PROCESS FOR PREPARATION OF 2-AMINO-1,3-PROPANEDIOL COMPOUNDS AND SALTS THEREOF Russian patent published in 2018 - IPC C07C215/28 C07D213/00 

FIELD: chemistry.

SUBSTANCE: invention relates to an improved process for the preparation of fingolimod - 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6) or a hydrochloride thereof. Method comprises carrying out the following steps: a) reacting a compound of Formula 3 with diethylacetamidomalonate (Formula 2) in an organic solvent in the presence of a phase transfer catalyst selected from a tetralkylammonium halide, to obtain diethyl ether of 2-(acetylamino)-2-(2-(4-octylphenyl)ethyl)propanedioic acid (Formula 4)

and b) converting the resulting diethyl ether of Formula 4 in a solvent to 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6)

or c) converting the diethyl ether of Formula 4 to N-(1,1-bis-hydroxymethyl-3-(4-oxylphenyl)propyl)-acetamide (Formula 5) followed by its hydrolysis to obtain 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6)

or d) converting the diethyl ether of Formula 4 to N-(1,1-bis-hydroxymethyl-3-(4-oxylphenyl)-propyl)-acetamide (Formula 5) followed by conversion of the acetamide of Formula 5 to 2-acetamido-2-(4-octylphenethyl)propane-1,3-diyl diacetate (Formula 5a) and subsequent hydrolysis of diacetate (Formula 5a) to obtain 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6),

and optionally, (e) converting the 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol of Formula 6 obtained in steps (b) or (c) or (d) into its hydrochloride, and optionally (g) recrystallisation of 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol of Formula 6 or its hydrochloride. Invention also relates to novel polymorphic forms of fingolimod. Polymorphic form A 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6) has the values 2θ XRPD: 3.876, 5.744, 7.739, 11.65, 14.886, 15.356, 16.774, 17.65, 18.008, 18.963, 19.473, 20.845, 21.626, 23.431, 24.643, 27.389, 27.894, 30.566, 31.421, 34.267, 35.01, 35.5, 38.756, 42.214, 43.767, 46.201, 48.026, 50.269 and 52.314. Polymorphic form Y of 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride has the values 2θ XRPD: 3.549, 5.185, 5.832, 7.052, 8.62, 9.305, 10.625, 12.149, 12.82, 14.163, 14.713, 15.174, 15.61, 16.374, 17.329, 17.749, 18.254, 18.698, 19.255, 19.948, 20.879, 21.389, 22.248, 22.578, 22.838, 23.527, 24.449, 24.953, 25.847, 26.139, 27.127, 28.094, 28.604, 29.47, 29.697, 31.786, 32.24, 33.147, 36.955 and 44.474. Method is safe, does not require additional chromatographic purification, which allows it to be used for large-scale production. High-quality product is obtained - up to 99.5-99.7% of chromatographic purity.

EFFECT: fingolimod is an immunomodulator and is used to treat multiple sclerosis.

25 cl, 4 dwg, 12 ex

формула - formula