Preparation of sterol and stanol-esters

Details Preparation of sterol and stanol-esters Preparation of sterol and stanol-esters

2002-05-06

2003-10-21

Badio, Barbara P. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S552000, C552S555000

Reexamination Certificate

active

06635774

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the preparation of discrete sterol and stanol-esters through a highly efficient route free of catalyst producing a light colored product suitable for food use.
BACKGROUND OF THE INVENTION
It has been shown that the addition of plant sterols, such as. &bgr;-sitosterol, to diets will reduce serum cholesterol levels. The sterols reduce serum cholesterol through the disruption of intestinal absorption of dietary cholesterol by displacing it from bile acid micelli. More recently, &bgr;-sitosterol's saturated derivative, &bgr;-sitostanol, has been shown to be more effective in the reduction of intestinal cholesterol absorption. The sitostanol itself is virtually unabsorbed, so it does not contribute at all to in vivo serum sterol concentration upon consumption. Unfortunately, typical sterols and stanols are insoluble in the micelli phase of the alimentary canal and have only limited solubility in oils and/or fats or water. Hence, free sterols or stanols themselves are not optimum candidates for use in typical pharmaceutical or dietary dosage forms as cholesterol reducing agents.
U.S. Pat. No. 5,502,045 discloses the interesterification of stanols with a fatty acid ester from an edible oil to produce a waxy sterol-ester mixture with improved fat solubility characteristics. Specifically, this patent discloses the reaction of sitostanol interesterified with fatty acids from methyl esters of edible oil such as rapeseed oil specifically via a base catalyzed transesterification reaction. This is a process that is widely used in the food industry. From a pharmaceutical standpoint, however, interesterification processes such as this have some distinct disadvantages. Primarily, the composition profile of the sterol-ester products are difficult to control since the profile is dependent on the array of fatty acids present in the edible oil employed in the reaction. Also the need to use a large excess of methyl esters to drive the reaction to completion and the production of methanol, makes the purification to food grade material difficult.
In a different approach, German Patent 2035069 discloses the esterification of sterol-esters to fatty acids via a non-food grade process. In particular, thionyl chloride is employed as a reactant which when reacted forms HCl gases as a by-product. Such techniques are not suitable for the production of food grade materials, and they are undesirable in general for large scale reactions.
Japanese Patent 76-11113 discloses a catalyst free esterification of higher fatty acid esters of sterols or related vitamins. However this process employs a significant molar excess of fatty acid, a minimum of 25% up to 50%, which in turn requires the use of an alkali refining process to recover the ester product. The stoichiometric excess fatty acid and the isolation techniques result in a product that is discolored.
From a pharmaceutical standpoint, there is an unmet need for a method for the synthesis of discrete stanol/sterol-esters via a bulk food grade process. Discrete compounds are more desirable than mixtures for three main reasons: 1) the composition and performance specifications can be controlled better; 2) structure/activity studies are more feasible; and 3) the physicochemical and chemical properties can be controlled. These advantages of discrete stanol/sterol-esters will be elaborated on later.
SUMMARY OF THE INVENTION
The present invention comprises a method for the direct esterification of stanols or sterols with fatty acids to form discrete stanol/sterol-esters that are light in color, free of off flavors and odors. The method provides a one step synthetic route that is amenable to large scale production of the sterol-esters/stanol-esters and other related cholesterol reducing compound esters in high yield and purity by a food grade process that in a preferred embodiment is free of organic solvents, mineral acids and avoids the production of objectionable by products. The method ultimately provides a convenient process that enables one to rationally design discrete stanol/sterol-esters with various physical and biological properties.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides the direct esterification of stanols and sterols through the reaction of the stanol/sterol and a fatty acid substantially free of the use of a catalyst. As used in the present invention, substantially free of catalyst is understood to means less than about 0.15% by weight of reaction, and in a preferred embodiment the reaction takes place in the absence of a catalyst. Suitable catalyst include toluene sulfonic acid, methane sulfonic acid, sodium hydrogen phosphate, sodium bisulfite and the like. These catalysts are disclosed in U.S. Pat. No. 5,892,068 hereby incorporated by reference.
&bgr;-sitostanol, the most preferred starting material, is commercially produced from &bgr;-sitosterol by a hydrogenation reaction and is commercially available, from various sources including Henkel Corporation.
In the present invention the sterol and stanol-esters have the general formula depicted as FIG. I:
wherein R
1
is understood to include aliphatic straight or branched carbon chains having a length of from C
4
-C
24
, preferably from C
6
-C
20
, about C
6
to about C
20
and most preferably C
12
-C
18
about C
12
to about C
18
and R
2
is understood to include aliphatic straight or branched carbon chains ranging C
3
-C
15
, about C
3
to about C
15
, preferably C
6
-C
12
, C
6
to C
12
and most preferably, C
8
-C
10
, about C
8
to about C
10
. More preferably, R
2
is selected from the group (C
1
-C
12
) alkyl, (C
1
-C
8
) alkoxy, (C
2
-C
8
) alkenyl, (C
2
-C
8
) alkynyl, (C
3
-C
8
) cycloalkyl, halo (C
2
-C
8
) alkenyl, halo (C
2
-C
8
) alkynyl) where halo is understood to include chloro, fluoro, bromo, iodo and the like. Alkyl includes both straight and branched chain groups of carbon atoms. Typical alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, neopentyl, isopentyl, hexyl, heptyl and the like. The alkyl groups may be halogenated with one, two three or more halogen atoms. R
2
may also be a saturated branched alkane chain.
The terms alkenyl and alkynyl included branded and straight chain hydrocarbons having at least one unsaturated bond.
The acids, which include the associated salts, reacted in the present invention contain from 4 to 24 carbon atoms. The acids include saturated acids, but are preferably unsaturated fatty acids, including polyunsaturated fatty acids. The saturated fatty acids reacted in the present invention are of the formulae CH
3
—(CH
2
)
n
—CO
2
H wherein n is an integer of from about 2 to about 22, and more preferably n is from about 12 to about 20. The term fatty acid is well known and understood to those with skill in the art, see for example,
Hawley's Condensed Chemical Dictionary,
Eleventh edition. The fatty acids include both saturated acids, such as stearic, butyric, lauric, palmitic and the like. Unsaturated fatty acids can also be used in the present invention and include oleic, linoleic, linolenic, docosohexanoic acid, conjugated linoleic acid (9,11-octadecadienoic acid, 10,12-octadecadienoic acid) mixtures of the acids, and the like.
In a more preferred embodiment, the sterol and stanol-esters have the general formula depicted as FIG. II:
wherein R
1
is understood to have the same meaning as set forth above. Unsaturation at C
5
as shown gives the corresponding sterol-ester.
The present invention can be employed to esterify a wide range of cholesterol lowering or cholesterol limiting substances. These substances, including stanols or sterols, all contain a hydroxy functional hydroxy group which is suitable for esterification by the process described herein. Stanols that are capable of being esterified in the present invention include, but are not limited to &bgr;-sitostanol (depicted in FIG. III below) as well as other related compounds including cholestanol, ergostanol, brassicastanol, avenastanol, alpha-amyrin, c

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