Methyl 15-hydroxy activity

Inoue K, Yamazaki H, Imiya K, Akasaka S, Guengerich FP, Shimada T. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxy-lation and S-mephenytoin 4 -hydroxyla-tion activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997 7[2] 103—113. 

A convenient asymmetric synthesis of a-hydroxyaldehydes begins with the addition of a Grignard reagent to the methoxycarbonyl aminal (238) prepared from methyl hydroxy-methoxyacetate and diamine (236) (79CL705). Treatment of the derived keto aminal (239) with a second Grignard reagent and hydrolysis of the resulting hydroxy aminal (240) yields the optically active a-hydroxyaldehyde (241). Enantiomeric excesses vary between 78 and... 

The method for producing chiral 1,2-diol units is also applicable to the construction of asymmetric quaternary carbons contained in aldol units. In the presence of a chiral promoter consisting of the chiral diamine 1, tin(II) trifluoromethanesulfonate, and di-n-butyltin diacetate, various optically active a-alkoxy-a-methyl- -hydroxy thioesters and esters are synthesized in good yields with high stereoselectivities (eqs 28 and 29). ... 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

Ecample Miller and Rich investigated the conformational consequences of substitutions on an amino acid in cyclosporin A, an important immunosuppressive drug. One of the amino acids in this cyclic undecapeptide is (2, 3r, 4r, 6e)-3-Hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (MeBmt). It is essential for biological activity. 

Mocimycin has been chemically converted to aurodox by protection of the 4-hydroxy group at the pyridone moiety as the benzoylformate, followed by /V-methylation and hydrolytic removal of the protective group (1,55). Whereas aurodox esters are active growth promotors in animals, goldinamines that are A/-acylated by acids other than goldinonic acid, such as acetic, benzoic, or arylsulfonic acids, lack useful antimicrobial or growth-promoting activity (1). 

An important dmg in the regulation of cholesterol metaboHsm is lovastatin [75330-75-5] which is an HMG—CoA reductase inhibitor (see Cardiovascularagents). p-Hydroxy-p-methyl glutarate—coenzyme A (HMG—CoA) reductase is the rate-limiting enzyme of cholesterol synthesis. Lovastatin is actually a prodmg, which is eventually hydrolyzed in the Hver to its active, P-hydroxylated form (5). 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

From the various modifications that have been made on the phenylbutazone structure in order to increase activity and reduce toxicity it has been found that the activity persists when methyl, chloro, hydroxy or nitro groups are introduced into the para position of one or both benzene rings (see oxyphenbutazone (712) as an example). Mofebutazone (714) has also been used in Europe for several years as an antirheumatic drug. 

Indazole, 5,5-dimethyl-3-trifluoromethyl-4,5-dihydro-trichomonacidal activity, 5, 291 Indazole, 2-ethoxycarbonyl-reactions, 5, 269 Indazole, 3-fluoro-synthesis, S, 263 Indazole, 1-germyl-synthesis, 5, 236 Indazole, 1-glycosyl-synthesis, 5, 289 Indazole, 2-glycosyl-synthesis, 5, 289 Indazole, halo-reactions, S, 266 Indazole, 2-hydroxy-methylation, 5, 269 Indazole, 3-hydroxy-reactions, S, 264 Indazole, 6-hydroxy-diazo coupling, 5, 86 Indazole, hydroxyphenyl-synthesis, S, 288 Indazole, 3-iodo-synthesis, S, 241 Indazole, l-isopropyl-3-phenyl-reduction, 5, 243 Indazole, 3-mercapto-1 -substituted tautomerism, 5, 265 Indazole, methoxy-... 

Metronidazole — see also Imidazole, 1-(2-hydroxy-ethyl)-2-methyl-5-nitro-antiprotozoal activity, 1, 180 veterinary use, 1, 208 mode of action, 1, 208 Metyrapol metabolism, 1, 234 Metyrapone... 

Pyrazole, 5-hydroxy-3-methyl-l-phenyl-4-[(o-tolylazo)]-as dyestuff, 5, 299 Pyrazole, 4-iodo-synthesis, 5, 241 Pyrazole, IV-iodo-reactions, 5, 270 synthesis, 5, 234 Pyrazole, 5-mercapto-tautomerism, 5, 265 Pyrazole, methoxy-pharmaceutical activity, 5, 294 reactions... 

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