Methods for the preparation of amphillic nitrogen containing imidazolinium derivative compounds
The disclosure provides new methods for preparing nitrogen-containing amphiphiles and their use in the preparation of liposomes and other lipid-containing carriers of pharmaceutical substances, including nucleic acids used in gene therapy.
1. A method for preparing a compound of formula (I):
comprising the step of heating a compound of formula (II) between about 30° C. to about 60° C. in a trihaloalkyl/alcohol solvent, and in the presence of molecular sieves, to produce the compound of formula (I):
wherein:
R and R 1 are each independently a C 11 -C 29 straight-chain aliphatic hydrocarbyl group;
and
Y is a halogen, acetate, succinate or citrate.
2. The method of claim 1 , wherein R and R 1 are each:
Y is chloro.
3. The method of claim 1 , wherein the trihaloalkyl/alcohol solvent is about a 4:1 v/v mixture.
4. The method of claim 3 , wherein the trihaloalkyl solvent is chloroform or bromoform; and the alcohol solvent is methanol, ethanol, propanol, or isopropanol.
5. The method of claim 4 , wherein the trihaloalkyl solvent is chloroform; and the alcohol solvent is methanol.
6. The method of claim 1 , wherein the molecular sieves are 4 Å molecular sieves and is present in about a 1:1 to about a 3:1 w/w ratio of 4 Å molecular sieves/compound of formula (II).
7. The method of claim 6 , wherein the 4 Å molecular sieves is present in about a 1:2 w/w ratio of 4 Å molecular sieves/compound of formula (II).
8. The method of claim 1 , wherein the compound of formula (II) is heated to about 55° C. for about 4 to about 24 hours.
9. The method of claim 1 , further comprising purifying the compound of formula (I) by silica gel chromatography (with silica gel or silica gel pre-packed cartridges) and recrystallization from acetone.
10. The method of claim 1 , wherein the compound of formula (I) has formula (III):
11. A method for preparing a compound of formula (I):
comprising the steps of:
a) protecting the secondary amino groups in the compound of formula (IV) to provide the compound of formula (V):
b) protecting the primary alcohol groups in the compound of formula (V) to provide the compound of formula (VI):
c) deprotecting the compound of formula (VI) to provide the compound of formula (II):
d) heating the compound of formula (II) between about 30° C. to about 60° C. in a trihaloalkyl/alcohol solvent, and in the presence of molecular sieves, to produce the compound of formula (I):
wherein:
R and R 1 are each independently a C 11 -C 29 straight-chain aliphatic hydrocarbyl group;
X′ is di-tert-butyldicarbonate ((BOC) 2 O);
X is tert-butyloxycarbonyl (BOC);
Y is a halogen, acetate, succinate or citrate;
Z in OCOR or OCOR 1 .
12. The method of claim 11 , wherein R and R 1 are each:
Y is chloro.
13. The method of claim 12 , wherein the trihaloalkyl/alcohol solvent is about a 4:1 v/v mixture.
14. The method of claim 13 , wherein the trihaloalkyl solvent is chloroform or bromoform; and the alcohol solvent is methanol, ethanol, propanol, or isopropanol.
15. The method of claim 14 , wherein the trihaloalkyl solvent is chloroform; and the alcohol solvent is methanol.
16. The method of claim 12 , wherein the molecular sieves are 4 Å molecular sieves and is present in about a 1:1 to about a 3:1 w/w ratio of 4 Å molecular sieves/compound of formula (II).
17. The method of claim 16 , wherein the 4 Å molecular sieves is present in about a 1:2 w/w ratio of 4 Å molecular sieves/compound of formula (II).
18. The method of claim 12 , wherein the compound of formula (II) is heated to about 55° C. for about 4 to about 24 hours.
19. The method of claim 12 , further comprising purifying the compound of formula (I) by silica gel chromatography and recrystallization from acetone.
20. The method of claim 12 , wherein the compound of formula (I) has formula (III):
21. The method of claim 1 , wherein R and R 1 are each independently a C 11 -C 29 straight-chain aliphatic hydrocarbyl group.