Methyl acetoacetate → 6-(2-[4-Aminomethylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

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Reaction Steps

Sodium 4-[(1-methoxycarbonyl-2-propenyl)aminomethyl]phenylacetate is prepared from 4-aminomethylphenylacetic acid [Zaugg and Horrom, J. Am. Chem. Soc., 80, 4317 (1958)] and methyl acetoacetate by the method described by Dane and Dockner [Chem. Ber., 98, 789, (1965)]. A suspension of this salt (2.15 g, 7.5 mmole), 7 drops of N-methylmorpholine and 100 ml. of tetrahydrofuran is stirred at -20° C.; ethyl chloroformate (0.81 g. 7.5 mmole) is added and the mixture is stirred for 60 minutes. 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam (1.80 g., 7.5 mmoles) is suspended in a 50:50 mixture of tetrahydrofuran and water (40 ml), and the pH is adjusted to 7.5 with 1N sodium hydroxide solution whereby a homogeneous solution is obtained. This is added to the above suspension, in one portion, the new mixture is stirred at -20° C. for 1 hour and then it is allowed to warm to room temperature over 1 hour. Most of the tetrahydrofuran is removed in vacuo, the resultant aqueous solution is cooled in an ice bath, and the pH is adjusted to 1.5 with 3N hydrochloric acid. After 30 minutes the pH is adjusted to 2.5, and the solution is extracted with ethyl acetate. The aqueous phase is adjusted to pH 6.0 and freeze-dried. The resultant lyophylate is combined with that from another preparation (5 mmoles) and chromatographed on Sephadex LH-20 (150 g) eluting with water. Like fractions (tlc analysis) are combined and freeze-dried, yielding the title compound as a colorless amorphous solid (570 mg., 11% yield), m.p. 190°-200° C. IR(KBr): 1770, 1650 and 1515 cm-1. NMR (DMSO-d6 -D2O): 7.4 ppm (s, 4H), 5.65 ppm (d, J=4Hz, 1H), 5.45 ppm (d, J=4Hz, 1H), 5.2 ppm (s, 1H), 4.1 ppm (s, 2H), 3.6 ppm (s, 2H), 1.6 ppm (s, 3H) and 1.0 ppm (s, 3H).

Provenance & Evidence