【药物名称】Dolasetron mesilate, MDL-73147EF, Anzemet, Anemet
化学结构式(Chemical Structure):
参考文献No.8224
标题:Esters of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3(4H)-one and related compds.
作者:Gittos, M.W. (Merrell Pharmaceuticals, Inc.)
来源:AU 8780596; EP 0266730; JP 1988258476
合成路线图解说明:

The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.

参考文献No.123983
标题:Potent 5-HT3 antagonists incorporating a novel bridged pseudopelletierine ring system
作者:Gittos, M.W.; Fatmi, M.
来源:Actual Chim Ther 1989,16187
合成路线图解说明:

The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.

参考文献No.209239
标题:Dolasetron Mesylate
作者:Gittos, M.W.; Fatmi, M.; Galvan, M.
来源:Drugs Fut 1993,18(6),506
合成路线图解说明:

The cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.

Drug Information Express,Drug R&D,Chemical Database,Patent Search.
Copyright © 2006-2024 Drug Future. All rights reserved.Contact Us