CA1267891A - Process for the preparation of sphingosine derivatives - Google Patents
Process for the preparation of sphingosine derivativesInfo
- Publication number
- CA1267891A CA1267891A CA000515738A CA515738A CA1267891A CA 1267891 A CA1267891 A CA 1267891A CA 000515738 A CA000515738 A CA 000515738A CA 515738 A CA515738 A CA 515738A CA 1267891 A CA1267891 A CA 1267891A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- group
- azido
- process according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
- C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Abstract The application relates to a new process for the preparation of the sphingosine derivatives described in European Patent Application No. 146,810, of the formula:
Description
-` 126789~
New process for the preparation of s hin osine deriva-tives pc~
European Patent Application~No. 146,810 relates to new sphingosine derivatives of the formulae:
~Rl Rl R~ ~ R2 ~0- ~ O OH ~ ~ ~ Od HO OH (I~-D HO
OH ~ L
and processes ~or their preparation.
In the above formulae, Rl denotes the acyl radical of a fatty acid with 14 to 24 carbon atoms or the corresponding acyl radicals with a hydroxyl group in the ~-position or;with one or two double bonds in the cis-configuration, and R2 denotes the pentadecanyl or heptadecanyl radical or the corresponding Cls-and C17~radicals~with one, two or three double bonds, in each case one of which is in the 1,2-position and has the trans-configura-tion and the other or others, if present, have the cis-configuration.
These compounds have the erythro-configuration and correspond to the already known neutral glycosphingolipids. They are distinguished~by wound healing-promoting or cell and tissue regenerating properties and are suitable for therapeutic use on wounds of any origin, i~n particular wounds or ulcerations~which heal poorly or s~lowly. They~ln fact~lead, especially when ~
applied topically to~wounds, ~to the formatlon of healthy~new tissue with good circulation, without troublesome scars. The sphingosine ~ ~ ~
~6~a~
derivatives of the formula tl)-D are preferred, because of their higher therapeutic eff;cacy.
The preparation of the abovementioned compounds starts from corresponding ceramides of the formulae:
' Rl . 1 / ~ R
HN~
~ and/r,r HO OH ~ (II)-D H OH (II)-L
The ceramides in turn can be prepared from the C1g- or C20-sphingosines by N-acylat~ion by means of a fatty acid of the formula R1-OH. Depe~nding on whether an~optically ac$ive or a racemic sphîngosine is used as the starting substance, the compounds of the formula (I)-D or (I)-L are obtained in an opt;cally uniform form, or a mixture of the diastereomers (I)-~ and tI)-L is obtained; in the latter case, the diastereomers m~ust be resolved at a certain process stage.
It has recently been possible to obtain the race-mic sphingos;nes in a good yield from glycine by a simple synthesis by R~R. Schmidt and R. Klager ~Angew. Chem. 94, 215 - 216 ~1q82); Angew. Chem. Int. Ed. Engl~ 21, 210 -211 (1982~ and Angew. Chem. Suppl. 1982, 393 ~ 397~.
Although the preparat~ion process descr;bed above likewise gives a satisfactory y;eld of the sphingosine derivatives of the formula (I)-D or (I)-L, a process wh;ch manages w;thout resolut;o~n of diastereomers would be preferable -especially cons;dering that the more act;ve compounds belong to the D series.
On the;other hand, various syntheses are known which use a chiral compound selected ad hoc as t~he start-;ng substance~and thus lead~, without resolution of d;-astereomers, ~to the optically active sphingosines of erythro-configurat;on and the D series, and therefore to ~: :
1 1 ~æ~
the naturally occurring sphingosines.
The somewhat older synthesis of E.J. Reist and P.H. Christie ~J. Org. Chem. 35, 3521 and ~t27 (1970)], starting from D-glucose, and that of H. Newman ~J. Am.
Chem. Soc~ 95, 4098 (1973)~ and of P~ Tkaczuk and E.R.
Thornton tJ. Org. Chem. 46, 4393 (1981)], both starting from L-serine, each comprise a reaction stage with a low yieLd, that is to say the preparation of 3-amino-3-deoxy-di-(O-isopropylidene)-~-D-ailofuranose or the addition reaction bet~een trans-v;nylalane and an aldehyde derived from L-serine.
A more recent synthesis of B. ~ernet and A. Vasella ~Tetrahedron Letters 24, 5491 - 5494 (1983)~ gives ~-erythro-c1g-sphin9osine ~ith an overall yield of 33% after 6 reaction stages. Ho~ever, it starts from pentadecyne, which is not directly obta;nable and the preparation of which has a detrimen~al effect on the number of stages and the overall yield.
Finally, the synthesis of a ceramide by K. Koike, Y. Nakahara and T. Oga~a tGlycoconjugate J. 1, 107 - 109 (1984)] wh;ch starts from a D-glucose der;vative~ com-prises 12 reaction stages and gives the ceramide in a yield of about 20X should be mentioned. The process can probably be used for the preparation of sphingosines of naturally occurring configuration.
The use of optically active D-sphingosines as starting substances, ~hich ;s in itself more advantageous, in the above preparation of sphingosine derivatives of the formula tI)-D has thus hitherto been impaired by the fact that provision of these starting substances is labour-intensive and/or unsatisfactory in yield~
It has now been found that optically uniform sphingosine derivatives of the formula (I) - see sheet of formulae - can be obtained by a ne~ process which starts from commercially available D-galactose, comprises a total of 9 or 12 sta~es and gives the desired compounds in a satisfactory overall yield.
In formula ~I), R1 deno~es the same acyl radicals ~L2~91 ~, as described ab~ve in the discussion of the formulae (I~-D
and (I)-L, whilst R3 represents an aliphatic radical with 13 to 19 carbon atoms, at least 13 of which are present in a straight chaln and, if appropriate, not more S than 4 are present as lateral methyl groups, it being possible for this radical to conta;n up to three double bonds of cis- or trans-configuration or up to three triple bonds.
The process according to the invention comprises reacting D-galactose with a lower aliphatic ketone or an aromatic aldehyde of the formula R-C0-R', in which R and R' each denote a Lower alkyl rad;cal or one of the rad;-cals R and R' denotes a hydrogen atom and the other de-notes an aromatic radical, to give a D-galactose protec-ted in the 4- and 6-positions, of the formula (II), splitting this compound ~ith an oxidizing agent which splits vicinal diols to give the corresponding D-threose protected in the 2- and 4-positions, of the formula (lII), reacting the protected D-threose with an R3-CH2-phosphonate or an R3-CH2-triPhenylphosphonium halide, in ~hich R3 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), converting the free hydroxyl group in this compound into an azido group by activation, liberating the resulting azido compound of the formula tV) from the protective group on the hydroxyl groups in the 1- and 3 positions of the al;phat;c cha;n to form a 2-azido-1,3-dihydroxy com-pound of the formula (VI), reacting the latter with an organic reagent which is capable of r.eacting selectively with a primary hydroxyl group, to form a compound of the formula (VlII), in which R" denotes a hydroxyl-protective group, blocking the secondary hydroxyL group in the eom-pound of the formula (VIIl) with a protective gr~oup R"', splitting off the hydroxyl-protective group R" from the resulting compound of the formula (IX) to form a compound of the formula (X), glycosidating the compound previously obtained, of the formula (VI), or the compound:of the formula ~X) with the 0-trifluoro- or 0-trichloro-, ~2~ 8~
acetimidate or the 1-halogen der;vative 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 (VIl) or (XI), splitting off the S acyl groups Ac or the acyl groups Ac and the protective group R"' from the resulting compound to form the same compound of the formula ~XII), converting the azido group in this into a primary amino group and subjecting the resulting compound of the formula (XIII) to N-acylation with a fatty acid of the formula R1-OH.
The invention is described ;n more deta;l below~
The organic carboxylic acid R1-OH from which the acyl group R1 in the sphingosine derivatives of the for-mula (I) is derived is, for example, myristic acid C14H2g02, palmitic acid C16H3z02, stearic acid C1gH3602, oleic acid C1gH3402, linole;c acid C18H3202~ arachidic acid C20H4002, behenic acid C22H~402 or - at the upper limit of the meaning g;ven for R1 - tetracosanoic acid (ligno-ceric acid) C24H482~ cis-15-tetracosenoic acid (nervonic acid) Cz4H4602, 2-hydroxy-tetracosanoic acid (cerebronic acid) C24H4gO3, 2-hydroxy-15-tetracosenoic acid ~hyclroxy-nervonic acid) C24H4603 or the 2-hydroxy-17-tetracosenoic acid, which is isomeric ~ith the previous acid.
The aliphatic radical R3 can be an unbranched chain or can carry one, two, three or four methyl groups as substituents. The chain can furthermore be saturated or unsaturated; in the latter case, it contains one to three double bonds or one to three triple bonds. The double bonds have the cis- or the trans-configuration.
Preferred aliphatic rad;cals R3 are those with an uneven number of carbon atoms, in particular the C13- and C1s-radicals.
In the first stage of the process, a lower ali-phatic ketone, such as acetone, ethyl methyl ketone or diethyl ketone, or an aldehyde of the aromatic seriesr such as benzaldehyde or a benzaldehyde substituted on the phenyl ring, can be used to pro~ect the hydroxyl groups in the 4- and 6-position of the D-galactose. The use of `` ~æ~789l benzaldehyde is preferred for this. Suitable condensing agents for the reaction are in general Lewis acids, such as 2inc chloride, boron trifluor;de, aluminium chloride and iron chloride, or ar~nsted acids, such as p-toluene-S sulphonic acid. The D-galactose can be converted into 4,6-O-benzylidene-D-galactose, for example, by the method of E.G. Gros and V. Deulofeu [J. Org. Chem. 29, 3647 3654 (1964)~, and the reaction of D-galactose with acetone to give 4,6-0-isopropylidene-D-galactose can be carried out by the method of J. 6elas and D~ Horton ~Carbohydr. Res~
71, 103-121 (1979)].
The oxidizing agent used in the second process stage can be an alkali metal periodate, for example the lithium, sodium or potassium salt, or lead tetraacetate;
sodium periodate is preferabLy used. The oxidation is advantageously carried out at a pH of about 7 to 8, for example in a corresponding buffer solution, at room tem-perature.
The Witt;g reaction ;n the third stage of the process is as a rule carried out in an inert gas atmos-phere, for example under nitrogen, at low temperatures, for example at -10 to -20C, using an R3-CH2-phosphon;um halide ;n the presence of a salt, for example l;thium bromide, sodium chloride or potassiu~ bromide. Suitable bases are, inter alia, organic lithium compounds, in par-ticular phenyllithium or lithium methylate, and further-more sod;um am;de, sod;um methylate and sodium carbonate.
Solvents kh;ch can be used are aromatic hydrocarbons, such as benzene, toluene or xylene, or ethers, such as diethyl 3û ether, tetrahydrofuran or dioxane; the solvent should be anhydrous~
The conversion of the free hydroxyl group into an azido group by act;vat;on can advantageously be carried out by O-sulphonation of the compound (IV) and subsequent reaction of the Q-sulphonyl der;vative formed, for example the methanesulphonyL, tr;fluoromethanesulphonyl or p-toluenesulphonyl derivative, with an alkali metal azide; inversion of the configuration on C2 of the D-threose thereby takes place. '~e /
O~sulphonation can be carried out by the methods described in "Ullmanns Encyklopadie der technischen Chemie" ~"Ull-mann's Encyclopaedia of Industrial Chemistry"), 4th edition, Volume 11, pages 91 et seq., Verlag Chemie GmbH, Weinheim FRG (1976). An acid halide or an acid anhydride of a lower aliphatic sulphonic acid or of a monocyclic aromatic sulphonic acid, for example methanesulphonyl chloride, p-toluenesulphonyl chLoride, methanesulphonic acid anhydride or trifluoromethanesulphonic acid anhydride, is as a rule used. The û-sulphonation is preferably carried out in the presence of a base. S;nce anhydrous reaction conditions should be maintained and an organic solvent, such as benzene, toluene, tetrahydrofuran, di-ethyl ether or methylene chloride, is to be used~ suit-able bases are, in particular, tertiary organic bases,such as triethylamine, dimethylaniline, pyridine, colli-dine, lutidine and the like. The subsequent reaction with the aLkali metal azide, for example lithium a2ide, sodium azide or potassium azide, is advantageously carried out without purification of the 0-sulphonyl derivatlve. Both reactions are preferably carried out in an inert gas atmosphere, for example under nitrogen, at low tempera-tures or room temperature.
In the fifth stage of the process, the protective ~roup can be split off from the compound (Y) by ac;d hydrolysis. For example, the compound is djssolved in an organic solvent, such as methylene chloride or dimethyl-formamide, and a small amount of concentrated hydrochloric acid and water is then allowed to act on the solution for some time, preferably at room temperature.
The compound tVI) can now be subjected directly to glycosidat;on to form a compound (VII), or can be con-verted, via the intermediate products (VIII), (IX3 and (X), into a compound ~XI), which only then is subjected to glycosidation. Although th~;s second process variant com-prises three more reaction stages, it gives a higher over-all yield and is therefore particularly suitable for pro-duction on an industrial scale. It is explained ;n more detail belo~.
Protection of the primary hydroxyl group of the
New process for the preparation of s hin osine deriva-tives pc~
European Patent Application~No. 146,810 relates to new sphingosine derivatives of the formulae:
~Rl Rl R~ ~ R2 ~0- ~ O OH ~ ~ ~ Od HO OH (I~-D HO
OH ~ L
and processes ~or their preparation.
In the above formulae, Rl denotes the acyl radical of a fatty acid with 14 to 24 carbon atoms or the corresponding acyl radicals with a hydroxyl group in the ~-position or;with one or two double bonds in the cis-configuration, and R2 denotes the pentadecanyl or heptadecanyl radical or the corresponding Cls-and C17~radicals~with one, two or three double bonds, in each case one of which is in the 1,2-position and has the trans-configura-tion and the other or others, if present, have the cis-configuration.
These compounds have the erythro-configuration and correspond to the already known neutral glycosphingolipids. They are distinguished~by wound healing-promoting or cell and tissue regenerating properties and are suitable for therapeutic use on wounds of any origin, i~n particular wounds or ulcerations~which heal poorly or s~lowly. They~ln fact~lead, especially when ~
applied topically to~wounds, ~to the formatlon of healthy~new tissue with good circulation, without troublesome scars. The sphingosine ~ ~ ~
~6~a~
derivatives of the formula tl)-D are preferred, because of their higher therapeutic eff;cacy.
The preparation of the abovementioned compounds starts from corresponding ceramides of the formulae:
' Rl . 1 / ~ R
HN~
~ and/r,r HO OH ~ (II)-D H OH (II)-L
The ceramides in turn can be prepared from the C1g- or C20-sphingosines by N-acylat~ion by means of a fatty acid of the formula R1-OH. Depe~nding on whether an~optically ac$ive or a racemic sphîngosine is used as the starting substance, the compounds of the formula (I)-D or (I)-L are obtained in an opt;cally uniform form, or a mixture of the diastereomers (I)-~ and tI)-L is obtained; in the latter case, the diastereomers m~ust be resolved at a certain process stage.
It has recently been possible to obtain the race-mic sphingos;nes in a good yield from glycine by a simple synthesis by R~R. Schmidt and R. Klager ~Angew. Chem. 94, 215 - 216 ~1q82); Angew. Chem. Int. Ed. Engl~ 21, 210 -211 (1982~ and Angew. Chem. Suppl. 1982, 393 ~ 397~.
Although the preparat~ion process descr;bed above likewise gives a satisfactory y;eld of the sphingosine derivatives of the formula (I)-D or (I)-L, a process wh;ch manages w;thout resolut;o~n of diastereomers would be preferable -especially cons;dering that the more act;ve compounds belong to the D series.
On the;other hand, various syntheses are known which use a chiral compound selected ad hoc as t~he start-;ng substance~and thus lead~, without resolution of d;-astereomers, ~to the optically active sphingosines of erythro-configurat;on and the D series, and therefore to ~: :
1 1 ~æ~
the naturally occurring sphingosines.
The somewhat older synthesis of E.J. Reist and P.H. Christie ~J. Org. Chem. 35, 3521 and ~t27 (1970)], starting from D-glucose, and that of H. Newman ~J. Am.
Chem. Soc~ 95, 4098 (1973)~ and of P~ Tkaczuk and E.R.
Thornton tJ. Org. Chem. 46, 4393 (1981)], both starting from L-serine, each comprise a reaction stage with a low yieLd, that is to say the preparation of 3-amino-3-deoxy-di-(O-isopropylidene)-~-D-ailofuranose or the addition reaction bet~een trans-v;nylalane and an aldehyde derived from L-serine.
A more recent synthesis of B. ~ernet and A. Vasella ~Tetrahedron Letters 24, 5491 - 5494 (1983)~ gives ~-erythro-c1g-sphin9osine ~ith an overall yield of 33% after 6 reaction stages. Ho~ever, it starts from pentadecyne, which is not directly obta;nable and the preparation of which has a detrimen~al effect on the number of stages and the overall yield.
Finally, the synthesis of a ceramide by K. Koike, Y. Nakahara and T. Oga~a tGlycoconjugate J. 1, 107 - 109 (1984)] wh;ch starts from a D-glucose der;vative~ com-prises 12 reaction stages and gives the ceramide in a yield of about 20X should be mentioned. The process can probably be used for the preparation of sphingosines of naturally occurring configuration.
The use of optically active D-sphingosines as starting substances, ~hich ;s in itself more advantageous, in the above preparation of sphingosine derivatives of the formula tI)-D has thus hitherto been impaired by the fact that provision of these starting substances is labour-intensive and/or unsatisfactory in yield~
It has now been found that optically uniform sphingosine derivatives of the formula (I) - see sheet of formulae - can be obtained by a ne~ process which starts from commercially available D-galactose, comprises a total of 9 or 12 sta~es and gives the desired compounds in a satisfactory overall yield.
In formula ~I), R1 deno~es the same acyl radicals ~L2~91 ~, as described ab~ve in the discussion of the formulae (I~-D
and (I)-L, whilst R3 represents an aliphatic radical with 13 to 19 carbon atoms, at least 13 of which are present in a straight chaln and, if appropriate, not more S than 4 are present as lateral methyl groups, it being possible for this radical to conta;n up to three double bonds of cis- or trans-configuration or up to three triple bonds.
The process according to the invention comprises reacting D-galactose with a lower aliphatic ketone or an aromatic aldehyde of the formula R-C0-R', in which R and R' each denote a Lower alkyl rad;cal or one of the rad;-cals R and R' denotes a hydrogen atom and the other de-notes an aromatic radical, to give a D-galactose protec-ted in the 4- and 6-positions, of the formula (II), splitting this compound ~ith an oxidizing agent which splits vicinal diols to give the corresponding D-threose protected in the 2- and 4-positions, of the formula (lII), reacting the protected D-threose with an R3-CH2-phosphonate or an R3-CH2-triPhenylphosphonium halide, in ~hich R3 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), converting the free hydroxyl group in this compound into an azido group by activation, liberating the resulting azido compound of the formula tV) from the protective group on the hydroxyl groups in the 1- and 3 positions of the al;phat;c cha;n to form a 2-azido-1,3-dihydroxy com-pound of the formula (VI), reacting the latter with an organic reagent which is capable of r.eacting selectively with a primary hydroxyl group, to form a compound of the formula (VlII), in which R" denotes a hydroxyl-protective group, blocking the secondary hydroxyL group in the eom-pound of the formula (VIIl) with a protective gr~oup R"', splitting off the hydroxyl-protective group R" from the resulting compound of the formula (IX) to form a compound of the formula (X), glycosidating the compound previously obtained, of the formula (VI), or the compound:of the formula ~X) with the 0-trifluoro- or 0-trichloro-, ~2~ 8~
acetimidate or the 1-halogen der;vative 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 (VIl) or (XI), splitting off the S acyl groups Ac or the acyl groups Ac and the protective group R"' from the resulting compound to form the same compound of the formula ~XII), converting the azido group in this into a primary amino group and subjecting the resulting compound of the formula (XIII) to N-acylation with a fatty acid of the formula R1-OH.
The invention is described ;n more deta;l below~
The organic carboxylic acid R1-OH from which the acyl group R1 in the sphingosine derivatives of the for-mula (I) is derived is, for example, myristic acid C14H2g02, palmitic acid C16H3z02, stearic acid C1gH3602, oleic acid C1gH3402, linole;c acid C18H3202~ arachidic acid C20H4002, behenic acid C22H~402 or - at the upper limit of the meaning g;ven for R1 - tetracosanoic acid (ligno-ceric acid) C24H482~ cis-15-tetracosenoic acid (nervonic acid) Cz4H4602, 2-hydroxy-tetracosanoic acid (cerebronic acid) C24H4gO3, 2-hydroxy-15-tetracosenoic acid ~hyclroxy-nervonic acid) C24H4603 or the 2-hydroxy-17-tetracosenoic acid, which is isomeric ~ith the previous acid.
The aliphatic radical R3 can be an unbranched chain or can carry one, two, three or four methyl groups as substituents. The chain can furthermore be saturated or unsaturated; in the latter case, it contains one to three double bonds or one to three triple bonds. The double bonds have the cis- or the trans-configuration.
Preferred aliphatic rad;cals R3 are those with an uneven number of carbon atoms, in particular the C13- and C1s-radicals.
In the first stage of the process, a lower ali-phatic ketone, such as acetone, ethyl methyl ketone or diethyl ketone, or an aldehyde of the aromatic seriesr such as benzaldehyde or a benzaldehyde substituted on the phenyl ring, can be used to pro~ect the hydroxyl groups in the 4- and 6-position of the D-galactose. The use of `` ~æ~789l benzaldehyde is preferred for this. Suitable condensing agents for the reaction are in general Lewis acids, such as 2inc chloride, boron trifluor;de, aluminium chloride and iron chloride, or ar~nsted acids, such as p-toluene-S sulphonic acid. The D-galactose can be converted into 4,6-O-benzylidene-D-galactose, for example, by the method of E.G. Gros and V. Deulofeu [J. Org. Chem. 29, 3647 3654 (1964)~, and the reaction of D-galactose with acetone to give 4,6-0-isopropylidene-D-galactose can be carried out by the method of J. 6elas and D~ Horton ~Carbohydr. Res~
71, 103-121 (1979)].
The oxidizing agent used in the second process stage can be an alkali metal periodate, for example the lithium, sodium or potassium salt, or lead tetraacetate;
sodium periodate is preferabLy used. The oxidation is advantageously carried out at a pH of about 7 to 8, for example in a corresponding buffer solution, at room tem-perature.
The Witt;g reaction ;n the third stage of the process is as a rule carried out in an inert gas atmos-phere, for example under nitrogen, at low temperatures, for example at -10 to -20C, using an R3-CH2-phosphon;um halide ;n the presence of a salt, for example l;thium bromide, sodium chloride or potassiu~ bromide. Suitable bases are, inter alia, organic lithium compounds, in par-ticular phenyllithium or lithium methylate, and further-more sod;um am;de, sod;um methylate and sodium carbonate.
Solvents kh;ch can be used are aromatic hydrocarbons, such as benzene, toluene or xylene, or ethers, such as diethyl 3û ether, tetrahydrofuran or dioxane; the solvent should be anhydrous~
The conversion of the free hydroxyl group into an azido group by act;vat;on can advantageously be carried out by O-sulphonation of the compound (IV) and subsequent reaction of the Q-sulphonyl der;vative formed, for example the methanesulphonyL, tr;fluoromethanesulphonyl or p-toluenesulphonyl derivative, with an alkali metal azide; inversion of the configuration on C2 of the D-threose thereby takes place. '~e /
O~sulphonation can be carried out by the methods described in "Ullmanns Encyklopadie der technischen Chemie" ~"Ull-mann's Encyclopaedia of Industrial Chemistry"), 4th edition, Volume 11, pages 91 et seq., Verlag Chemie GmbH, Weinheim FRG (1976). An acid halide or an acid anhydride of a lower aliphatic sulphonic acid or of a monocyclic aromatic sulphonic acid, for example methanesulphonyl chloride, p-toluenesulphonyl chLoride, methanesulphonic acid anhydride or trifluoromethanesulphonic acid anhydride, is as a rule used. The û-sulphonation is preferably carried out in the presence of a base. S;nce anhydrous reaction conditions should be maintained and an organic solvent, such as benzene, toluene, tetrahydrofuran, di-ethyl ether or methylene chloride, is to be used~ suit-able bases are, in particular, tertiary organic bases,such as triethylamine, dimethylaniline, pyridine, colli-dine, lutidine and the like. The subsequent reaction with the aLkali metal azide, for example lithium a2ide, sodium azide or potassium azide, is advantageously carried out without purification of the 0-sulphonyl derivatlve. Both reactions are preferably carried out in an inert gas atmosphere, for example under nitrogen, at low tempera-tures or room temperature.
In the fifth stage of the process, the protective ~roup can be split off from the compound (Y) by ac;d hydrolysis. For example, the compound is djssolved in an organic solvent, such as methylene chloride or dimethyl-formamide, and a small amount of concentrated hydrochloric acid and water is then allowed to act on the solution for some time, preferably at room temperature.
The compound tVI) can now be subjected directly to glycosidat;on to form a compound (VII), or can be con-verted, via the intermediate products (VIII), (IX3 and (X), into a compound ~XI), which only then is subjected to glycosidation. Although th~;s second process variant com-prises three more reaction stages, it gives a higher over-all yield and is therefore particularly suitable for pro-duction on an industrial scale. It is explained ;n more detail belo~.
Protection of the primary hydroxyl group of the
2-azido-1,3-dihydroxy compound (VI) should be carried out with reagents ~hich, in the presence of a primary and a secondary hydroxyl group~ react selectively with the ~or-mer. Particularly suitable protective groups R" are thus those which occupy a large space, such as, for example, the tert.-butyl, triphenylmethyl (trityl), trichloro-acetyl, trimethylsilyl, tert.-butyldimethyls;lyL or tert.-butyldiphenylsilyl group. The triphenylmethyl, monomethoxytriphenylmethyl, tert.-butyldimethylsilyl and tert.-butyldiphenylsilyl group are preferred.
The protective group R" is introduced by the known methods of organic chemistry, depending on the nature of the protective group chosen~ For example, the triphenyl-methyl group can be introduced by treatment of the compound (VI) with a corresponding halide, such as triphenyl-chloromethane or triphenylbromomethane. The corresponding halide, preferably the chloride or the bromide~ can also advantageously be used for the tert.-butyldimethyLsilyl and the tert.-butyldiphenylsilyl group.
The compound protected in the 1-position, of the formula (VIII), is then protected on the hydro~yl group in the 3-pos;tion by a protective group R"', for example by esterification with an organic carboxylic ac;d Ac'OH
or a reactive ~unctional derivative thereof. Simple, al;phatic carboxylic acids and aromatic, in particular monocycl;c aromatic, carboxylic acids, above all, are suitable for this; the use of benzoic acid, a substituted benzoic acid or pivalic acid is preferred.
The ester;fication ~;th the carboxylic acid Ac'OH
can be carried out by the methods described in "Ullmanns Encyklop'adie der technischen Chemie" ("Ullmann's Encyclo-paedia of Industrial Chemistry"~, 4th edition, Volume 11, pages ~1 et seq., Verlag Chem;e GmbH, Weinheim FRG t1976).
It is advantageously carr;ed out using a carboxylic acid halide in the presence of a tertiary organic base, such as triethylamine, pyridine or dimethylaniline, in an ~9~
anhydrous or~an;c solvent, such as benzene, toluene, tetrahydrofuran, diethyl ether or methylene chloridea The protective group R on the hydroxyl group ;n the 1-posit;on of the compound of the formula (IX) can be split off by acid hydroLysis (triphenylmethyl protective groups and silyl protective groups) or by treatment ~ith boron trifluoride-etherate (triphenylmethyl groups). The compound of the formula tX), in which the hydroxyl group in the 3-position is still blocked by the protective group R but the primary hydroxyl group in the 1-position is free again, is obtainedO
The reaction of the compound tIX) or that of the compound (Vl) with the 0-trichloro- or 0 trifluoro-acet-îmidate of a D-glucose, the hydroxyl groups of which, apart from that on the 1-position, are proteceed by acyl radicals Ac,`is advantageously catalysed by a Le~is acid, such as boron trifluoride-etherate or trimethylsilyltri-fluoromethanesuLphonate. It is in general carried out in an anhydrous organic solvent, such as a hydrocarbon (hexane) or a halogenated hydrocarbon tmethylene chloride).
Acyl radicals which are used to protect the hydroxyl groups in the 2-, 3-, 4- and 6-posit;ons of the D~glucose are, preferably, lower aliphatic acyl groups, such as the acetyl, propionyl, pivaloyl, trifluoroaçetyl or methane-sulphonyl group~ Details on the preparat;on of the re-agent can be found in the pu~lication by R.R. Schmidt and M. Stumpp tLiebigs Ann. Chem. 1983, 1249-1Z56) and R.R. Schmidt, J. Michel and M. Roos (Liebigs Ann. Chem.
1984, 1343-1357).
The corresponding reaction with the 1-halogen derivative of the 0-tetraacylated D-glucose, for example with 0-acetyl-~-D-glucopyranosyl chloride or hromide (the latter is also called ~-D-0-acetobromoglucose)~ is as a rule carried out in the presence of a heavy metal com-pound, such as silver oxide, a heavy metal saltr such as silver carbonate or mercury cyan;de~ or an organic base, which ~unction as an acid-bindiny agent tUllmanns Encyklo-padie der technischen Che:ie ~Ullmann s Encyclopaedia of .
Industria~ Chemistry), 4th edition, Volume 24, page 757, Verlag Chemie GmbH, Weinheim FRG l983).
Splitt;ng off of the acyl radicals Ac and the pro-tective group R"' from the compound (VII) or (XI) is in general catalysed by bases; the use of sodium methanolate - in anhydrous methanol at room temperature is particularly advantageous for this.
In the penultimate stage of the process, the con-version of the azido group into the primary amino group is best effected by treatment of the compound (XII) with hydrogen sulphide at room temperature. For this, the com-pound is dissolved, for example, in a mixture (1:1) of water and pyridine. The same conversion can aLso be car-ried out by hydrogenation with sodium borohydride or another reducing agent, such as, for exampLe, sodium cyanoborohydride.
The N-acylation of the compound (XIII) with the organic carboxylic acid of the formula R1-OH (last stage of the process) can be carried out by the method of 2û D. Shapiro and co-workers ~J. Am. Chem. Soc. 86, 4472 (1~64)]. In general, the carboxylic acid itself, in the presence of a dehydrating agent, such as dicyclohexyl-carbodi;m;de in methylene chloride, or a functional reac-tive der;vative of the carboxyl;c ac;d, such as an activa-ted ester or a halide, in the presence of an inorganicbase, such as sodium acetate, or of a tertiary organic base, is used. The N-ac~ylation ;s advantageously carried out at room temperature.
The compounds obtained at each process stage are isolated and purified by the customary methods of organic chemistry.
The following examples illustrate preferred embod;-ments of the ;nvention.
1H-NMR spectra were recorded with the 250 MH~
apparatus WM 250 Cryospec from aruker, Spectrospin, Industriestrasse 26, CH-8117 Fallanden/Zurich. The shifts are based on tetramethylsilane (TMS) as the internal standard and are stated in Ppm.
~L~;789~
The melting points stated were determ;ned on a copper block and are uncorrected.
SiLica gel plates from E. Merck AG, Darmstadt (FRG) were used for the analyt;cal thin layer chromato-graphy ~TLC). Where the substances were not UV-active, the thin layer chromatograms were sprayed with 15% strength sulphuric acid and developed at 120C.
Preparative column chromatography was carried out with silica gel 60 (0.062-0.200 mm) from Merck. Pre-packed columns according to D. Flockerzi, begree thesis,Stuttgart Un;vers;ty/FRG (1978) containing the silica geL
"L;Chroprep S; 60, 15-25" were used for the medium pres-sure chromatography.
The y;elds have been stated at the pur;f;cat;on stage at which no ;mpurities were to be detected by NMR
spectroscopy and by means of thin layer chromatography.
The f;gures in parentheses aga;nst the solvent m;xtures denote parts by volume.
Example 1 2s~3R-2-Hexadecanoylamino-3-hydroxy-1-(B-D-glucopyranosyl . _ . ...
oxy)-4-trans-eicosene a) 4,6-0-~enzyl;dene-D-galactose See J. Org. Chem. 29, 3647-3654 t1964).
b) 2,4-0-~enzyl;dene-D-threose ~1) . . _ _ . . . _ _ . .
30 g (0.111 mol) of 4,6-U-benzylidene-G-galactose are dissolved in about 1,200 ml of phosphate bu~Ffer of pH
7.6. 55 9 (0.257 mol) of sod;um periodate are added, while stirring vigorously. The pH is kept at about 7 to 8 by dropwise addition of 2 N sodium hydroxide solution.
The mixture is stirred at room temperature for 1.5 hours.
Thereafter, it is concentrated to dryness under a water-pump vacuum. The solid res;due is extracted~four times with 250 ml of ethyl acetate each time. The extract is filtered, dried over magnesium sulphate and concentrated.
Yield: 20 9 (85%), RF = 0.64 in toluene/ethanol (3:1).
c) 2R,3R-1,3-0-~enzylide _ 4-trans-eicosene (2) 70 9 (0.12 mol) of hexadecyltriphenylphosphonium bromide are suspended under nitrogen in abOut 1 l~tre of anhydrous toluene saturated ~ith nitrogen. Phenyllithium which has been prepared from 6.5 g ~0.94 mol) of lithium and 74 9 ~0.47 mol) of bromobenzene in about 200 mL of an-hydrous ether is added drop~ise without further purifica-tion. At the same time, the mixture is cooled to -15C.
Thereafter, 20 9 tO.096 mol) of compound (I) in about 150 ml of anhydrous tetrahydrofuran are added dropwise in the course of 20 m;nutes, under nitrogen. After a further 20 minutes, first 150 ml of methanol and then 250 ml of water are added. The mixture is stirred vigor-ously. After removal of the aqueous phase, the organic phase ;s concentrated. For purification, the residue is chromatographed over silica gel with petroleum etheri ethyl acetate (9:1).
Yield: 27 g (68%), RF = 0.21 in petroleum ethertethyl acetate (9:1).
d) 2S,3R-2-Azido-1,3-0-benzylidene-4-trans-eicosene (3) 10 g (0.025 mol) of compound (2) are dissolved in about 70 ml of anhydrous methylene chloride containing 5 ml of anhydrous pyridine. The solution is cooled to -15C, under nitrogen. 8.12 g ~0.029 mol) of tr;fluoro-methanesulphon;c acid anhydride are sLowly added dropw;se.
After 15 minutes, the mixture is filtered over silica gel and eluted with methylene chloride/petroleum ether (1:1).
The receiver is flushed continuously with nitrogen. The eluate is cor,centrated and the oil which remains is taken up in 50 ml of anhydrous dimethylformamide. 7.5 g (0.1 mol) of sodium azide are added, under nitrcgen~ The m;x-ture is stirred at room temperature for 2 hours. There~
after, it is diluted ~ith about 350 ml of methylene chloride and filtered and the filtrate is concentrated under a waterpump vacuum. For purification, the residue is chromatographed over silica gel with petroleum ether/
ethyl acetate (9:1). Yield: 8 9 (75%j, RF = 0.8 in petroleum ether/ethyl acetate (9:1).
e) 2S,3R-2-Azido-1,3-dihydroxy-4-trans-eicosene (4) .. . _ . . . . . _ . ~, _ _ 8 9 (0.018 mol) of compound (3) are dissolved in 100 ml of methylene chloride. 5 ml of concentrated ~æ678~L
.
chlor;c ac;d and 3 ml of water are added and the m;xture is sti'rred v;gorously at room temperature for 12 hours.
Thereafter, it is extracted by shaking with aqueous sodium b;carbonate solution. The organic phase is separated of~, dried over sodium sulphate and concentrated. F~r purifi-- cation, the residue is chromatographed over s;lica gel with methylene chloride/methanol (95:5). Yield: 4.3Z g (68%~, RF = 0.46 in methylene chloride/methanol (95:5), melting point: 56-57C.
Elemental analysis: calculated C 67.95 H 11.11 N 11.88 found 67.62 11.12 11~85 1H-NMR (25û MHz, CDfl3 in ppm) of compound (4):
5.83 ~m, 1H, -CH2-CH=C); 5.55 ~dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 6.5 Hz); 4.25 (m, 1H, -CH-N3); 3.8 (m, 2H, -CH2-OH, CH-OH); 3.52 (m, 1H, -CH2-OH?; 2.05 (m, 4H, OH, C-CH CH2); 1.45-1.18 (m, 26H, aliphatic); and Q.88 (t, 3H, CH3).
f) 2S,3R-2-Azido-3-hydroxy-1-(2,3,4,6-tetra-0-acetyl-~-D-glucopyranosyloxy)-4-trans-eicosene (6) 0.5 g (1.41 mmol) of compound (4) is dissolved in 50 ml of anhydrous hexane. û.1 ml of 0.5 M boron tri-~luoride-etherate in methylene chloride and a spatula-tip of molecular sieve 4 A are added. 0.7 9 (1.41 mmol) of' 0-(2,3,4,6-tetra-û-acetyl-~-D-glucopyranosyl)-trichloro-acetimidate is dissolved in 3 ml of anhydrous toluene and the solution is slowly added dropwise. After 4 hours, the mixture is washed with 30 ml of saturated sodium bicarbon-ate solution. The aqueous phase is extracted three times by shaking with 30 ml of methylene chloride each time.
The organic phases are dried over sodium sulphate and concentrated. For p~urification, the residue is chromato-graphed over silica gel ~;th methylene chloride~methanol ~97.5:2.5). Y;eld: 0.385 9 ~40%), RF ~ 0.7 in methylene chloride/methanol (95:5).
1H-NMR (250 MHz, CDCl3 in ppm) of compound (6):
5.78 (m, 1H, -CH2-CH=C); 5.5 ~dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 7.3 Hz~; 5.3-4.98 (m, 3H, H-2, H-3, H-4);
4.58 (d, 1H, H-1, J = 7.6 Hz); 4.35-4.13 (m, 3H, H-6, H-6;
~ Z~i7691 -CH-N3); 4.05 (dd, 1H, -CH2-0-~; 3.73 ~m, 2H, H-5, -CH2-0); 3.47 (m, 1H, ,CH-OH); 2.24 (d, 1H, OH, J = 4.8 Hz); 2.1b-1.94 (m, 14H, acetyl, C=CH-CH2); 1.45-1.15 (m, 26H, aliphatic); and 0.88 (t, 3H, -CH3).
9) 2S,3R-2~Azido-3-hydroxy-1-(B-D-glucopyranosyloxy)-4-trans-eicosene (7) Ou4 9 (0.585 mol) of compound (6) is dissolved in 30 ml of anhydrous methanol. 0.2 ml of a 1 M solution of sodium methylate in methanol is added. The mixture ;s stirred at room temperature for one hour. Thereafter, it ;s neutral;zed with the ion exchan~er Amberlit IR 120 (H~
form). The ion exchanger is f;ltered off, the f;ltrate is concentrated and the residue ;s chromatographed over sil;ca gel w;th chloroform/methanol (9:1). Yield: 0.26 9 (86X), RF = 0.22 in chloroform/methanol (9:1).
1H-NMR (250 MHz, DMSO-d6 ;n ppm) of compound t7):
4.1û (d, 1H, H~1, J = 7.6 Hz).
h) 2s~3R-2-Am;no-}-hydroxy-1-(B-D-9lucopyranosyloxy) .
4-trans-eicosene (8) -0.2S 9 (0.5 mmol) of compound (7) ;s d;ssolved in a mixture of 4 ml of pyridine and 4 ml of water. The solut;on is saturated w;th hydrogen sulphide. The mixture is stirred at room temperature for 24 hours. It ;s con-centrated to dryness and the residue is çhromatographed over silica gel, f;rst with chloroform/methanol (6:4) and then with chloroform/methanol/water (5:4:1).
Yield: 0.234 9 (96%), RF = 0.65 ;n chloroform/methanol/
water (5:4:1).
1H-NMR (25û MHz, DMSO-d6 ;n ppm) of compound (8):
4.10 (d, 1H, H-1, J = 7.6 Hz).
;) 2S,3R-2-Hexadecanoylamino~3-hydroxy-1-(B-D-gluco~
pyranosyloxy?-4~trans~eicosene (9) 0.23 g (0.47 mmol) of compound (8) is dissolved in 5 ml of tetrahydrofuran. 5 ml of a 5~0% strength aque~
ous sod;um acetate solution are added. 0.19 9 ~0.7 mmol) - of hexadecanoyl chloride is added to the m;xture at room temperature, with v;gorouS stirring. After about 2 hours, the organlc phase is separated off. The aqueous phase is extracted three t;mes by shaking w;th 2 ml of chloroform each t;me. The organ;c phases are dr;ed over sod;um sulphate and concentrated. For purification, the residue is chromatographed over sil;ca gel with chloro-form/methanol (9~ Yield: 0.3 9 (90%), RF = 0.50 inchloroformtmethanol (9:1).
1H-NMR (250 MHz, DMSO-d6 in ppm) of compound (9):
7.5 ~d, 1H, NH, J = 8.7 Hz); S.52 (m, 1H, -CH2-CH=C);
5.35 (dd, 1H, C=CH-, J = 15.2 Hz, J = 6.5 Hz); 5.03 (d, 1H, OH, J = 3.4 Hz); 4.92 (m, 3H, OH); 4.5 (t, 1H, OH, J =
4.9 Hz); 4.09 (d, lH, H-1, J = 7.6 Hz); 4.0-3.55 (m, 4H);
The protective group R" is introduced by the known methods of organic chemistry, depending on the nature of the protective group chosen~ For example, the triphenyl-methyl group can be introduced by treatment of the compound (VI) with a corresponding halide, such as triphenyl-chloromethane or triphenylbromomethane. The corresponding halide, preferably the chloride or the bromide~ can also advantageously be used for the tert.-butyldimethyLsilyl and the tert.-butyldiphenylsilyl group.
The compound protected in the 1-position, of the formula (VIII), is then protected on the hydro~yl group in the 3-pos;tion by a protective group R"', for example by esterification with an organic carboxylic ac;d Ac'OH
or a reactive ~unctional derivative thereof. Simple, al;phatic carboxylic acids and aromatic, in particular monocycl;c aromatic, carboxylic acids, above all, are suitable for this; the use of benzoic acid, a substituted benzoic acid or pivalic acid is preferred.
The ester;fication ~;th the carboxylic acid Ac'OH
can be carried out by the methods described in "Ullmanns Encyklop'adie der technischen Chemie" ("Ullmann's Encyclo-paedia of Industrial Chemistry"~, 4th edition, Volume 11, pages ~1 et seq., Verlag Chem;e GmbH, Weinheim FRG t1976).
It is advantageously carr;ed out using a carboxylic acid halide in the presence of a tertiary organic base, such as triethylamine, pyridine or dimethylaniline, in an ~9~
anhydrous or~an;c solvent, such as benzene, toluene, tetrahydrofuran, diethyl ether or methylene chloridea The protective group R on the hydroxyl group ;n the 1-posit;on of the compound of the formula (IX) can be split off by acid hydroLysis (triphenylmethyl protective groups and silyl protective groups) or by treatment ~ith boron trifluoride-etherate (triphenylmethyl groups). The compound of the formula tX), in which the hydroxyl group in the 3-position is still blocked by the protective group R but the primary hydroxyl group in the 1-position is free again, is obtainedO
The reaction of the compound tIX) or that of the compound (Vl) with the 0-trichloro- or 0 trifluoro-acet-îmidate of a D-glucose, the hydroxyl groups of which, apart from that on the 1-position, are proteceed by acyl radicals Ac,`is advantageously catalysed by a Le~is acid, such as boron trifluoride-etherate or trimethylsilyltri-fluoromethanesuLphonate. It is in general carried out in an anhydrous organic solvent, such as a hydrocarbon (hexane) or a halogenated hydrocarbon tmethylene chloride).
Acyl radicals which are used to protect the hydroxyl groups in the 2-, 3-, 4- and 6-posit;ons of the D~glucose are, preferably, lower aliphatic acyl groups, such as the acetyl, propionyl, pivaloyl, trifluoroaçetyl or methane-sulphonyl group~ Details on the preparat;on of the re-agent can be found in the pu~lication by R.R. Schmidt and M. Stumpp tLiebigs Ann. Chem. 1983, 1249-1Z56) and R.R. Schmidt, J. Michel and M. Roos (Liebigs Ann. Chem.
1984, 1343-1357).
The corresponding reaction with the 1-halogen derivative of the 0-tetraacylated D-glucose, for example with 0-acetyl-~-D-glucopyranosyl chloride or hromide (the latter is also called ~-D-0-acetobromoglucose)~ is as a rule carried out in the presence of a heavy metal com-pound, such as silver oxide, a heavy metal saltr such as silver carbonate or mercury cyan;de~ or an organic base, which ~unction as an acid-bindiny agent tUllmanns Encyklo-padie der technischen Che:ie ~Ullmann s Encyclopaedia of .
Industria~ Chemistry), 4th edition, Volume 24, page 757, Verlag Chemie GmbH, Weinheim FRG l983).
Splitt;ng off of the acyl radicals Ac and the pro-tective group R"' from the compound (VII) or (XI) is in general catalysed by bases; the use of sodium methanolate - in anhydrous methanol at room temperature is particularly advantageous for this.
In the penultimate stage of the process, the con-version of the azido group into the primary amino group is best effected by treatment of the compound (XII) with hydrogen sulphide at room temperature. For this, the com-pound is dissolved, for example, in a mixture (1:1) of water and pyridine. The same conversion can aLso be car-ried out by hydrogenation with sodium borohydride or another reducing agent, such as, for exampLe, sodium cyanoborohydride.
The N-acylation of the compound (XIII) with the organic carboxylic acid of the formula R1-OH (last stage of the process) can be carried out by the method of 2û D. Shapiro and co-workers ~J. Am. Chem. Soc. 86, 4472 (1~64)]. In general, the carboxylic acid itself, in the presence of a dehydrating agent, such as dicyclohexyl-carbodi;m;de in methylene chloride, or a functional reac-tive der;vative of the carboxyl;c ac;d, such as an activa-ted ester or a halide, in the presence of an inorganicbase, such as sodium acetate, or of a tertiary organic base, is used. The N-ac~ylation ;s advantageously carried out at room temperature.
The compounds obtained at each process stage are isolated and purified by the customary methods of organic chemistry.
The following examples illustrate preferred embod;-ments of the ;nvention.
1H-NMR spectra were recorded with the 250 MH~
apparatus WM 250 Cryospec from aruker, Spectrospin, Industriestrasse 26, CH-8117 Fallanden/Zurich. The shifts are based on tetramethylsilane (TMS) as the internal standard and are stated in Ppm.
~L~;789~
The melting points stated were determ;ned on a copper block and are uncorrected.
SiLica gel plates from E. Merck AG, Darmstadt (FRG) were used for the analyt;cal thin layer chromato-graphy ~TLC). Where the substances were not UV-active, the thin layer chromatograms were sprayed with 15% strength sulphuric acid and developed at 120C.
Preparative column chromatography was carried out with silica gel 60 (0.062-0.200 mm) from Merck. Pre-packed columns according to D. Flockerzi, begree thesis,Stuttgart Un;vers;ty/FRG (1978) containing the silica geL
"L;Chroprep S; 60, 15-25" were used for the medium pres-sure chromatography.
The y;elds have been stated at the pur;f;cat;on stage at which no ;mpurities were to be detected by NMR
spectroscopy and by means of thin layer chromatography.
The f;gures in parentheses aga;nst the solvent m;xtures denote parts by volume.
Example 1 2s~3R-2-Hexadecanoylamino-3-hydroxy-1-(B-D-glucopyranosyl . _ . ...
oxy)-4-trans-eicosene a) 4,6-0-~enzyl;dene-D-galactose See J. Org. Chem. 29, 3647-3654 t1964).
b) 2,4-0-~enzyl;dene-D-threose ~1) . . _ _ . . . _ _ . .
30 g (0.111 mol) of 4,6-U-benzylidene-G-galactose are dissolved in about 1,200 ml of phosphate bu~Ffer of pH
7.6. 55 9 (0.257 mol) of sod;um periodate are added, while stirring vigorously. The pH is kept at about 7 to 8 by dropwise addition of 2 N sodium hydroxide solution.
The mixture is stirred at room temperature for 1.5 hours.
Thereafter, it is concentrated to dryness under a water-pump vacuum. The solid res;due is extracted~four times with 250 ml of ethyl acetate each time. The extract is filtered, dried over magnesium sulphate and concentrated.
Yield: 20 9 (85%), RF = 0.64 in toluene/ethanol (3:1).
c) 2R,3R-1,3-0-~enzylide _ 4-trans-eicosene (2) 70 9 (0.12 mol) of hexadecyltriphenylphosphonium bromide are suspended under nitrogen in abOut 1 l~tre of anhydrous toluene saturated ~ith nitrogen. Phenyllithium which has been prepared from 6.5 g ~0.94 mol) of lithium and 74 9 ~0.47 mol) of bromobenzene in about 200 mL of an-hydrous ether is added drop~ise without further purifica-tion. At the same time, the mixture is cooled to -15C.
Thereafter, 20 9 tO.096 mol) of compound (I) in about 150 ml of anhydrous tetrahydrofuran are added dropwise in the course of 20 m;nutes, under nitrogen. After a further 20 minutes, first 150 ml of methanol and then 250 ml of water are added. The mixture is stirred vigor-ously. After removal of the aqueous phase, the organic phase ;s concentrated. For purification, the residue is chromatographed over silica gel with petroleum etheri ethyl acetate (9:1).
Yield: 27 g (68%), RF = 0.21 in petroleum ethertethyl acetate (9:1).
d) 2S,3R-2-Azido-1,3-0-benzylidene-4-trans-eicosene (3) 10 g (0.025 mol) of compound (2) are dissolved in about 70 ml of anhydrous methylene chloride containing 5 ml of anhydrous pyridine. The solution is cooled to -15C, under nitrogen. 8.12 g ~0.029 mol) of tr;fluoro-methanesulphon;c acid anhydride are sLowly added dropw;se.
After 15 minutes, the mixture is filtered over silica gel and eluted with methylene chloride/petroleum ether (1:1).
The receiver is flushed continuously with nitrogen. The eluate is cor,centrated and the oil which remains is taken up in 50 ml of anhydrous dimethylformamide. 7.5 g (0.1 mol) of sodium azide are added, under nitrcgen~ The m;x-ture is stirred at room temperature for 2 hours. There~
after, it is diluted ~ith about 350 ml of methylene chloride and filtered and the filtrate is concentrated under a waterpump vacuum. For purification, the residue is chromatographed over silica gel with petroleum ether/
ethyl acetate (9:1). Yield: 8 9 (75%j, RF = 0.8 in petroleum ether/ethyl acetate (9:1).
e) 2S,3R-2-Azido-1,3-dihydroxy-4-trans-eicosene (4) .. . _ . . . . . _ . ~, _ _ 8 9 (0.018 mol) of compound (3) are dissolved in 100 ml of methylene chloride. 5 ml of concentrated ~æ678~L
.
chlor;c ac;d and 3 ml of water are added and the m;xture is sti'rred v;gorously at room temperature for 12 hours.
Thereafter, it is extracted by shaking with aqueous sodium b;carbonate solution. The organic phase is separated of~, dried over sodium sulphate and concentrated. F~r purifi-- cation, the residue is chromatographed over s;lica gel with methylene chloride/methanol (95:5). Yield: 4.3Z g (68%~, RF = 0.46 in methylene chloride/methanol (95:5), melting point: 56-57C.
Elemental analysis: calculated C 67.95 H 11.11 N 11.88 found 67.62 11.12 11~85 1H-NMR (25û MHz, CDfl3 in ppm) of compound (4):
5.83 ~m, 1H, -CH2-CH=C); 5.55 ~dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 6.5 Hz); 4.25 (m, 1H, -CH-N3); 3.8 (m, 2H, -CH2-OH, CH-OH); 3.52 (m, 1H, -CH2-OH?; 2.05 (m, 4H, OH, C-CH CH2); 1.45-1.18 (m, 26H, aliphatic); and Q.88 (t, 3H, CH3).
f) 2S,3R-2-Azido-3-hydroxy-1-(2,3,4,6-tetra-0-acetyl-~-D-glucopyranosyloxy)-4-trans-eicosene (6) 0.5 g (1.41 mmol) of compound (4) is dissolved in 50 ml of anhydrous hexane. û.1 ml of 0.5 M boron tri-~luoride-etherate in methylene chloride and a spatula-tip of molecular sieve 4 A are added. 0.7 9 (1.41 mmol) of' 0-(2,3,4,6-tetra-û-acetyl-~-D-glucopyranosyl)-trichloro-acetimidate is dissolved in 3 ml of anhydrous toluene and the solution is slowly added dropwise. After 4 hours, the mixture is washed with 30 ml of saturated sodium bicarbon-ate solution. The aqueous phase is extracted three times by shaking with 30 ml of methylene chloride each time.
The organic phases are dried over sodium sulphate and concentrated. For p~urification, the residue is chromato-graphed over silica gel ~;th methylene chloride~methanol ~97.5:2.5). Y;eld: 0.385 9 ~40%), RF ~ 0.7 in methylene chloride/methanol (95:5).
1H-NMR (250 MHz, CDCl3 in ppm) of compound (6):
5.78 (m, 1H, -CH2-CH=C); 5.5 ~dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 7.3 Hz~; 5.3-4.98 (m, 3H, H-2, H-3, H-4);
4.58 (d, 1H, H-1, J = 7.6 Hz); 4.35-4.13 (m, 3H, H-6, H-6;
~ Z~i7691 -CH-N3); 4.05 (dd, 1H, -CH2-0-~; 3.73 ~m, 2H, H-5, -CH2-0); 3.47 (m, 1H, ,CH-OH); 2.24 (d, 1H, OH, J = 4.8 Hz); 2.1b-1.94 (m, 14H, acetyl, C=CH-CH2); 1.45-1.15 (m, 26H, aliphatic); and 0.88 (t, 3H, -CH3).
9) 2S,3R-2~Azido-3-hydroxy-1-(B-D-glucopyranosyloxy)-4-trans-eicosene (7) Ou4 9 (0.585 mol) of compound (6) is dissolved in 30 ml of anhydrous methanol. 0.2 ml of a 1 M solution of sodium methylate in methanol is added. The mixture ;s stirred at room temperature for one hour. Thereafter, it ;s neutral;zed with the ion exchan~er Amberlit IR 120 (H~
form). The ion exchanger is f;ltered off, the f;ltrate is concentrated and the residue ;s chromatographed over sil;ca gel w;th chloroform/methanol (9:1). Yield: 0.26 9 (86X), RF = 0.22 in chloroform/methanol (9:1).
1H-NMR (250 MHz, DMSO-d6 ;n ppm) of compound t7):
4.1û (d, 1H, H~1, J = 7.6 Hz).
h) 2s~3R-2-Am;no-}-hydroxy-1-(B-D-9lucopyranosyloxy) .
4-trans-eicosene (8) -0.2S 9 (0.5 mmol) of compound (7) ;s d;ssolved in a mixture of 4 ml of pyridine and 4 ml of water. The solut;on is saturated w;th hydrogen sulphide. The mixture is stirred at room temperature for 24 hours. It ;s con-centrated to dryness and the residue is çhromatographed over silica gel, f;rst with chloroform/methanol (6:4) and then with chloroform/methanol/water (5:4:1).
Yield: 0.234 9 (96%), RF = 0.65 ;n chloroform/methanol/
water (5:4:1).
1H-NMR (25û MHz, DMSO-d6 ;n ppm) of compound (8):
4.10 (d, 1H, H-1, J = 7.6 Hz).
;) 2S,3R-2-Hexadecanoylamino~3-hydroxy-1-(B-D-gluco~
pyranosyloxy?-4~trans~eicosene (9) 0.23 g (0.47 mmol) of compound (8) is dissolved in 5 ml of tetrahydrofuran. 5 ml of a 5~0% strength aque~
ous sod;um acetate solution are added. 0.19 9 ~0.7 mmol) - of hexadecanoyl chloride is added to the m;xture at room temperature, with v;gorouS stirring. After about 2 hours, the organlc phase is separated off. The aqueous phase is extracted three t;mes by shaking w;th 2 ml of chloroform each t;me. The organ;c phases are dr;ed over sod;um sulphate and concentrated. For purification, the residue is chromatographed over sil;ca gel with chloro-form/methanol (9~ Yield: 0.3 9 (90%), RF = 0.50 inchloroformtmethanol (9:1).
1H-NMR (250 MHz, DMSO-d6 in ppm) of compound (9):
7.5 ~d, 1H, NH, J = 8.7 Hz); S.52 (m, 1H, -CH2-CH=C);
5.35 (dd, 1H, C=CH-, J = 15.2 Hz, J = 6.5 Hz); 5.03 (d, 1H, OH, J = 3.4 Hz); 4.92 (m, 3H, OH); 4.5 (t, 1H, OH, J =
4.9 Hz); 4.09 (d, lH, H-1, J = 7.6 Hz); 4.0-3.55 (m, 4H);
3.45 (m, 2H); 3.15-2.9 (m, 4H); 2.1-1.88 (m, 4H); 1.45 (m, 2H); 1.22 (m, 54H, aliphatic); and 0085 (m, 6H, CH3).
Appendix To conf;rm the structure attr;buted to the com-pound of the formula (VI), compound (4) was subjected to the same treatment with hydrogen sulphide (see below), as is described in section (h) of the preceding example.
Compound (S) was in fact thereby obtained, its physico-chemical properties co;nciding completely with those of erythro-D-C1g-sphingosine prepared from natural sources.
2S,3R-2-Amino-1,3-d;hydroxy-4-trans-eicosene t5) 0.25 9 (0.7 mmol) of compound (4) is dissolved in a mixture of 5 ml of pyridine and 2 ml of water. The solution ;s saturated with hydrogen sulphideO The mixture is stirred at room temperature for 48 hours. It is con-centrated to dryness. The res;due is chromatographed over silica gel, first with chloroform, then with chloroform/
methanol (9:1) and f;nally with chloroform/methanoL/water (8:2:0.25). ~ield: 0.215 9 (95~), RF = O.Z in chloroform/
methanol ~1:1), melt;ng po;nt: 70-72C.
H-NMR (250 MHz, CDCl3 in ppm) of compaund (S):
5.78 (m, 1H, -CH2-CH-C); 5.47 (dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 7.3 Hz); 4.12 (dd, 1H~ C=CH-~CH-OH, J = 6.1 Hz);
3.7 tm, 2H, CH2-OH); 2.93 (m, 1H, -CH-NH2); 2.57 (m, 4H, NH2, OH); 2.06 (m, 2H, C=CH-CH2); 1.45-1.1~8 (m, 26 H, aliphatic); and 0.88 (t, 3H, -CH3).
~L;it67891 Example 2 2s~3R-z-Hexadecanoylamino-3-hyclroxy-?-(B-D-glucopyranosyl oxy)-4-trans-octadecene .__ j) 2R,3R-1,3-0-0enzyl;dene-2-hydroxy-4-trans-octadecene t10) .
70 9 ~0.13 mol) of tetradecyltr;phenylphosphonium bromide are suspended under nitrogen in about 1 litre of anhydrous toluene saturated with nitrogen. Phenyllithium which has been prepared from 6.5 g (0.94 mol) of lithium and 74 9 (0.47 mol) of bromobenzene in about 200 ml of anhydrous ether is added dropwise, without further purifi-cation. At the same time, the mixture is cooled to -15C.
Thereafter, 21.6 9 (0.104 mol) of 2,4-0-benzylidene-D-threose [see Example 1, compound (1)~ in about 150 ml of anhydrous tetrahydrofuran are added dropwise in the course of 20 minutes, under nitrogen. After a further 20 min-utes, first 150 ml of methanol and then 250 ml of water are added. The mixture is stirred vigorously. After removal of the aqueous phase, the oryanic phase ;s con-centrated. For purification, the residue is chromato-graphed over silica gel with petroleum ether/ethyl ace-tate (9:1). Yield: 27 9 (68%), RF = 0~21 in petroleum ether/ ethyl acetate (9:1), melting point: 54 - 55C.
k) 2S,3R-2-Azido-1,3-0-benzylidene-4-trans-octadecene ~11) _ _ . .. . , . _ . ~ _ 10 g (0.025 mol) of compound ~10) are dissolved in about 70 ml of anhydrous methylene chloride containing 5 ml of anhydrous pyridine~ The solution is cooled to -15C, under nitrogen. 8.7 9 (0.31 mol~ of tr;fluoro-methanesulphonic acid anhydride are slo~ly added dropw;se.
After 15 minutes, the mixture is filtered over silica gel and eluted with methylene chloride/petroleum ether (1:1).
The receiver is flushed continuously ~ith n;trogen. The eluate is concentrated and the oil which remains is taken up in 50 ml of anhydrous dimethylformamide. 7.5 9 (0.1 mol) of sodium azide are added, under nitrogen. The mix-ture is stirred at room temperature for 2 hours~ There-after, it is diluted with about 350 ml of methylene chloride and filtered and the fil~rate is concentrated under a waterpump vacuum. For purification, the residue is chromatographed over silica gel with petroleum ether/
ethyl a~etate (9:1). Yield: 7.8 9 (75%), RF = 0.8 in petroleum ether/ethyl acetate (9:1).
l) 2S,3R-?-Azido-1,3-d;hydroxy-4-trans-octadecene (12) 7 9 (0.017 mo~) of compound (11) are dissolved ;n 100 mL of methylene chloride. 5 ml of concentrated hydro-chloric acid and 3 ml of water are added and the m;xture is stirred vigorously at room temperature for 12 hours.
Thereafter, it is extracted by shaking with aqueous sodium bicarbonate solution. The organic phase is separated off, dried over sodium sulphate and concentrated. For purifi-cation, the residue is chromatographed over silica gel with methylene chloride/methanol ~95:5). Yield: 3.76 9 (68%), RF = 0.46 in methylene chloride/methanol (95:5).
1H-NMR (250 MHz, CDCl3 in ppm) of compound (12):
5.83 (m, 1H, CH2-CH=C); 5.55 (dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 6.5 Hz); 4.25 (m, 1H, -CH-N3); 3.8 (m, 2H, -CH2-ûH, ` CH-OH); 3.52 (m, 1H, -CH2-OH); 2.05 (m, 4H, OH, C=CH-CH~); 1.45-1.18 (m, 22H, al;phatic); and 0.88 (t, 3H, CH3).
m) 25,3R-2-Azido-3-hydroxy-1-0-triphenyLmethyl-4-trans-octadecene (13)
Appendix To conf;rm the structure attr;buted to the com-pound of the formula (VI), compound (4) was subjected to the same treatment with hydrogen sulphide (see below), as is described in section (h) of the preceding example.
Compound (S) was in fact thereby obtained, its physico-chemical properties co;nciding completely with those of erythro-D-C1g-sphingosine prepared from natural sources.
2S,3R-2-Amino-1,3-d;hydroxy-4-trans-eicosene t5) 0.25 9 (0.7 mmol) of compound (4) is dissolved in a mixture of 5 ml of pyridine and 2 ml of water. The solution ;s saturated with hydrogen sulphideO The mixture is stirred at room temperature for 48 hours. It is con-centrated to dryness. The res;due is chromatographed over silica gel, first with chloroform, then with chloroform/
methanol (9:1) and f;nally with chloroform/methanoL/water (8:2:0.25). ~ield: 0.215 9 (95~), RF = O.Z in chloroform/
methanol ~1:1), melt;ng po;nt: 70-72C.
H-NMR (250 MHz, CDCl3 in ppm) of compaund (S):
5.78 (m, 1H, -CH2-CH-C); 5.47 (dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 7.3 Hz); 4.12 (dd, 1H~ C=CH-~CH-OH, J = 6.1 Hz);
3.7 tm, 2H, CH2-OH); 2.93 (m, 1H, -CH-NH2); 2.57 (m, 4H, NH2, OH); 2.06 (m, 2H, C=CH-CH2); 1.45-1.1~8 (m, 26 H, aliphatic); and 0.88 (t, 3H, -CH3).
~L;it67891 Example 2 2s~3R-z-Hexadecanoylamino-3-hyclroxy-?-(B-D-glucopyranosyl oxy)-4-trans-octadecene .__ j) 2R,3R-1,3-0-0enzyl;dene-2-hydroxy-4-trans-octadecene t10) .
70 9 ~0.13 mol) of tetradecyltr;phenylphosphonium bromide are suspended under nitrogen in about 1 litre of anhydrous toluene saturated with nitrogen. Phenyllithium which has been prepared from 6.5 g (0.94 mol) of lithium and 74 9 (0.47 mol) of bromobenzene in about 200 ml of anhydrous ether is added dropwise, without further purifi-cation. At the same time, the mixture is cooled to -15C.
Thereafter, 21.6 9 (0.104 mol) of 2,4-0-benzylidene-D-threose [see Example 1, compound (1)~ in about 150 ml of anhydrous tetrahydrofuran are added dropwise in the course of 20 minutes, under nitrogen. After a further 20 min-utes, first 150 ml of methanol and then 250 ml of water are added. The mixture is stirred vigorously. After removal of the aqueous phase, the oryanic phase ;s con-centrated. For purification, the residue is chromato-graphed over silica gel with petroleum ether/ethyl ace-tate (9:1). Yield: 27 9 (68%), RF = 0~21 in petroleum ether/ ethyl acetate (9:1), melting point: 54 - 55C.
k) 2S,3R-2-Azido-1,3-0-benzylidene-4-trans-octadecene ~11) _ _ . .. . , . _ . ~ _ 10 g (0.025 mol) of compound ~10) are dissolved in about 70 ml of anhydrous methylene chloride containing 5 ml of anhydrous pyridine~ The solution is cooled to -15C, under nitrogen. 8.7 9 (0.31 mol~ of tr;fluoro-methanesulphonic acid anhydride are slo~ly added dropw;se.
After 15 minutes, the mixture is filtered over silica gel and eluted with methylene chloride/petroleum ether (1:1).
The receiver is flushed continuously ~ith n;trogen. The eluate is concentrated and the oil which remains is taken up in 50 ml of anhydrous dimethylformamide. 7.5 9 (0.1 mol) of sodium azide are added, under nitrogen. The mix-ture is stirred at room temperature for 2 hours~ There-after, it is diluted with about 350 ml of methylene chloride and filtered and the fil~rate is concentrated under a waterpump vacuum. For purification, the residue is chromatographed over silica gel with petroleum ether/
ethyl a~etate (9:1). Yield: 7.8 9 (75%), RF = 0.8 in petroleum ether/ethyl acetate (9:1).
l) 2S,3R-?-Azido-1,3-d;hydroxy-4-trans-octadecene (12) 7 9 (0.017 mo~) of compound (11) are dissolved ;n 100 mL of methylene chloride. 5 ml of concentrated hydro-chloric acid and 3 ml of water are added and the m;xture is stirred vigorously at room temperature for 12 hours.
Thereafter, it is extracted by shaking with aqueous sodium bicarbonate solution. The organic phase is separated off, dried over sodium sulphate and concentrated. For purifi-cation, the residue is chromatographed over silica gel with methylene chloride/methanol ~95:5). Yield: 3.76 9 (68%), RF = 0.46 in methylene chloride/methanol (95:5).
1H-NMR (250 MHz, CDCl3 in ppm) of compound (12):
5.83 (m, 1H, CH2-CH=C); 5.55 (dd, 1H, -CH2-CH=CH-, J =
15.5 Hz, J = 6.5 Hz); 4.25 (m, 1H, -CH-N3); 3.8 (m, 2H, -CH2-ûH, ` CH-OH); 3.52 (m, 1H, -CH2-OH); 2.05 (m, 4H, OH, C=CH-CH~); 1.45-1.18 (m, 22H, al;phatic); and 0.88 (t, 3H, CH3).
m) 25,3R-2-Azido-3-hydroxy-1-0-triphenyLmethyl-4-trans-octadecene (13)
4 9 (12.3 mmol) of compound (12) are d;ssolved in 45 ml of a mixture of in each case anhydrous pyr;dine/
chloroform/tetrahydrofuran (1:1:1). 6 9 (21.5 mmol) of trityL chloride are added. The mixture is stirred at room temperature for 48 hours. Thereafter, it is concentrated under a ~aterpump vacuum. The residue is taken up in 200 ml of d;ethyl ether and the mixture is extracted by shaking with 100 ml of water. The organic phase is dried over magnesium sulphate and concentrated. For purifica-tion, the residue is chromatographed over silica gel with petroleum ether/ethyl acetate (9:1). Yield: 6.3 9 (90%), RF = 0.39 in petroleu~ ether/ethyl acetate (~ 1)o 1H-NMR (250 MHz, CDCl3 in ppm) of compound (13):
7.55-7.15 (m, 15 H, aromatic); 5.75-5.58 ~m, 1H, CH2-CH=C);
chloroform/tetrahydrofuran (1:1:1). 6 9 (21.5 mmol) of trityL chloride are added. The mixture is stirred at room temperature for 48 hours. Thereafter, it is concentrated under a ~aterpump vacuum. The residue is taken up in 200 ml of d;ethyl ether and the mixture is extracted by shaking with 100 ml of water. The organic phase is dried over magnesium sulphate and concentrated. For purifica-tion, the residue is chromatographed over silica gel with petroleum ether/ethyl acetate (9:1). Yield: 6.3 9 (90%), RF = 0.39 in petroleu~ ether/ethyl acetate (~ 1)o 1H-NMR (250 MHz, CDCl3 in ppm) of compound (13):
7.55-7.15 (m, 15 H, aromatic); 5.75-5.58 ~m, 1H, CH2-CH=C);
5.38-5.26 (dd, 1H, CH-2-CH=CH-! J = 15.5 Hz, J = 7.3 Hz);
4.20 (m, 1H, -CH-N3); 3.53 (m, 1H, -CH-OH); 3.35 (d, 2H, O-CH2-, J = 5.4 Hz); Z.03-1.188 ~m, 3H, -OH, CH=CH-CH2);
1.40~1.10 (m, 22H, al;phatic); and 0.88 (t, 3H, CH3).
n) 2S,3R-2-Azido-3-benzoyloxy-1-0-triphenylmethyl-4 trans-octadecene t14) .
4.20 (m, 1H, -CH-N3); 3.53 (m, 1H, -CH-OH); 3.35 (d, 2H, O-CH2-, J = 5.4 Hz); Z.03-1.188 ~m, 3H, -OH, CH=CH-CH2);
1.40~1.10 (m, 22H, al;phatic); and 0.88 (t, 3H, CH3).
n) 2S,3R-2-Azido-3-benzoyloxy-1-0-triphenylmethyl-4 trans-octadecene t14) .
6.3 g ~11.1 mmol) of compound (13) are d;ssolved ;n 30 ml of a mi~ture of in each case anhydrous toluene/
pyrid;ne (4:1). 3 g (21.3 mmol) of benzoyl chlor;de are added~ The mixture is stirred at room temperature for 1Z
hours. Thereafter, it ;s poured onto about 200 ml o~
water and extracted tw;ce with 100 ml of diethyl ether each time. The organic phase is dried over magnesium sulphate and concentrated. For purification, the residue is chromatographed over silica gel w;th petroleum ether/
ethyl acetate (95:5). Y;eld: 6.7 9 (90%), RF = O.hO ;n petroleum ether/ethyl acetate (9:1).
o) 2S,3R-2-Az;do-3-benzoyloxy-1-hydroxy-4-trans-octadecene (15) _ 6.7 9 (9.97 mmol) of compound (14) are dissolved ;n a mixture of 30 ml of anhydrous toluene and S ml of an-hydrous methanol. 10ml of 3 M boron tr;fluoride-etherate in methylene chlor;de are added. After 5 hours, the mix-ture is poured onto sa ml of ~ater and the organic phase is separated off. After drying over magnes;um sulphate, the organ;c phase is concentrated and the residue ;s chromatographed first ~ith petroleum ether/ethyl acetdte (9:1) and then with petroleum ether/ethyl acetate (8:2).
Y;eld: 3.8 (90X), RF = û.13 ;n petroleum ether/ethyl ace-tate (9:1).
Elemental analys;s for C2sH3gN303 (molecular we;ght 4Z9.56) - 30 calculated: C 69.90 H 9~14 N 9.78 found: 69.92 9.16 9.65 H-NMR (250 MHz, CDCl3 in ppm) of compound (15)~
8.14 (m, 2H, aromatic); 7.58 (m, 1H, aromatic); 7.47 (m, 2Hr aromatic); 6.05-5.87 ~m, 1H, CHz-CH=C); 5.6~-5.53 (m, 2H, CH2-CH=CH-, CH-OBz); 2.15-1.95 (m, 3H, -OHj C=CH-CH2);
1.47-1.13 (m, 22H, aliphatic); and 0.86 (t, 3H, CH3)~
p) 2S,3R-2-Azido-3-benzoyloxy 1-(2,3,4,6-tetra-0-pivaloyl-B-D-glucopyranosyloxy)-4-trans-octadecene (16) 2 9 (4.6 mmol) of compound (15) and 4.6 9 (7.0 mmol) of 2,3,4,6-tetra-0-pivaLoyl-~-D-gLucopyranosyltr;~
chloroacetimidate are d;ssolved ;n 40 ml of anhydrous methylene chlor;de and the solution is st;rred ~ith mol-ecular sieve 4 A for 30 minutes. Thereafter, 0.2 ml of û.1 M boron trifLuoride-etherate in methylene chloride is added. A further 2 ml of 0.1 M boron trifluoride-etherate are added in portions of in each case 0.5 ml in the course of the reaction. After 48 hours, the mixture is diluted with 200 ml of petroleum ether and filtered. The f;ltrate is extracted by shaking with S0 ml of aqueous sodium bi-carbonate solution and the organic phase is clried over sodium sulphate and concentrated. For purification, the residue is chromatographed over silica gel with toluene/
acetone (97.5:2.5). Yield 4 g t94~), RF = 0.57 in toluene/acetone (97.5:2.5).
1H-NMR (250 MHz,. CDCl3 in ppm) of compound (16):
8005 (m, 2H, aromatic~; 7.58 (m, 1H, aromatic); 7.45 (m, 2H, aromatic); 5.99-5.83 (m, 1H, CH2-CH=C); 5.65-5.46 (m, 2H, CH2-CH=CH, CH-O~z); 5.37-5.02 (m, 3H, H-2, H-3, H-4);
4.58 (d, 1H, H-1, 1 = 7.9 H~); 4.25-3.58 (m, 6H, H-6, H-6', H-5, CH-N3, CH2-0); 2.06 (m, 2H, CH=CH-CH2); 1.4S-1AO4 (m, 58H, pivaloyl, aliphatic); and 0.89 (t, 3H, CH3).
q) 2S,3R~2-Azido-3-hydroxy-1-(B D-glucopyranosyloxy)-4-trans-octadecene (17) . .
4 9 (4.3 mmol) of compound (16) are dissolved in 50 ml of anhydrous methylene chloride. 8 ml of a 0.05 M
sodium methylate solution in anhydrous methanol are added.
The m;xture is st;rred at room temperature for three days~
Thereafter, it is neutralized ~ith the ion exchanger Amberlit JR 120 (H~ form). The ion exchanger is filtered off, the filtrate is concentrated and the resldue is chromatographed over silica gel with chloroform/methanol (8.5:1.5). Y~ield: 1.65 9 (?8%), RF - 0.20 in chloroform/
methanol (9:1).
1H-NMR (250 MHz, DMSQ-d6 in ppm) of compound (17): 4.10 (d, 1H, H-1, J = 7.6 Hz).
r) 2s~3R-2-Amino-3-hydroxy-1-(B-D-glucopyranosyloxy)-4 trans-octadecene (18) 1.65 9 (3.4 mmol) of compound ~17) are dissolved in 50 ml of a mixture of pyridine/water (1:1). The sol-ution is saturated with hydrogen sulphide. The mixtureis stirred at room temperature for 24 hours. lt ;s con-centrated to dryness and chromatographed over silica gel, first with chloroform/methanol (9:1) and then with chloro-form/methanol/water (5:4:1). Yield: 1.47 9 (94%)~ RF =
0.64 in chloroform/methanol/water (5:4:1).
1H-NMR (250 MHz, DMSO-d6 in ppm) of compound (18):
4.10 (d, 1H, H-1, J = 7.6 Hz).
s) 2S,3R-2~Hexadecanoylamino-3-hydroxy-1-(B-D-gluco-pyranosyloxy)-4-trans-octadecene (19) 1.47 9 (3.2 mmol) of compound (18) are dissolved in 50 ml of tetrahydrofuran. 50 ml Of a 50% aqueous so-dium acetate solution 3re added. 0.87 9 (3.2 mmol) of hexadecanoyl chloride are added to the m;xture at room temperature, with vigorous stirring. After about 2 hours, the mixture is diluted with 350 ml of tetrahydrofuran and the aqueous phase ;s removed. The organic phase is ex-tracted by sh~king twice with 50 ml of saturated sodium chloride solution each time and is concentrated. The residue is dried under a high vacuum. For purification, the residue is chromatographed over silica gel, first with chloroform and then with chloroformtmethanol (9:1).
Yield: 1.81 9 (81%), RF = 0-4 in chloroform/methanol (8.5:1.5).
H-NMR (250 MHz, DMSO-d6 in ppm) of compound (19):
pyrid;ne (4:1). 3 g (21.3 mmol) of benzoyl chlor;de are added~ The mixture is stirred at room temperature for 1Z
hours. Thereafter, it ;s poured onto about 200 ml o~
water and extracted tw;ce with 100 ml of diethyl ether each time. The organic phase is dried over magnesium sulphate and concentrated. For purification, the residue is chromatographed over silica gel w;th petroleum ether/
ethyl acetate (95:5). Y;eld: 6.7 9 (90%), RF = O.hO ;n petroleum ether/ethyl acetate (9:1).
o) 2S,3R-2-Az;do-3-benzoyloxy-1-hydroxy-4-trans-octadecene (15) _ 6.7 9 (9.97 mmol) of compound (14) are dissolved ;n a mixture of 30 ml of anhydrous toluene and S ml of an-hydrous methanol. 10ml of 3 M boron tr;fluoride-etherate in methylene chlor;de are added. After 5 hours, the mix-ture is poured onto sa ml of ~ater and the organic phase is separated off. After drying over magnes;um sulphate, the organ;c phase is concentrated and the residue ;s chromatographed first ~ith petroleum ether/ethyl acetdte (9:1) and then with petroleum ether/ethyl acetate (8:2).
Y;eld: 3.8 (90X), RF = û.13 ;n petroleum ether/ethyl ace-tate (9:1).
Elemental analys;s for C2sH3gN303 (molecular we;ght 4Z9.56) - 30 calculated: C 69.90 H 9~14 N 9.78 found: 69.92 9.16 9.65 H-NMR (250 MHz, CDCl3 in ppm) of compound (15)~
8.14 (m, 2H, aromatic); 7.58 (m, 1H, aromatic); 7.47 (m, 2Hr aromatic); 6.05-5.87 ~m, 1H, CHz-CH=C); 5.6~-5.53 (m, 2H, CH2-CH=CH-, CH-OBz); 2.15-1.95 (m, 3H, -OHj C=CH-CH2);
1.47-1.13 (m, 22H, aliphatic); and 0.86 (t, 3H, CH3)~
p) 2S,3R-2-Azido-3-benzoyloxy 1-(2,3,4,6-tetra-0-pivaloyl-B-D-glucopyranosyloxy)-4-trans-octadecene (16) 2 9 (4.6 mmol) of compound (15) and 4.6 9 (7.0 mmol) of 2,3,4,6-tetra-0-pivaLoyl-~-D-gLucopyranosyltr;~
chloroacetimidate are d;ssolved ;n 40 ml of anhydrous methylene chlor;de and the solution is st;rred ~ith mol-ecular sieve 4 A for 30 minutes. Thereafter, 0.2 ml of û.1 M boron trifLuoride-etherate in methylene chloride is added. A further 2 ml of 0.1 M boron trifluoride-etherate are added in portions of in each case 0.5 ml in the course of the reaction. After 48 hours, the mixture is diluted with 200 ml of petroleum ether and filtered. The f;ltrate is extracted by shaking with S0 ml of aqueous sodium bi-carbonate solution and the organic phase is clried over sodium sulphate and concentrated. For purification, the residue is chromatographed over silica gel with toluene/
acetone (97.5:2.5). Yield 4 g t94~), RF = 0.57 in toluene/acetone (97.5:2.5).
1H-NMR (250 MHz,. CDCl3 in ppm) of compound (16):
8005 (m, 2H, aromatic~; 7.58 (m, 1H, aromatic); 7.45 (m, 2H, aromatic); 5.99-5.83 (m, 1H, CH2-CH=C); 5.65-5.46 (m, 2H, CH2-CH=CH, CH-O~z); 5.37-5.02 (m, 3H, H-2, H-3, H-4);
4.58 (d, 1H, H-1, 1 = 7.9 H~); 4.25-3.58 (m, 6H, H-6, H-6', H-5, CH-N3, CH2-0); 2.06 (m, 2H, CH=CH-CH2); 1.4S-1AO4 (m, 58H, pivaloyl, aliphatic); and 0.89 (t, 3H, CH3).
q) 2S,3R~2-Azido-3-hydroxy-1-(B D-glucopyranosyloxy)-4-trans-octadecene (17) . .
4 9 (4.3 mmol) of compound (16) are dissolved in 50 ml of anhydrous methylene chloride. 8 ml of a 0.05 M
sodium methylate solution in anhydrous methanol are added.
The m;xture is st;rred at room temperature for three days~
Thereafter, it is neutralized ~ith the ion exchanger Amberlit JR 120 (H~ form). The ion exchanger is filtered off, the filtrate is concentrated and the resldue is chromatographed over silica gel with chloroform/methanol (8.5:1.5). Y~ield: 1.65 9 (?8%), RF - 0.20 in chloroform/
methanol (9:1).
1H-NMR (250 MHz, DMSQ-d6 in ppm) of compound (17): 4.10 (d, 1H, H-1, J = 7.6 Hz).
r) 2s~3R-2-Amino-3-hydroxy-1-(B-D-glucopyranosyloxy)-4 trans-octadecene (18) 1.65 9 (3.4 mmol) of compound ~17) are dissolved in 50 ml of a mixture of pyridine/water (1:1). The sol-ution is saturated with hydrogen sulphide. The mixtureis stirred at room temperature for 24 hours. lt ;s con-centrated to dryness and chromatographed over silica gel, first with chloroform/methanol (9:1) and then with chloro-form/methanol/water (5:4:1). Yield: 1.47 9 (94%)~ RF =
0.64 in chloroform/methanol/water (5:4:1).
1H-NMR (250 MHz, DMSO-d6 in ppm) of compound (18):
4.10 (d, 1H, H-1, J = 7.6 Hz).
s) 2S,3R-2~Hexadecanoylamino-3-hydroxy-1-(B-D-gluco-pyranosyloxy)-4-trans-octadecene (19) 1.47 9 (3.2 mmol) of compound (18) are dissolved in 50 ml of tetrahydrofuran. 50 ml Of a 50% aqueous so-dium acetate solution 3re added. 0.87 9 (3.2 mmol) of hexadecanoyl chloride are added to the m;xture at room temperature, with vigorous stirring. After about 2 hours, the mixture is diluted with 350 ml of tetrahydrofuran and the aqueous phase ;s removed. The organic phase is ex-tracted by sh~king twice with 50 ml of saturated sodium chloride solution each time and is concentrated. The residue is dried under a high vacuum. For purification, the residue is chromatographed over silica gel, first with chloroform and then with chloroformtmethanol (9:1).
Yield: 1.81 9 (81%), RF = 0-4 in chloroform/methanol (8.5:1.5).
H-NMR (250 MHz, DMSO-d6 in ppm) of compound (19):
7.5 (d, 1H, NH, J = 8.7 Hz); 5.52 ~m, 1H, -CH2-CH-C);
5.35 (dd, 1H, CH2-CH=CH-, J = 15.2 Hz, J = 6.5 Hz); 5.03 (d, 1H, OH, J = 3.4 Hz); 4.92 (m, 3H, OH); 4.5 ~tr 1H, OH, J = 4.9 Hz); 4.09 (d, 1H, H-1, J = 7~6 Hz); 4.0-3.55 (m, 4H); 3.45 (m, 2H); 3.15-2.9 (m, 4H); 2.1-1.88 (m, 4H);
1.45 (m, 2H); 1.22 (m, 50H~ aliphatic); and 0~85 (t, 6H, CH3)-.
H 1:~1~ R~ R~---HO~, J~R D-Galactose ~ ~ H
(I) (II) / (III~
3 3 ~ ~~7 N ~ H
(VI ~ \ 3 3 R3 \ (V) (IV) ~ : :
~R 8~ 3~`'R3 OAc ~3 (VIII~ (IX) Ac0~-- , ~3 Ac0~~
OAc l)H
(VII) ~ ~
AcO ~o , 3 R"10 OH
AcO ~ ~8 OAc OR"' ~
XI) N3 3 _~ 3 ~ NO~~ ~ ( I j (XII) (XIII~
5.35 (dd, 1H, CH2-CH=CH-, J = 15.2 Hz, J = 6.5 Hz); 5.03 (d, 1H, OH, J = 3.4 Hz); 4.92 (m, 3H, OH); 4.5 ~tr 1H, OH, J = 4.9 Hz); 4.09 (d, 1H, H-1, J = 7~6 Hz); 4.0-3.55 (m, 4H); 3.45 (m, 2H); 3.15-2.9 (m, 4H); 2.1-1.88 (m, 4H);
1.45 (m, 2H); 1.22 (m, 50H~ aliphatic); and 0~85 (t, 6H, CH3)-.
H 1:~1~ R~ R~---HO~, J~R D-Galactose ~ ~ H
(I) (II) / (III~
3 3 ~ ~~7 N ~ H
(VI ~ \ 3 3 R3 \ (V) (IV) ~ : :
~R 8~ 3~`'R3 OAc ~3 (VIII~ (IX) Ac0~-- , ~3 Ac0~~
OAc l)H
(VII) ~ ~
AcO ~o , 3 R"10 OH
AcO ~ ~8 OAc OR"' ~
XI) N3 3 _~ 3 ~ NO~~ ~ ( I j (XII) (XIII~
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a sphingosine derivative of the general formula (I) (I) wherein R1 denotes the acyl radical of a fatty acid with 14 to 24 carbon atoms or the corresponding acyl radicals with a hydroxyl group in the .alpha.-position or with one or two double bonds in the cis-configuration and R3 denotes an aliphatic radical with 13 to 19 carbon atoms, at least 13 of which are present in a straight chain and not more than 4 are present as lateral methyl groups, it being possible for this radical to contain up to three double bonds of cis- or trans-configuration or up to three 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 form a D-galactose protected in the 4- and 6-positions, of the formula (II) (II) splitting this compound with an oxidizing agent which splits vicinal diols, to form the corresponding D-threose projected in the 2- and 4-positions, of the formula (III), (III) reacting the protected D-threose with an R3-CH2-phosphonate or an R3-CH2-triphenylphosphonium halide, wherein R3 has the above defined meaning, in the presence of a base or of a base and a salt to form a compound of the formula (IV), (IV) converting the free hydroxyl group in this compound into an azido group by activation, to produce a compound of formula (V), (V) removing from the resulting azido compound of the formula (V) the protective group on the hydroxyl groups in the 1- and 3-position 22a 20152-1173 of the aliphatic chain to form a 2-azido-1,3-dihydroxy compound of the formula (VI), (VI) reacting the latter with an organic reagent which is capable of reacting selectively with a primary hydroxyl group, to form a compound of the formula (VIII), (VIII) wherein R" denotes a hydroxyl-protective group, blocking the secondary hydroxyl group in the compound of the formula (VIII) with a protective group R''' to form a compound of the formula (IX), (IX) 22b 20152-1173 splitting off the hydroxyl-protective group R" from the resulting compound of the formula (IX) to form a compound of the formula (X) (X) glycosidating either the compound of the formula (VI) obtained previously or the compound of the formula (X) with the O-tri-fluoro- 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 form a compound of the formula (VII) or (XI), (VII) (XI) 22c splitting off the acyl groups Ac or the acyl groups Ac and the protective group R''' from the resulting compound (VII) or (XI) to form a compound of the formula (XII), (XII) converting the azido group in compound (XII) into a primary amino group and subjecting the resulting compound of the formula (XIII) (XIII) to N-acylation with a fatty acid of the formula R1-OH, wherein R1 has the above defined meaning.
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 form a D-galactose protected in the 4- and 6-positions, of the formula (II) (II) splitting this compound with an oxidizing agent which splits vicinal diols, to form the corresponding D-threose projected in the 2- and 4-positions, of the formula (III), (III) reacting the protected D-threose with an R3-CH2-phosphonate or an R3-CH2-triphenylphosphonium halide, wherein R3 has the above defined meaning, in the presence of a base or of a base and a salt to form a compound of the formula (IV), (IV) converting the free hydroxyl group in this compound into an azido group by activation, to produce a compound of formula (V), (V) removing from the resulting azido compound of the formula (V) the protective group on the hydroxyl groups in the 1- and 3-position 22a 20152-1173 of the aliphatic chain to form a 2-azido-1,3-dihydroxy compound of the formula (VI), (VI) reacting the latter with an organic reagent which is capable of reacting selectively with a primary hydroxyl group, to form a compound of the formula (VIII), (VIII) wherein R" denotes a hydroxyl-protective group, blocking the secondary hydroxyl group in the compound of the formula (VIII) with a protective group R''' to form a compound of the formula (IX), (IX) 22b 20152-1173 splitting off the hydroxyl-protective group R" from the resulting compound of the formula (IX) to form a compound of the formula (X) (X) glycosidating either the compound of the formula (VI) obtained previously or the compound of the formula (X) with the O-tri-fluoro- 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 form a compound of the formula (VII) or (XI), (VII) (XI) 22c splitting off the acyl groups Ac or the acyl groups Ac and the protective group R''' from the resulting compound (VII) or (XI) to form a compound of the formula (XII), (XII) converting the azido group in compound (XII) into a primary amino group and subjecting the resulting compound of the formula (XIII) (XIII) to N-acylation with a fatty acid of the formula R1-OH, wherein R1 has the above defined meaning.
2. Process according to claim 1, characterized in that 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'.
3. Process according to claim 1, characterized in that an alkali metal periodate or lead tetraacetate is used as the oxidizing agent and the oxidation of the compound of the formula (II) is carried out at a pH of about 7 or 8 at room temperature.
22d 20152-1173
22d 20152-1173
4. Process according to claim 1, characterized in that the reaction of the protected D-threose of the formula (III) with the R3-CH2-phosphonate or the R3-CH2-triphenylphosphonium halide is carried out in the presence of phenyllithium, lithium ethylate, sodium amide, sodium methylate or sodium carbonate in an anhydrous hydrocarbon or ether under a nitrogen atmosphere at low temperatures and, when using an R3-CH2-phosphonium halide, with the addition of a salt.
5. Process according to claim 1, characterized in that the conversion of the free hydroxyl group of the compound of the formula (IV) into an azido group is carried out by O-trifluoromethanesulphonation, methanesulphonation or p-toluenesulphonation and subsequent reaction of the O-sulphonyl derivative with an alkali metal azide.
6. Process according to Claim 1, characterized in that the protective group R-CO-R' is split off from the compound of the formula (V) or the protective group R" is split off from the compound of the formula (IX) by acid hydrolysis.
7. Process according to Claim 1, characterized in that a spatially large group, such as the triphenylmethyl, monomethoxytriphenylmethyl, tert.-butyl, trichloroacetyl, trimethyl, tert.-butyldimethylsilyl or tert.-butyldiphenyl-silyl group is used as the hydroxyl-protective group R".
8. Process according to Claim 1, characterized in that the acyl radical of an aliphatic or aromatic carboxy-lic acid or a tert.-butoxycarbonyl group, preferably the acyl radical of benzoic acid or of a substituted benzoic acid or of pivalic acid, is used as the protective group R'''.
9. Process according to Claim 1, characterized in that the glycosidation of the compound of the formula (VI) or (X) with the said O-trifluoro- or O-trichloro-acet-imidate 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.
10. Process according to Claim 1, characterized in that the acyl groups Ac and the protective group R''' are split off from the compound of the formula (VII) or (XI) by basic catalysis.
11. Process according to Claim 1, characterized in that the azido group of the compound of the formula (XII) is converted into a primary amino group by treatment with hydrogen sulphide in a mixture (1:1) of water and pyridine or by hydrogenation with sodium borohydride or another reducing agent.
12. Process according to Claim 1, characterized in that the N-acylation of the compound of the formula (XIII) is carried out by means of the fatty acid of the formula R1-OH 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.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH3472/85 | 1985-08-13 | ||
| CH347285 | 1985-08-13 | ||
| CH938/86 | 1986-03-07 | ||
| CH93886 | 1986-03-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1267891A true CA1267891A (en) | 1990-04-17 |
Family
ID=25686169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000515738A Expired - Fee Related CA1267891A (en) | 1985-08-13 | 1986-08-12 | Process for the preparation of sphingosine derivatives |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4937328A (en) |
| EP (1) | EP0212400B1 (en) |
| AR (1) | AR242395A1 (en) |
| AT (1) | ATE71104T1 (en) |
| AU (1) | AU603773B2 (en) |
| CA (1) | CA1267891A (en) |
| DE (1) | DE3683214D1 (en) |
| DK (1) | DK165984C (en) |
| ES (1) | ES2001208A6 (en) |
| FI (1) | FI82058C (en) |
| HU (1) | HU197916B (en) |
| NO (1) | NO163453C (en) |
| PL (1) | PL149578B1 (en) |
| YU (1) | YU142886A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0299201A3 (en) * | 1987-06-12 | 1990-08-22 | Wilhelm Dr. Hoerrmann | Pharmaceutical composition containing a fatty amino-alcohol |
| DE3819870A1 (en) * | 1987-06-12 | 1988-12-29 | Hoerrmann Wilhelm | Pharmaceuticals based on fatty amino alcohols |
| IT1235162B (en) * | 1988-12-02 | 1992-06-22 | Fidia Farmaceutici | LYSOSPHINGOLIPID DERIVATIVES |
| FR2673179B1 (en) * | 1991-02-21 | 1993-06-11 | Oreal | CERAMIDES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS IN COSMETICS AND DERMOPHARMACY. |
| GB9207182D0 (en) * | 1992-04-01 | 1992-05-13 | Enzymatix Ltd | Glycolipids and their preparation |
| AU683026B2 (en) * | 1992-10-22 | 1997-10-30 | Kirin Pharma Kabushiki Kaisha | Novel shingoglycolipid and use thereof |
| WO1995003028A1 (en) * | 1993-07-23 | 1995-02-02 | Morris Herstein | Cosmetic, skin-renewal stimulating composition with long-term irritation control |
| CA2174431C (en) * | 1993-10-18 | 2005-12-06 | Tomas Hudlicky | Synthesis of sphingosines |
| US5663151A (en) * | 1994-03-04 | 1997-09-02 | Bristol-Myers Squibb Company | Sulfated α-glycolipid derivatives as cell adhesion inhibitors |
| CA2142153A1 (en) * | 1994-03-04 | 1995-09-05 | Jacques Banville | Sulfated .beta.-glycolipid derivatives as cell adhesion inhibitors |
| US5686426A (en) * | 1994-11-17 | 1997-11-11 | Bristol-Myers Squibb Company | Dicarboxymethylated glycolipid derivatives as cell adhesion inhibitors |
| BR9906444A (en) | 1998-05-14 | 2000-09-26 | Dsm Nv | Acylation process for amino alcohols |
| AU770635B2 (en) * | 1999-05-10 | 2004-02-26 | Lipiderm Ltd. | Process for large scale preparation of sphingosines and ceramides |
| US7156661B2 (en) * | 2002-08-22 | 2007-01-02 | Align Technology, Inc. | Systems and methods for treatment analysis by teeth matching |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2478104B1 (en) * | 1980-03-17 | 1986-08-08 | Merieux Inst | NEW GANGLIOSIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION |
| EP0146810A3 (en) * | 1983-12-05 | 1987-05-13 | Solco Basel AG | Process for the preparation of sphingosin derivatives |
-
1986
- 1986-08-02 EP EP86110694A patent/EP0212400B1/en not_active Expired - Lifetime
- 1986-08-02 AT AT86110694T patent/ATE71104T1/en not_active IP Right Cessation
- 1986-08-02 DE DE8686110694T patent/DE3683214D1/en not_active Expired - Fee Related
- 1986-08-11 AR AR86304868A patent/AR242395A1/en active
- 1986-08-11 HU HU863523A patent/HU197916B/en not_active IP Right Cessation
- 1986-08-11 US US06/895,181 patent/US4937328A/en not_active Expired - Fee Related
- 1986-08-11 DK DK382486A patent/DK165984C/en not_active Application Discontinuation
- 1986-08-12 AU AU61083/86A patent/AU603773B2/en not_active Ceased
- 1986-08-12 PL PL1986261011A patent/PL149578B1/en unknown
- 1986-08-12 YU YU01428/86A patent/YU142886A/en unknown
- 1986-08-12 CA CA000515738A patent/CA1267891A/en not_active Expired - Fee Related
- 1986-08-12 ES ES8601030A patent/ES2001208A6/en not_active Expired
- 1986-08-12 NO NO863251A patent/NO163453C/en unknown
- 1986-08-12 FI FI863272A patent/FI82058C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO863251D0 (en) | 1986-08-12 |
| EP0212400A3 (en) | 1987-10-28 |
| EP0212400A2 (en) | 1987-03-04 |
| EP0212400B1 (en) | 1992-01-02 |
| FI863272A (en) | 1987-02-14 |
| FI82058B (en) | 1990-09-28 |
| FI863272A0 (en) | 1986-08-12 |
| DK382486A (en) | 1987-02-14 |
| ES2001208A6 (en) | 1988-05-01 |
| DK165984B (en) | 1993-02-22 |
| AR242395A1 (en) | 1993-03-31 |
| ATE71104T1 (en) | 1992-01-15 |
| DE3683214D1 (en) | 1992-02-13 |
| AU6108386A (en) | 1987-02-19 |
| FI82058C (en) | 1991-01-10 |
| PL261011A1 (en) | 1987-06-01 |
| DK382486D0 (en) | 1986-08-11 |
| AU603773B2 (en) | 1990-11-29 |
| US4937328A (en) | 1990-06-26 |
| YU142886A (en) | 1988-06-30 |
| HUT42500A (en) | 1987-07-28 |
| NO163453C (en) | 1990-05-30 |
| DK165984C (en) | 1993-07-19 |
| NO163453B (en) | 1990-02-19 |
| HU197916B (en) | 1989-06-28 |
| PL149578B1 (en) | 1990-02-28 |
| NO863251L (en) | 1987-02-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1267891A (en) | Process for the preparation of sphingosine derivatives | |
| GB1598705A (en) | 3-de-o-methylfortimicins | |
| US5998595A (en) | Azidohalogenobenzyl derivatives, sugar compounds and protection of hydroxy groups | |
| US4730058A (en) | Sialosylceramides and production method thereof | |
| JP3231765B2 (en) | Method for producing demethyl epipodophyllotoxin | |
| US4751290A (en) | Sialosylcerebrosides | |
| Izumi et al. | A facile synthesis of 5-thio-L-fucose and 5-thio-D-arabinose from D-arabinose | |
| CA1320951C (en) | Disaccharide derivatives | |
| Lassaletta et al. | Silyl Group Migration in 1-O-Silyl Protected Sugars-Convenient Synthesis of 2-O-Unprotected Sugars | |
| Klotz et al. | Anomeric O-alkylation of O-acetyl-Protected Sugars | |
| US5262531A (en) | Process for preparing 2'-deoxy-β-adenosine | |
| US5006646A (en) | Process for preparing 2'-deoxy-5-trifluoromethyl-beta-uridine | |
| AU2013340901A2 (en) | Method of preparation of alpha-galactosyl ceramides compounds | |
| US4774327A (en) | N-glycolylneuraminic acid derivative | |
| US4914195A (en) | Process for preparing N-acetylneuraminic acid derivatives | |
| US5712387A (en) | High yield stereospecific mannosylation | |
| JPH0692349B2 (en) | A new method for producing optically active unsaturated amino alcohol derivatives. | |
| JPS6239597A (en) | Production of sphingosine derivative | |
| Wong et al. | The synthesis of derivatives of lactosamine and cellobiosamine to serve as probes in studies of the combining site of the monoclonal anti-I Ma antibody | |
| JP3049565B2 (en) | Method for producing trehalose isomer | |
| US4284763A (en) | Sugar acetals, their preparation and use | |
| EP0070444B1 (en) | Method for the preparation of 1,1'-diacetals | |
| US4855417A (en) | Anomeric deacetylation | |
| KR100609799B1 (en) | High Yield Stereospecific Mannosylation | |
| EP0582153B1 (en) | Method of preparing 4-deoxy-D-mannose |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |