Process for the preparation of sphingosine derivatives

Claim 2

A process for preparation of sphingosine derivatives of the formula (I) ##STR6## in which R 1 denotes an acyl radical of a fatty acid with 14 to 24 carbon atoms or the corresponding acyl radical with a hydroxyl group in the α-position or with one or two double bonds in the cis-configuration, and R 3 denotes an aliphatic radical with 13 to 19 carbon atoms, at least 13 carbon atoms of which are present in a straight chain and 0-4 carbon atoms of which are present as lateral methyl groups, said aliphatic radical containing 0-3 double bonds of cis- or trans-configuration or 0-3 triple bonds, which process comprises: reacting D-galactose with a lower aliphatic ketone or an aromatic aldehyde of the formula R--CO-R' in which R and R' each denote a lower alkyl radical or one of the radicals R and R' denotes a hydrogen atom and the other denotes an aromatic radical, to give a D-galactose protected in the 4- and 6-positions, of the formula (II) ##STR7## in which R and R' have the above meanings, reacting the protected D-galactose with an alkali metal periodate or lead tetraacetate, to give the corresponding D-threose protected in the 2- and 4-positions, of the formula (III) ##STR8## in which R and R' have the above meanings, reacting the protected D-threose with an R 3 --CH 2 -phosphonate or an R 3 --CH 2 -triphenylphosphonium halide, in which R 3 has the above meaning, in the presence of a base or of a base and a salt to give a compound of the formula (IV) ##STR9## in which R, R' and R 3 have the above meanings, sulphonating the free hydroxyl group in the compound of formula (IV) with an acid halide or an acid anhydride of a lower aliphatic sulphonic acid or of a monocyclic aromatic sulphonic acid and reacting the resultant O-sulphonyl derivative with an alkali metal azide, to give an azido compound of the formula (V) ##STR10## in which R, R' and R 3 have the above meanings, removing the protective groups on the hydroxyl groups in the 1- and 3-positions of the aliphatic chain in the compound of formula (V) by acid hydrolysis to form a 2-azido-1, 3-dihydroxy compound of the formula (VI) ##STR11## in which R 3 has the above meaning, glycosidating the compound of formula VI with the O-trifluoro- or O-trichloro-acetimidate or the 1-halogen derivative of a D-glucose, the hydroxyl groups of which in the 2-, 3-, 4- and 6-positions are protected by acyl radicals Ac, to give a compound of the formula (VII) ##STR12## in which Ac and R 3 have the above meanings, and removing the acyl groups Ac from the compound of formula (VII) by basic catalysis to form a compound of the formula (XII) ##STR13## in which R 3 has the above meaning, treating the compound of formula (XII) with hydrogen sulphide, sodium borohydride or sodium cyanoborohydride to convert the azido group in the compound of formula (XII) into a primary amino group, to give a compound of the formula (XIII) ##STR14## in which R 3 has the above meaning, and subjecting the compound of formula (XIII) to N-acylation with a fatty acid of the formula R 1 -OH in which R 1 is as defined above, or with a functional reactive derivative of the fatty acid, to form the compound of formula (I).

Claim 3

The process according to claim 1, wherein the reaction of the protected D-galactose with the alkali metal periodate or lead tetraacetate is carried out at a pH of about 7 to 8 at room temperature.

Claim 4

A process for preparation of sphingosine derivatives of the formula (I) ##STR15## in which R 1 denotes an acyl radical of a fatty acid with 14 to 24 carbon atoms or the corresponding acyl radical with a hydroxyl group in the α-position or with one or two double bonds in the cis-configuration, and R 3 denotes an aliphatic radical with 13 to 19 carbon atoms, at least 13 carbon atoms of which are present in a straight chain and 0-4 carbon atoms of which are present as lateral methyl groups, said aliphatic radical containing 0-3 double bonds of cis- or trans-configuration or 0-3 triple bonds, which process comprises: reacting D-galactose with a lower aliphatic ketone or an aromatic aldehyde of the formula R--CO-R, in which R and R' each denote a lower alkyl radical or one of the radicals R and R' denotes a hydrogen atom and the other denotes an aromatic radical, to give a D-galactose protected in the 4- and 6-positions, of the formula (II) ##STR16## in which R and R' have the above meanings, reacting the protected D-galactose with an alkali metal periodate or lead tetraacetate, to give the corresponding D-threose protected in the 2- and 4-positions, of the formula (III) ##STR17## in which R and R' have the above meanings, reacting the protected D-threose with an R 3 --CH 2 -phosphonate or an R 3 --CH 2 -triphenylphosphonium halide, in which R 3 has the above meaning, in the presence of a base or of a base and a salt to give a compound of the formula (IV) ##STR18## in which R, R' and R 3 have the above meanings, sulphonating the free hydroxyl group in the compound of formula (IV) with an acid halide or an acid anhydride of a lower aliphatic sulphonic acid or of a monocyclic aromatic sulphonic acid and reacting the resultant O-sulphonyl derivative with an alkali metal azide, to give an azido compound of the formula (V) ##STR19## in which R, R' and R 3 have the above meanings, removing the protective groups on the hydroxyl groups in the 1- and 3-positions of the aliphatic chain in the compound of formula (V) by acid hydrolysis to form a 2-azido-1,3-dihydroxy compound of the formula (VI) ##STR20## in which R 3 has the above meaning, reacting the compound of formula (VI) with an organic reagent which is capable of reacting selectively with a primary hydroxyl group, to form a compound of the formula (VIII) ##STR21## in which R" denotes a hydroxyl-protective group and R 3 has the above meaning, esterifying the secondary hydroxyl group in the compound of formula (VIII) with an organic carboxylic acid Ac'OH or a reactive functional derivative thereof, wherein Ac' is acyl to give a compound of the formula (IX) ##STR22## in which R", Ac' and R 3 have the above meanings, removing the hydroxyl-protective group R" from the compound of formula (IX) by acid hydrolysis or treatment with boron trifluoride-etherate to form a compound of the formula (X) ##STR23## in which Ac' and R 3 have the above meanings, glycosidating the compound of formula (X) with the O-trifluoro- or O-trichloro-acetimidate or the 1-halogen derivative of a D-glucose, the hydroxyl groups of which in the 2-, 3-, 4- and 6-positions are protected by acyl radicals Ac, to give a compound of the formula (XI) ##STR24## in which Ac, R 3 and Ac' have the above meanings, and removing the acyl groups Ac and Ac' from the compound of formula (XI) by basic catalysis to form a compound of the formula (XII) ##STR25## in which R 3 has the above meaning, treating the compound of formula (XII) with hydrogen sulphide, sodium borohydride or sodium cyanoborohydride to convert the azido group in the compound of formula (XII) into a primary amino group, to give a compound of the formula (XIII) ##STR26## in which R 3 has the above meaning, and subjecting the compound of the formula (XIII) to N-acylation with a fatty acid of the formula R 1 --OH in which R 1 is as defined above, or with a functional reactive derivative of the fatty acid, to form the compound of formula (1).

Claim 5

A process for preparation of sphingosine derivatives of the formula (I) ##STR15## in which R 1 denotes an acyl radical of a fatty acid with 14 to 24 carbon atoms or the corresponding acyl radical with a hydroxyl group in the α-position or with one or two double bonds in the cis-configuration, and R 3 denotes an aliphatic radical with 13 to 19 carbon atoms, at least 13 carbon atoms of which are present in a straight chain and 0-4 carbon atoms of which are present as lateral methyl groups, said aliphatic radical containing 0-3 double bonds of cis- or trans-configuration or 0-3 triple bonds, which process comprises: reacting D-galactose with a lower aliphatic ketone or an aromatic aldehyde of the formula R--CO-R, in which R and R' each denote a lower alkyl radical or one of the radicals R and R' denotes a hydrogen atom and the other denotes an aromatic radical, to give a D-galactose protected in the 4- and 6-positions, of the formula (II) ##STR16## in which R and R' have the above meanings, reacting the protected D-galactose with an alkali metal periodate or lead tetraacetate, to give the corresponding D-threose protected in the 2- and 4-positions, of the formula (III) ##STR17## in which R and R' have the above meanings, reacting the protected D-threose with an R 3 --CH 2 -phosphonate or an R 3 --CH 2 -triphenylphosphonium halide, in which R 3 has the above meaning, in the presence of a base or of a base and a salt to give a compound of the formula (IV) ##STR18## in which R, R' and R 3 have the above meanings, sulphonating the free hydroxyl group in the compound of formula (IV) with an acid halide or an acid anhydride of a lower aliphatic sulphonic acid or of a monocyclic aromatic sulphonic acid and reacting the resultant O-sulphonyl derivative with an alkali metal azide, to give an azido compound of the formula (V) ##STR19## in which R, R' and R 3 have the above meanings, removing the protective groups on the hydroxyl groups in the 1- and 3-positions of the aliphatic chain in the compound of formula (V) by acid hydrolysis to form a 2-azido-1,3-dihydroxy compound of the formula (VI) ##STR20## in which R 3 has the above meaning, reacting the compound of formula (VI) with an organic reagent which is capable of reacting selectively with a primary hydroxyl group, to form a compound of the formula (VIII) ##STR21## in which R" denotes a hydroxyl-protective group and R 3 has the above meaning, esterifying the secondary hydroxyl group in the compound of formula (VIII) with an organic carboxylic acid Ac'OH or a reactive functional derivative thereof, wherein Ac' is acyl to give a compound of the formula (IX) ##STR22## in which R", Ac' and R 3 have the above meanings, removing the hydroxyl-protective group R" from the compound of formula (IX) by acid hydrolysis or treatment with boron trifluoride-etherate to form a compound of the formula (X) ##STR23## in which Ac' and R 3 have the above meanings, glycosidating the compound of formula (X) with the O-trifluoro- or O-trichloro-acetimidate or the 1-halogen derivative of a D-glucose, the hydroxyl groups of which in the 2-, 3-, 4- and 6-positions are protected by acyl radicals Ac, to give a compound of the formula (XI) ##STR24## in which Ac, R 3 and Ac' have the above meanings, and removing the acyl groups Ac and Ac' from the compound of formula (XI) by basic catalysis to form a compound of the formula (XII) ##STR25## in which R 3 has the above meaning, treating the compound of formula (XII) with hydrogen sulphide, sodium borohydride or sodium cyanoborohydride to convert the azido group in the compound of formula (XII) into a primary amino group, to give a compound of the formula (XIII) ##STR26## in which R 3 has the above meaning, and subjecting the compound of the formula (XIII) to N-acylation with a fatty acid of the formula R 1 --OH in which R 1 is as defined above, or with a functional reactive derivative of the fatty acid, to form the compound of formula (1).

Claim 6

The process according to claim 3, wherein acetone, ethyl methyl ketone or diethyl ketone, or benzaldehyde or a benzaldehyde substituted on the phenyl ring is used as the aldehyde or ketone of the formula R--CO--R'.

Claim 7

The process according to claim 3, wherein the reaction of the protected D-galactose with the alkali metal periodate or lead tetraacetate is carried out at a pH of about 7 or 8 at room temperature.

Claim 8

The process according to claim 3, wherein the glycosidation of the compound of the formula (X) as defined in claim 3 with the said O-trifluoro- or O-trichloro-acetimidate is carried out in the presence of a Lewis acid catalyst and in an anhydrous hydrocarbon or halogenated hydrocarbon, and that with the said 1-halogen derivative is carried out in the presence of an acid-binding agent or a heavy metal salt.

Claim 9

The process according to claim 3, wherein the azido group of the compound of the formula (XII) as defined in claim 3 is converted into a primary amino group by treatment with hydrogen sulphide in a 1:1 mixture of water and pyridine or by hydrogenation with sodium borohydride or sodium cyanoborohydride.

Claim 10

The process according to claim 3, wherein the N-acylation of the compound of the formula (XIII) as defined in claim 3 is carried out by means of the fatty acid of the formula R 1 --OH as defined in claim 3 in the presence of a dehydrating agent or by means of an activated ester of the fatty acid or by means of a halide thereof in the presence of an inorganic base or a tertiary organic base.

Claim 11

The process according to claim 3, wherein the reaction of the protected D-threose of the formula (III) with the R 3 --CH 2 -phosphonate or the R 3 --CH 2 -triphenylphosphonium halide wherein R 3 is as defined in claim 3 is carried out in the presence of phenyllithium, lithium methylate, lithium ethylate, sodium amide, sodium methylate or sodium carbonate in an anhydrous hydrocarbon or ether under a nitrogen atmosphere at a temperature of -10° to -20° C. and, when using the R 3 --CH 2 -triphenylphosphonium halide, with the addition of a salt.

Claim 12

The process according to claim 3, wherein the sulphonation of the free hydroxyl group of the compound of the formula (IV) as defined in claim 3 is carried out by O-trifluoromethanesulphonation, methanesulphonation or p-toluenesulphonation.

Claim 13

The process according to claim 1, wherein acetone, ethyl methyl ketone or diethyl ketone, or benzaldehyde or a benzaldehyde substituted on the phenyl ring is, used as the aldehyde or ketone of the formula R--CO--R'.

Claim 14

The process according to claim 3, wherein a triphenylmethyl, monomethoxytriphenylmethyl, tert.-butyl, trichloroacetyl, trimethylsilyl, tert.-butyldimethylsilyl or tert. -butyldiphenylsilyl group is used as the hydroxyl-protective group R".

Claim 15

The process according to claim 1, wherein the glycosidation of the compound of the formula (VI) as defined in claim 1 with the said O-trifluoro- or O-trichloro-acetimidate is carried out in the presence of a Lewis acid catalyst and in an anhydrous hydrocarbon or halogenated hydrocarbon, and that with the said 1-halogen derivative is carried out in the presence of an acid-binding agent or a heavy metal salt.

Claim 16

The process according to claim 1, wherein the azido group of the compound of the formula (XII) as defined in claim 1 is converted into a primary amino group by treatment with hydrogen sulphide in a 1:1 mixture of water and pyridine or by hydrogenation with sodium borohydride or sodium cyanoborohydride.

Claim 17

The process according to claim 1, wherein the N-acylation of the compound of the formula (XIII) as defined in claim 1 is carried out by means of the fatty acid of the formula R 1 --OH as defined in claim 1 in the presence of a dehydrating agent or by means of an activated ester of the fatty acid or by means of a halide thereof in the presence of an inorganic base or a tertiary organic base.

Claim 18

The process according to claim 1, wherein the reaction of the protected D-threose of the formula (III) as defined in claim 1 with the R 3 --CH 2 -phosphonate or the R 3 --CH 2 -triphenylphosphonium halide wherein R 3 is as defined in claim 1 is carried out in the presence of phenyllithium, lithium methylate, lithium ethylate, sodium amide, sodium methylate or sodium carbonate in an anhydrous hydrocarbon or ether under a nitrogen atmosphere at a temperature of -10° to -20° C. and, when using the R 3 --CH 2 -triphenylphosphonium halide, with the addition of a salt.

Claim 19

The process according to claim 1, wherein the sulphonation of the free hydroxyl group of the compound of the formula (IV) as defined in claim 1 is carried out by O-trifluoromethanesulphonation, methanesulphonation or p-toluenesulphonation.

Claim 20

The process according to claim 3, wherein an acyl radical of an aliphatic or aromatic carboxylic acid or a tert.-butoxycarbonyl group is used as the protective group Ac'.

Claim 21

The process according to claim 18, wherein the acyl radical is an acyl radical of benzoic acid, a substituted benzoic acid or pivalic acid.