Synthesis of 4-amino-3-isoxazolidinone (cycloserine)

Abstract

A synthesis of 4·amino·3·isoxazolidinone (I) (Cycloserine) pivoting on 1·t rityl-2-carbomethoxyethyleneimine (IV) is described. This key intermediate was prepared from N-tritylserine m ethyl ester via theO-mesylderivative in 80 % overall y ield. The hydroxamic acid VII corresponding to this ester on treatment with hydrogen chloride yielded 66 % of the hydrochloride of a:-amino -~-ch lo ropropiohydl'oxamic acid (X) together with a small amount of its position isomer XI. The former isomer was converted to 4-amino·3--isoxazolidinone (I) by treatm ent with a lkali or with strongly basic anion exchangers .4-Benzylamino-3-isoxazolidinone (Va) and 4-benzhydrylamino-3-isoxazolidinone (Vb) we re synthesised as models.The antibiotic cycloserine (Oxamycin, Seromycin), isolated in 1955 from a strain of St1'eptomyces\ possesses a broad antibacterial spectrum2, low toxicity and has been found to give encouraging results in the chemotherapy of tuberculosis, particularly with streptomycin and isonicotinyl hydrazide resistant strains 4 • It has also been found to be a powerful synergist of other antibiotics 5 and is hence thought to be a drug of high promise.The structure of the antibiotic as D-4-amino-3-isoxazolidinone (1) and its first synthesis have been disclosed in preliminary form 6 -B • In view of its relatively simple structure and clinical promise cycloserine thus is the second antibiotic -following chloramphenicol -whose production by synth esis rather than by fermentation appears as a practical possibility. Synthetic work in this field, attractive from the theoretical point of view on account of the somewhat unusual structure of cycloserine, thus also possesses considerable practical inter est.Little attention had hitherto b een devoted to the isoxazolidinone system. An analysis of the possible synthetic approaches to an aminoisoxazolidinone shows that the key step of its synthesis, i. e. the ring closure, can in principle be realised in two alternative ways. The first is the amidic ring closure of an ester of an lX-amino-~-aminooxypropionic acid (a), the second is the cyclisation of an cx-amino-~-halogenopropiohydroxamic acid or its derivatives (b).CHz-CH-COOCH a ~

5-Carboxamido-4-amino-3-isoxazolidone, an asparagine analog

“…Anal. (C20H18N2O8) C, , N. Ethynylestradiol 3-dimethylaminopropionate (1), norethindrone 3-(0-dimethylaminopropyl)oxime (syn and anti isomers, 2a and 2b), and testosterone 3-(0-dimethylaminopropyl)oxime (3) have been prepared and converted to zinc and aluminum tannate complexes as potentially long-acting prodrug forms of the parent steroids. The basic derivatives and the complexes showed the appropriate hormonal activities although they were less active in acute tests than the respective parents.…”

“…As a preliminary test of this strategem, we have synthesized basic derivatives of three representative steroids, specifically the estrogen ethynylestradiol, the progestin norethindrone, and the androgen testosterone. Derivatization involved attachment of a dimethylamino group via an ester or oximino function to provide ethynylestradiol 3-dimethylaminopropionate (1), norethindrone 3-(0-dimethylaminopropyl)oxime, syn and anti isomers (2a and 2b), and testosterone 3-(O-dimethylaminopropyl)oxime (3). Both 1 and 2a were found to have the appropriate hormonal activity (testing carried out by the National Institute of Child Health and Human Development) and were converted to zinc and aluminum tannate complexes.…”

“…Chloro compounds of this type have been previously obtained from oxazolines,1 /3-hydroxyamino acids,2 and aziridines. 3 In our work toward 1, we examined both a route using /3-hydroxyaspartic acid and an oxazoline-4,5-dicarboxylic ester4 as approaches to 3 without success.…”

Regulation of the γ‐Aminobutyric AcidA Receptor by γ‐Aminobutyric Acid Levels Within the Postsynaptic Cell

“…All injections were intramuscular. Racemic gabaculine was prepared as described by Rando and Bangerter (1977), and L-cycloserine was prepared by the procedure of Smrt et al (1957).…”

Antibiotics

“…(I) The synthesis of this compound was subsequently described by STAMMER et al (1955) and STAMMER et al (1956). Since the original synthetic work, there have been a number of syntheses described for cycloserine (PLATTNER et al, 1957; BRETSCHNEIDER and VETTER, 1959; KocHETKOW et al, 1956;SMRT et al, 1957a; RATOUIS and BEHAR, 1957) and, in addition, many analogs have been synthesized (see Table 2). The synthetic chemistry of D-cycloserine has been extensively reviewed (KoTSCHETKOW, 1961).…”