Preparation of sterol and stanol-esters

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

1999-06-21

2001-02-06

Henley, III, Raymond (Department: 1614)

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

Organic compounds

Tetracyclo naphthacene configured ring system having at...

Reexamination Certificate

active

06184397

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the preparation of discrete sterol and stanol-esters through a highly efficient catalyzed route in the presence of a color deactivating agent.
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 an 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. In addition methanol a by-product of this reaction must be carefully removed and the use of methyesters requires large excesses to be used making recycle 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.
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 products that are 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.
In addition there is a need for food grade esters of sterols/stanols which are light in color food preparation of appealing food products. Also processes that reduce processing losses and equipment costs are needed.
SUMMARY OF THE INVENTION
The present invention comprises a method for the direct esterification of stanols or sterols with catalysts, in the presence of a color deactivating agent to form discrete stanol/sterol-esters. The catalyst can be either a weak acid in the classic sense, or a Lewis acid, or traditional basic materials. The method provides a synthetic route that is amenable to large scale production of the stanol-esters in high yield and purity by a food grade process that in a preferred embodiment is free of organic solvents or mineral acids and produces limited by-products. The method ultimately provides a convenient process that enables one to 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 fatty acids using either acid or basic catalyst. &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 Raisio Corporation.
The acids, which include the associated salts, reacted in the present invention contain from about 4 to about 24 carbon atoms. The acids include saturated acids, but are preferably unsaturated acids, including polyunsaturated 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 2 to 22, 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 term includes acids themselves and salts of these acids. The fatty acids include saturated acids, such as stearic, butyric, lauric, palmitic and the like. Unsaturated fatty acids, including polyunsaturated fatty acids can also be used in the present invention. Suitable unsaturated fatty acids include oleic, linoleic, linolenic, docosohexanoic acid, conjugated linoleic acid and the like. As disclosed in U.S. Pat. No. 5,554,646, column 1, lines 44-48, conjugated linoleic acid is 9,11-octadecadienoic acid, 10,12-octadecadienoic acid, and mixtures thereof. The present invention includes both straight and branched acids, with straight chain acids being preferred.
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 about C
3
-C
24
, preferably from C
6
-C
22
and most preferably C
12
-C
21
groups, and R
2
is understood to include aliphatic straight or branched carbon chains ranging C
3
-C
15
, preferably C
6
-C
12
, and most preferably, C
9
groups. 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, isobuytyl, 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.
The terms alkenyl and alkynyl included branded and straight chain hydrocarbons having at least one unsaturated bond.
Unsaturation at C
5
provides the corresponding sterol-ester. Any stanol or sterol that is functionalized with a hydroxy group is suitable for esterification by the process described herein. Provided below is a generic formula of the stanol/sterols that can be esterified in the present invention:
R
2
is understood to have the same meaning as set forth above.
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, avenastenol, alpha-amyrin, cyclartenol, lupenol and the like.
For example, this process is also amenable to sterols such as □□sitosterol (unsaturated at C
5
, as shown in FIG. III above).
The molar ratios of the starting materials for the esterification reaction, notably the stanol/sterol and the fatty acid, are provided in stoichiometr

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