A HIGH YIELD PROCESS FOR PREPARING BETA-LACTAM ANTIBIOTICS HAVING A HIGH PURITY DEGREE

Abstract: A high yield process for preparing beta-lactam antibio­ tics having a high purity degree, in particular derivatives of the cephalosporanic and penicillanic acids, of the formula: by condensation of the compounds where X = H -OCH₃, (suitably blocked), with a chloride of the formula wherein R = H, OH in which said condensation is carried out in the presence of a nicotinic or isonicotinic base.

Description: The invention relates to the high yield production of beta-lactam antibiotics having a high purity degree,characterized in that the acylation reaction of the beta-lactam intermediate is carried out in the presence of a hydrogen chloride acceptor nicotinic or isonicotinic base.More in particular the instant invention concerns the high yield production of derivatives of the cephalosporanic and penicillanic acids of the formula: by silylation of the compounds wherein X = -O-CO-CH₃ with usual silylating agents such as trimethyl-chlorosilane, hexamethyldisilazane, dimethyldichlorosilane and the like, followed by acylation with chlorides of D- α -amino acids, wherein the amine group is blocked as a hydrochloride, of the general formula wherein R = H, OH in the presence of HCl acceptors of the general formula wherein -COOR₄ ; -COOH ; -CN wherein R₂ =R₃ =H, or R₂=H, and R₃= straight or branched C₁-C₅ chain alkyl; R₂=R₃= straight or branched C₁-C₅ chain alkyl; R₂≠ R₃ = straight or branched C₁-C₅ chain alkyl; R₄ = straight or branched C₁-C₅ chain alkyl. US-A-4 182709 discloses a process for preparing semi-synthetic penicillin antibiotics, especially ampicillin, which comprises acylating a silylated 6-aminopenicillanic acid in the presence of primary or secondary carboxamide bases as hydrogen halide acceptors. For example, according to the instant invention, the silylation reaction may be carried out either with hexamethyldisilazane in methylene chloride or with trimethylchlorosilane in the presence of a base, such as trimethylamine or diethylamine at a temperature of 0°C to 42°C. These hydrogen chloride acceptor bases have the advantage of showing very low toxicity as regards to the ones usually employed for said reactions, such as pyridine and dimethylaniline. The reaction of acylation of the previously silylated compound (III) and (IV) is carried out according to per se known methods, by employing the compounds of formula (V), however in the presence of such bases as (VI) or (VII). Bases (VI) and (VII) have, further, the advantage of being soluble in water as well as in the organic solvents, and, therefore, they can be easily eliminated. The acylation reaction can be effected at a temperature from -40°C to +40°C. By operating according to the process of the present invention, recovery of the products which are to be prepared can easily be effected either by extracting and precipitating the zwitterion of isoelectric pH, or by precipitating the hydrochloride by addition of alcohols such as methanol, ethanol, isopropanol, n-propanol and butanol to the reaction mixtures. The hydrochloride may then be converted to the zwitterion by treating with a suitable base an aqueous solution of the above said product till the isoelectric point. The process of this invention will now be illustrated by the following examples, limitedly to particular cephalosporins and penicillins; however , one skilled in the art could, without any difficulty, use this procedure for the preparation of further beta-lactam antibiotics, without there by exceeding the scope of the present invention. Example 1 6-(D-α-aminophenyl-acetamido)-2,2-dimethyl-penam-3-carboxylic acid. To a suspension of (6-APA) 6-aminopenicillanic acid (54g; 0.25 mole) in methylene chloride (450 ml), diethylamine (36.5; 0.5 mole) is added. To the so obtained solution, at a temperature from 0 to +5°C,trimethylchlorosilane (54.5g;0.5 mole) is added. After 90 minutes at 25°-30°C, the silylating reaction is completed. The reaction mixture is cooled to -30°C and nicotinamide (36.6 g; 0.3 mole) and D-α-phenylglycine chloride hydrochloride (51.5 g; 0.25 mole) are added. The suspension is kept two hours at -5°C and, thereafter, 30 minutes at + 10°C. It is treated with water (300 ml) and the phases are separated. The aqueous phase is treated with concentrated NH₄OH to the isoelectric point (pH=4.5). After 1 hour at 0°/+5°c, the antibiotic is filtered off and then it is washed with H₂O until disappearance of Cl⁻. It is dried under vacuum, to obtain 85g of ampicillin. 3H₂O. Yield : 84.3 % H₂O = 13.4% (Karl Fisher) Mercurimetric titre = 850 µg/mg Acidimetric titre = 860 µg/mg Acidimetric titre = 98.2% Amine titre = 97.69 % Example 2 6-(D- α - amino-p.HO-phenylacetamido)-2,2-dimethyl-penam-3 carboxylic acid. At the conditions of Example 1, by utilizing D-α-p.HO-phenylglycine chloride hydrochloride, amoxicillin 3 H₂0 (84.5 g) is obtained. Yield : 80.66 % H₂O= 13.5% (Karl Fisher) Microbiologic titre = 870 µg/mg Mercurimetric titre = 868 µg/mg Acidimetric titre = 97.6% Amine titre = 99.9% Example 3 7-(D- α -aminophenyl-acetamido)-3-methyl-3-cephem-4-carboxylic acid (7-ADCA) At the conditions of Example 1, by employing equimolecular amounts of 7-ADCA instead of 6-APA,cephalexin. H₂O (69g) is obtained. Yield : 77.5 % H₂0= 6.6% (Karl Fisher Microbiologic titre = 930 ug/mg Spectrophotometric titre = 920 ug/mg Acidimetric titre = 98.7% Amine titre = 97.9 % Example 4 7- [D-α-amino-(p.HO-phenyl)-acetamido]-3-methyl-3-cephem-4-carboxylic acid. At the conditions of Example 3, by employing p.HO-phenylglycine chloride hydrochloride, cefadroxil. H₂0 (73.8g) is obtained. Yield : 77.5% H₂O= 5.6 (Karl Fisher) Microbiologic titre = 930 µg/mg Spectrophotometric titre = 933 µg/mg Acidimetric titre = 99.1 % Amine titre = 97.7% Example 5 6-(D-α -aminophenyl-acetamido)-2,2-dimethyl-penam-3-carboxylic acid. To a suspension of 6-APA (54g; 0.25 mole) and nicotinic acid (30.75g;0.25 mole), Et₃N (75.9g;0.75 mole) is added. To the so obtained solution, at a temperature from 0 to +5°C, trimethylchlorosilane (81.75g;0.75 mole) is added. After 90 minutes at 25°-30°C, the reaction mixture is cooled to -30°C and thereafter D-α-phenylglycine chloride hydrochloride (51.5g; 0.25 mole) is added. The suspension is kept two hours at -5°C and then one further hour at +10°C. It is treated with water (300ml) and the phases are separated. The aqueous phase is treated with concentrated NH₄OH to achieve the isoelectric point (pH=4.5). The product as precipitated is filtered off and then it is washed with water. It is dried under vacuum to obtain 78g of ampicillin . 3H₂O. Yield : 77.4% H₂O = 14.78% (Karl Fisher) Microbiologic titre =840 µg/mg Mercurimetric titre =830 µg/mg Acidimetric titre = 96.8% Amine titre = 96.0% Example 6 7-(D-α -aminophenyl-acetamido)-3-methyl-3-cephem-4 carboxylic acid. At the same conditions as in Example 5, by utilizing (7-ADCA) 7-aminodeacetoxycephalosporanic acid instead of 6-APA cephalexin H₂O (67g) is obtained. Yield : 73.4% H₂O = 7.5% (Karl Fisher) Microbiologic titre = 905 µg/mg Spectrophotometric titre =900 µg/mg Acidimetric titre = 97.8% Amine titre= 96.9% Example 7 7-(D-α-aminophenyl-acetamido)-3-methyl-3-cephem-4-carboxylic acid. To a suspension of 7-ADCA (53.5g;0.25 mole) in methylene chloride (450ml) Et₂NH (36.5g;0.5 mole) is added. To the so obtained solution, at a temperature of 0° to +5°C,trimethylchlorosilane (54.5g;0.5mole) is added. After 90 minutes at -35°C, the reaction mixture is cooled to -30°C and methyl isonicotinate (34.5g;0.25 mole) and D-α- phenylglycine chloride hydrochloride (51.5g;0.25 mole) are added. One proceedes as in Example 5 and cephalexin H₂0 (77g) is obtained. Yield : 84.3% H₂O=7.5% (Karl Fisher) Microbiologic titre = 920 µg/mg Spectrophotometric titre = 920 µg/mg Acidimetric titre = 99% Amine titre 98.2% Example 8 7-(D-α -aminophenyl-acetamido)-3-methyl-3-cephem-4-carboxylic acid. At the same conditions as Example, 7, by employing methyl nicotinate instead of methyl isonicotinate, cephalexin.H₂O (78g.) is obtained. Yield = 85% H₂O=7.4% (Karl Fisher) Microbiologic titre = 920 µg/mg Spectrophotometric titre = 915 µg/mg Acidimetric titre = 99.2% Amine titre= 98.5%

Claims: A process for preparing beta-lactam antibiotics by acylation of a beta-lactam intermediate with an acid chloride in the presence of a pharmacologically non-toxic hydrogen chloride acceptor nicotinic or isonicotinic base. A process according to claim 1 for preparing derivatives of the cephalosporanic and penicillanic acids of formula by silylation of the compounds wherein X = -O-CO-CH₃ followed by acylation with a chloride of the formula : wherein R=H, OH characterized in that said acylation is carried out in the presence of a hydrogen chloride acceptor nicotinic or isonicotinic base. A process according to claim 1 or 2, characterized in that the acylation reaction is carried out in the presence of a compound of the formula : (*) wherein -COOR₄ ; -COOH ; -CN wherein R₂=R₃=H R₂=H R₃=straight or branched C₁-C₅ chain alkyl R₂=R₃=straight or branched C₁-C₅ chain alkyl R₂≠R₃=straight or branched C₁-C₅ chain alkyl R₄= straight or branched C₁-C₅ chain alkyl A process according to claim 2 ,characterized in that the derivatives of the cephalosporanic and penicillanic acids of the formula (I)and (II) are the following:amoxicillin trihydrate, ampicillin trihydrate, cephalexin monohydrate, cefadroxil monohydrate, cephaloglycin and p-hydroxycephaloglycin .

Inventors: FARINA, PAOLO, MAROTTA, VITTORIO, VALCAVI, UMBERTO
Applicants: IBI- ISTITUTO BIOCHIMICO ITALIANO  GIOVANNI LORENZINI S.P.A.
Application year: 1985
Main classification: C07D501
IPC codes: C07D499, A61K31, A61P31, C07D501