Europaisches Patentamt (19) European Patent Office Office europeenpeen des brevets EP 0 633 875 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) intci.6: C07C 231/02, C07C 309/00, of the grant of the patent: C07C 233/18, C07C 233/20, 02.01.1997 Bulletin 1997/01 C07C 235/08 (21) Application number: 93908917.3 (86) International application number: PCT/EP93/00849 (22) Date of filing: 02.04.1993 (87) International publication number: WO 93/20038 (14.10.1993 Gazette 1993/25) (54) SELECTIVE N-ACYLATION OF AMINO ALCOHOLS SELEKTIVE N-ACYLATION VON AMINOALKOHOLEN N-ACYLATION SELECTIVE D'AMINO-ALCOOLS (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL EP-A- 0 023 453 EP-A- 0 187 702 PT SE EP-A- 0 255 443 EP-A- 0 398 340 (30) Priority: 03.04.1992 EP 92200968 JOURNAL OF ORGANIC CHEMISTRY, vol. 56, no. 17, 16 August 1991, E ASTON US pages 5132 (43) Date of publication of application: - 8 M. BARTRA ET. AL. 'Cyclisation of 18.01.1995 Bulletin 1995/03 9-substituted decanoic acid derivatives to 9-decanolide and 9-decanelactam' (73) Proprietor: GIST-BROCADES N.V. CHEMICAL ABSTRACTS, vol. 86, no. 13, 28 NL-2600 MA Delft (NL) March 1977, Columbus, Ohio, US; abstract no. 891 25r, J.F.W. KEANA ET. AL. 'Stearoyl (72) Inventors: p-toluenesulfonate. A powerful acylating agent • SMEETS, Jan, Willem, Hubert for lipid synthesis.' page 484 ;column 1 ; NL-3732 GJ De Bilt (NL) CHEMISTRY AND PHYSICS OF LIPIDS vol. 17, • WEBER, Pieter, Gijsbert no.4, SHANNON, Ir pages 402 - 6 NL-2985 BN Ridderkerk (NL) (74) Representative: Visser-Luirink, Gesina, Dr. c/o GIST-BROCADES N.V., Patents and Trademarks Dept., Wateringseweg 1, P.O. Box 1 2600 MA Delft (NL) DO Is- 00 CO CO CO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice the Patent Office of the Notice of shall be filed in o to European opposition to European patent granted. opposition a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. a. 99(1) European Patent Convention). LU Printed by Jouve, 75001 PARIS (FR) EP 0 633 875 B1 Description The present invention concerns the production of N-acyl amino alcohols via the selective acylation of the amino group of amino alcohols. 5 Background of the Invention The efficient, selective synthesis of reaction products wherein only one of multiple functional groups in a starting material is reacted remains a continuing challenge in organic chemistry. One such example is the selective acylation 10 of the amino group of amino alcohols. N-acylated amino alcohols are especially important since among these compounds sphingolipids, particularly ce- ramides and derivatives thereof such as cerebrosides, gangliosides and sphingomyelins are of commercial and ther- apeutic importance. Ceramides, for example, are of great commercial potential in cosmetics and pharmaceuticals such as hair and skin care products (Zysman, A. et al. (1991) European Patent Application Publication No. 0 420 722 A2). is Ceramides are a class of polar lipids endogenous to the epidermis. Ceramides play a major role in the water- retaining properties of the epidermis. It has been found that topical applications of ceramide- and pseudoceramide- containing compositions are effective in restoring the water content of dry skin and may be effective in relieving atopic eczema (Kerscher, M. et al. (1991) Eur. J. Dermatol., J_, 39-43; Imokawa, G. et al. (1989) J. Soc. Cosmet. Chem.,40, 273-285). 20 Sphingolipids have been found to exhibit therapeutic properties such as wound and ulcer healing through the promotion of cell restoration and growth (Tschannen, R. et al. (1985) European Patent Application Publication No. 0 146 810 A2). In current practice, sphingolipids, especially ceramides, are primarily obtained via extraction and isolation from animal tissues, usually from bovine brain or porcine epidermal tissue. These extracts are primarily comprised of gly- 25 coceramides and generally contain only a few percent ceramides. Obviously, using this method, the production of ceramides is rather costly on an industrial scale. It would thus be desirable to find an alternative cost-efficient, high yield method for obtaining these valuable products. Chemical synthesis methods may provide a suitable alternative. Sphingolipids, as mentioned above, are charac- terized by a fatty N-acyl moiety. The acylation of amines may be achieved via a number of methods known in the art. 30 Among these methods, Heymes, R. et al. ((1983) European Patent No. 0 023 453 B1) described a method for the acylation of the 7-amino group of cephalosporins via the formation of a mixed anhydride by reacting the acid moiety to be coupled to the amino group with a sulfonyl halide, followed by reacting the mixed anhydride with the amino group. EP-A-0, 187,702 disloses the preparation of N-(omega,omega-1-dialkoxy)- and N-(omega,omega-1-dialkenloxy)- alk-1-yl-N,N,N,-trisubstituted ammonium surfactants. In this preparation the tosylate of oleic acid can be used. 35 Other mixed anhydrides are known from J. Org.Chem. 56 5132-8 (1991) which describes the mesityl sulfonate of 10-undecenoic acid, and from Chemical Abstracts 86 no. 891 25r (1977) which discloses the tosylate of stearic acid. EP-A-0, 398, 340 describes the N-acylation of 2-amino-4-octen-1 ,3-diol with octanoyl chloride in a two phase sys- tem. However, sphingosine and derivatives thereof are polyfunctional compounds containing multiple free hydroxyl moi- 40 eties as well as a free amino group. As mentioned above, the selective synthesis of monosubstituted compounds from starting materials having multiple functional groups present special complications not encountered in the reaction of starting materials having a single functional group. Indeed Ong, D. and Brody, R. ((1972) J. Lipid Res., J_3, 819-822) teach that the acylation of compounds such as sphingenine (sphingosine) and sphinganine (dihydrosphingosine) which have more than one free hydroxyl group as well as a free amino group with fatty acid chlorides suffer from lack of 45 selectivity and can lead to the formation of di-O-acyl-N-acyl compounds, even as compared to compounds having a free amino group and a single free hydroxyl moiety. The formation of O-acylated analogs necessitates an extra step to cleave the O-acyl linkages in order to obtain the desired monosubstituted N-acyl amino alcohol. Other attempts to refine this latter method to favor the formation of the desired N-acylated products (without concomitant formation of di-O-acyl-N-acyl compounds) provided only low yields (Weiss, B. and Raizman, P. (1958) J. Amer. Chem. Soc, 80, so 4657-4658). Thus, it can not be predicted whether the method described by Heymes et al. (supra) will lead to the selective acylation of the amino group of amino alcohols having more than one free hydroxyl moiety with good yield of the desired N-acylated product. 55 Summary of the Invention The present invention provides a chemical synthesis method which not only leads to the efficient, selective pro- duction of sphingolipids, but is generally applicable to the production of N-acyl amino alcohols via the selective acylation 2 EP 0 633 875 B1 of the free amines of amino alcohols. According to the present invention, N-acyl amino alcohols are produced by reacting an organic acid or a salt thereof with an alkyl sulfonyl chloride or an alkyl phenyl sulfonyl chloride, in an organic solvent and in the presence of an organic base, to form the corresponding mixed anhydride, followed by reacting the mixed anhydride with an amino 5 alcohol or a salt thereof to form the corresponding N-acyl amino alcohol. Both steps may be carried out in the same reaction vessel, thus avoiding the necessity of isolating of the mixed anhydride intermediate product. The process according to the present invention provides the desired N-acyl amino alcohol in good yield, even in large scale, and thus is attractive for use on an industrial scale. 10 Detailed Description of the Invention According to the present invention, a method for the production of N-acyl amino alcohols is provided wherein, as a first step, an organic acid (or a salt thereof) of the formula: 15 R-COOH wherein 20 R is a straight chain or branched alkyl group having up to 55 carbon atoms, the alkyl chain may optionally be interrupted by an oxygen atom or by an internal ester group; may optionally contain one or more double bonds; and may optionally be substituted with one or more protected hydroxyl moieties, is reacted with a C-,.6 alkyl sulfonyl chloride or a C-,.6 alkyl phenyl sulfonyl chloride, in an organic solvent and in the presence of an organic base, to form the corresponding mixed anhydride of the general formula: 25 R-CO-0-S02R"' wherein R'" is a C^g alkyl or a C^g alkyl phenyl group. 30 In a preferred embodiment, R is a straight chain or branched alkyl group having 10 to 50 carbon atoms; optionally interrupted by an oxygen atom or by an internal ester group; may optionally contain one or more double bonds; and optionally having a protected hydroxyl moiety. In a most preferred embodiment, R is a straight chain alkyl group having 14 to 48 carbon atoms; optionally inter- rupted by an oxygen atom or by an internal ester group; may optionally contain one or more double bonds; and optionally 35 having a protected omega hydroxyl moiety.