DE967224C - Process for the preparation of 4- (p-aminobenzenesulfonamido) pyrimidine compounds - Google Patents

Description

The condensation of benzenesulfohalides with 4-aminopyrimidines is preferably carried out in the presence of hydrochloric acid binding agents. The benzenesulfonyl halides used are preferably benzenesulfonyl chlorides which are in the p-position to the sulfochloride group by a, in the amino group convertible substituents are substituted. The 4-aminopyrimidine is preferred 4-amino-2,6-dimethylpyrimidine into consideration. Hydrochloric acid binding agents are pyridine, Trimethylamine and other tertiary bases have been suggested. It is known that trimethylamine takes a special position here and the implementation of the implementation otherwise difficult-to-react amines of the heterocyclic series, such as the 4-aminopyrimidines, with good ones Yields made possible.

It has now been found that the reaction of benzenesulfohalides with 4-aminopyrimidines can advantageously be carried out in such a way that the reaction is carried out in the presence of dimethylalkylamines carries out, the alkyl radical of which has 2 to 4 carbon atoms. Connections of this type are the Dimethyläthylaniin, the Dimethylpropyl- and isopropylamine and dimethylbutyl or isobutylamine. The reaction conveniently becomes such carried out that one works in the presence of an inert solvent or suspending agent and the amount of dimethylalkylamine added to the amount formed in the reaction is equivalent to hydrohalic acid.

Although it is known from French patent specification 990 389 that the condensation of 4-aminopyrimidine derivatives with p-acylamino-

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benzenesulfohalides for the preparation of 4- (p-aminobenzenesulfon amido) pyrimidine derivatives carry out in the presence of trimethylamine as a condensing agent and this yields on the bis-compounds obtained as intermediates up to approximately 100% can be obtained. Compared to this known method, however, the present mode of operation offers the following technical Advantages: When working using ίο trimethylamine can be used even when using of closed equipment or when processing the intermediate and end products a certain amount Unpleasant odor due to the unpleasant and clinging fish-like odor of this condensation agent in the case of the people involved in this, while procedurally used dimethylalkylamines this fishy and clinging odor not own.

In addition, the trimethylamine used in the known method at room temperature is gaseous and therefore for the actual condensation reaction, as in the examples the French patent 990 389 illustrated embodiments show advantageous in Benzene solution is applied. The gaseous nature of trimethylamine further forces the Storage and dosing vessels in which it is kept in the form of its benzene solution, continuously to cool to low temperatures to avoid evaporation losses or the formation of undesirable Avoid overpressing. All such procedural measures are omitted in the present process, since the dimethylalkylamines consistently have significantly higher boiling points and are liquid at room temperature.

In addition, their physical state, which is liquid at room temperature, allows them to be without solvents to keep storable and to be supplied to the reaction vessel.

It must also be taken into account that the mixture of condensation partners and condensation agents must be carefully kept at a temperature of 15 to 35 ° in the actual reaction vessel, on the one hand to maintain a sufficient reaction speed and on the other hand to prevent the occurrence to avoid undesirable overpressures due to the gaseous trimethylamine. Similar careful monitoring of the Reaction vessel with regard to the temperature is unnecessary when using the dimethylalkylamines, since their vapor pressures are much lower than that of the trimethylamine in the corresponding Temperatures, and for this reason also condensation temperatures up to about 6o °, each depending on the type of solvent used, can be complied with.

Finally, the present method also offers nor advantages with regard to the recovery of the basic condensing agent used insofar as the conversion of the trimethylamine obtained as hydrochloride after the condensation in the known process in the anhydrous base the application either works well Salt molecule cooler, the cooling medium of which must have a temperature of -ιo ° and below, or of makes working under pressure coolers necessary, whereas the analogous work-up of the Dimethylalkylamine hydrochloride is already possible using ordinary water coolers.

In addition, the present process involves the separation of the trimethylamine solvent of the different solvent that is used in the actual condensation reaction is used, in discontinuation.

These multiple advantages procedural nature are so significant in their totality that they largely have the disadvantage of a possibly somewhat lower yield of condensation product make up for it.

Finally, if one also takes into account that the present method allows the person skilled in the art for the preparation of the therapeutically important 4- (p-aminobenzenesulfonamido) -pyriniidines available, particularly effective condensation agent is significantly expanded, so It is clear that the chemical technology in this sector is supported by the present process pharmaceutical chemistry will undoubtedly be greatly enriched.

example

! 2.3 g (0.1 mol) of finely powdered 4-amino-2,6-dimethylpyrimidine, 46.8 g (o.1 mole) of finely pulverized anhydrous Acetylsulfanilsäurechlorid and 90 cc of anhydrous methylene chloride in a three-necked flask at a bath temperature of 40 ⁰ with stirring 14.6 g of anhydrous ethyldimethylamine are added. The amine is added very slowly at first until a clear solution has formed, the rest quickly. After 2 hours, a further 3.5 g of the amine are added to make up for losses. The mixture is stirred at 40 ^{0 for} 6 hours. The mixture does not discolor.

After 6 hours, the solvents are evaporated off, the residue is stirred with 200 ecm of hot water until the organic solvents have been driven off. The mixture was slightly acidic, and therefore sodium hydroxide solution to p _H was added. 6 Then left to stand for 1 day at room temperature. The soil body looks colorless and good.

After filtering and washing, 42.2 g of condensation product are obtained. Theory for bis-compound: 51.7 g. The condensation product is subjected to hydrolysis. Yield, to 4 "(p - aminobenzenesulfonamido) -2,6 - dimethylpyrimidin: 20.2 g = 72, y ° / o, F. 238.5 °.

Claims (1)

PATENT CLAIM: Process for the preparation of \ On4- (p-aminobenzenesulfonamido) pyrimidine derivatives by reacting benzenesulfohalides with a convertible into an amino group Substituents in the p-position to the sulfo group with 4-aminopyrimidines, which are replaced by alkyl groups in the core can be substituted in the presence of tertiary amines as condensing agents and subsequent conversion of the substituent in the p position to the sulfo group into the free amino group or and cleavage of a benzenesulfonyl residue from bis (benzenesulfonamido) pyrimidines formed, there characterized in that dimethylalkylamines are used as the condensing agent, whose alkyl radicals contain 2 to 4 carbon atoms. Documents considered: French Patent No. 990 389.