Chemistry of oxazoles

Turchi, Ignatius J.; Dewar, Michael J. S.

doi:10.1021/cr60296a002

Cited by 330 publications

(121 citation statements)

References 154 publications

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“…36) In fact, replacement of the 2-chloro group on oxazole with other moieties is an extremely facile process in the preparation of 2-amino-, 2-alkoxy-, and 2-hydrainooxazoles. 37) Therefore, the 4-chloride of streptochlorin oxazole was likely replaced by a hydroxy group followed by tautomerization to the ketone metabolite M3. It is proposed that an oxidative cleavage of oxazolidinedione ring of M3 results in the formation of oxoacetamide metabolite M4 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Zhou

Choi

Kim

et al. 2018

Biological & Pharmaceutical Bulletin

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The purpose of this study was to investigate the pharmacokinetics and metabolism of streptochlorin and its derivative 5-hydroxy-2′-isobutyl streptochlorin (HIS) in mice. Plasma concentration of streptochlorin declined rapidly resulting in a high sustemic plasma clearance (CL p ) (5.8 1.7 L/h/kg), a large volume of distribution (V ss ) (1.4 0.9 L/kg) and a short half-life (t 1/2 ) (0.4 0.1 h) after a single intravenous administration (5 mg/kg). Oral bioavailability (F) was 10.3 3.4% after a single oral administration (10 mg/kg). HIS also showed a rapid plasma decline with a high CL p (11.3 8.8 L/h/kg), a high V ss (0.8 1.0 L/kg) and a short t 1/2 (0.070 0.004 h) following intravenous administration. It was not detected in plasma after oral administration. Metabolic stability studies using mouse liver microsomes and S9 fractions predicted a high hepatic clearance for both compounds, consistent with the in vivo data. Metabolite identification studies revealed three metabolic pathways for streptochlorin: monooxygenation, glucuronidation of the indole moiety and oxidative opening of the 4-chlorooxazole ring. HIS was metabolized via monooxygenation of the isobutyl chain and glucuronidation of the indole ring. These results may aid in structural optimization to mitigate the metabolic liability of streptochlorin.Key words streptochlorin; 5-hydroxy-2′-isobutyl streptochlorin; pharmacokinetics; metabolism Terrestrial organisms have been a rich source of natural products for drug discovery and development for thousands of years. Since the mid-twentieth century, studies have shown that marine creatures, especially microbes, have provided many bioactive compounds with novel structures. These include compounds such as ziconotide which is an analgesic agent for severe and chronic pain treatment, trabectedin, an anticancer drug, and eribulin for metastatic breast cancer and liposarcoma treatment.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Zhou

Choi

Kim

et al. 2018

Biological & Pharmaceutical Bulletin

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“…Finally, because oxazoles are also an important class of heterocyclic compounds, [22][23][24] we attempted the preferential synthesis of 2,4-disubstituted-5-(4,6-dimethoxy-1,3,5-triazin-2-yloxy) oxazoles 5 by modifying the present one-pot method. As described above, the conversion of oxazolones 4 to oxazoles 5 could be promoted by the deprotonation of 4 or their enol form with a strong base.…”

Section: Chart 2 Reaction Balances For the Reactants And The Productmentioning

confidence: 99%

One-Pot Preparation of Oxazol-5(4<i>H</i>)-ones from Amino Acids in Aqueous Solvents

Fujita

Kunishima

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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A method for one-pot synthesis of oxazol-5(4H)-ones has been developed using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), which is available for the activation of carboxylic acids in an aqueous solvent. The oxazolones were prepared by the N-acylation of amino acids with carboxylic acids and the subsequent cyclodehydration of the resulting N-acylamino acids by the addition of N,N-diethylaniline. Since both these reactions proceed effectively with the same coupling reagent, DMT-MM, in aqueous solvents, the procedure is simplified and becomes easy to perform. In addition, 5-(triazinyloxy)oxazole derivatives have been synthesized by controlling the basicity of the reaction system. Key words oxazolone; oxazole; dehydrocondensation; cyclodehydration; aqueous solvent Oxazol-5(4H)-ones (henceforth referred to as oxazolones) are useful precursors for the synthesis of substituted heterocyclic compounds, 1) natural products, 2) and chiral amino acids. 3,4)In general, the preparation of oxazolones from amino acids is effected by two-step synthesis: N-acylation of the amino group followed by cyclodehydration involving the activation of the carboxy group. The N-acylation of amino acids can be carried out in an aqueous solvent, typically using Schotten-Baumann conditions, 5) while the cyclodehydration of the resulting N-acylamino acids to form oxazolones is performed under anhydrous conditions with dehydrating reagents, such as carbodiimides and acid anhydrides. Thus, these reactions must be performed in separate vessels. If the latter reaction occurs in an aqueous solvent, both reactions can be conducted in the same vessel using water-soluble amino acids as a starting compound. Therefore, the procedure for preparing oxazolones becomes simplified. In this study, we focused on 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) 6) as a dehydrocondensing reagent because the chemoselective activation of carboxy groups using DMT-MM efficiently proceeds even in an aqueous solvent. 7)We report here a one-pot method for the synthesis of oxazolones from amino acids. In this method, DMT-MM is utilized successfully for both the N-acylation of amino acids with carboxylic acids and the subsequent cyclodehydration of the resulting N-acylamino acids. 8,9) Results and DiscussionTo find the optimum reaction conditions for the one-pot method, we first examined each reaction separately using Lleucine (2a) as a model compound.10,11) After several attempts, we succeeded in finding the optimum reaction conditions for the first reaction. Benzoic acid (1) was treated with DMT-MM in the presence of N-methylmorpholine (NMM) in acetone-H 2 O (3 : 1) at room temperature for 15 min; then an aqueous solution of 2a and NaOH was added (Chart 1). As a result, N-benzoyl-L-leucine (3a) was obtained in a satisfactory yield (91%). The addition of NaOH as a base was found to be essential to complete the coupling reaction.The second reaction needs to follow the final conditions of the former reaction to achie...

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“…The unprotected amino acid 6a was activated by reaction with HBT-mesylate (8) Antimicrobial Activity Using cefotaxime as a reference compound, the minimum inhibitory concentrations (MIC) of 12 and 13 against a variety of Gram-positive and Gram-negative bacteria were determined by an agar dilution technique13). These results are outlined in Table 2.…”

Section: Chemistrymentioning

confidence: 99%

“…1H NMR spectra were recorded on a Varian EM-390 (90 MHz) spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shifts (8) are reported in parts per million relative to TMS. UV spectra were determined on a Carry Model 219 spectrophotometer in the solvent indicated.…”

Section: Chemistrymentioning

confidence: 99%

The synthesis and biological evaluation of 7.BETA.-(2-(2-aminooxazol-4-yl)-2-Z-methoximinoacetamido)cephalosporin antibiotics.

Wheeler¹,

Finley²,

Messenger³

et al. 1986

J. Antibiot.

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Chemistry of oxazoles

Cited by 330 publications

References 154 publications

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

Pharmacokinetics and Metabolism of Streptochlorin and Its Synthetic Derivative, 5-Hydroxy-2′-isobutyl Streptochlorin, in Mice

One-Pot Preparation of Oxazol-5(4<i>H</i>)-ones from Amino Acids in Aqueous Solvents

The synthesis and biological evaluation of 7.BETA.-(2-(2-aminooxazol-4-yl)-2-Z-methoximinoacetamido)cephalosporin antibiotics.

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