Isoxazoles hydroxy-, preparation

Two polymorphic forms of 3- 2-[4-(6-fluorobenzisoxazol-3-yl)-l,2,3,6-tetrahydropyridin-l-yl]ethyl -2-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n] pyrimidin-4-one (137 R = H) were prepared (99MIP1). Racemic 9-hydroxy-2-methyl-3- 2-[4-(6-fluorobenzo[r/ isoxazol-3-yl)-l,2,3,6-tetrahydro-l-pyridyl] ethyl -6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidin-4-one was resolved into its (R)- and (5)-isomers (OOMIPIO). 

Several reactions giving rise to hydroxy- and amino-isoxazoles have also been investigated. Thus the reaction of alkoxymethylene-cyanoacetates and hydroxylamine leading to 5-amino- or 5-hydroxy-isoxazoles proved to be rather useful.It is of particular interest that, by changing the reaction conditions, Bauer and Nambury succeeded in obtaining isomeric aminoisoxazolones (24 25 26). It is also possible to prepare isoxazol-3-ones from some /S-ketoesters. ... 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

Bis(isoxazole) (1323) was prepared in 62% yield when hydroxy-(5-methylisoxazol-4-yl)methylenemalonate (1322) was reacted with hydrox-ylamine hydrochloride in boiling ethanol for 3 hr [88JCS(P1)1875]. 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

R)-3-(4-fluorophenyl)-2-hydroxy propionic acid 1 is a building block for the synthesis of Rupintrivir, a rhinovirus protease inhibitor currently in human clinical trials to treat the common cold (Fig. 1) [1, 2], Retrosynthetically, Rupintrivir was prepared from four fragments the lactam derivative Pi, the chiral 2-hydroxy acid P2 (compound 1), the valine derivative P3, and an isoxazole acid chloride P4 (Fig. 1). In this chapter the preparation of 1 using a biocatalytic reduction performed in a membrane reactor will be discussed in detail. 

An interesting rearrangement was observed35,36 during the preparation of4-hydroxy-JV-(5-methyl-3-isoxazolyl)-2-methyl-2/M,2-benzothiazine-3-carboxamide 1,1-dioxide (43) (Eq. 9). Sodium methoxide cleaved the benziso-thiazoline derivative 40 to the expected benzoate ester 41, but this was cyclized by base to a 4-hydroxy-2//-1,2-benzothiazine (42) with simultaneous conversion of the isoxazole moiety to an oxadiazole. Compound 42 was N-methylated by methyl iodide and the product converted to the desired amide 43 by treatment with triethylamine in xylene, a process which simultaneously reconverts the oxadiazole side chain to an isoxazole. 

Isoxazoles are also masked P-hydroxy-ketones, which may be prepared in a chiral fashion, as exemplified by a recent synthesis of (+)-(S)-[6]-gingerol (Scheme 26). ... 

The method presented in this chapter allows the direct preparation of isoxazole derivatives from primary nitro compounds and dipolarophiles with harmless reagents in catalytic amount, avoiding stoichiometric reagents and drastic reaction conditions. Moreover, this procedure is compatible with most common functional groups, including hydroxy, carboxy, and ammonium since yields are in general satisfactory, the procedure can be profitably employed with preparative purposes and has been exploited by other authors for the preparation of useful intermediates (see Table 8.3). A... 

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