Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-01-07
2002-07-16
Siegel, Alan (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S143000, C536S018500, C536S018600, C536S124000
Reexamination Certificate
active
06420604
ABSTRACT:
This application is a 371 of PCVEP99/03250 filed May 7, 1999.
FIELD OF THE INVENTION
The present invention relates to the field of acylation of amino alcohols.
BACKGROUND OF THE INVENTION
Ceramides are the main lipid component in the upper layer of the skin, the stratum corneum. This skin layer has an important barrier function in that external compounds generally are kept out whereas loss of moisture from the skin is limited. Ceramides are applied in cosmetics for instance because of their moisture retaining effects on the skin.
Typically, ceramides for use in cosmetics are obtained either from a natural source, via chemical synthesis routes or via a combined fermentative and chemical synthesis process. The latter routes are preferred due to the fact that potentially harmful infectious agents may be present in mammalian sources.
Various methods to synthesize ceramides are known in the art. The methods most frequently used involve a sphingoid base and a suitable fatty acid component as the starting materials. The fatty acid component is thereby coupled to the amino group of the sphingoid base via an amide linkage.
WO 93/20038 describes the acylation of amino alcohols whereby the fatty acid is coupled to the amino group as a mixed anhydride. It is essential for this reaction using a mixed anhydride that it occurs under essentially non-aqueous conditions.
Philippe et al. (Int. J. Cosm. Sci. 17, 133-146, 1995) describe an acylation method wherein the fatty acid is coupled to the amine as an acid halogenide, using tetrahydrofuran (THF) as the solvent and triethylamine as the organic base. In this method, the coupling reaction also occurs in a non-aqueous environment.
The requirement for non-aqueous conditions is an important disadvantage in those cases that one or both starting compounds are delivered as a water-containing material. For instance, in the case that the sphingoid base is contained within a wet crystal cake originating from a microbial fermentation process.
A further disadvantage of the above desribed methods is that they only result in a moderate product yield.
Still another acylation method is known applying a solvent system wherein THF is mixed with an equal volume of a 50% NaAc solution (see EP 212400). Although water is present in this system, the additional presence of a high salt concentration is required. A high salt concentration is undesired in that it is expensive and increases the waste load.
It is therefore desirable to be able to apply an acylation process wherein it is not required that the sphingoid base reactant is essentially water-free, which additionally does not require a high salt concentration and which gives a higher product yield than the currently known processes.
DESCRIPTION OF THE INVENTION
The present invention discloses a process for the acylation of an amino alcohol using a fatty acid being in the form of an acid halogenide, wherein the coupling occurs in an organic solvent in the additional presence of water.
The fact that water is present in the reaction mixture has several important advantages. For instance, it is not necessary to dry the amino alcohol reactant before applying the same in the acylation process. This is especially advantageous when the amino alcohol, e.g. a sphingoid base, is obtained via microbial fermentation or as a product from a reaction occurring in an aqueous environment. In addition, the pH of the process can be advantageously controlled using a simple mineral base, such as NaOH, instead of a potentially hazardous organic base.
The process of the invention further neither requires the use of a high salt concentration, as is the case for the process disclosed in EP 212400, nor the use of stoichiometric amounts of auxiliary chemicals, as is the case for the process disclosed in WO93/20038. A further important advantage is that the acylated reaction product is recovered from the organic phase by simply washing the organic phase with water followed by azeotropic removal of water and crystallization. Unexpectedly, the process of the invention provides an acylated amino alcohol in a yield which is considerably higher than the yields obtained in WO 93/20038 or by Philippe et al. In addition, the product has a high purity, i.e. does not contain undesired byproducts, since O-acylation occurs only to a very minor extent.
In the process of the invention, an amino alcohol is acylated with an organic acid of formula RCOOH, the organic acid being in the form of an acid halogenide, said process comprising the steps of:
suspending or dissolving the amino alcohol, or a salt thereof, in an organic solvent in the presence of 0.01 to 10 volumes of water to one volume of organic solvent,
adding the organic acid halogenide as a pure compound or as a solution or suspension in the organic solvent used to suspend the amino alcohol, while keeping the pH at a value of about 5 to 12,
stirring the resulting mixture until the amino alcohol is converted to the N-acylated compound,
recovering the N-acylated aminoalcohol from the organic phase.
In the organic acid of formula RCOOH, R is hydrogen, an optionally unsaturated, optionally substituted, optionally one or more heteroatoms containing straight chain or branched alkyl group having up to 55 carbon atoms; an optionally unsaturated, optionally substituted, optionally one or more heteroatoms containing C
5-8
cycloalkyl group; an optionally substituted aryl or heteroaryl group; or an optionally substituted benzyl group.
In a preferred embodiment of the invention, the alkyl group is optionally interrupted by an oxygen atom or by an internal ester group. In another preferred embodiment, the alkyl group has 1 to 50 carbon atoms, more preferably 10 to 50 carbon atoms, most preferably 15 to 45 carbon atoms.
A preferred substituent of the above defined groups is a hydroxyl group, especially an &agr;-hydroxyl group.
In a preferred embodiment of the invention, the organic acid of formula RCOOH is hexanoic acid, octanoic acid, stearic acid, oleic acid, linoleic acid, 27-stearoyloxy-heptacosanoic acid, 27-linoleoyloxy-heptacosanoic acid, &agr;-hydroxy-stearic acid, lactic acid, retinoic acid, salicylic acid or ferulic acid.
Protecting groups for the optional hydroxyl groups are well known in the art and may be selected from appropriate groups as disclosed in Greene, T. (1981) Protective Groups in Organic Synthesis (John Wiley & Sons; New York). In one embodiment of the invention, a hydroxyl group is protected as an acetyl ester or a methoxy methyl ether.
In another embodiment of the invention, a hydroxyl group is provided by first coupling an acid halogenide containing a halogen group at the position corresponding to the future hydroxyl group and subsequently converting the halogen group, i.e. after coupling, to an oxygen function, for instance an acetoxy group. Conversion of the halogen group into an oxygen function and subsequent conversion of the oxygen function into a hydroxyl group are conveniently performed using commonly known methods. Preferably, the halogen group is a bromine group.
The present invention also envisages the option to use a mixture of related organic acids, for instance a mixture of fatty acids having an alkyl group of different chain lengths and/or different extent of unsaturation.
In another preferred embodiment of the invention, the amino alcohol is a sphingoid base of formula
R′—A—CH(OR′″)—C(NH
2
)—CH
2
—OR″
or a salt thereof, wherein:
R′ is a straight chain or branched alkyl group having 10 to 22 carbon atoms which may optionally contain one or more double bonds and/or may optionally be substituted, preferably with one or more hydroxyl groups, preferably is a straight chain alkyl group having 12 to 18 carbon atoms, more preferably is a straight chain alkyl group having 13 carbon atoms, and
R″ is hydrogen or a carbohydrate, such as a hexose or pentose moiety (optionally linked to further carbohydrate moieties), preferably hydrogen or a glucose or galactose moiety,
A is CH
2
—CH
2
, CH═CH or CH
2
—C(H)OR′″, and R′&P
De Vroom Erik
Weber Pieter Gijsbert
Cosmoferm B.V.
Morrison & Foerster / LLP
Siegel Alan
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