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AssigneeTakeda Chemical Industries, Ltd.
InventorsTadao Kawarasaki, Hideo Hashimoto, Kiminori Tomimatsu
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A process for easily and industrially advantageously producing both a tricyclic fused heterocyclic derivative having acetylcholinesterase inhibitory activity and an intermediate for the derivative. The process for producing the target compounds comprises the following reaction. 1
A process for producing a compound represented by the formula:
A process for producing 8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, which comprises reacting 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with 1-acetyl-4-piperidinepropionic acid in the presence of a phosphorus compound.
A process for producing a compound represented by the formula:
A process for producing 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, which comprises reacting 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with 1-acetyl-4-piperidinepropionic acid in the presence of a phosphorus compound, and deacetylating the resulting 8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one.
A process for producing a compound represented by the formula:
A process for producing 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, which comprises reacting 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with 1-acetyl-4-piperidinepropionic acid in the presence of a phosphorus compound, deacetylating the resulting 8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one, and reacting the resulting 8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with 3-fluorobenzyl chloride.
Dependencies are inferred from the claim text.
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In which the condensed system contains two hetero rings: peri-condensed systems
Containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy…:…
In which the condensed system contains two hetero rings: peri-condensed systems
Heterocyclic compounds
Term end not estimated
The present invention relates to a process for producing a tricyclic fused heterocyclic derivative having acetylcholinesterase inhibitory activity which is useful as a medicament and an intermediate thereof.
Until now, as a process for synthesizing a tricyclic fused heterocyclic derivative having acetylcholinesterase inhibitory activity and an intermediate thereof, Friedel-Crafts reaction of a tricyclic fused heterocyclic ring with an acid chloride in the presence of aluminium chloride in a halogen solvent has been reported (JP 7-206854 A).
Since in the aforementioned previous process, 1,2-dichloroethane and methylene chloride which are an environmental pollutant and are remarkably restricted in their use are used as a reaction solvent, and many steps are involved, it is desired to develop a process for producing a tricyclic fused heterocyclic derivative and an intermediate thereof, which is inexpensive and simple.
Synthesis of 8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one
A mixture of 2.5 kg of 1-acetyl-4-piperidinepropionic acid, 2.17 kg (1 equivalent) of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one and 26.0 kg of polyphosphoric acid was stirred at about 105° C. for 8 hours under nitrogen and 13 L of cold water at about 5° C. was slowly added dropwise thereto while maintaining about 70° C. Further, 25 L of a mixture of toluene-acetonitrile (1:1) was added at about 55° C. and pH was adjusted to about 8.5 by adding 25% aqueous ammonia solution (about 50 L) while maintaining about 55° C. The layers were separated, 10 L of a mixture of toluene-acetonitrile (1:1) was added to the aqueous layer, and the layers were separated. The organic layers were combined and concentrated to a volume of the solution of about 10 L. To the residue was added 9 L of isopropyl ether at about 20° C. to precipitate crystals. The mixture was stirred at about 20° C. for about 1.5 hours and then at about 5° C. for about 1.5 hours. Precipitated crystals were separated, washed with about 6 L of a mixture of isopropyl ether-ethyl acetate (1:1) cooled to about 5° C., and 10 L of isopropyl ether cooled to about 5° C., and dried to obtain 3.78 kg (yield 85%) of the desired compound as crystals.
Elementary Analysis