Evaluation of Protecting Groups for 3-Hydroxyisoxazoles − Short Access to 3-Alkoxyisoxazole-5-carbaldehydes and 3-Hydroxyisoxazole-5-carbaldehyde, the Putative Toxic Metabolite of Muscimol

Abstract

The regioselectivity of the 3‐hydroxyisoxazole‐5‐ester 1 is studied with respect to O‐ versus N‐alkylation. 3‐O‐Alkyl products 2 are highly favoured with benzyl, benzhydryl, and allyl bromide (≥ 91:9), in contrast to known uses of 5‐alkyl‐3‐hydroxyisoxazoles or when methylation with diazomethane (or methyl iodide) is effected. Methoxymethylation leads to the N‐substituted isoxazolinone 3e only. On reduction with DIBAH, the esters 2 afford 3‐O‐protected 3‐hydroxyisoxazole‐5‐carbaldehydes 4 (75−98%). For removal of the benzyl protecting groups, three variations (HBr/HOAc, H2‐Pd/BaSO4, NBS/AIBN) were found useful with 5‐ester, 5‐formyl, and 5‐hydroxymethyl derivatives. The free 3‐hydroxy‐5‐carbaldehyde 9, the putative toxic metabolite of the GABA agonist muscimol, is prepared accordingly. The O‐protected 3‐hydroxyisoxazole‐5‐carbaldehydes 4 constitute versatile intermediates in various routes to analogues of CNS‐active amino acids and can now be obtained in a highly efficient manner.

Process Research and Development of an Enantiomerically Enriched Allyic Amine, One of the Key Intermediates for the Manufacture of Synthetic Tetracyclines

“…The regioselective (O vs. N, 91:9 ratio) benzylation of the hydroxyl group of 5 using benzyl bromide in acetone has been described, 3 and was successful in our hands at small scale.…”

“…2d The cost of the starting material, acetylene dicarboxylic acid methyl ester (4), was high (>$1000/kg) and the 5 yield of the isoxazole forming step to provide 5 was modest (~50%) on laboratory scale when attempted at Tetraphase. The second step, benzylation of the hydroxyl group of intermediate 5, 3 gave the desired benzyl ether 6 but was contaminated with varying amounts of the regioisomeric N-Bn-isoxazole (10-20%, vide infra) that could only be removed by chromatography. The reduction of the ester 6 to the aldehyde 7 performed well on small scale, but increasing the scale led to the formation of over-reduced material (the corresponding alcohol) as well as substantial amounts of unconsumed 6, necessitating chromatographic purification to isolate 7.…”

“…3 However, the product was frequently contaminated with unacceptable amount of alcohol 19 necessitating a chromatographic purification. Since the downstream products resulting from the processing of 19…”

“…To the residual IPA solution, additional IPA (820 kg) was added and the mixture was heated to 45±5 °C. Water (697 kg) was added at 45±5 °C over a period of 5 h. After water addition, seeding using 34 (0 3. kg) was performed and after stirring for 30 min, new crystal solids formed.…”

A Photochromic Agonist of AMPA Receptors

“…The synthesis of ATA‐3 ( 7 c ) was modeled after the published route to BnTetAMPA ( 6 ),8 but relied on an improved protecting‐group strategy (Schemes and ). It commenced with the known hydroxy isoxazole 8 ,9 which was protected as an allyl ether to afford methyl ester 9 10. This intermediate was then converted into nitrile 10 in a two‐step procedure 11.…”