SYNTHESIS OF mRNA DELIVERY AGENT

Abstract

The present disclosure relates to synthesis of an mRNA delivery agent, in particular to a reaction of a related amino compound with ethylene oxide in the presence of ytterbium triflate.

Claims

1. A method for preparing an mRNA delivery agent, which is specifically a compound of formula XI, the method comprises reacting an amino compound of formula X with ethylene oxide in the presence of a solvent and an additive, and a reaction formula is as follows: ##STR00007## wherein R.sub.1 in the formulas X and XI is selected from the group consisting of H and C.sub.1-C.sub.10 alkyl, and R.sub.2 in the formulas X and XI is selected from the group consisting of H and C.sub.1-C.sub.10 alky, in the formulas X and XI, n is in the range of 2-10, z is in the range of 1-10, p is in the range of 2-10, and q is in the range of 1-11.

2. The method according to claim 1, wherein the solvent is selected from the group consisting of acetonitrile, dioxane, tetrahydrofuran (THF), dimethyl formamide (DMF), dimethylsulfoxide (DMSO), and 2-methyltetrahydrofuran (2-Me-THF).

3. The method according to claim 1, wherein the additive is ytterbium triflate.

4. (canceled)

5. (canceled)

6. The method according to claim 1, wherein the reaction is followed by the following steps: adding water to a system to quench the reaction, extracting the reaction system with ethyl acetate, combining an organic phase, drying the organic phase over anhydrous sodium sulfate, filtering, removing the solvent from a filtrate under reduced pressure, and purifying residues by column chromatography, to obtain the compound of formula XI.

7. The method according to claim 6, wherein an eluent for the column chromatography is dichloromethane and methanol at a volume ratio of 30:1.

8. An mRNA delivery agent wherein the agent is a compound having a structural formula shown in formula XI ##STR00008## wherein R.sub.1 is selected from the group consisting of H and C.sub.1-C.sub.10 alkyl, and R.sub.2 is selected from the group consisting of H and C.sub.1-C.sub.10 alky; n is in the range of 2-10, z is in the range of 1-10, p is in the range of 2-10, and q is in the range of 1-11.

9. The mRNA delivery agent compound according to claim 8, wherein the compound is 8,8′-((2-hydroxyethyl)azanediyl)dinonyl dicaprylate.

10. (canceled)

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0016] The present disclosure will be described with the following typical example. All simple substitutions and improvements of the present disclosure made by those skilled in the art are included in the technical solutions claimed by the present disclosure.

Example 1: Preparation of 8,8′-((2-hydroxyethyl)azanediyl)dinonyl dicaprylate.

[0017] ##STR00006##

[0018] 8,8′-Diazaalkylenedinonyl dicaprylate (10.0 g, 18.05 mmol) and acetonitrile (50 mL) were added successively to a four-neck round-bottom flask. After addition, the system was cooled down to −80° C., and the reaction system was bubbled with ethylene oxide (20 g, 0.45 mol); subsequently, ytterbium triflate (1.12 g, 1.81 mmol) was added to the reaction system. After addition, the reaction system was naturally heated to room temperature for reaction under stirring, and the reaction was tracked by thin layer chromatography (TLC) till the complete consumption of the starting material 8,8′-diazaalkylenedinonyl dicaprylate. After the reaction, water (100 mL) was added to the system to quench the reaction; the reaction system was extracted with ethyl acetate (3×80 mL); the organic phase was combined, dried over anhydrous sodium sulfate, and filtered; the solvent was removed from a filtrate under reduced pressure, and residues were purified by column chromatography (CH.sub.2Cl.sub.2/MeOH=30:1) to obtain 8,8′-((2-hydroxyethyl)azanediyl)dinonyl dicaprylate (9.18 g, 85.1%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ0.90 (m, 6H), 1.02-1.75 (m, 49H), 2.31 (m, 4H), 2.72-2.41 (m, 6H), 3.61 (m, 2H), 4.07 (m, 4H) Mass: 599 [M+H].sup.+.

[0019] Although the present disclosure is described in detail in conjunction with the foregoing example, it is only a part of, not all of, the examples of the present disclosure. Other examples can be obtained by persons based on the example without creative efforts, and all of these examples shall fall within the protection scope of the present disclosure.