NO144152B - 6-ACYL-AMINOPENICILLANIC ANHYRIDES USED AS PRESENT IN THE PREPARATION OF THE SIMILAR 7-ACYL-AMINODEACETOXY-CEPHALOSPORAN ACIDS - Google Patents

Description

The present invention relates to new 6-acyl-aminopenicillanic anhydrides which are to be used as starting materials in the production of 7-acyl-aminodesacetoxycephalosporanic acids.

The hitherto unknown 6-substituted aminopenicillanic anhydrides have the general formula:

where R means a benzyl or phenoxymethyl group and R., means an acetyl, propionyl or benzoyl group.

The 6-acyl-aminopenicillanic acid anhydrides of the general formula I can be prepared in a manner known per se for the preparation of acid anhydrides.

E.g. can a 6-acyl-aminopenicillanic acid sulfoxide with

the general formula:

where R is as defined above and Y means a hydrogen atom or an alkali metal (preferably sodium or potassium) atom, is reacted with a halide of the general formula:

where R 1 is as defined above and X means a halogen (preferably chlorine or bromine) atom. The reaction is carried out in an inert organic medium such as dichloroethane or chloroform at a temperature between -20°C and 60°C.

In the case where Y represents a hydrogen atom, the reaction is preferably carried out in the presence of a nitrogen-containing base, such as pyridine or picoline, which will react with the hydrogen halide to form

nes during the reaction.

6-acyl-aminopenicillanic acid sulfoxides of the general formula VI can be obtained by treating the corresponding 6-acyl-aminopenicillanic acids with an oxidizing agent according to methods known per se. To this end, the 6-acyl-aminopenicillanic acid derivative is treated in an inert organic solvent or water with a substance that provides active oxygen such as sodium periodate, a peracid, hydrogen peroxide or iodosobenzene, in an amount sufficient to oxidize the thiazolidine sulfur atom

to a -SO group.

The new 6-acyl-aminopenicillanic acid anhydrides with the general formula I are to be used as starting materials in a new process for the production of 7-acyl-aminodesacetoxycephalosporanic acids, described in the Norwegian patent application Mr. 2942/72, where the advantages achieved by the method are also explained. Example I.

Preparation of the mixed anhydride of phenoxymethylpenicillin sulfoxide and acetic acid.

A solution of 0.28 ml (3 mmol) of acetyl bromide in 5 ml of 1,2-dichloroethane was added to a solution of 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide and 0.72 ml (9 mmol) of pyridine in 20 ml of 1, 2-dichloroethane. After stirring for 1 hour at 0°C, the mixture was filtered and evaporated to dryness. The residual foam (1.08 g, 2.6 mmol) was the mixed anhydride of phenoxymethylpenicillin and acetic acid.

IR spectrum (in CHCl 3 ): 1820; 1800; 1758 and 1000 cm"<1>.

PMR spectrum (in CDC13); tetramethylsilane was used as an internal standard: 6 = 1.35 (s,3); 1.74 (p.3); 2.32 (p.3); 4.55 (S.2); 4.72 (s,l); 5.17 (d,l, J=4.5 Hz); 6.12 (q,l, J =

11 Hz and J = 4.5 Hz); about 7 (m,5).

Example II.

Preparation of the mixed anhydride of benzylpenicillin sulfoxide and acetic acid.

A solution of 1.05 g (3 mmol) of benzylpenicillin sulfoxide in 20 ml of alcohol-free chloroform was cooled to 0°C after the addition of 0.72 ml (9 mmol) of pyridine. While the temperature was maintained at 0°C and the mixture was stirred, 0.28 mL (3 mmol) of acetyl bromide was added dropwise; the addition was complete after 30 minutes. The reaction mixture was concentrated at room temperature

trip; the residue proved to be the anhydride.

IR spectrum (in CHCl3): 1820, 1800, 1760 and 1010 cm"1.

PMR spectrum (in CDCl 2 ); trimethylsilane was used as an internal standard: 6 = 1.131 (s,3); 1.68 (p.3); 2.30 (p.3); 3.59 (p.2); 4.62 (s,l); 5.15 (d,l; J = 4.5 Hz); 5.97 (q,l; J = 10 Hz and J = 4.5 Hz); about 7.40 (s.5) ppm.

Example III.

Preparation of the mixed anhydride of benzylpenicillin sulfoxide and propionic acid.

0.97 g (2.5 mmol) of potassium benzylpenicillin sulfoxide was suspended in 15 ml of dichloroethane. After gentle heating, a solution was obtained. The solution was then cooled to about 0°C resulting in a gel; 0.23 ml (2.5 mmol) of a solution of propionyl bromide in 5 ml dichloroethane was added slowly. The gel disappeared and a precipitate (potassium bromide) formed. After 30 minutes, the precipitate was removed by filtration. A precipitate could be obtained from the filtrate after dilution with cyclohexane; this precipitate proved to be the anhydride.

IR spectrum (in CHC13): 1820, 1800, 1755 and 1030 cm"<1.>

PMR spectrum (in CDC13); tetramethylsilane was used as an internal standard: 6 = 1.08 (t.3; 3=1 Hz); 1.31 (p.3);

1.69 (p.3); 2.56 (q,2; J = 7 Hz); 3.60 (p.2); 4.67 (s,l);. 5.02 (d,l; J = 4.5 Hz); 6.04 (q.4; J = 10 and J = 4.5 Hz); 7.29 (s.5) ppm.

Example IV.

Preparation of the mixed anhydride of benzylpenicillin sulfoxide and benzoic acid.

1.05 g (3 mmol) of benzylpenicillin sulfoxide and 0.72 ml

(9 mmol) of pyridine was dissolved in 20 ml of dichloroethane. After cooling to 0°C, a solution of 0.41 ml (3.5 mmol) of benzoyl bromide in 5 ml of dichloroethane was added dropwise. After 1 hour, the resulting precipitate of pyridine-HBr was removed by filtration,

and the filtrate was concentrated at room temperature by evaporation of the solvent, thereby obtaining a foam-like residue which proved to be the anhydride.

IR spectrum (in CHCl-J : 1810-1820, 1790, 1740 and 1000

-1 J

cm

Example V.

Preparation of the mixed anhydride of phenoxy-methyl-penicillin sulphoxide and benzoic acid.

The preparation was similar to that of the corresponding benzylpenicillin sulphoxide derivative which was prepared in Example

IV.

IR spectrum (in CHC1-,) : 1810-1820, 1790-1800, 1740-1750

-1 J

and 1000 cm

Claims (1)

6-acyl-airinopenicillanic anhydrides for use as starting materials in the production of the corresponding 7-acyl-aminodesacetoxycephalosporanic acids, characterized in that they have the general formula: where R means a benzyl or phenoxymethyl group and R 1 means an acetyl, propionyl or benzoyl group.