The methylation of 11-acetoxy-3-tetrahydropyranyloxy-16alpha,17-alpha-dimethyl-5alpha-pregnane-20-one (Ia) with lithium diisopropylamide and methyl iodide in THF gives 11beta-acetoxy-3beta-hydroxy-16alpha,17alpha,21-trimethyl-5alpha-pregnane-20-one (IIa), which is oxidized with chromic acid in acetone yielding 11beta-acetoxy-16alpha,17alpha,21-trimethylpregnane-3,20-dione (IIIa). This compound is dehydrogenated with dichlorodicyanobenzoquinone (A) in refluxing toluene affording 11beta-acetoxy-16alpha,17alpha,21-trimethyl-DELTA1,4-pregnadiene-3,20-dione (IVa), which is finally hydrolyzed with KOH in methanol. This sequence can also be perfomed with the 11beta-propoxy, 11beta-isobutyroxy derivatives of (Ib-c, IIb-c, IIIb-c and IVb-c).
The methylation of 3beta-tetrahydropyranyloxy-16alpha,17alpha-dimethyl-DELTA9(11)-5alpha-pregnene-20-one (V) with lithium diisopropylamide and methyl iodide in THF gives 3beta-hydroxy-16alpha,17alpha,21-trimethyl-DELTA[9(11)]-5alpha-pregnene-20-one (VI), which is then oxidized with chromic acid in acetone yielding 16alpha,17alpha,21-trimethyl-DELTA[9(11)]-5alpha-pregnene-3,20-dione (VII). This compound is dehydrogenated as before affording 16alpha,17alpha,21-trimethyl-DELTA[1,4,9(11)]-pregnatriene-3,20-dione (VIII), which is finally hydroxylated by treatment first with NBS and then with butanethiol and chromous acetate in DMSO. The pregnene (VII) can also be obtained by methylation of 3-dimethyl-ketal-16alpha,17alpha-dimethyl-DELTA[9(11)]-5alpha-pregnene-3,20-dione (IX) with lithium diisopropylamide and methyl iodide in THF. The pregnatriene (VIII) can also be obtained by dehydrogenation of 16alpha,17alpha,21-trimethyl-DELTA[1,4,9(11)]-pregnatriene-3,20-dione (X), which is with Br2 in acetic acid and dehydrobromination with CaCO3 and LiBr in dimethylacetamide.
A new synthesis of rimexolone from prednisolone has been described: The reaction of prednisolone (I) with tosyl chloride in pyridine gave the 21-tosylate (II), which was treated with sodium iodide in acetone to yield the 21-iodo derivative (III). The deiodination of (III) with refluxing acetic acid afforded 21-deoxyprednisolone (IV), which was dehydrated with semicarbazide in water at 80-5 C yielding the trienone (V). The silylation of (V) with TMS-Cl and pyridine gave the protected compound (VI), which was methylated with methyl iodide and lithium bis(trimethylsilyl)amide to the 21-methyl derivative (VII). A new methylation of (VII) with Me2Cu(CN)Li2 followed by silylation with TMS-Cl afforded the silylated dimethyl enol ether (VIII), which was submitted to a third methylation with methyl iodide and benzyltrimethylammonium fluoride in THF giving the silylated 16,17,21-trimethyl derivative (IX). Finally, this compound is desilylated to rimexolone with 6M HCl in methanol.