Intermediates for producing semi-synthetic penicillins and cephalosporins and methods of production
AssigneeAmerican Home Products Corporation
InventorJohn H. Sellstedt
Life of this patent
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Abstract
Novel 6-APA, 7-ACA, and 7-ADCA derivatives are described which comprise phosphorylated derivatives of 6-APA, 7-ACA, or 7-ADCA and the corresponding acylated derivatives thereof. The novel compounds are prepared by the reaction of 6-APA, 7-ACA, 7-ADCA or a salt thereof with a phosphorus halide in the presence of an acid acceptor and subsequently acylating the thus formed phosphorylated compound, to form a phosphorylated acylated derivative which upon hydrolysis with water splits off the protective group(s) to provide the corresponding semi-synthetic penicillin or cephalosporin having useful antibacterial activity.
Claims15
In a process for producing penicillins or cephalosporins of the formula:
- ##STR58## wherein:
- ##STR59## and R is hydrogen or acetoxy which comprises (a) reacting a salt from the group consisting of the alkali metal salts and tertiary amine salts of 6-aminopenicillanic acid or 7-aminocephalosporanic acids of the formula:
- ##STR60## wherein Y is the same as in formula A above with a protective forming agent in the presence of an acid binding agent, then (b) reacting the resulting compounds with an acylating agent from a reactive derivative of a carboxylic acid to form the corresponding N-acyl derivatives, the improvement consisting essentially of employing as the protective forming agent a three valence phosphorus compound of the formula:
- ##STR61## wherein R.sup.1 and R.sup.2 are lower alkyl, phenyl, halo(lower)alkyl or phenyl(lower)alkyl;
- or R.sup.1 and R.sup.2 together jointly form a ring compound selected from the group consisting of:
- ##STR62## wherein m is a whole number from 1 to 2 and R.sup.4 is selected from hydrogen and methyl;
- X signifies a halogen atom subjecting the N-acyl compounds of (b) above to hydrolysis to obtain the compounds of formula A, above.
A process for preparing a penicillin or cephalosporin having antibacterial activity against gram positive and/or gram negative microorganisms, which comprises:
- a. reacting a member selected from the class consisting of a compound of the formula:
- ##STR63## wherein R.sup.2 is selected from the class consisting of hydrogen, alkali metal and tertiary amine;
- R.sup.4 is selected from the class consisting of hydrogen, (lower)alkanoyloxy containing 2 to 8 carbon atoms, and a quaternary ammonium radical;
- with a phosphorylating agent of the formula ##STR64## in the presence of an acid binding agent to form a phosphorus anhydride derivative of said compound of formula A or B, wherein R.sup.5 and R.sup.6 are each selected from the class consisting of (lower)alkyl, phenyl, naphthyl, halo(lower)alkyl, phenyl(lower)alkyl and naphthyl (lower)alkyl;
- R.sup.5 and R.sup.6 when joined together with the phosphorus atom form the ring ##STR65## X is selected from the class consisting of oxygen, methylene and sulfur;
- m is an interger from 1 to 6;
- and R.sup.7 is selected from the class consisting of hydrogen and (lower)alkyl;
- b. reacting said phosphorus anhydride derivative obtained in step (a) with an acylating agent selected from an organic carboxylic acid and a reactive functional derivative of said organic carboxylic acid to form the corresponding N-acyl derivative of said phosphorus anhydride obtained in step (a);
- and
- c. subjecting said N-acyl compound obtained in step (b) to hydrolysis to obtain a compound selected from those of the formula:
- ##STR66## and an acid addition salt thereof.
A process for preparing a penicillin having antibacterial activity against gram positive and/or gram negative microorganism, which comprises:
- a. reacting 6-aminopenicillanic acid with a phosphorylating compound of the formula:
- ##STR68## wherein:
- R.sup.7 is selected from the class consisting of hydrogen and lower alkyl;
- in the presence of an acid binding agent to form a phosphorus anhydride derivative of 6-aminopenicillanic acid, the molar ratio of said phosphorylating compound to 6-aminopenicillanic acid being at least about 1:1;
- b. reacting said phosphorus anhydride derivative of said 6-aminopenicillanic acid with an acylating agent which is a reactive functional derivative of an organic carboxylic acid to form an N-acylated compound of the formula:
- ##STR69## and;
- (c) subjecting said N-acylated compound to hydrolysis to obtain a compound selected from the class consisting of:
- ##STR70## and an acid addition salt thereof.
A method of preparing an acid addition salt of D(-).alpha.-aminobenzyl penicillin which comprises reacting 2-chloro-1,3,2-dioxaphospholane with 6-aminopenicillanic acid in a molar ratio greater than 1:1 under anhydrous conditions in the presence of an acid binding agent and thereafter acylating the reaction product thus formed with D(-)-phenyl glycyl chloride, hydrochloride and subsequently hydrolyzing the thus formed product with water to obtain a hydrochloride salt of D(-).alpha.-aminobenzylpenicillin.
A process for preparing a cephalosporin having antibacterial activity against gram positive and/or gram negative microorganisms, which comprises:
- a. reacting a compound selected from the class consisting of 7-aminocephalosporanic acid and 7-amino-3-desacetoxycephalosporanic acid with a phosphorylating compound of the formula:
- ##STR72## wherein R.sup.7 is selected from the class consisting of hydrogen and lower alkyl;
- in the presence of an acid binding agent to form a phosphorus anhydride derivative of said 7-aminocephalosporanic acid or acid 7-amino-3-desacetoxycephalosporanic acid, the molar ratio of said phosphorylating compound to either one of said 7-aminocephalosporanic acid or 7-amino-3-desacetoxycephalosporanic acid being at least about 1:1;
- b. reacting said phosphorus anhydride derivative obtained in step (a) with an acylating agent which is a reactive functional derivative of an organic carboxylic acid to form the corresponding N-acylated phosphorus anhydride of said compound obtained in step (b);
- and
- c. subjecting said N-acylated compound obtained in step (b) to hydrolysis to obtain a compound selected from the class consisting of:
- ##STR73## wherein R.sup.4 is either hydrogen or acetoxy;
- and an acid addition salt thereof.
Dependencies are inferred from the claim text.