US 7,732,583 B2 · Glycolipids and synthetic method thereof as well as their synthetic intermediates, and synthetic intermediates, and synthetic method thereof

Abstract

Novel glycolipid derivatives, where the substituent of the sphingosine base part is a short carbon chain alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group or substituted or unsubstituted aralkyl group and efficient synthetic methods for practical mass production of the same and intermediates useful for the synthesis of these compounds. Glycolipids having the formula (I): where R3 indicates a substituted or unsubstituted C1 to C7 linear alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, or substituted or unsubstituted aralkyl group and R8 indicates a substituted or unsubstituted C1 to C35 alkyl group, substituted or unsubstituted aryl group or substituted or unsubstituted aralkyl group are chemically synthesized.

A method for preparing a glycolipid derivative comprising:

reacting a compound having a formula (II):
wherein R1 and R2 independently indicate a hydrogen atom;
C1 to C4 alkyl group which may be substituted with a substituent selected from the group consisting of halogen atom, methoxy group, ethoxy group and nitro group;
C6 to C12 aryl group which may be substituted with a substituent selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methoxy group, nitro group, cyano group and trifluoromethyl group, or R1 and R2 bond together to indicate a propylene group, butylene group, pentylene group or hexylene group, whereby a cyclic structure is formed, with any one of alkyl metal reagents having the formulae, (IIIa), (IIIb), (IIIc), (IIId):
(R3)2CuM, (IIIa)
R3M/CuX, (IIIb)
R3M/BF3, (IIIc)
R3M (IIId)
where R3 indicates a C1 to C7 linear alkyl group which may be substituted at a branch point with a substituent selected from the group consisting of methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, cyclopentyl group, cyclohexyl group, isobutyl group, cycloheptyl group, isopentyl group and isohexyl group;
C3 to C8 cycloalkyl group which may be substituted with a substituent selected from the group consisting of methyl group, ethyl group, propyl group, butyl group, methoxy group, chlorine atom, fluorine atom and trifluoromethyl group;
C6 to C18 aryl group which may be substituted with a substituent selected from the group consisting of methyl group, ethyl group, methoxy group, fluorine atom, chlorine atom, phenyl group, 2-fluorophenyl group, phenoxy group, phenylmethyl group, cyclopentyl group, cyclopentoxy group, trifluoromethyl group, acylamino group, cyano group, cycloheptyl group and cycloheptyloxy group;
or C7 to C18 aralkyl group which may be substituted with a substituent selected from the group consisting of fluorine atom, chlorine atom, methyl group, ethyl group, methoxy group, trifluoromethyl group, cyclopentyl group and cycloheptyloxy group, M indicates Li, MgCl, MgBr or MgI, and X indicates a chlorine atom, bromine atom, iodine atom or fluorine atom to obtain a compound having the formula (IV):
where R1, R2 and R3 are as defined above,
reacting the compound having the formula (IV) with an alkylsulfonyl halide, arylsulfonyl halide, aralkylsulfonyl halide, alkylsulfonic acid anhydride, arylsulfonic acid anhydride or aralkylsulfonic acid anhydride to obtain a compound having the formula (V):
where R1, R2 and R3 are the same as defined above and R4 indicates an alkylsulfonyloxy group, arylsulfonyloxy group or aralkylsulfonyloxy group,
reacting the compound having the formula (V) with an azidation agent to obtain a compound having the formula (VIa):
where R1, R2 and R3 are the same as defined above,
removing the protective acetal group of the compound having the formula (VIa) to obtain a compound having the formula (VII), or removing the protective acetal group of the compound having the formula (V) to obtain a compound having the formula (VIb):
where R3 and R4 are the same as defined above,
subsequently reacting the compound having the formula (VIb) with an azidation agent to obtain a compound having the formula (VII):
where R3 is as defined above,
again acetalizing the compound having the formula (VII) to obtain a compound having the formula (VIIIa):
where R3 is the same as defined above, R5 and R6 independently indicate a hydrogen atom;
a C1 to C5 alkyl group which may be substituted by a substituent selected from the group consisting of fluorine atom and methoxy group;
a C6 to C12 aryl group selected from the group consisting of phenyl group, p-tolyl group, m-tolyl group and naphtyl group;
a C7 to C12 aralkyl group which may be substituted by a substituent selected from the group consisting of methyl group, ethyl group, fluorine atom and methoxy group, or R5 and R6 bond together to indicate a propylene group, butylene group or pentylene group, whereby a cyclic structure is formed, or
protecting the two secondary hydroxy groups of the compound having the formula (VII) to obtain a compound having the formula (VIIIb)
where, R3 is the same as defined above and R7 indicates a benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group or di(p-nitrophenyl)methyl group,
reacting the compound having the above formula (VIIIa) or (VIIIb) with a compound having the formula (IX) in the presence of boron trifluoride or tetra-n-butylammonium halide:
where R7 and X are the same as defined above
to obtain a compound having the formula (Xa) or (Xb):
where R3, R5, R6 and R7 are the same as defined above,
reducing the azide group of the compound having the formula (Xa) or (Xb) to an amino group to obtain a compound having the formula (XIa) or (XIb):
where R3, R5, R6 and R7 are the same as defined above,
acylating the amino group of the compound having the formula (XIa) or (XIb) to obtain a compound having the formula (XIIa) or (XIIb):
where R3, R5, R6 and R7 are the same as defined above and R8 indicates —(CH2)m—CH3, where m is an integer of 10 to 25, a C6 to C35 aryl group which may be substituted with a substituent selected from the group consisting of alkyl group, alkoxy group and amide group, or a C7 to C35 aralkyl group which may be substituted with a substituent selected from the group consisting of alkyl group, alkoxy group and amide group,
removing the protective acetal of the compound having the formula (XIIa) to obtain the compound having the formula (XIII):
where R3, R7 and R8 are the same as defined above, and
removing the remaining protective groups of the compound having the above formula (XIIb) or (XIII) to obtain a compound having the formula (I):
where R3 and R8 are the same as defined above.

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Glycolipids and synthetic method thereof as well as their synthetic intermediates, and synthetic intermediates, and synthetic method thereof

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Glycolipids and synthetic method thereof as well as their synthetic intermediates, and synthetic intermediates, and synthetic method thereof

Life of this patent

Abstract

Claims4