Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-02-09
2004-10-05
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S224000
Reexamination Certificate
active
06800758
ABSTRACT:
The invention relates to a process for the preparation of 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinone of the formula (I).
The British patent specification No. 2 262 526 provides new 3(2H)-pyridazinone-4-substituted amino-5-halo derivatives which possess valuable antiarrhythmic properties and prevent ventricular and auricular fibrillations. The 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-amino]-propylamino}-3(2H)-pyridazinone of formula (I) is described in the above-mentioned British patent specification.
According to the British patent specification No. 2 262 526 the compound of formula (I) is prepared by reacting 4,5-di-chloro-3(2H)-pyridazinone of formula (XI)
with the amine of formula (X).
The drawback of the process resides in the fact that a mixture of the desired compound of formula (I) and the regioisomer thereof of formula (IA)
is obtained, wherein the main component is the undesired isomer of formula (IA), while the desired compound of formula (I) is present only as a side-product, in an amount of a few %. Only by expensive and cumbersome column chromatography can the compound of formula (I) be separated and isolated in a pure state from the thus-obtained mixture. A further disadvantage of the method is that a considerable (2.5-3-fold) molar excess of the expensive amino component of formula (X) obtained in a multi-step reaction is applied, which renders the method less economical.
The present invention aims at providing a more regio-selective method for the preparation of 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propyl-amino}-3(2H)-pyridazinone of the formula (I), which is devoid of the drawbacks of the hitherto known processes.
It has been found that the above aim can be achieved by producing the 5-chloro-4-{3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylamino]-propylamino}-3(2H)-pyridazinone of formula (I) and pharmaceutically acceptable acid addition salts thereof according to the method of the invention, which comprises
a
1
) reacting a compound of the general formula (II),
wherein X stands for a leaving group, with N-methyl-homoveratryl amine of the formula (VI);
or
a
2
) reacting a compound of the general formula (III),
wherein R stands for lower alkanoyl, aroyl or aryl-(lower alkanoyl), with an agent containing a leaving group of the formula X and reacting the thus-obtained compound of the general formula (II) with the compound of formula (VI); or
a
3
) reacting 4-(3-hydroxypropylamino)-3,5-dichloro-pyridazine of the formula (IV)
with an agent suitable for introducing a group of the formula R, reacting the thus-obtained compound of general formula (III) with an agent containing a leaving group of the formula X and reacting the thus-obtained compound of general formula (II) with the compound of formula (VI); or
a
4
) reacting 3,4,5-trichloropyridazine of the formula (V)
with 3-amino-1-propanol, reacting the thus-obtained compound of formula (IV) with an agent suitable for introducing a group of the formula R, reacting the thus-obtained compound of general formula (III) with an agent containing a leaving group of the formula X and reacting the thus-obtained compound of general formula (II) with a compound of the formula (VI); or
b
1
) removing the group of the formula R (wherein R is as stated above) from a compound of general formula (IX);
or
b
2
) reacting the compound of formula (VIII)
with an agent suitable for introducing a group of the formula R and removing the group of formula R from the thus-obtained compound of general formula (IX); or
b
3
) reacting a compound of the general formula (VII),
wherein X is as stated above, with a compound of the formula (VI), reacting the thus-obtained compound of formula (VIII) with an agent suitable for introducing a group of the formula R, and removing the group of the formula R from the thus-obtained compound of general formula (IX); or
b
4
) reacting the compound of formula (IV) with an agent containing a leaving group of the formula X, reacting the thus-obtained compound of general formula (VII) with the compound of formula (VI), reacting the thus-obtained compound of general formula (VIII) with an agent suitable for introducing a group of the formula R and removing the group of the formula R from the thus-obtained compound of general formula (IX);
and, if desired, converting the thus-obtained compound of formula (I) into an acid addition salt thereof.
The invention is based on the discovery that the regio-selectivity of the reaction can be improved considerably when using 3,4,5-trichloropyridazine of the formula (V) as starting substance. When reacting the compound of formula (V) with 3-amino-1-propanol an approximately 1:1 mixture of the desired compound of formula (IV) and the regioisomer thereof of formula (IVA)
is obtained. A further advantage of the application of the compound of formula (V) as starting substance resides in the fact that the isomers of formulae (IV) and (IVA) can readily be separated by crystallization, and thus the expensive column chromatography cumbersome on an industrial scale can be eliminated. A further advantage of the process according to the invention is that the regioisomers are separated at the beginning of the synthesis, when the first intermediate is formed, so the further reaction steps and the closing step are carried out with the application of only one regioisomer. Thus the desired product can be separated from the reaction mixture with a reduced loss and in a higher purity compared to the hitherto known processes. It was not aforeseen that the regioisomers of formulae (IV) and (IVA) can be separated so simply, by crystallization, and converted to the compounds of general formulae (II) and (III) with such a high yield.
In the first step of variant a) according to the invention 3,4,5-trichloropyridazine of the formula (V) is reacted with 3-amino-l-propanol. The reaction is carried out in an organic solvent. As reaction medium preferably lower alkanols (such as methanol, ethanol, n-propanol, preferably ethanol) or dipolar aprotic solvents (such as acetonitrile or dimethylformamide) are used. The reaction is carried out in the presence of an acid binding agent. For this purpose inorganic acid binding agents (e.g. alkali carbonates, such as sodium carbonate or potassium carbonate, alkali hydrogen carbonates, such as sodium hydrogen carbonate or potassium hydrogen carbonate), or organic acid binding agents (e.g. amines, such as triethylamine or diethyl isopropyl amine) can be used. According to a preferable embodiment of the process according to the present invention the excess of 3-amino-1-propanol used as reactant may serve as solvent. The reaction can be performed at a temperature between 50° C. and 100° C., preferably at the boiling point of the reaction mixture.
When the reaction has been accomplished the reaction mixture is preferably worked up by removing the solvent and treating the residue with distilled water or with a 5 to 15% sodium chloride solution. Thus the two isomers can readily be separated, as the precipitate rich in the undesired isomer of the formula (IVA) can be isolated easily, by filtration, from the aqueous solution rich in the desired isomer of the formula (IV). If desired, both isomers can be subjected to further purification. The isomer of formula (IVA) can be purified by re-crystallization from an alcohol, while the compound of formula (IV) can be purified by extraction carried out with an organic solvent (e.g. ethyl acetate or halogenated hydrocarbons, such as dichloroethane or chloroform) followed by drying and evaporating the extract and re-crystallizing the residue from diethyl ether.
In the second reaction step of variant a) the thus-obtained compound of formula (IV) is reacted with an agent suitable for introducing a group of the formula R, wherein R is a lower alkanoyl (e.g acetyl, propionyl or butyryl), aroyl (e.g. benzoyl opti
Balázs László
Barkóczy József
Domán Imre
Greff Zoltán
Karancsi Támas
Bernhardt Emily
Egis Gyogyszergyar Rt.
Smith Gambrell & Russell
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