GB1570094A - Substituted tetrazole-5-thiols - Google Patents

Description

PATENT SPECIFICATION

( 11) 1 570 094 Application No 19786/79 ( 22) Filed 26 Oct 1976 Divided out of No 1570093 Convention Application No 627164 Filed 30 Oct 1975 Convention Application No 665837 Filed 11 March 1976 Convention Application No 704142 Filed 12 July 1976 in United States of America (US)

Complete Specification published 25 June 1980

INT CL 3 C 07 D 257/04 Index at acceptance C 2 C 1464 20 Y 215 220 22 Y 247 250 252 25 Y 292 29 X 29 Y 305 Y 321 32 Y 332 342 34 Y 371 373 37 Y 380 385 512 513 522 601 613 614 620 62 X 650 75 X 76 X 78 X AA RC RE RM SC SL Inventor DAVID ALAN BERGES ( 54) SUBSTITUTED TETRAZOLE-5-THIOLS ( 71) We, SMITHKLINE CORPORATION, of 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-

This invention relates to substituted tetrazole 5 thiols which are useful as intermediates in preparing cephalosporin compounds which have antibacterial activity and are described and claimed in our copending Application 44441/76, (Serial No 1,570,093) and they are also useful in preparing other intermediates for preparing such cephalosporin compounds, these other intermediates being described and claimed in our copending Application 19863/79 (Serial 1570095).

According to the present invention there are provided compounds of the formula:

N f HS / I N (CH 2)n N Hs O 3 H where N is an integer from two to five.

The compounds of formula I can be prepared by reaction of an appropriate I aminoalkyl 5 ( 2,4 dinitrophenylthio)tetrazole with sulfur trioxide trimethylamine complex with subsequent cleavage of the 2,4 dinitrophenyl protecting group, the I aminoalkyl 5 ( 2,4 dinitrophenylthio)tetrazole being prepared by reaction of 2,4 dinitrofluorobenzene and a 1 acetamidoalkyltetrazole 5 thiol, followed by acid hydrolysis of the acetamido moiety The I acetamidoalkyltetrazole 5 thiols can be prepared by reaction of an acetamidoalkyldithiocarbamate, such as methyl 2 acetamidoethyldithiocarbamate, with an azide such as sodium azide The acetamidoalkyldithiocarbamates can be prepared by reaction of an N aminoalkylacetamide, such as N ( 2aminoethyl) acetamide, with carbon disulfide and an alkyl halide such as methyl iodide in the presence of a base such as triethylamine.

The invention also includes salts of the compounds of formula I, for example with the alkali metals, such as sodium or potassium, the alkaline earth metals such as calcium, or the ammonium cation These salts can be prepared by standard methods.

The following Examples illustrate the invention but are not to be construed as limiting the scope thereof Temperatures are in degrees Centigrade ( C) unless otherwise stated.

EXAMPLE 1

I ( 2 Sulfaminoethyl) tetrazole 5thiol To a solution of 20 4 g ( 0 20 mol) of N ( 2 aminoethyl) acetamide in 200 ml of 950 ethanol were added 27 9 ml ( 0 20 mol) 0 0 r( 21) ( 62) ( 31) ( 32) ( 31) ( 32) ( 31) ( 32) ( 33) ( 44) ( 51) ( 52) ( 72) 2 1,570094 2 of triethylamine and 12 0 ml ( 0 20 mol) of carbon disulfide The resulting exothermic reaction mixture reached reflux and was then cooled to ambient temperature over a 1 5 hour period Methyl iodide ( 28 4 g, 0 20 mol) was added, which also produced an exothermic reaction After 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 sodium thiosulfate, dried (Mg SO 4), and evaporated to dryness to give methyl 2 acetamidoethyldithiocarbamate.

To a solution of 38 4 g ( 0 198 mol) of methyl 2 acetamido ethyldithiocarbamate in 100 mol of 95 % ethanol was added 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, and then it was cooled and concentrated under reduced pressure to about half volume The solution was cooled to 15 , and ml of 6 N sulfuric acid were added The acidic solution was filtered and the filtrate was concentrated to about 100 ml and chilled at 5 to induce crystallization of 1 ( 2 acetamido ethyl) 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 ( O 0)50 mol) of 1 ( 2 acetamidoethyl)tetrazole 5 thiol and 6 85 ml ( 0 050 mol) of triethylamine in I 00 ml of acetone, and the reaction mixture was stirred for 1 hour The solid material was collected by filtration and it was recrystallized form acetonitrile to give 1 ( 2 acetamidoethyl) 5 ( 2,4 dinitrophenylthio)tetrazole, mp 197-198 .

A mixture of 6 5 g ( 0 02 mol) of I ( 2 acetamidoethyl) 5 ( 2,4 dinitrophenylthio)tetrazole, 100 ml of 12 N 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 which crystallized upon addition of ethanol to give 1 ( 2aminoethyl 5 ( 2,4 dinitrophenylthio)tetrazole hydrochloride, mp 217-219 (d).

To a solution of 3 5 g ( 0 01 mol) of 1 ( 2 aminoethyl) 5 2,4 dinitro phenylthio)tetrazole hydrochloride in 30 ml of dry dimethylformamide were added 1 4 g ( 0 01 mol) of sulfur trioxide trimethylamine complex, followed by 1 4 ml ( 0.01 mol) of triethylamine The mixture was stirred for 0 5 hour and then filtered The filtrate was evaporated in vacuo, acetone was added to the residue, the precipitate was removed by filtration, and the filtrate was evaporated to dryness Methanol was added to the residue, and the solid material produced upon scratching was removed by filtration The methanolic filtrate was brought to p H 11 3 by the addition of 5 O, methanolic sodium methoxide The filtrate was then stirred for 1 25 hours, filtered, and diluted with 300 ml of ether The resulting solid was removed by filtration, and the filtrate was evaporated to dryness to give a residue which was triturated with 95 % ethanol to induce crystallization The solid product was collected by filtration and dissolved in methanol, and the methanolic solution was concentrated to 10 ml, diluted with 75 ml of 95 % ethanol, and reconcentrated to 5 ml to give I ( 2sulfaminoethyl)tetrazole 5 thiol disodium salt, mp 122-127 .

C 3 Hs N 50352 2 Na 1 5 1 H 20 Calculated:

12.16 % C; 2 72 % H; 23 64 % N Found:

12.25 % C; 2 98 % H; 23 77 % N A solution of 1 ( 2 sulfaminoethyl)tetrazole 5 thiol disodium salt in water is passed through an Anberlite IR-120 H (registered Trade Mark) ion exchange resin column to give, after lyophilization, I ( 2 sulfaminoethyl)tetrazole 5 thiol.

EXAMPLE 2

When an equivalent amount of an N aminoalkylacetamide listed below:

N ( 3 aminopropyl)acetamide N ( 4 aminobutyl)acetamide N ( 5 aminopentyl)acetamide is used in the procedure of Example 1 in place of N ( 2 aminoethyl) acetamide, and the resulting dithiocarbamates are treated with sodium azide to produce the corresponding 1 acetamidoalkyltetrazole 5 thiols which are converted to the 1 sulfaminoalkyl derivatives, all as described therein, the following 1 sulfaminoalkyltetrazole 5 thiols are obtained:

1 ( 3 sulfaminopropyl)tetrazole 5thiol 1 ( 4 sulfaminobutyl)tetrazole 5 thiol 115 1 ( 5 sulfaminopentyl)tetrazole 5 thiol

Claims (7)

WHAT WE CLAIM IS:- 1 A compound of the formula:

1,570,094 3 1,570,094 3 N L HS / I -N (CH)n NH So 3 H in which N is two to five.

2 1 ( 2 Sulfaminoethyl)tetrazole 5 thiol.

3 A compound of claim 1 or claim 2, in the form of its sodium or potassium salt.

4 A compound as claimed in claim I as herein specifically described in Examples 1 and 2.

5 A process for preparing a compound for formula I (as defined in claim 1) which comprises reacting an appropriate I acetamidoalkyltetrazole 5 thiol with 2,4 dinitrofluorobenzene to form the corresponding I acetamidoalkyltetrazole 5 thiol 2,4 dinitrophenyl thioether followed by acid hydrolysis thereof to form the corresponding I aminoalkyltetrazole 5 thiol 2,4 dinitrophenyl thioether, reaction of the I aminoalkyltetrazolyl 2,4 dinitrophenyl thioether produced with sulfur trioxide trimethylamine complex, and subsequent cleavage of the 2,4 dinitrophenyl protecting group of the 1 sulfaminoalkyltetrazole 5 yl 2,4 dinitrophenyl thioether.

6 A process for preparing a compound of any of claims I to 3, substantially as described in the Examples.

7 A compound according to claim 1 whenever prepared by a process according to claim 5 or claim 6.

G.H HARGREAVES, Chartered Patent Agent.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1980 Published by The Patent Office, 25 Southampton Buildings London, WC 2 A l AY, from which copies may be obtained.

1,570,094