Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-05-10
2002-10-22
Carr, Deborah (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C554S078000
Reexamination Certificate
active
06469148
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to synthetic methods for the preparation of D-erythro sphingosines and ceramides of high isomeric purity, and in particular to methods suitable for large scale production.
REFERENCES
Gros, E. G. and Deulofeu, V.,
J. Org. Chem
. 29:3647-54 (1964).
Herold,
Helv. Chim. Acta
71:354 (1988).
Kerscher, M. et al.,
Eur. J. Derinatol
. 1:39-43 (1991)
Imokawa, G. et al.,
J. Soc. Cosmet. Chem
. 40:273-285 (1989).
Kiso, M. et al.,
Carbohydrate Research
158:101-111 (1986).
Liotta, D. and Merrill, A. H., U.S. Pat. No. 5,110,987 (1992).
Polt et al.,
J. Org. Chem
. 57:5469 (1992).
Schiemenz, G. P. and Thobe,
J., Chem. Ber
. 99:2263 (1966).
Schmidt, R. R. and Zimmerman, P.,
Tetrahedron Lett
. 27(4):481-86 (1986).
Schmidt, R. R. and Zimmerman, P.,
Liebigs Ann. Chem
. 663-667 (1988).
Schmidt, R. R. and Zimmerman, P., U.S. Pat. No. 4,937,328 (1990).
BACKGROUND OF THE INVENTION
Sphingosines constitute a group of related long-chain aliphatic 2-amino-1,3-diols, of which Derythro-1,3-dihydroxy-2-amamino-1,3-diols, of which D-erythro-1,3-dihydroxy-2-amino-4,5-trans-octadecene is the most frequently occurring in animal tissues. N-acylsphingosines are also referred to as ceramides. Sphingosines, ceramides, and their glycosides, glycosphingolipids, are of great interest because of their diverse bioactivities and biological roles. These activities include inhibition of protein kinase C activity and transfer of information between developing vertebrate cells. Sphingosines also serve as chain terminators in various gangliosides. Galactosyl ceramide has been shown to be a receptor for HIV binding in cells lacking the CD4 receptor.
Skin ceramides are also believed to play an important role in the water permeability properties of the skin, providing an epidermal water barrier which strengthens the skin structure and reduces water loss. Ceramides and synthetic analogs have thus been used as components of skin care compositions, and have been found effective in restoring the water content of dry skin and in relieving atopic eczema (Kerscher et al.; Imokawa et al.).
These compounds have proven difficult to extract from natural sources, where they are present in low concentrations. Chemical synthetic methods reported to date have generally been laborious and expensive. Several reported methods of synthesizing optically pure sphingosines and their derivatives rely on the use of serine as a chiral building block. See, for example, Polt et al., Herold, and U.S. Pat. No. 5,110,987. However, methods utilizing serine as a starting material are quite lengthy and thus are not amenable to potential scale-up. Other synthetic approaches to the preparation of isomerically pure sphingosines and ceramides have employed other chiral starting materials, such as carbohydrates, L-glyceric and D-tartaric acids, and/or asymmetric reactions. Although successful as gram-scale procedures, these strategies generally fail or become prohibitively expensive when applied to kilogram scale processes. Enzymatic methods of synthesis have also been described but are often unpredictable, giving varying results depending on medium or the particular enzyme preparation.
Accordingly, a reliable, convenient and versatile method of large scale preparation of these compounds is desirable.
SUMMARY OF THE INVENTION
The present invention includes, in one aspect, a convenient process for the large scale preparation of sphingosine, a sphingosine analog, or a ceramide. The process comprises the following series of steps. A stirred slurry of benzaldehyde and a Lewis acid, preferably ZnCl
2
, is formed and contacted with D-galactose, with continued stirring. The resulting mixture is filtered to obtain a solid precipitate and a filtrate. The filtrate is then diluted with a mixture of diethyl ether and a hydrocarbon solvent, preferably a paraffinic solvent such as hexane, ligroin, or, more preferably, petroleum ether, typically in approximately equal proportions. The resulting mixture is extracted with cold water to provide an aqueous extract, which is treated with a base, such as an alkaline or alkaline earth carbonate or bicarbonate, to. produce a precipitate of zinc salts. This precipitate is removed to provide an aqueous solution of 4,6-O-benzylidene-D-galactose. Alternatively, the zinc cation may be removed by treatment with an ion exchange resin. The resulting solution is then treated, preferably without isolation, with an oxidizing agent, preferably sodium periodate, which oxidatively cleaves the 4,6-O-benzylidene-D-galactose, to produce the protected hydroxy aldehyde, 2,4-O-benzylidene-D-threose. This compound is then reacted with a Wittig reagent, e.g. (Ar)
2
P═CHR, where Ar is aryl and R is a C
4
-C
26
branched or unbranched alkyl or alkenyl chain, to produce a hydroxy olefin.
The hydroxyl group of the resulting hydroxy olefin is then converted to a suitable leaving group, such as a tosylate, mesylate, or trifluoromethanesulfonate. Preferably, the hydroxy olefin is reacted with a tritlating agent, such as trifluoromethyl sulfonic anhydride. Subsequent reaction with sodium azide, followed by a hydride reducing agent, such as LiAlH
4
or NaBH
4
, produces an amino olefin. Finally, this compound is deprotected (i.e. the benzylidene group is removed) by contacting it with an acidic ion exchange resin, to produce sphingosine (where R is n-C
13
H
27
, tridecyl) or a sphingosine analog (where R is a longer or shorter alkyl chain, e.g. C
4
-C
12
or C
14
-C
26
).
Alternatively, for the production of ceramides, the amino olefin is acylated, by treating with a C
2
-C
26
acylating agent, such as an acyl halide, anhydride, or carboxylic acid, in the presence of any necessary acylating catalyst, prior to the deprotection step.
The invention also provides convenient large scale processes for the production of two of the intermediates, i.e. 4,6-O-benzylidene-D-galactose and 2,4-O-benzylidene-D-threose, by carrying out the process described above up to the oxidative cleavage step, or through the oxidative cleavage step, respectively. D-threose may also be obtained in large quantities by deprotection of the intermediate, 2,4-O-benzylidene-D-threose.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.
REFERENCES:
patent: 4937328 (1990-06-01), Schmidt et al.
patent: 5110987 (1992-05-01), Liotta et al.
Schmidt et al, Synthisis of Sphingosines. 4. Synthesis of erythrosphingosines via their azido derivatives, Tetrahedron Letters, 1988, vol. 7, 663-7, see abs AN 1988:473824.*
Schmidt et al, Synthesis of phingosines, Pt. 2 Synthesis d-erythro=sphingosines, Tetrahedron Letters 1986, vol. 27 iss 4, 481-484, see abs, AN 1986:460459.*
Ohashi, et al., Synthesis of D-Erythro-1-Deoxydihydroceramide-1-Sulfonic Acid, Tetrahedron Letters, 1988; 29(10): 1185-1188.
Schiemenz, et al., Aromatic Phosphines with Second-Order Substituents, III2: A New Variant on the Wittig Reaction, Chem. Ber., 1966; 99: 2663-2668.
Polt, et al., Aluminoxy Acetals from &agr;-Amino Esters: Chirality Transfer via Sequential Addition of Hydride and C-Nucleophiles. 2-Amino Alcohols and Sphingosines, J. Org. Chem., 1992; 57: 5469-5480.
Kiso, et al., A Novel Route to D-erythro-Sphingosine and Related Compounds from Mono-O-Isopropylidene-D-Xylose or D-Galactose, Carbohydrate Research, 1986; 158: 101-111.
Imokawa, et al., Water-retaining Function in the Stratum Corneum and Its Recovery Properties by Synthetic Pseudoceramides, J. Soc. Cosmet. Chem., 1989; 40: 273-285.
Kerscher, et al., Skin Ceramides: Structure and Function, European Journal of Dermatology, 1991; 1: 39-43.
Herold, Synthesis of D-erythro-and D-threo-Spingosine Derivatives from L-Serine, Helvelica Chemica Acta, 1988; 71: 354-362.
Gros, et al., Reaction of Ammonia with Some Acetylated and Benzoylated Monosaccharides. IX. The Migration of Benzoyl Groups in the Ammonolysis of 1,2,3,4,6-PentaO-benzoyl-D-galactoses, J. Org. Chem., 1964; 2
Browdy and Neimark
Carr Deborah
Lipiderm Ltd.
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