CN-122028910-A - Synthetic triterpene composition, production method and application thereof

Abstract

The present invention claims a synthetic triterpene composition (e.g., squalene) and a method for producing the composition via a novel chemical synthetic route. The squalene produced by the synthetic method covered in the preparation of the invention has high purity and is suitable for preparing vaccine adjuvants, antioxidant preparations and drug delivery agents.

Inventors

• Nande Kumar Deoka
• RAMAN BAHULEKAR
• Eric J. Sorensen
• Marcel Akhtenhaan
• Thomas. Xiduofu

Assignees

• 安万托特性材料股份有限公司
• 普林斯顿大学董事会

Dates

Publication Date

20260512

Application Date

20240808

Priority Date

20230907

Claims (13)

1. 1. A high purity squalene composition comprising squalene having a purity of at least 98 wt% and a heavy metal of less than 1 ppm.
2. 2. A process for preparing squalene, comprising: (1) Making trans, trans-farnesol With a reagent to form a bis-farnesamine And (C) sum (2) By reacting bifarnesyl amine Reaction to form squalene Wherein R1 is benzyl and R2, R3 and R4 are independently C 1-10 alkyl.
3. 3. The method of claim 2, wherein R2, R3, and R4 are methyl.
4. 4. The process of claim 2, wherein the reagents in step (1) and step (2) are p-toluenesulfonamide, cyanmethylene tributylphosphine (CMBP) and sodium naphthalene.
5. 5. The process of claim 2, wherein in step (1), trans-farnesol is reacted with a reagent to form an intermediate , Wherein X is p-toluenesulfonyl, the intermediate reacts with sodium naphthalene to form diminution, X can be trityl, the intermediate reacts with any acid, or X can be nitrobenzenesulfonyl, the intermediate reacts with thioglycollic acid and a base to form diminution.
6. 6. The process of claim 4 wherein in step (1), trans-farnesol is reacted with p-toluenesulfonamide and ‌ (tributylphosphine) acetonitrile solution or cyanomethylene tributylphosphine (CMBP) to form bis-farnesyl-p-toluenesulfonamide , The bis-farnesyl tosylamide then reacts with sodium naphthalene to form bis-farnesyl amine.
7. 7. The method of claim 2, wherein the synthesis is performed in the absence of a transition metal catalyst.
8. 8. A composition comprising high purity squalene prepared using the method of claim 2, wherein the high purity squalene comprises greater than 98 wt% squalene.
9. 9. A method of preparing a vaccine formulation comprising adding the high purity squalene of claim 8 to an oil-in-water emulsion to form a vaccine formulation.
10. 10. A method of preparing a drug delivery formulation comprising adding the high purity squalene of claim 8 to an oil-in-water emulsion to form a drug delivery formulation.
11. 11. A method of preparing a cosmetic formulation comprising adding the high purity squalene according to claim 8 to a cosmetic formulation.
12. 12. A method of improving the anti-inflammatory and antioxidant properties of a Lipid Nanoparticle (LNP) formulation comprising adding the high purity squalene according to claim 8 to a lipid nanoparticle formulation.
13. 13. The method of claim 2, wherein the reagent in step (1) is 2-nitrobenzenesulfonamide.

Description

Synthetic triterpene composition, production method and application thereof Cross Reference to Related Applications The present application claims priority from U.S. provisional application Ser. No. 63/537,012 filed on 7 at 9 at 2023 and U.S. provisional application Ser. No. 63/653,454 filed on 5 at 2024, the disclosures of which are incorporated herein by reference in their entireties. Technical Field The present invention relates generally to a synthetic triterpene composition (e.g., squalene), and a method for producing the composition via a novel chemical synthesis route. Squalene produced by the synthetic methods encompassed in the formulations of the present invention is suitable for use in the preparation of vaccine adjuvants, antioxidant formulations and drug delivery agents. Background Squalene is a naturally occurring polyunsaturated hydrocarbon lipid of the formula C 30H50, chemical name 2,6,10,15,19, 23-hexamethyltetracos-2, 6,10,14,18, 22-hexaene, belonging to the class of triterpenes (comprising triterpene units). As mentioned above, squalene is mainly derived from animals (sharks) or plants, which are considered to be non-sustainable sources. Certain derivatives of squalene are precursors to a variety of triterpenes. Squalene is used mainly in the pharmaceutical industry, as part of formulations (as excipient) to design drug delivery systems, and also in the cosmetic industry. Squalene has been used as an adjuvant in vaccine formulations. Squalene-based emulsions have been shown to help enhance immune responses against a variety of diseases in preclinical and clinical settings. The anti-inflammatory effect of squalene has been demonstrated in zebra fish models. Reactive Oxygen Species (ROS) and free radicals are known to cause damage to proteins, lipids and DNA. Several studies have been reported in the literature to demonstrate the antioxidant properties of squalene. The antioxidant activity of squalene has been evaluated in vitro by the 2, 2-diphenyl-1-picrylhydrazine (DPPH) assay. The activity was found to be dose-dependent, with the highest free radical scavenging activity at 1% squalene concentration. Therefore, squalene may also be used to enhance the anti-inflammatory and antioxidant capacity of Lipid Nanoparticle (LNP) formulations. The process of separating squalene from various sources is well documented in the literature. However, the process of isolating squalene from plant or animal sources is tedious and economically inefficient, and may not always produce squalene of sufficient purity to be required, in particular, for pharmaceutical applications. As the demand for squalene increases in the future, it is reasonable to say that squalene of natural or biosynthetic origin will be far from satisfactory for supply. Thus, there is a need to develop new synthetic routes which are not only sustainable, but also produce squalene in high purity. The present invention solves this problem by providing a novel, fully synthetic route to squalene. U.S. patent application Ser. No. 16/972,291 to Fisher et al uses farnesene, which is generally obtained as a mixture of geometric olefin isomers, which are reflected in squalene as impurities. The present invention relates to the production of homogeneous squalene free of unwanted geometric and positional isomers by using pure farnesol as starting material. Pure farnesol is superior to a mixture of farnesenes as a raw material for the synthesis of squalene. This will help overcome the disadvantages of any olefin isomer mixture in the feed. Furthermore, routes starting from pure farnesol require relatively few steps. Disclosure of Invention The invention encompasses a high purity composition for the synthesis of squalene. High purity compositions refer to squalene having a purity of greater than 97% and no isomers, i.e., clear, colorless or pale yellow oily liquids. Typically, squalene is obtained from animal (shark liver) and vegetable (olive oil) sources. However, these sources are not considered optimal when squalene is used in pharmaceutical applications because (1) the separation, extraction and fractional crystallization processes for making squalene are cumbersome, (2) they do not produce squalene in the high purity required for pharmaceutical applications, and (3) there is a risk of pathogens, allergens. Therefore, a viable alternative synthetic route for high purity squalene, particularly for pharmaceutical applications, is important and desirable. In the present invention, a novel chemical synthesis process for producing such high purity compositions is disclosed. In certain embodiments, the present invention provides a novel method for synthesizing high purity squalene by chemical reaction. In particular embodiments, the key starting material is bifonamide. Certain embodiments of the method further comprise converting the trans, trans-farnesol to bis-farnesamine. Other embodiments of this synthetic route also include the conversion of bis-