Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-03-10
2000-05-30
Stockton, Laura L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D27728
Patent
active
060692561
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP97/04705 filed Aug. 29, 1997.
The present invention relates to a novel process for the preparation of nizatidine, N-[2-[[[2-(dimethylamino)methyl-4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2 -nitro-1,1-ethenediamine, and pharmaceutically acceptable salts thereof.
The preparation of nizatidine by fusing 4-chloromethyl-2-dimethylaminomethylthiazole with N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine has been suggested generically in EP 49618. However, we have found that N-(2-mercaptoethyl)-N'-methyl-2-nitro-1,1-ethenediamine cannot be isolated and stored. Our attempts to prepare this compound have always produced the disulphide, N-methyl-[N'-[2-(N"-methyl-2-nitro-1,1-ethenediamine)ethyldisulphanyl]ethy l]-2-nitro-1,1-ethenediamine and 3-methylamino-5,6-dihydro-[1,4]-thiazin-2-one oxime.
The present invention provides a novel process for the preparation of nizatidine I ##STR3## and pharmaceutically acceptable salts thereof, comprising reacting a compound of formula II ##STR4## with a compound of formula III ##STR5## or a salt thereof, in which X represents a leaving group, in the presence of methylamine in the presence of an inert diluent.
The present invention represents a considerable improvement, over the known processes for the preparation of nizatidine, in that it allows a one-pot process with high yields, low production costs, fast processing times and avoids the problems of the known processes. In addition, the process of the present invention allows the possibility of an extremely cost-efficient continuous process.
The reactants involved in this process II, III and methylamine may be mixed in a number of different ways. In one embodiment of the present invention II and III or a salt thereof are combined to give a mixture and methylamine is added to this mixture.
In a second embodiment II is combined with methylamine to give a mixture and III or a salt thereof is added to the mixture. Optionally further methylamine is added as III or a salt thereof is added.
In a third embodiment II, III and methylamine are combined together simultaneously. Optionally further methylamine is added.
The second embodiment is preferred.
In a most preferred embodiment of the present invention the process is continuous and III or a salt thereof is added simultaneously with methylamine to a reaction mixture comprising II and methylamine and after a suitable time period the product is removed and the vessel is re-charged with reactants and the process is continued.
The term inert diluent as used herein means a liquid which is inert to the reactants and products in the process under the conditions used in the process. Any such liquid may be used. Preferably the inert diluent is water or an organic solvent selected from a nitrile, a C.sub.1-8 alcohol, a halogenated alkane, an ether, N,N-dimethylformamide, dimethyl sulphoxide and mixtures thereof. More preferably the inert diluent is water, acetonitrile, methanol, ethanol, propanol, dichloromethane or tetrahydrofuran or mixtures thereof. Most preferably the inert diluent is acetonitrile or water or mixtures thereof.
Surprisingly it has been found that the process may be carried out in the presence of water. This means that the process may be carried out in inert diluents which do not have to be rigorously dried. In addition aqueous solutions of methylamine may be used which are easier to use on a production scale than gaseous methylamine leading to cost savings.
The tolerance of the process to water also leads to considerable improvements in the physical handling of the materials during the process. The use of water means that a salt of III may be added as a solution at ambient temperature thus eliminating the necessity of heating to keep III in solution during the addition or the necessity of using acidic adjuncts which may corrode the reaction vessels.
The process may be carried out without batchwise addition of starting materials at set time intervals which is costly. Instead a simple continuous addition of reactants may be employed wh
REFERENCES:
patent: 4968808 (1990-11-01), Mosdorf et al.
patent: 5541335 (1996-07-01), Manning
Knoll Aktiengesellschaft
Stockton Laura L.
LandOfFree
Process for the preparation of nizatidine does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of nizatidine, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of nizatidine will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1911322