Methods for making tocoflexols and analogues thereof
Inventors
Zheng, Guangrong • Compadre, Cesar • Hauer-Jensen, Martin • Crooks, Peter • Breen, Philip
Assignees
US Department of Veterans Affairs • BioVentures LLC
Publication Number
US-9309547-B2
Publication Date
2016-04-12
Expiration Date
2033-03-13
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Abstract
Methods for the synthesis of tocoflexols of Formula (I) and (II) and a number of related tocol analogs are provided herein. The methods are economical and amenable to large scale production and can be performed using either pure of partially purified tocotrienols as the starting material.
Core Innovation
The invention provides methods for synthesizing tocoflexols of Formula (I) and (II) and related tocol analogs. These methods are economical and suitable for large-scale production, utilizing either pure or partially purified tocotrienols as starting materials. The tocoflexols are derivatives with modifications to the hydrocarbon tail, enabling more efficient binding and uptake by the α-tocopherol transfer protein (αTTP), compared to tocotrienols which have limited bioavailability due to their lower binding affinity and shorter half-life in the body.
The synthesis approach involves a novel and economical synthetic route comprising multiple steps, including introducing protective groups, oxidative cleavage, Horner-Wadsworth-Emmons reactions, reductions, and coupling reactions. The methods enable production starting from partially purified tocotrienols obtained from natural oils such as annatto, oat, barley, wheat germ, rice bran, and palm, thereby providing significant commercial feasibility. The resulting tocoflexols have increased flexibility in the hydrocarbon tail and improved biological activity due to better αTTP binding and prolonged half-life.
Claims Coverage
The patent includes one independent claim describing a multi-step method for making tocoflexols, supported by several dependent claims further specifying reaction conditions and reagents.
Method for introducing protective groups to tocotrienol phenolic hydroxyl
Introducing a protective group to the phenolic hydroxyl group of pure or partially purified tocotrienol of formula (X) using an aprotic solvent at a reaction temperature between −20°C and 120°C for 5 minutes to 24 hours to form product of formula (XI).
Oxidative cleavage step using OsO4/NaIO4 or ozonolysis
Performing oxidative cleavage of double bonds in the protected tocotrienol using OsO4/NaIO4 or ozonolysis with reaction solvents such as tetrahydrofuran mixed with water or various ethers and maintaining reaction temperature below 40°C.
Horner-Wadsworth-Emmons reaction conditions
Reacting the aldehyde intermediate with trialkyl 2-phosphonopionate using bases including sodium hydride within a temperature range of −78°C to 30°C for 1 to 12 hours in solvents such as tetrahydrofuran, diethyl ether, or dimethylformamide.
Reduction reaction conditions
Reducing the Horner-Wadsworth-Emmons reaction product using diisobutylaluminium hydride or other hydride reagents within −78°C to 30°C for 1 to 12 hours in ether solvents.
Protection and deprotection specifications
Specifying t-butyldimethylsilyl as a preferred protective group and reaction conditions of −5°C to 25°C for 30 minutes to 3 hours in the protection step, with standard de-protection methodologies in the final step to obtain tocoflexols of formula (I) or (II).
Use of crude tocotrienol mixtures as starting materials
Using pure or partially purified tocotrienols derived from natural sources including bran oil, palm oil, and annatto oil as starting materials for the synthesis method.
The claims collectively define a methodical and economical multi-step synthetic process for producing tocoflexols from pure or partially purified tocotrienols, incorporating specific reaction conditions, protective groups, and reagents to achieve compounds with improved properties relevant to αTTP binding and bioavailability.
Stated Advantages
The methods are highly economical and amenable to large-scale production by enabling the use of inexpensive partially purified tocotrienol preparations rather than costly pure tocotrienols.
Tocoflexols produced have increased binding affinity to αTTP, resulting in a longer half-life in the body which reduces dosage frequency and quantity required.
The extended half-life and improved αTTP binding potentially provide enhanced biological activity compared to tocotrienols.
The synthetic process is simple and commercially feasible due to compatibility with natural oil-derived tocotrienol mixtures.
Documented Applications
Tocoflexols may be used to treat a wide variety of conditions and possess anti-inflammatory, radio-protective, and antioxidant properties.
The compounds demonstrate increased cell uptake and antioxidant potency, exemplified by δ-tocoflexol showing nearly double cell uptake relative to α-tocopherol and being five times more potent as an antioxidant.
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