Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-20
2001-10-30
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S318000, C546S326000
Reexamination Certificate
active
06310214
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with a new process for the preparation of chloropyridine sulphonic acid chlorides.
Chloropyridine sulphonic acid chlorides serve as starting materials for the preparation of a series of pharmaceuticals with anti-inflammatory, anti-pyretic, cardiovascular, blood sugar-sinking and diuretic properties. Thus, for example, 4-chloropyridine-3-sulphonamide serves for the preparation of torasemide and thus of related blood sugar-sinking sulphonylureas which also inhibit inflammation and act diuretically (see J. Delarge Arzneimitt.-Forsch./Drug Res., 38(1), 1988, 144). The sulphonarnide is, in turn, prepared from 4-chloro-pyridine-3-sulphonic acid chloride.
In DE 25 14 334 A1 is described a process for the preparation of chlorinated pyridine-3-sulphonic acid derivatives, whereby, starting from 4-pyridinol-3-sulphonic acid chlorides, there first takes place the chlorination by means of a mixture of PCl
5
and POCl
3
. The excess POCl
3
and PCl
5
is stripped off in a vacuum, and the remaining residue is worked up in a complicated way in several steps. Similar processes with the use of PCl
5
/POCl
3
are known from the literature (see L. Thunus, Annales pharmaceutiques francais, 33, 1975, 487; Tullio et al., Tetrahedron, 51, 1995, 3221, as well as EP 0 618 209 A1, DE 25 14 334 and FR 88,352).
The chlorination thereby takes place in one step by the substitution of the OH group on the ring and in the sulphonic acid residue with formation of hydrogen chloride and POCl
3
. As halogenation agent, there serves exclusively phosphorus pentachloride, always used in excess, whereas phosphorus oxychloride is used as solvent since it is always obtained in the reaction mixture in the case of the reaction of the phosphorus pentachloride. Phosphorus oxychloride does not itself lead to the chlorination. After the reaction, it can be removed from the mixture by distillation and, without further purification steps, can be used again for the next batch.
Other chlorination agents, for example thionyl chloride, sulphuryl chloride or also phosphorus tri-chloride, essentially only replace the phenolic OH group and are, therefore, not suitable for the reaction.
It is a disadvantage of the known processes that, in the case of batches of large-scale size, the starting materials cannot be mixed together from the beginning, since this can lead to a longer controllable course of the reaction with a vigorous evolution of gas. Therefore, according to the prior art, there takes place a slow, measured addition of the acid to the boiling mixture of phosphorus pentachloride and phosphorus oxychloride, as well as possibly an after-dosing of PCl
5
.
However, the dosing in of the solid reactants present in solid state (hydroxypyridine-sulphonic acid and PCl
5
) leads to considerable problems. There are several possibilities for the addition. Either the reactors must be opened, whereby the aggressive chemicals HCl and POCl
3
are liberated, or the addition takes place with the help of transport means for solid materials, for example transport screws. In this case, too, problems arise since the contact of the solid substances with the boiling POCl
3
leads to no longer transportable adhesions and encrustations.
Since phosphorus pentachloride is always used in excess, unreacted PCl
5
sub-limes in the case of the distilling off of the solvent (POCl
3
) and leads to encrustations and stoppages of the cooler. Furthermore, additional reaction steps for the decomposition of the excess halogenation agent by hydrolysis on ice, possible neutralisation with alkali and subsequent extraction are necessary. The yields of the known processes lie at about 70%.
SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to provide a process that overcomes the disadvantages of the prior art.
It is another object of the present invention to provide a process with which chlorinated pyridine-sulphonic acid derivatives can be prepared technically simply and in high yield.
In accomplishing these objects, there has been provided according to the present invention a process for preparing chlorinated pyridinesulphonic acid chlorides of the general formula I
from hydroxypyridine-sulphonic acids of the general formula II
comprising
a) passing chlorine gas into a mixture of a hydroxypyridine-sulphonic acid and of phosphorus trichloride,;
b) heating the mixture of a) to temperatures of about 100 to about 120° C.;
c) removing any phosphorus oxychloride formed and any excess phosphorus trichloride by distillation;
d) taking up the residue with an organic solvent;
e) distilling the liquid phase in a vacuum, thereby obtaining the chlorinated pyridine-sulphonic acid chloride.
Further objects, features and advantages of the present invention will become apparent from the detailed description of preferred embodiments that follows.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention concerns a new process for the preparation of chloropyridine-sulphonic acid chlorides of the general formula I
from hydroxypyridine-sulphonic acids of the general formula II
by substitution of the ring OH group and of the OH group of the acid residue by a chlorination agent, whereby, as chlorination agent, there is used a mixture of phosphorus trichloride in excess up to the stoichiometric amount and chlorine gas in stoichiometric amount up to a small insufficiency referred to the hydroxy pyridine-sulphonic acid used and whereby chlorine gas is passed into a mixture of hydroxypyridine-sulphonic acid and of phosphorus trichloride at temperatures of 100 to 120° C., the phosphorus oxychloride formed and possibly excess phosphorus trichloride are removed distillatively, the residue is taken up with an organic solvent and the liquid phase distilled in a vacuum for obtaining the chlorinated pyridine-sulphonic acid chloride.
The present invention addresses the deficiencies of the art in that chlorination of hydroxypyridine-sulphonic acids can be carried out with the help of a phosphorus trichloride-chlorine mixture known from carboxylic acid chemistry (see, inter alia, DE-OS 1 795 361, DE 28 31 777 A1), whereby, according to the present invention,
a) into a mixture of hydroxypyridine-sulphonic acid and of phosphorus trichloride, chlorine gas is passed in at temperatures of 70 to 90° C. and whereby phosphorus trichloride is used in excess up to the stoichiometric amount and chlorine gas in stoichiometric amount up to a slightly insufficient amount referred to the hydroxypyridine-sulphonic acid;
b) subsequently heating to temperatures of 100 to 120° C.;
c) the phosphorus oxychloride formed and possibly the excess phosphorus trichloride removed by distillation;
d) the residue is taken up in an organic solvent;
e) the liquid phase is distilled in a vacuum for obtaining the chlorinated pyridine-sulphonic acid chloride.
For this purpose, the liquid phosphorus trichloride and the acid are taken and the mixture heated under reflux. Subsequently, chlorine is passed into the reaction mixture with heating, whereby there takes place not only a substitution of the phenolic OH group but also of the hydroxyl group in the acid residue. Surprisingly, no nuclear chlorination of the pyridine thereby takes place by the chlorine used but rather exclusively the exchange of the hydroxyl groups.
Post-reaction is allowed to take place in known manner and phosphorus oxychloride and possibly excess PCl
3
distilled off. The residue is taken up with a preferably halogen-free solvent, for example toluene or methyl tert-butyl ether (MTBE) and possibly filtered. In the same way, there can also be used balogenated solvents, for example methylene chloride, ethylene chloride or also chloroform. However, from environmental points of view, the use of halogen-free solvents is preferred.
Due to the stoichiometric or insufficient use of chlorine, almost no unreacted chlorination agent remains in the reaction mixture. Thus, the sulphonic acid chloride can be obtained directly distillatively from the residue taken up with the
Biedenbach Bruno
Michel Hans-Peter
Foley & Lardner
Rotman Alan L.
Ruetgers Organics GmbH
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