mmol) of l-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride in 100 ml of pyridine was added 1.5 ml (2.2 g, 19.2 mmol) of methanesulfonyl chloride. The mixture was stirred for 1.5 hours, then an additional 0.5 ml of methanesulfonyl chloride was added and the mixture was stirred for another hour. The pyridine was removed by evaporation and the residue v/as dissolved in a small volume of dimethylformamide. Water was added to the solution and the resulting precipitate was collected by filtration, washed with water and air-dried. The precipitate v/as dissolved in a minimum amount of dimethyl formamide and the solution was diluted v/ith ethyl acetate and treated with Darco G-60 (Darco is a Trade Mark). The mixture was filtered and evaporated to dryness to give a syrupy residue which was crystallized from ethyl acetate to give 5-(2,4-dinitrophenylthio)-l-(2-methanesulfonamidoethy1)-tetrazole. Calculated for C10HnN70gS2 : C; 2.85% H; 25.18% N; Found: 31.08% C; 3.09% H; 25.17% N. - 4 -4S393 -(2,4-Dinitrophenylthio)-l-(2-methanesulfonamidoethyl )tetrazcle (4.46 g, 11.5 mmol) was added to 60 ml of 5% sodium methoxide in «te-thanol. After 1 hour water was added and the solid material was removed by filtration. The filtrate was concentrated in vacuo and 3N hydrochloric acid was added to the residue to bring the pH to 1.4. The acidic solution was filtered and the filtrate was extracted twice with ethyl acetate. The extracts were combined and concentrated to give a residue which crystallized upon addition of ethyl acetate to give 1-(2methanesulfonamidoetnyljtetrazole-o-thiol, mp 131-132°. Calculated for : 21.55 C; 4.055 rt; 31.375 li; Found : 2:.61» C; 4.195 rt; 31.63% N.

Claims (6)

1. 0 CLAIMS

1. A tetrazole-5-thiol of the structural formula in which n is from 2 to 5 and R is alkyl of from 1 to 4 carbon atoms.

2. A compound aeccrdir.g to Claim 1, in which n is 2. 55

3. The compound of Claim 2, which is l-(2-metnanesulfonamidoethyl)tetrazole-5thiol.

4. A process for preparing a compound according to any preceding claim, in which a corresponding 1-aminoa*:kyi-5--(2,4-dinitrophenylthio)tetrazole is reacted with an aikanesulfonyl halide and the 2,4-dinitrophenyl group is subsequently 20 cleaved.

5. A process according to Claim 4, substantially as described in the Example.

6. A tetrazole-b-thiol of Claim 1, whenever prepared by the process of Claim 4 or Claim 5.