Pyridine-2,5-diones, 6-hydroxy

Unexpectedly strong intermolecular hydrogen bonding has been reported by IR spectroscopic studies for tetrahydro-4,7-phenanthroline-l,10-dione-3,8-dicarboxylic acids, which exist in the oxo-hydroxy form 165 in both solid state and in solution [78JCS(CC)369].Tlie conclusion was based on comparison of B-, C-, and D-type bands for 165 and their dimethyl esters (detection of hydrogen bonding) and on analysis of IR spectra in the 6 /xm region (pyridine- and pyridone-like bands). 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A <" -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

The synthesis of halcinonide is summarized in Figure 1, starting with 16a-hydroxy-9a-fluorohydrocortisone (A1 -pregnene-9a-fluoro-llg,16a,17a,21-tetrol-3,20-dione dihydrotriamcinolone, I), which is available commercially.10-13 This tetrahydroxy steroid is slurried in acetone, and then 70% perchloric acid is added slowly. The acetonide, II (9a-fluoro-llg, 16a, 17, 21-tetrahydroxypregn-4-ene-3, 20-dione, cyclic 16,17-acetal with acetone dihydrotriamcinolone-acetonide) precipitates spontaneously from solution. Mesyl chloride is added to the acetonide in pyridine to give the 21-mesylate derivative (dihydrotriamcinolone acetonide-21-mesylate, III). Compound III is dissolved in dimethylformamide, lithium chloride is added and the mixture is refluxed to produce halcinonide (IV), which is recrystallized from a solution of ft-propanol in water. 

This enzyme [EC 1.1.1.50], also referred to as hydroxy-prostaglandin dehydrogenase, catalyzes the reaction of androsterone with NAD(P)+ to produce 5a-androstane-3,17-dione and NAD(P)H. Other 3a-hydroxysteroids can act as substrates as well as 9-, 11- and 15-hydroxy-prostaglandins. The stereochemistry is B-specific with respect to the pyridine coenzymes. 

Pyrano-fused heterocycles, namely pyrano[3,2-f]quinoline-2,5(6//)-diones, pyrano[3,2-f]benzopyran-2,5(6//)-dione, and pyrano[3,2-f]pyridine-2,5(67T)-diones, have been efficiently prepared by the condensation of 4-hydroxy-2-(l//)-quinolines, 4-hydroxycoumarin, or 4-hydroxy-(17/)-pyridone with a-acetyl-y-butyrolactone or the sodium salt of a-formyl-y-butyro-lactone in the presence of ammonium acetate <1999JHC467>. 

Pyrimidine-annulated methanooxepene 35a is formed via regioselective heterocyclization of 6-cyclopent-2-enyl-5-hydroxy-l,3-dimethylpyrimidine-2,4(1/7,3//)-dione in the presence of concentrated sulfuric acid. The above-mentioned pyrimidinedione and 5-cyclopent-2-enyl-6-hydroxy-l,3-dimethylpyrimidine-2,4(1/7,3/7)-dione give similar annulated bromomethanooxepenes 35b and 36, respectively, when cyclization is performed with pyridine hydrotribromide or hexamethylenetetramine hydrotribromide <2003M1137>. 

A solution of 3p-hydroxy-5a-pregn-16-ene-ll,20-dione (39.6 g) in dry pyridine (165 ml) was treated with toluene-p-sulfonyl chloride (43.9 g) to give the toluene sulfonate (56.7 g), melting point 147-151°C. A portion (10.7 g) of this material was crystallized from ethyl acetate-petroleum to give the pure 3p-toluene-p-sulfonyloxy-5a-pregn-16-ene-ll,20-dione (9.2 g) as plates, melting point 154°-155°C. 

Chemical Name 3-Pyridine carboxylic acid compounded with 3,7-dihydro-7-[2-hydroxy-3-[(2-hydroxymethyl)methylamino]propyl]-l,3-dimethyl-lH-purine-2,6-dione (1 1)... 

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