6-Methyl-2 -dione

Whilst the solution is still hot, add dilute hydrochloric acid until the stirred solution is just acid to litmus, and then distil off as much ethanol as possible, using the water-bath. Now add more dilute hydrochloric acid to the residual hot solution until it is just acid to methyl-orange. The 5,5-dimethyl-cyclohexan-1,3-dione separates as an oil which solidifies on cooling. Filter the product at the pump, wash it with ice-cold water, and dry it in a desiccator. Yield of the pale cream-coloured crystals, 12 g. m.p. 136-145 (preliminary softening). 

Chloro-9-fluoro-llb-hydroxy-16b-methyl-17-(l-oxopropoxy)-pregna-l,4-diene-3,20-dione. See Clobetasol propionate. 

Fluoro-llb,21-dihydroxy-16a-methyl-21-(phosphonooxy)-pregna-l,4-diene- 3,20-dione, disodium salt. See Dexamethasone sodium phospate. 

Methylation of hydrocortisone/prednisolone ia positions C-4, C-7, C-12, and C-21 failed to give useful products. Methylation at C-16, ia contrast, led to 16a- and 16P-methyl-9a- uoroprednisolones which were exceptionally useful. Both series were prepared usiag 3a-acetoxy-5a-pregn-16-ene-ll,20-dione derived from desoxychoHc acid (80). A much shorter route was subsequentiy developed from... 

See stmcture (107). This 4,5-position is saturated. 5-Isopropyl-8-methyl-6,8-nonadien-2-one. 5-Isopropyl-3-nonene-2,8-dione. 

Interest in the synthesis of 19-norsteroids as orally active progestins prompted efforts to remove the C19 angular methyl substituent of readily available steroid precursors. Industrial applications include the direct conversion of androsta-l,4-diene-3,17-dione [897-06-3] (92) to estrone [53-16-7] (26) by thermolysis in mineral oil at about 500°C (136), and reductive elimination of the angular methyl group of the 17-ketal of the dione [2398-63-2] (93) with lithium biphenyl radical anion to form the 17-ketal of estrone [900-83-4] (94) (137). 

IV-Methylated pyridazinones can be obtained from 3,6-dialkoxypyridazines by treatment with alkyl halides or dialkyl sulfates. Methyl iodide and dimethyl sulfate are most frequently used. According to the proposed mechanism, an intermediate quaternary pyridazinium salt is formed, followed by elimination of a group R from the alkoxy group. At higher temperature, l,2-dimethylpyridazine-3,6(l//,2//)-dione is formed with dimethyl sulfate. 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

Both thermal and Hilbert-Johnson reactions occur quite readily in 2- and 4/6-alkoxyquinazolines. For example, distillation of 2,4-bis-/3-diethylaminoethoxyquinazoline in vacuo yields l,3-bis-/3-diethylaminoethylquinazolin-X4(l/J,3H )-dione (60JCS3546). A complicated example is furnished by heating a tetramethoxybipyrimidine with methyl iodide to give four separable products progressively (81AJC1157). 

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