597940 Disclosed herein is a method the manufacture of 3alpha-hydroxy, 3beta-methyl-5alpha-pregnan-20-one (ganaxolone) comprising: reacting 5alpha-pregnane-3,20-dione (Dione 2) with an organometallic methylating agent in an inert solvent and thereby obtaining ganaxolone, wherein the organometallic methylating agent contains iron, titanium or a combination thereof. The method additionally comprising heating the obtained ganaxolone in an organic solvent, such as ethyl acetate, to obtain purified ganaxolone. The method additionally comprising generating the organometallic methylating agent by adding about 2 to about 4 equivalents of methyl magnesium halide or methyl lithium to a solution of anhydrous ferric halide or anhydrous ferrous halide in the inert solvent and thereby forming the organometallic methylating agent(s). The method additionally comprising adding lithium chloride to iron halide in the inert solvent prior to generating the organometallic methylating agent, wherein the amount of lithium chloride added is about 0.1 to about 4 equivalents of lithium chloride to equivalent of iron halide. The method wherein the organometallic methylating agent is dimethyl iron (Me2Fe), methyl triethoxy titanium, methylchloro diethoxy titanium ((CH3)Cl(CH3CH2O)2Ti), methyl trichlorotitanium (CH3Cl3Ti), tetramethyltitanium ((CH3)4Ti), dimethyl dichloro titanium ((CH3)2Cl2Ti), trimethyl chlorotitanium ((CH3)3ClTi) or methyl iron chloride (CH3FeCl). The method wherein the organometallic methylating agent is an ate complex containing a (Me)3Fe- anion and either lithium or MgX as a cation, wherein X is a halide.
