Lipid compositions
Disclosed herein are lipid compositions comprising a cationic lipid of formula (I), a neutral lipid, a sterol and a PEG or PEG-modified lipid, wherein formula (I) is Also disclosed are methods of producing the cationic lipid of formula (I).
1. A method of making a compound of formula (IV)
wherein each R is independently H, alkyl,
provided that at least one R is
R 1 , for each occurrence, is independently H, R 3 ,
wherein R 3 is optionally substituted with one or more substituent;
R 2 , for each occurrence, is independently, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; each of which is optionally substituted with one or more substituent;
R 3 , for each occurrence, is independently, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; each of which is optionally substituted with one or more substituent;
Y, for each occurrence, is independently, O, NR 4 , or S;
R 4 , for each occurrence, is independently, H alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl; each of which is optionally substituted with one or more substituent;
the method comprising contacting an enantiomerically enriched β-hydroxyalkyl synthetic equivalent that is a precursor to R, wherein the functional groups provided by the β-hydroxyalkyl synthetic equivalent undergo further reactions to afford the final R group(s) in the compound of formula (IV), the β-hydroxyalkyl group being optionally substituted with one or more substituent, with a compound of formula (VIII)
wherein R 5 , for each occurrence, is independently, H, alkyl, or an amine protecting group, wherein alkyl is optionally substituted with one or more substituent; and R 6 , for each occurrence, is independently, H, —(CH 2 ) 2 N(R 5 ) 2 , or an amine protecting group.
2. The method of claim 1 , wherein the compound of formula (VIII) is
or a mixture thereof.
3. The method of claim 1 , wherein the enantiomerically enriched β-hydroxyalkyl synthetic equivalent includes an enantiomerically enriched 1,2-epoxyalkane.
4. The method of claim 3 , wherein the enantiomerically enriched 1,2-epoxyalkane is (R)-1,2-epoxydodecane.
5. The method of claim 1 , wherein the enantiomerically enriched β-hydroxyalkyl synthetic equivalent includes a protected a-hydroxyaldehyde.
6. The method of claim 5 , wherein the protected a-hydroxyaldehyde is 2-(O-Pg)-dodecanal, wherein O-Pg represents a protected hydroxyl group.
7. The method of claim 1 , further comprising contacting a primary alcohol trapping reagent with a product of a reaction between the enantiomerically enriched β-hydroxyalkyl synthetic equivalent and the compound of formula (VIII).
8. The method of claim 1 , further comprising contacting 1-(2-(phthalimido)ethyl)-piperazine with 1-(2-chloroethyl)imidazolidin-2-one.