IE44609B1 - 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 5 the structural formula N — N Formula I N-N (CHR^SOgR2 in which each individual R^ is hydrogen or lower alkyl, n is from 1 to 10, and 2 R is hydroxy, amino, (lower alkyl)amino or di - (lower alkyl)amino, TO and their alkali metal and amine salts.

By lower alkyl is meant an alkyl group having from 1 to 4 carbon atoms; such a lower alkyl group is preferably methyl or ethyl. ι 2 Preferably R is hydrogen and n is from 1 to 5. Preferably also R is hydroxy or amino.

In a process of the invention a tetrazole - 5 - thiol of Formula I where R is hydroxy, (lower alkyl)amino or di - (lower alkyl)amino is prepared by reaction of a corresponding N - substituted alkyl 4 6 0 9 dithiocarbamate of formula rZso^chrUhNhcssr, where R is alkyl, or its sodium or potassium salt, with sodium azide. Examples of suitable starting materials are methyl 2 5 sulfoethyl di thi ocarbamate and methyl 3 - ( N - t- butylsulfamoylpropyl)dithiocarbamate.

The N - substituted alkyl di thiocarbamates can be prepared by treatment of an ami noalkane sulfonic acid, for example 2 - aminoethanesulfonic acid, or an aminoalkane(N - alkyl or N,N - di al kyl) sulfonamide such as 3 - aminopropane -N-tbutylsulfonamide or its corresponding salt, with carbon disulfide and an alkyl halide such as methyl iodide in the presence of a base such as sodium or potassium hydroxide.

The aminoalkane (N - alkyl or N,N - di alkyl)sulfonamides can be prepared by reaction of hydrazine with an N - alkyl or N,N dialkyl - phthalimidoalkylsulfonamide, obtained by treatment of a phthalimidoalkylsulfonyl halide, preferably chloride, with an alkyl - or di alkyl - amine. The phthalimidoalkylsulfonyl halides are known or can be prepared as described by Winterbottom et al_., J.· Amer. Chem. Soc. 69:1393 (1947) and Griffin and Hey, 2· Chem. Soc., 3334 (1952).

The compounds of Formula I where R^ is amino can be prepared by removal of the N - alkyl group from the corresponding - (N - alkyl sulfamoyl alkyl )tetrazo1e - 5 - thiol, preferably a - (N - t - butylsulfamoylalkyl)tetrazole - 5 - thiol, with, for example, Zb anisole and trifluoroacetic acid. 46UB The tetrazole - 5 - thiols of the invention are useful for the production of antibacterial agents, for example the cephalosporins with a sulfo - or sulphamoyl - alkyl - substituted tetrazolyl - thiomethyl group at the 3 - position of the cephem nucleus described and claimed in our Patent Specification No. 557/76.

The following Examples illustrate the invention. Temperatures are in °C. Amberlite is a trade mark.

EXAMPLE 1 - Sulphomethyltetrazole - 5 - thiol To a solution of 112 g. (2.0 mol.) of potassium hydroxide and 111 g. (1.0 mol.) of aminomethanesulfonic acid in 250 ml. of water at 25° was added 71 ml. of carbon disulfide. The reaction mixture was stirred for 12 hours and 250 ml. of ethanol was added. The reaction vessel was fitted with a reflux condenser and 62 ml. (1.0 mol.) of methyl iodide was added. After an exothermic reaction the mixture was allowed to cool to ambient temperature, and the solid product was collected by filtration. The solid was extracted with hot methanol and the extract was concentrated to give methyl sulfomethyl dithiocarbamate as the potassium salt.

A mixture of 45.3 g. (0.19 mol.) of methylsulfomethyldithiocarbamate potassium salt and 16.9 g. (0.26 ml.) of sodium azide in 425 ml. of water was heated at 80° for 4.75 hours. The reaction mixture was passed through an Amberlite IR-120H ion exchange resin column and eluted with water until the pH of the eluant became 3.5. The eluant was extracted 4 6 0 9 with ether and the aqueous solution was evaporated to dryness to give 1 - sulfomethyltetrazole - 5 - thiol.

- Sulfomethyltetrazole - 5 - thiol was dissaved in acetone and a 30% solution of sodium 2 - ethaylhexanoate in isopropanol was added.

- Sulfomethyltetrazole - 5 - thiol sodium salt precipitated and was collected by filtration.

EXAMPLE 2 1-(2- Sulfamoylethy1)tetrazole - 5 - thiol A solution of 2.73 g. (0.01 mol.) of 2 - phthalimidoethanesulfonyl chloride in 20 ml. of chloroform was added dropwise to a solution of 2.19 g. (0.03 mol.) of t - butylamine in 20 ml of chloroform at 5°.

The reaction mixture was warmed to ambient temperature and stirred for three hours. The precipitate was removed by filtration and the filtrate was evaporated to dryness to give a residue which was purified by chromatography on silica with 19:1 chloroform - methanol as eluant to give N - t - butyl - 2 - phthalimidoethanesulfoamide.

N - t - Butyl - 2 - phthalimidoethanesulfonamide (2.10 g., 6.78 mmol.) was suspended in 20 ml. of ethanol and 0.344 g. of hydrazine hydrate was added. The reaction mixture was refluxed for three hours, then evaporated to dryness. The residue was suspended in 45 ml. of water and acidified to pH 3.0 by addition of dilute hydrochloric acid. The acid mixture was filtered and the filtrate evaporated to dryness to give - aminoethane - N - t - butyl - 2 - phthalimidoethanesulfonamide hydrochloride.

- Aminoethane - N - t - butylsulfonamide hydrochloride (1.25 g. .78 mmol.) was added to a solution of 1.17 g. (11.56 mmol.) of triethylamine in 20 ml, of ethanol. Carbon disulfide (0.44 g., 5.78 mmol.) was added, the mixture was stirred at 25° for 1.5 hours, then 0.82 g. (5.78 mmol.) of methyl iodide in 5 ml. of ethanol was added and the resulting mixture was stirred for 1.5 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acidified to pH 2.0 with dilute hydrochloric acid. The aqueous mixture was extracted with ethyl acetate and the extract was dried (MgSO^) and evaporated to dryness to give methyl 2 - (N - t - butylsul famoyl)ethyldi thi ocarbamate.

Methyl 2 - (N - i; - butylsulfamoyljethyldicarbamate was heated in solution with 4% aqueous sodium azide solution (1.4 molar equivalents) to 80° for 35 minutes to give 1 - (2 - N - t butylsulfamoylethyljtetrazole - 5 - thiol, which was isolated after acidification to pH 3.5. - (2 - N - t - Butylsulfamoylethyl)tetrazole - 5 - thiol (1.0 g.) was suspended in 10 ml. of anisole and 20 ml. of trifluoroacetic acid was added. The solution was heated at 56° for 3.5 hours, then cooled.

The precipitate was collected by filtration and washed with petroleum ether to give 1-(2- sulfamoylethyl)tetrazole - 5 - thiol.

EXAMPLE 3 Ί - (2 - N - Methylsulphamoylethyl)tetrazole - 5 - thiol Use of methylamine in the reaction with 2 - phthalimidoethanesulfonyl chloride described in Example 2, followed by the subsequent synthetic steps described therein'gives 1 - (2 - N - methylsulfamoylethyl)tetrazole 5 - thiol.

EXAMPLE 4 1-(2- Sulphoethyl)tetrazole - 5 - thiol - Aininoethanesulfonic acid (50 g., 0.4 mol.) was added to a solution of 45 g. (0.8 mol.) of potassium hydroxide in 100 ml. of water at 25°. Carbon disulfide (24.4 ml., 0.4 mol.) was added and the reaction mixture was refluxed for 2.5 hours.

Ethanol was added to the warm solution, the mixture was cooled to ambient temperature, 57 g. (0.4 mol.) of methyl iodide was added and the resulting mixture was stirred for 1.5 hours. The mixture was evaporated in vacuo and the residue recrystallized from hot ethanol containing 3% water to give methyl 2 - sulfoethyl di thiocarbamate potassium salt.

A mixture of 21.5 g, (0.087 mol.) of methyl 2 - sulfoethyldi thiocarbamate potassium salt (0.5 hydrate) and 7.16 g. (0.11 mol.) of sodium azide in 200 ml. of water was refluxed for two hours. The solution was cooled to 25° and extracted with ethyl acetate. The aqueous phase was treated with Amberlite IR-120H resin, washed with ether and evaporated to give an oil. The oil was taken up in acetone, the mixture was filtered and the filtrate was evaporated to dryness to give 1-(2- sulfoethyl)tetrazole - 5 - thiol. The thiol was dissolved in isopropanol, cyclohexylamine was added until pH 8-9 and acetonitrile was added to give 1-(2- sulfoethyl)tetrazole 5 - thiol as the di - cyclohexylamine salt. 1-(2- Sulfoethyl)tetrazole - 5 - thiol di - cyclohexylamine salt was dissolved in water and treated with Amberlite IR-120H resin to give 1-(2- sulfoethylJtetrazole - 5 - thiol. 446«θ EXAMPLE 5 - Sulfamoylmethyltetrazole - 5 - thiol A suspension of 15.1 g. (0.136 mol.) of aiiilnopthanesiilfonii- acid and T4.2 g. (0.145 mol.) of anhydrous potassium acetate in 48 ml. of acetic acid is refluxed for ten minutes. Phthalic anhydride (21.4 g., 0.145 mol.) is then added and the resulting mixture is refluxed for 2.5 hours. The product is collected by filtration and washed with acetic acid and ethanol to give phthalimidomethanesulfonic acid potassium salt.

To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium salt in 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed on a steam bath for one hour, then an additional 22.5 g. of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated to dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimido methanesulfonyl chloride.

When phthalimidomethanesulfonyl chloride is substituted in the procedure of Example 2 for 2 - phthalimidoethanesulfonyl chloride, N-t - butyl phthal imi domethanesulfonamide is prepared and is converted to 1 - N - _t - butylsulfamoylmethyltetrazole - 5 - thiol as described therein. Treatment of 1 - N - t - butylsulfamoylmethyltetrazole - 5 - thiol with trifluoroacetic acid and anisole as described in Example 2 gives 1 - sulfamoylmethyltetrazole - 5 - thiol. 4 6 0 a EXAMPLE 6 - (2 - Ν,Ν - Dimethylsulfamoylethyl)tetrazole - 5 - thiol - (2 - N,N - Dimethylsulfamoylethyl)tetrazole - 5 - thiol is prepared by reaction of dimethyl amine and 2 - phthalimidoethanesulfonyl chloride, followed by conversion of the product thus obtained to the tetrazole - thiol by the reaction sequence described in the procedure of Example 2.

EXAMPLE 7 1-(3- Sulfopropyl)tetrazole - 5 - thiol When an equivalent amount of 3 - aminopropanesulfonic acid was substituted in the. procedure of Example 4 for - aminoethanesulfonic acid, methyl 3 - sulfopropyl di thiocarbamate potassium salt was prepared.

Reaction of methyl 3 - sulfopropyldithiocarbamate potassium salt with sodium azide, as described in Example 4, gave 1-(3- sulfopropyl)tetrazole - 5 - thiol.

EXAMPLE 8 1-(3- Sul famoyl propyl) tetrazole - 5 - thiol When 3 - phthalimidopropanesulfonyl chloride is substituted in the procedure of Example 2 for 2 - phthalimidoethanesulfonyl chloride, N - - butyl - 3 - phthalimidopropanesulfonamide is prepared, and is converted to 1 - (3 - N - t - butylsulfamoylpropyl)tetrazole - 5 thiol as described therein. Treatment of 1 - (3 - (N - jfc butylsulfamoylpropyl) - tetrazole - 5 - thiol with trifluoroacetic acid and anisole as described in Example 2 gives 1-(3- sulfamoylpropyl)tetrazole - 5 - thiol.

EXAMPLE 9 1-(5- Sulfopentyl)tetrazo1e - 5 - thiol Substitution of an equivalent amount of 5 - aminopentanesulfonic acid in the procedure of Example 4 for 2 - aminoethanesulfonic acid gave methyl 5 - sulfopentyldithiocarbamate potassium salt.

Reaction of methyl 5 - sulfopentyldi thiocarbamate potassium salt with sodium azide, as described in Example 4, gave 1-(5- sulfopentyl)tetrazole - 5 - thiol.

EXAMPLE 10 1-(5- Su1famoy1pentyl)tetrazole - 5 - thiol Use of 5 - aminopentanesulfonic acid in the procedure of Example 5 in place of aminomethanesulfonic acid, followed by reaction of the product thus obtained with phosphorus pentachloride, gives 5 - phthalimidopentanesulfonyl chloride.

When 5 - phthalimidopentanesuTfonyl chloride is used as a starting material in the sequence described in Example 2, - (5 - N - t - butylsulfamoylpentyl)tetrazole - 5 - thiol is obtained. Treatment of 1 - (5 - N - t - butylsulfamoylpentyl)tetrazole - 5 - thiol with trifluoroacetic acid and anisole as described in Example 2 gives 1-(5- sulfamoylpentyl)tetrazole 5 - thiol.

EXAMPLE 11 1-(10- Sulfodecyl )tetrazole - 5 - thiol A suspension of 56 g. (1.0 mol.) of potassium hydroxide and 118.7 g. (0.5 mol.) of 10 - aminodecanesulfonic acid in 170 ml. 4 β U Μ of water is stirred for 30 minutes at 25°, then 40 g. (0.52 mol.) of carbon disulfide and 80 ml. of ethanol are added and the reaction mixture is stirred at 25° for 12 hours. The mixture is refluxed gently for two hours and cooled. Methyliodide (71 g., 0.3 mol.) and 130 ml. of ethanol are added to the mixture and it is stirred at 25° for 12 hours. The mixture is evaporated to remove the ethanol and the solid residue is collected by filtration to give methyl 10 - sulfodecyldithiocarbamate.

Methyl 10 - sulfodecyldithiocarbamate (31.4 g., 0.096 mol.) is reacted with 6.5 g. (0.1 mol.) of sodium azide as described in Example 1 to give 1-(10- sulfodecyl) - tetrazole - 5 - thiol.

EXAMPLE 12 1-(10- Sulfamoyl decyl)tetrazole - 5 - thiol Use of 10 - aminodecanesulfonic acid in the procedure of Example 5 in place of aminomethanesulfonic acid, followed by reaction of the product thus obtained with phosphorus pentachloride, gives 10 - phthalimidodecanesulfonyl chloride.

When 10 - phthalimidodecanesulfonyl chloride is used as a starting material in the sequence described in Example 2, - (10 - N - t - butylsu1famoyldecyl)tetrazole - 5 - thiol is obtained.

Treatment of 1 - (10 - N - t - butyl sulfamoyl decyl)tetrazole - 5 thiol with trifluoroacetic acid and anisole gives 1-(10sulfamoyldecyl)tetrazole - 5 - thiol.

EXAMPLE 13 1-(2- Sulfo - 1 - methylethyl)tetrazole - 5_ -_ thiol Substitution of an equivalent amount of 2 - aminopropansulfonic acid in the procedure of Example 4 for 2 - ami noethanesulfonic acid gives methyl (2 - sulfo - 1 - methyl ethyl)dithiocarbamate potassium salt.

Treatment of methyl (2 - sulfo - 1 - methylethyl dithiocarbamate potassium salt with sodium azide, also as described in Example 4, gives 1-(2- sulfo - 1 - methylethyl)tetrazole - 5 - thiol.

Claims (13)

1. A tetrazole - 5 - thiol compound of the formula N-N • I N-(I (CHR^nSOgR 2 in which each individual R^ is hydrogen or lower alkyl, p n is from 1 to 10, and R is hydroxy, amino, (lower alkyl)amino or di(lower alkyl)amino; or its alkali metal or amine salt.

2. A compound according to Claim 1 in which R 1 is hydrogen and n is from 1 to 5.

3. A compound according to Claim 2 in which R is hydroxy or amino.

4. 1 - Sulfomethyltetrazole - 5 - thiol.

5. 1-(2- Sulfoethyl)tetrazole - 5 - thiol.

6. 1 - Sulfamoylmethyltetrazole - 5 - thiol.

7. 1-(2- Sulfamoylethyl)tetrazole - 5 - thiol.

8. 1 - N - J; - butylsulfamoylmethyl - tetrazole - 5 - thiol.

9. 1 - (2 - N - t - butyl sulfamoyl ethyl)tetrazole - 5 - thiol.

10. A compound according to Claim 1 of any one of Examples 3 and 6 to 13.

11. A process for preparing a compound according to Claim 1 or Claim 2 where R is hydroxy, (lower alkyl)amino or di - (lower alkyl)amino, or a compound according to any one of Claims 4, 5, 8 and 9, in which a corresponding N - substituted alkyl dithiocarbamate of formula R^OgiCHR 1 ) NHCSSR where R is alkyl, or its sodium or potassium salt, is reacted with 5 sodium azide.

12. A process for preparing a compound according to Claim 1 substantially as described in any one of the Examples.

13. A compound according to Claim 1 whenever prepared by a process according to Claim 11 or Claim 12.