Method for the Synthesis of Ionizable Lipids Using a Doubly Alkylated Intermediate

A method for producing an ionizable, cationic amino lipid, the method comprising:

• (i) reacting a double alkylated nucleophilic intermediate under conditions effective to convert the intermediate to a ketone,
• wherein the double alkylated nucleophilic intermediate has a structure as defined below:
• wherein Z is isocyano and Z′ is tosyl, or wherein Z is SCH3 and Z′ is S(O)CH3;
• wherein the ketone has a structure as defined below:
• wherein the R1 and R2 groups are linear, branched and/or cyclic, optionally substituted C3 to C30 alkyl groups, optionally comprising 0-3 carbon-carbon double bonds, optionally comprising heteroatoms selected from N, O and/or S, optionally comprising homocyclic or heterocyclic ring structures;
• and
• wherein R1 and R2 are identical or different;
• and
• (ii) preparing the ionizable, cationic amino lipid from the ketone thereof using one or more synthesis steps resulting in an addition of an ionizable head group moiety to (a) the ketone;
• or (b) an alcohol produced from an optional reduction of the ketone to produce the alcohol, thereby producing the ionizable, cationic amino lipid, wherein the ionizable, cationic amino lipid has a protonatable amino head group and comprises two lipophilic chains comprising the R1 and R2 groups respectively and wherein the ionizable, cationic amino lipid has (i) a pKa of between 6 and 7.5;
• and (ii) a logP of at least 11.