Aspoxicillin

Description

Aspoxicillin is an injectable, amino acid-type penicillin highly active against Gram-positive and Gram-negative bacteria, including the β-lactamase producing Bacillus frugilis. It is reportedly effective in the treatment of peritonitis, pneumonia and bronchitis.

Originator

Tanabe (Japan)

The Uses of Aspoxicillin

Aspoxicillin is a broad-spectrum antibiotic.

Definition

ChEBI: Aspoxicillin is a peptide.

Manufacturing Process

1). 3 g (23.6 millimoles) of D-2-amino-3-N-methylcarbamoyl-propionic acid hydrochloride (D-N'-methylasparagine HCl), 4.5 g of benzyloxycarbonyl chloride, 30 g of water, 30 ml of tetrahydrofuran and 12 g of potassium carbonate are mixed at 5° to 10°C. Then, the mixture is stirred at the same temperature for 2 hours. During the reaction, the mixture is kept at a slightly alkaline pH (pH 8) with potassium carbonate. 10 ml of water are added to the reaction mixture, and insoluble materials are filtered off. The filtrate is washed twice with ethyl acetate, acidified with citric acid and then extracted three times with 50 ml of ethyl acetate. The ethyl acetate extracts are washed with water, dried and evaporated to remove solvent. 5.1 g of D-2- benzyloxycarbonylamino-3-N-methylcarbamoyl-propionic acid are obtained. MP: 142°-143°C.
2). 2.8 g (10 millimoles) of D-2-benzyloxycarbonylamino-3-Nmethylcarbamoyl- propionic acid, 2.27 g of dicyclohexylcarbodiimide, 1.27 g of N-hydroxysuccinimide and 120 ml of tetrahydrofuran are mixed at 0° to 5°C, and the mixture is stirred at the same temperature for 16 hours. Insoluble materials are filtered off. Then, the filtrate is evaporated at 20°C under reduced pressure to remove the solvent, and the crystalline precipitates thus obtained are washed with a mixture of benzene-ether. 2.6 g of N-(D-2- benzyloxycarbonylamino-3-N-methylcarbamoyl-propionyloxy)succinimide are obtained. MP: 132°-134°C.
3). 3.75 g of N-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionyloxy) succinimide are dissolved in 50 ml of tetrahydrofuran. 12.5 ml of an aqueous 1 N-sodium hydroxide solution containing 2.3 g of p-hydroxy-D-phenylglycine are added to the solution. The mixture is stirred at room temperature for 24 hours. 20 ml of ethyl acetate and 20 ml of water are added to the reaction mixture, and said mixture is shaken. Then, the aqueous layer is separated, adjusted to pH 3 with citric acid and extracted with a mixture of 20 ml of tetrahydrofuran and 10 ml of ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue thus obtained is washed with ether. 3.0 g of D-2-(D-2- benzyloxycarbonylamino-3-N-methylcarbamoylpropionamido)- 2-phydroxyphenylacetic acid are obtained as colorless crystalline powder. MP: 154°-156°C(decomp.).
4). 429 mg of D-2-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionamido)- 2-p-hydroxyphenylacetic acid and 382 mg of 6-aminopenicillanic acid triethylamine salt are dissolved in 10 ml of dimethylformamide. 303 mg of diphenylphosphoric azide [N3PO(OC6H5)2] and 110 mg of triethylamine are added to the solution at -5°C, and the mixture is stirred at -5°C for 15 hours. After the reaction, the mixture is adjusted to pH 3 with an aqueous 5% citric acid solution and extracted with a mixture of 15 ml of tetrahydrofuran and 10 ml of ethyl acetate. The extract is washed with water, dried and then evaporated at below 40°C to remove the solvent. Ether is added to the residue obtained, and precipitates are collected by filtration. 509 mg of 6-[D-2-(D-2-benzyloxycarbonylamino-3-Nmethylcarbamoylpropionamido)- 2-p-hydroxyphenylacetamido]penicillanic acid are obtained as a colorless powder.
5). 627 mg of 6-[D-2-(D-2-benzyloxycarbonylamino-3-N-methylcarbamoylpropionamido)- 2-p-hydroxyphenylacetamido]penicillanic acid and 400 mg of 30% palladium-BaCO3 are suspended in 10 ml of methanol. The suspension is shaken at room temperature for 30 minutes. Said shaking step is carried out in a hydrogen gas atmosphere under atmospheric pressure. After the reaction is completed, the catalysts are removed by filtration. The filtrate is evaporated at below 40°C to remove the solvent, and ether is added to the residue. Then, a colorless crystalline powder is collected by filtration and washed with tetrahydrofuran. 443 mg of 6-[D-2-(D-2-amino-3-N-methylcarbamoylpropionamido)- 2-p-hydroxyphenylacetamido]penicillanic acid are obtained. MP: 198°-201°C(decomp.).

brand name

Doyle

Therapeutic Function

Antibiotic

Antimicrobial activity

An acylaminopenicillin, synthesized from amoxicillin. It is more active than carbenicillin against Ps. aeruginosa and is less active than piperacillin against Staph. aureus, H. influenzae, the Enterobacteriaceae and Ps. aeruginosa. It is not absorbed when dosed orally; the plasma half-life is 87 min after intravenous infusion.
Aspoxicillin has been used in the treatment of respiratory, skin and soft tissue and urinary infections in adults and children, and, in combination with aminoglycosides, against gynecological infections and infections in patients with hematological disorders.