Processes for preparing 7-hydroxy-3,4-dihydro-2(1H)-quinolinone and the use in aripiprazole preparation thereof
OwnerVladimir Naddaka, Guy Davidi +3inventors
InventorsVladimir Naddaka, Guy Davidi, Eyal Klopfer, Oded Arad, Joseph Kaspi
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Abstract
The present invention provides improved processes for preparing the intermediate 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (7-HQ), which may be used in preparing the drug aripiprazole. Among these processes are included three efficient processes for preparing 7-hydroxy-3,4-dihydro-2(1H)-quinolinone comprising reacting N-(3-methoxyphenyl)-3-chloropropionamide with AlCl3 using novel reaction conditions thus obtaining a substantially pure product, which may be used in the subsequent steps for obtaining aripiprazole without further purification.
Claims22
An improved process for preparing 7-hydroxy-3,4-dihydroquinolinone (7-HQ) by reacting N-(3-methoxyphenyl)-3-chloropropionamide (3-MPCA) with a Lewis acid, wherein 7-HQ is obtained having a purity greater than 98.5%, preferably greater than 99% and more preferably equal to or greater than 99.3%, without using chromatographic purification.
An improved process for preparing 7-hydroxy-3,4-dihydroquinolinone (7-HQ) in the presence of an inorganic salt;
- the process comprising:
- a) reacting one equivalent of 3-MPCA with 2-8 equivalents of AlCl3, preferably with 4-6 equivalents of AlCl3 and more preferably with about 5 equivalents of AlCl3 in the presence of an inorganic salt at a temperature of 140-220° C.;
- b) quenching the reaction mixture with aqueous solution of an inorganic acid and isolating a complex of 7-HQ with AlCl3;
- c) slurrying the complex in water in order to eliminate excess of salts from the compound;
- d) decomposing the complex of 7-HQ with AlCl3 by preparing a solution in a C1-C4 alcohol and adding a base to produce pH of about 7;
- and
- e) isolating 7-HQ by filtration.
An improved process for preparing 7-hydroxy-3,4-dihydroquinolinone (7-HQ) in a melt;
- the process comprising:
- a) reacting one equivalent of 3-MPCA with 2-8 equivalents of AlCl3, preferably with 4-6 equivalents of AlCl3 and more preferably with about 5 equivalents of AlCl3 at a highest concentration attainable, i.e. in a melt, at a temperature ranging from 140° C. to 220° C. for a period of time sufficient to completely converting 3-MPCA to a complex of 7-HQ with AlCl3;
- b) quenching the reaction mixture with aqueous solution of an inorganic acid and isolating a complex of 7-HQ with AlCl3;
- c) decomposing the complex of 7-HQ with AlCl3 by preparing a solution in a C1-C4 alcohol and adding a base to produce pH of about 7;
- and
- d) isolating 7-HQ by filtration.
A process of preparing aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-quinolinone) or any pharmaceutically acceptable salt thereof, by converting 7-HQ, prepared essentially as described herein, to said aripiprazole.
Dependencies are inferred from the claim text.