Patent GB-1184665-A (GB)
Title: Penicillins
Inventor: EKSTROM BERTIL AKE
IPC: C07D499/00
Filed: 1966-12-28
Abstract: 1,184,665. Penicillins; phosphorus esterchlorides. ASTRA A.B. 8 Dec., 1967 [28 Dec., 1966; 29 March, 1967], Nos. 57987/66 and 14332/67. Headings C2A and C2C. The invention comprises phosphinylamino and phosphinothiolylamino penicillins of general Formula I and non-toxic salts thereof, wherein APA is the residue R<SP>1</SP> is H, or a C 1-5  alkyl, C 1  to C 10  aralkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic heterocyclic group; R<SP>2</SP> is R<SP>4</SP> or OR<SP>4</SP>, wherein R<SP>4</SP> is H, or a C 1-5  alkyl, C 1-10  aralkyl, monocyclic or bicyclic aryl or monocyclic heterocyclic group; R<SP>3</SP> is H, or a C 1-5  alkyl, C 1-10  aralkyl, monocyclic or bicyclic aryl or monocyclic heterocyclic group; which substituents R<SP>1</SP>, R<SP>3</SP> and R<SP>4</SP> may be substituted; X and X<SP>1</SP> are O or S, at least one of X and X<SP>1</SP> being O; and R<SP>3</SP> and R<SP>4</SP> may be connected and internally form a ring. The penicillins are prepared by reacting an amino penicillin of formula with (A) a compound of formula wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, X and X<SP>1</SP> have the above meaning and Z is an atom (or group of atoms) which can be split off together with one of the hydrogen atoms of the amino group of the amino-penicillin to produce penicillins of Formula I; or with (B) a compound of formula wherein R<SP>1</SP>, R<SP>2</SP> and X have the above meaning except that R<SP>2</SP> is not H and Z<SP>1</SP> gives OH on hydrolysis e.g. is Cl or phenoxy; or with (C) a compound of formula wherein R<SP>1</SP> and Z have the above meaning, R<SP>5</SP> is R<SP>7</SP> or OR<SP>7</SP> and R<SP>7</SP> is C 1-5  alkyl, monocyclic or bicyclic aryl or monocyclic heterocyclic, which may be substituted, R<SP>6</SP> is a group such as benzyl or phenyl which can be cleaved hydrogenolytirally ; or with (D) a compound of formula in which R<SP>1</SP>, R<SP>6</SP> and Z have the above meanings. Alternatively, a 6-aminopenicillanic acid or a salt or derivative thereof of formula is acylated with a compound of formula wherein R<SP>1</SP>, X and X<SP>1</SP> have the above meaning, R<SP>8</SP> and R<SP>9</SP> are the same or different and are C 1-5  alkyl, C 1-10  aralkyl, monocyclic or bicyclic aryl or monocyclic heterocyclic, which may be substituted, or may form a ring; Y is H or, at the same time as R<SP>10</SP>, is a di- or tri-alkylsilyl group, R<SP>10</SP> is H, a cation, dialkylsilyl, trialkylsilyl, trialkyltin, phenacyl which may be substituted; and COZ<SP>2</SP> is an acid chloride or its functional equivalent. Typical compounds are 6-[D-α- (hydroxymethoxyphosphinyl amino) phenylacetamido] penicillanic acid and 6-[D-α-(methoxyphenylphosphinothiolylamino) -phenyl - acetamido penicillanic] acid. Benzyloxy (methoxy)-phosphinyl chloride is prepared by treating benzyl methyl phosphonate with sulphuryl chloride. Methoxyphenylphosphinothiolyl chloride is prepared by treating phenylphosphinothiolyl dichloride with methanol and triethylamine in benzene. The penicillins are antibacterial agents, e.g. for treatment of mastitis in cattle, and nutritional supplements in animal feeds.