Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1991-07-31
1993-04-06
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
562555, C07C26900
Patent
active
052005518
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to an improved method for the preparation of the intermediate for bambuterol, i.e. for the preparation of the 2'-bromo-3,5-di[N,N-dimethyl-carbomoyloxy]acetophenone, having the formula ##STR1## In U.S. Pat No.4,451,663 a method of manufacturing the intermediate 2'-bromo-3,5-di[N,N-dimethylcarbamoyloxy]acetophenone of the formula (1) is disclosed, called route A2 therein, according to which 3,5-dihydroxyacetophenone, having the formula ##STR2## is reacted with N,N-dimethylcarbamoylchloride (DMCC) having the formula ##STR3## using pyridine as solvent and base for the uptake of hydrochloric acid formed during the reaction. The resulting compound, 3,5-di[N,N-dimethylcarbamoyloxy]acetophenone having the formula ##STR4## is not isolated but further reacted with bromine in dioxan solvent resulting in the formation of 2'-bromo-3,5-di[N,N-dimethylcarbamoyloxy]acetophenone (1).
There is a great desire to avoid working with pyridine as a solvent. One method was tested in order to avoid using pyridine as a solvent, according to which the reaction was performed in methylene chloride with potassium carbonate as a base with catalytical amount of pyridine present. The drawbacks with the process was a long reaction time for N,N-dimethylcarbamoylchloride (DMCC), >24 hours, and a long quenching time for DMCC, >24 hours, and separation problems in the work-up step (emulsion and small density difference). Methylene chloride is not a preferred solvent either, because of its toxicity.
The object of the invention is to provide an improved method for the preparation of the intermediate 2'-bromo-3,5-di -[N,N-dimethylcarbamoyloxy]acetophenone (1) for the production of bambuterol avoiding the use of pyridine and methylene chloride as solvents and eliminating the separation problems in the work-up step.
This is attained according to the present invention by reacting 3,5-dihydroxyacetophenone ##STR5## with N,N-dimethylcarbamoylchloride, (CH.sub.3).sub.2 NCOCl, in a solvent, quenching with water, removing the solvent and dissolving of the resulting 3,5-di-[N,N-dimethylcarbamoyloxy]acetophenone ##STR6## in ethyl acetate, to which is added dissolved hydrogen bromide and then bromine, whereupon the resulting intermediate (1) is collected in the form of crystals, wherein the reaction between said 3,5-dihydroxyacetophenone (2) and N,N-dimethylcarbamoylchloride (3) is carried out in ethylacetate, isopropylacetate, butylacetate, ethylmethylketone or isobutylmethylketone as the solvent with a small amount of pyridine as a catalyst using a base comprising crystallized potassium carbonate.
According to a preferred embodiment of the invention potassium carbonate having a crystal water content of 11-13% is used. This might be achieved by using a mixture of crystallized and calcinated potassium carbonate, resulting in a easily stirred two-phase system.
Calcinated potassium carbonate (completely dry) gives a slow and non-complete reaction, and the addition of water to the calcinated potassium carbonate results in a sticky mass which is difficult to stir. Further, free water should not be present in the reaction mixture because of the risk of hydrolysis of the reactants.
The bromination step which according to the invention first involves the addition of HBr, preferably dissolved in ethanol, and a second step charging with bromine, Brt.sub.2, has the advantage that the bromination will proceed calmly. When bromination is performed directly with bromine, the reaction will start very slowly and at a certain point it will proceed vigorously and will be hard to control.
The invention will now be described more in detail.
In the first step of the process the base, potassium carbonate, will take care of hydrochloric acid formed. According to the prior art process pyridine will act both as base and solvent. In the process according to the invention however, pyridine will only be present in catalytic amounts. Here the pyridine will initially take up the hydrochloric acid formed, which then will be transferred to the potassi
REFERENCES:
patent: 3404975 (1968-10-01), Wilson et al.
patent: 4419364 (1983-12-01), Olsson et al.
patent: 4451663 (1984-05-01), Olsson et al.
patent: 4925971 (1990-05-01), Aoki et al.
Aktiebolaget Astra
Clarke Vera C.
Dees Jos,e G.
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