Zosuquidar trihydrochloride, LY-335979, RS-33295-198

合成路线:Reaction of alcohol (IV) with 48% HBr or with PBr3 affords the anti-bromo derivative (XII),which is condensed with pyrazine (XIII) in refluxing acetonitrile to give anti-1-[10,11-(difluoromethano)dibenzosuber-5-yl]pyrazinium bromide (XIV).Reduction of compound (XIV) with NaBH4 in ethyl acetate provides the piperazine derivative (VIII),which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) ?obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl 4-nitrobenzene- sulfonate (XV) by means of K2CO3 in DMF ?in hot ethanol.

参考文献标题:Process for preparing 10,11-methanobenzosuberane derivs.
文献作者:Le Tourneau,M.E.; Wilson,T.M.; Huff,B.E.; Bush,J.K.; Reutzel-Edens,S.M.(Eli Lilly and Company)
参考来源:WO 0075121


合成路线:Condensation of the anti-bromo derivative (XII) with piperazine (XVI) in refluxing acetonitrile provides 1-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine as a mixture of syn- and anti-isomers (XVII),which is separated by crystallization.Finally,the desired anti-isomer (VIII) is condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in hot ethanol.

参考文献标题:Process for preparing a 10,11-methanodibenzosuberane deriv.
文献作者:Barnett,C.J.; Wilson,T.M.; Astleford,B.A.; Kobierski,M.E.(Eli Lilly and Company)
参考来源:WO 0075132


合成路线:Condensation of dibenzosuberenone (I) with sodium 2-chloro-2,2-difluoroacetate (II) in diglyme at 165 C gives 10,11-(difluoromethano)benzosuberone (III),which is reduced with NaBH4 in THF/methanol to yield the corresponding syn-alcohol (IV).Reaction of alcohol (IV) with hot SOCl2 affords a mixture of the syn- and anti-chloro derivatives (V).This mixture (V) is treated with 1-for-mylpiperazine (VI) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (VI),which is separated by chromatography.The desired anti-isomer (VII) is then treated with KOH in refluxing ethanol/water to give the piperazine derivative (VIII),which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in refluxing isopranol.5-[2(R),3-Epoxypropoxy]quinoline (IX) is obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl tosylate (XI) by means of NaH in DMF.

参考文献标题:Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents
文献作者:Bruno,N.A.; Nelson,J.T.; Wu,H.; Muehldorf,A.V.; Makra,F.; Cheung,P.; Slate,D.L.; Zutshi,N.; Casey,S.M.; Pfister,J.R.
参考来源:Bioorg Med Chem Lett 1995,5(21),2473


合成路线:Condensation of dibenzosuberenone (I) with sodium 2-chloro-2,2-difluoroacetate (II) in diglyme at 165 C gives 10,11-(difluoromethano)benzosuberone (III),which is reduced with NaBH4 in THF/methanol to yield the corresponding syn-alcohol (IV).Reaction of alcohol (IV) with hot SOCl2 affords a mixture of the syn- and anti-chloro derivatives (V).This mixture (V) is treated with 1-for-mylpiperazine (VI) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (VI),which is separated by chromatography.The desired anti-isomer (VII) is then treated with KOH in refluxing ethanol/water to give the piperazine derivative (VIII),which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in refluxing isopranol.5-[2(R),3-Epoxypropoxy]quinoline (IX) is obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl tosylate (XI) by means of NaH in DMF.

合成路线:Reaction of alcohol (IV) with 48% HBr or with PBr3 affords the anti-bromo derivative (XII),which is condensed with pyrazine (XIII) in refluxing acetonitrile to give anti-1-[10,11-(difluoromethano)dibenzosuber-5-yl]pyrazinium bromide (XIV).Reduction of compound (XIV) with NaBH4 in ethyl acetate provides the piperazine derivative (VIII),which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) ?obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl 4-nitrobenzene- sulfonate (XV) by means of K2CO3 in DMF ?in hot ethanol.

合成路线:Condensation of the anti-bromo derivative (XII) with piperazine (XVI) in refluxing acetonitrile provides 1-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine as a mixture of syn- and anti-isomers (XVII),which is separated by crystallization.Finally,the desired anti-isomer (VIII) is condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in hot ethanol.

参考文献标题:Zosuquidar Trihydrochloride.
文献作者:Sorbera,L.A.; Castar,J.; Silvestre,J.S.; Bay閟,M.
参考来源:Drugs Fut 2003,28(2),125-136


合成路线:Condensation of dibenzosuberenone (I) with sodium 2-chloro-2,2-difluoroacetate (II) in diglyme at 165 C gives 10,11-(difluoromethano)benzosuberone (III),which is reduced with NaBH4 in THF/methanol to yield the corresponding syn-alcohol (IV).Reaction of alcohol (IV) with hot SOCl2 affords a mixture of the syn- and anti-chloro derivatives (V).This mixture (V) is treated with 1-for-mylpiperazine (VI) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (VI),which is separated by chromatography.The desired anti-isomer (VII) is then treated with KOH in refluxing ethanol/water to give the piperazine derivative (VIII),which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in refluxing isopranol.5-[2(R),3-Epoxypropoxy]quinoline (IX) is obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl tosylate (XI) by means of NaH in DMF.
参考文献标题:Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines
文献作者:Vo,D.; Wolowyk,M.W.; Knaus,E.E.
参考来源:Drug Des Discov 1992,9(1),69