Intermediate compounds and process for the preparation of fingolimod

A process for the preparation of Fingolimod of formula (1), or a pharmaceutically acceptable salt thereof, comprising the steps of:

• a) reacting octylbenzene with a 3-nitropropanoic acid derivative of formula A:
• wherein X is a halogen or an anhydride, so as to obtain 3-nitro-1-(4-octylphenyl)propan-1-one of formula (12):
• b) reducing 3-nitro-1-(4-octylphenyl)propan-1-one (12) with a reducing agent to obtain 3-nitro-1-(4-octylphenyl)propan-1-ol;
• c) protecting the hydroxyl group of 3-nitro-1-(4-octylphenyl)propan-1-ol so as to obtain compound (13A):
• wherein P is a hydroxyl protecting group;
• d) bis-hydroxymethylation of compound (13A) with formaldehyde or an equivalent thereof in the presence of catalyst, and removal of the hydroxyl protecting group to obtain compound (14):
• e) reducing compound (14) to Fingolimod (1);
• and
• f) optionally, converting Fingolimod (1) to a pharmaceutically acceptable salt thereof.

A process for the preparation of Fingolimod of formula (1), or a pharmaceutically acceptable salt thereof, comprising the steps of:

• a) reacting 3-nitropropylbenzene with an octanoic acid derivative of formula B:
• wherein X is a halogen or an anhydride so as to generate 1-(4-(3-nitropropyl)phenyl)nonan-1-one of formula (17):
• b) bis-hydroxymethylation of compound (17) with formaldehyde or an equivalent thereof in the presence of a catalyst to generate a compound of formula (18):
• c) reducing compound (18) to Fingolimod (1);
• and
• d) optionally, converting Fingolimod (1) to a pharmaceutically acceptable salt thereof.

A process for the preparation of Fingolimod of formula (1), or a pharmaceutically acceptable salt thereof, comprising the steps of:

• a) bis-hydroxymethylation of 3-nitropropylbenzene with formaldehyde or an equivalent thereof in the presence of catalyst to generate a compound of formula (19):
• b) converting compound (19) to an acetal or ketal represented by the structure of formula (20A):
• wherein R1 and R2 are each independently H, an alkyl or an aryl;
• c) reacting compound (20A) with an octanoic acid derivative of formula B
• wherein X is a halogen or an anhydride so as to generate a compound of formula (21A):
• d) reducing compound (21A) followed by removal of the ketal or acetal group so as to obtain to Fingolimod (1);
• and
• e) optionally, converting Fingolimod (1) to a pharmaceutically acceptable salt thereof.

A process for the preparation of Fingolimod of formula (1), or a pharmaceutically acceptable salt thereof, comprising the steps of:

• a) reacting an aldehyde of formula (24A)
• with a Wittig reagent of formula (23A) or a phosphonate of formula (25A);
• wherein
• Y is O or H2;
• R1 and R2 are each independently H, an alkyl or an aryl;
• R3 and R4 are each independently alkyl or aryl;
• P′ is a nitrogen protecting group;
• and
• Z is a counter-ion;
• in the presence of a base so as to obtain a compound of formula (26A);
• wherein R1, R2, Y and P′ are as described above;
• b) reducing compound (26A) to generate compound (27A)
• followed by removal of the acetal or ketal and nitrogen protecting group so as to obtain Fingolimod (1);
• and
• c) optionally, converting Fingolimod (1) to a pharmaceutically acceptable salt thereof.