IE45976B1

IE45976B1 - Tetrazolylthiol derivatives

Info

Publication number: IE45976B1
Application number: IE2277/81A
Authority: IE
Original assignee: Smithkline Corp
Priority date: 1976-11-02
Filing date: 1977-10-27
Publication date: 1983-01-12
Also published as: IE812277L; IE812276L; IE45975B1

Description

This invention relates to certain tetrazolyl thiol derivatives and a process for their preparation.

Our co-pending Patent Application No 45976 discloses and claims certain novel antibacterially active cephalosporin derivatives. The thiols of this invention are useful as intermediates in the preparation of these cephalosporins.

Accordingly the invention provides a thiol of formula (I) :- (CH ) —P-OR' 2 n | (I) 2' 3 where n is one to five and R and R are each hydrogen or lower alkyl.

Herein lower alkyl means alkyl.

Preferably n is one.

One particular thiol within the scope of this invention is :1-diethoxyphosphinylmethyltetrazole-5-thiol.

According to this invention compounds of formula (I) can be prepared by reacting a compound of formula (II) :S II NH(CH-) 2 n OR' (II) where n is as defined with reference to formula (I) and R'\ 2 3 R and 2 are lower alkyl with an alkali metal azide, and thereafter optionally hydrolysing the product so obtained either under basic conditions to produce a compound of formula (I) 3 where one of R and R is hydrogen and the other is lower alkyl or hydrolysing the product so obtained with a mixture of concentrated hydrochloric and acetic acids to produce 2 3 a compound of formula (I) where R and R are both hydrogen.

An example of a compound of formula (II) which can be used in this process is methyl 1-(diethoxyphosphinyl)methyldithiocarbamate.

An example of an alkali metal azide which can be used in thi3 process is sodium azide.

The compound of formula (II) can be prepared by reacting the corresponding di-lower alkyl amine lower alkyl phosphonate for example diethyl aminomethylphosphonate with carbon disulfide and a lower alkyl halide for example methyl iodide in the presence of a base for example potassium hydroxide.

The aminoalkylphosphonate diloweralkyl esters not known to the art can be prepared by reaction of a dialkyl phthalimidoalkylphosphonate with hydrazine according to the procedure of Yamauchi et al., Bull. Chem. Soc. Japan 48:3285 (1975). The dialkyl phthalimidoalkylphosphonates can be prepared via reaction of a N-hydroxyalkylphthalimide with phosphorus tribromide followed by reaction of the Nbromoalkylphthalimide thus formed with a trialkylphosphite as described by Yamauchi et al., Bull. Chem, Soc, Japan 45:2531 (1972).

The following Example illustrate the invention.

EXAMPLE Carbon disulfide (0.88 ml, 1.11 g) was added dropwise to a stirred solution of diethyl aminomethylphosphonate (2.45 g; 14.6 mmol) and of potassium hydroxide (0.82 g; 14.6 mmol) in ethanol (25 ml). During addition the temperature of the reaction mixture rose form 26° to 33°C. A second portion of carbon disulfide (0.88 ml) was added and the mixture was stirred at 50°C for 1 hour. The mixture was cooled to ambient temperature, methyl iodide (2.08 g; 14.6 mmol) was added dropwise and the resulting mixture was stirred for 1.5 hours. The mixture was evaporated to dryness, the residue v?as dissolved in x-jater and the aqueous solution was extracted twice with ethyl acetate. The extracts were combined, dried (MgS04) and evaporated- to dryness to give methyl l-diethoxyphosphinylmethyldithiocarbamate.

To a solution of methyl 1-diethoxyphosphinylmethyldithiocarbamate (2.85 g; 11.1 mmol) in ethanol (25 ml) was added a solution of sodium azide (0.72 g; 11.1 mmol) in water (5 ml). The reaction mixture was refluxed for 2.5 hours then evaporated to near dryness. Water (20 ml) was added and the aqueous mixture was layered with ethyl acetate (40 ml) and acidified to pH 2.2 by addition of 6N sulfuric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate.

The ethyl acetate solutions were combined, dried (MgSO^) and evaporated to dryness to give 1-diethoxyphosphinylmethyltetrazole-5-thiol; NMR (CDCl^ + CCl^) :^4.87 (d.2H,J=13), 4.52 (q,2H,J=7), 4.33 (q,2H,J=7.5), 1.43 (t,6H,J=7-8).

C6H13N4°3PS Calculated : 28.57¾ C? 5.20S H? 22.21¾ N Found : 29.39% C; 5.42% H. 22.30% N

Claims

1. I. A compound of formula (1) HS w if |l (CH,) 2 n -OR * 3 OR (I) 2. 3 where n is one to five and R and R are each hydrogen or lower alkyl.

2. A compound as claimed in claim 1 where n is one. 15

3. , l-diethoxyphosphinylmethyltetrazole-5-thiol.

4. A process for preparing a compound as claimed in claim 1 which comprises reacting a compound of formula (II) :S 0 0 1 z\ ·· 2 R S z x NH(CH 2 ) —P—OR OR (II) •where n is as defined with reference to formula (I) and R^, 2 3 R and R are lower alkyl with an alkali metal azide, and thereafter optionally hydrolysing the product so obtained either under basic conditions to produce a compound of 2 3 formula (I) where one of R and R is hydrogen and the other is lower alkyl or with a mixture of concentrated hydrochloric and acetic acids to produce a compound of 2 3 formula (I) where R and R are both hydrogen. 4597®

5. A process as claimed in claim 4 where the azide is sodium azide.

6. A process as claimed in claim 4 substantially as described in the Example herein.

7. A compound as claimed in claim 1 whenever prepared by a process as claimed in anyone of claims 4 to 6.