DE1008299B - Process for the manufacture of sulfonamide cones - Google Patents

Description

The invention relates to a new process for the preparation of sulfonamide compounds, in particular of substituted on the nitrogen atom of the sulfonamide group by a heterocyclic radical p-aminobenzene sulfonamides, such as 6- (p-aminobenzene sulfonamido) -2,4-dimethylpyrimidine, by reaction of aromatic sulfonic acid halides with amines in the presence of a tertiary amine.

It is known to use aromatic sulfonic acid halides with amines in the presence of tertiary amines as condensation agents, usually with pyridine. The yields are, however, in certain cases, in particular in the implementation of benzenesulfonic acid halides with 6-amino-pyrimidines, such as the 6-amino-2,4-dimethylpyrimidine, unsatisfactory. Trimethylamine has also been used as a suitable condensing agent or dimethylaminoalkylamines, the alkyl radical of which has 2 to 4 carbon atoms, are proposed. These do not seem to be generally useful as condensing agents, since e.g. B. in condensation of 6-amino-pyrimidines with benzenesulfonic acid halides in the presence of triethylamine only poor yields can be achieved. The use of these compounds, especially trimethylamine, however, there are various defects; above all, they have a low boiling point. So is E.g. the handling of trimethylamine is made difficult by its extremely low boiling point of only 3.5 °; furthermore, regeneration is difficult because of its great volatility; further can be a nuisance to those employed, even when using closed apparatus Individuals by the intense and clingy fishy Do not avoid odor.

It has now been found that these disadvantages can be avoided if the reaction of aromatic sulfonic acid halides with amines is carried out in the presence of ω, ω'- BLs-dimethylamine alkanes whose alkylene chain has at least 6 carbon atoms, especially in the presence of ω, ftZ -Bis-dimethylamino-alkanes, the alkylene chain of which has 6 to 9 carbon atoms. The alkylene chain of the compounds mentioned is preferably unsubstituted; however, it can also be substituted by low molecular weight alkyl radicals, in particular methyl radicals. Compared to trimethylamine, these diamines have the advantage of a high boiling point, so that they are easy to handle and they can also be used at condensations which require relatively higher temperatures, without the need to use an autoclave. The regeneration can be carried out in a simple manner. Another particular advantage is that they are not noticeable by an unpleasant odor.

Process for the preparation of sulfonamide derivatives

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

ίο Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority: Switzerland of June 15, 1954

Dr. Paul Müller and Robert Trefzer, Basel (Switzerland), have been named as inventors

The process is particularly suitable for the condensation of benzenesulfonic acid halides, particularly the chlorides which in the p-position have a substituent which can be converted into an amino group, e.g. Legs Acetylamino, carbalkoxyamino or a nitro group, with heterocyclic amines, preferably with 6-amino-pyrimidines, such as 6-amino-2,4-dimethylpyrimidine. After condensation can the substituent which can be converted into an amino group is converted into a free amino group in the customary manner will. If sulfonamides substituted by a sulfonic acid residue are formed during the reaction, then so can this remainder in the usual way, for. B. cleaved by treatment with hydrolyzing agents are, optionally in the formation of the free amino group.

The condensations are preferably in the presence of diluents at lower or higher Temperature. As a diluent, for. B. hydroxyl group-free, organic Solvents, such as substituted or unsubstituted, aromatic or cycloaliphatic hydrocarbons, z. B. benzene, toluene, methylene chloride, ethylene chloride, chlorobenzene or nitrobenzene, also ketones and Esters are used. The starting materials and the condensing agent can be in stoichiometric Conditions are applied. But you can also especially the sulfonic acid halide, for. B. in Molar ratio of 1 mole of Amki to 2 moles of sulfonic acid halide, and accordingly use the condensing agent in excess.

739 509402

The invention is described in the following examples.

example 1

held at 65 ° for 1 hour and 69.4 g of _{1,6-bis-dimethylaminohexane (b.p. 15 mm} 96 °), dissolved in 75 ecm of nitrobenzene, added dropwise over 10 hours at 45 °. The light brown reaction mixture is stirred for a further 12 hours at 45 ° and then neutralized with 50% sulfuric acid until a drop of the neutralized mixture on moistened brilliant yellow paper is only slightly orange. This will be at a pressure of about 10 to

Vigorously stirred with 940 g of 12.5% sodium hydroxide solution for 3 hours at 85 to 90 °, then at 45 to 50 °

The saponification liquor is stirred for a further 5 hours at 96 ° to 98 °. This is followed by at 20 ° with approx 120 ecm of dilute hydrochloric acid (1: 1 v / v) of the alkali

800 ecm of nitrobenzene are presented and under
vigorous stirring at 20 to 25 ° 60 g of o-amino-2,4-dimethylpyrimidine and then 171 g of anhydrous
ρ - Acetylaminobenzenesulfonic acid chloride entered.
Thereupon are with the exclusion of moisture
45 ° internal temperature, 65 g of 1,6-bis ~ dimethylamino- io 12 mm mercury column and a distillation hexane (boiling point 15 mm 96 °) were _{added dropwise over the course of 6 hours.} temperature of about 85 to 95 ° 495 ecm nitrobenzene The yellow solution is distilled off for 15 hours at. The brown distillation residue is stirred for a further 40 to 45 °. You slowly add
600 g of 30% sodium hydroxide solution and then heated under
good stirring for 2 hours at 90 °. After the nitrobenzene still present is separated off and the cooling to 30 to 40 °, the precipitated saponification liquor is filtered off twice with 100 ecm of benzene with sodium salt each time, and the precipitate is stirred out at 30 ° / 45 to 50 °. The solvents which have been rinsed off in this way by sodium hydroxide solution and finally removed in portions from the saponification liquor are washed out with 300 cm of fresh nitrobenzene. 1,6-bis-dimethylaminohexane can be regenerated in good yield. The residue is taken up in 1000 ecm of water.

and the nitrobenzene still contained therein azeotropically The obtained after separation of the solvent

removed in vacuo with continual replacement of the
distilled water. The remaining aqueous
Solution is filtered hot with animal charcoal. After neutralization of the sodium salt solution with a dilute excess, the solution is treated with decolourising hydrochloric acid (1: 1 v / v = 1 volume of concentrated hydrochloric acid and filtered. After neutralization of the acid diluted with 1 volume of water), sodium salt solution with dilute hydrochloric acid is obtained (1: 1 v / v)

the 6- (p-aminobenzenesulfonamido) -2,4-dimethylpyrimidine is obtained in a yield of 77%, calculated on the 6-amino-2,4-dimethylpyrimidine used. That The product can be further purified using the sodium salt.

The recovery of the 1,6-bis-dimethylaminohexane used as a condensing agent from the

vigorous stirring at 20 to 25 ° 93.5 g ~ anhydrous 35 separated solvent mixture is as follows ρ - Acetylaminobenzenesulfonic acid chloride entered. performed:

The solution separated from the saponification liquor is then added at 25 ° over the course of 4 hours.

A solution of 20.05 g of 2-aminothiazole in 120 ecm nitro-medium layers of nitrobenzene and benzene is added to benzene and the solution is combined for a further hour, after which the base solution is initially stirred. With the exclusion of moisture +0 distilling off the benzene through a column at then at 25 ° 41.35 g of 1, 6-bis-dimethylaminohexan atmospheric pressure simultaneously azeotropically dried (Kp. 96 _lsinm ^s) added dropwise over 10 hours, and is. The benzene recovered in this way contains about the light brown suspension for a further 6 hours at 25 ° 1 to 2% of the 1,6-bis-dimethylamino used and stirred for 2 hours at 55 °. 512 g of hexane are then added and 12.5% strength sodium hydroxide solution is added to extract the saponification liquor and used during a subsequent batch.

Then the remaining nitrobenzene solution is in vacuo at a pressure of about 15 mm of mercury and a temperature of

the 6 - (p - aminobenzolsutlf onamido) - 2, 4 - dimethylpyrimidm in a yield of 70%, calculated on 6-amino-2,4-dimethylpyrimidine used.

Example 2 250 ecm of nitrobenzene are placed and under

Vigorously stirred for 1 hour at 80 °. It is then allowed to settle at 45 to 50 °, the nitrobenzene is separated off and stirs the separated saponification liquor with 100 ecm of benzene, which is also removed at 45 to 50 °

about 95 ° distilled off to dryness. By

be separated. The basic nitrobenzene distillate retained from the solvent is about 91

contain up to 93% of the 1,6-bis-dimethylaminohexane used. This solution can after supplement on the required salary again directly for the

Saponification is still for 3 hours
96 to 98 ° stirred, whereupon 135 g with water cooling
Caustic soda (90%) are added. The precipitated sodium salt is after cooling
filtered and the precipitate is washed out with 100 ecm of 30% benzene and nitrobenzene distillate. The sodium obtained, about 93 to 94% of the 1,6-bis-dimethyl salt used, is dissolved in 200 ecm of water at 55 to 60 °, with
Stir the decolorizing charcoal and filter. After neutralizing the sodium salt solution with dilute
Hydrochloric acid (1: 1 v / v) with cooling gives the 60
2- (p-Aminobenzenesulfonamido) thiazole in a yield of 87%, calculated on the 2-aminothiazole used.

next condensation can be used. With the

aminohexane recovered.

Example 4 Example 3

495 ecm of nitrobenzene are initially introduced and 60 g of 6-amino-2,4-dimethylpyrimidine are added at 20 ° to 25 ° with vigorous stirring and then 171 g of anhydrous ρ - acetylaminobenzene sulfonic acid chloride

200 ecm of nitrobenzene are introduced and, with vigorous stirring at 20 to 25 °, 30 g of 6-amino-2,4-dimethylpyrimidine and then 99.6 g of anhydrous ρ-acetylaminobenzene sulfonic acid chloride are added. This will be maintained under exclusion of moisture for 1 hour at 65 ° and 43.9 g 1, 7-Bisdimethylaminoheptan (Kp. 105 ° _umm) dissolved in 200 cc of nitrobenzene, was added dropwise over 6 hours at 45 °. The light brown reaction mixture is

carried. Then, with the exclusion of moisture, stirring is continued for 12 hours at 45 ° and then with

a little 50% sulfuric acid neutralized until a drop of the neutralized mixture on moistened Brilliant yellow paper only shows faintly orange. This will be at a pressure of about 10 to 12 mm mercury column and a distillation temperature of 85 to 95 ° 200 ecm nitrobenzene im Distilled off under vacuum. The brown distillation residue is with 690 g of 10% sodium hydroxide solution during Vigorously stirred for 3 hours at 85 to 90 °, then separated off the nitrobenzene still present at 45 to 50 ° and the saponification liquor was stirred twice with 100 ecm of benzene each time at 45 to 50 °. From the Solvents separated from the saponification liquor in this way can contain 1,7-bis-dimethylaminoheptane can be regenerated in good yield. The saponification liquor obtained after the solvents have been separated off is stirred for 5 hours at 96 to 98 °. This is followed by a dilution of about 120 ecm at 20 ° , Hydrochloric acid (1: 1 v / v) neutralizes excess alkali, the solution is treated with decolorizing charcoal and filtered. After neutralization of the sodium salt solution with dilute hydrochloric acid (1: 1 v / v) the 6 - (p - aminobenzene sulfonamido) - 2,4 - dimethylpyrimidine is obtained in a yield of 86%, calculated on the 6-amino-2,4-dimethylpyrimidine used.

Example 5

455 ecm of nitrobenzene are introduced and, with vigorous stirring at 20 to 25 °, 60 g of 6-amino-2,4-dimethylpyrimidine and then 171 g of anhydrous ρ-acetylaminobenzene sulfonic acid chloride are added. The mixture is then kept at 65 ° for 1 hour with the exclusion of moisture and 80.7 g of 1,8-bisdimethylaminooctane ( _{b.p. 1 mm} 78 °) dissolved in 75 ecm of nitrobenzene are added dropwise at 45 ° over the course of 10 hours. The light brown reaction mixture is stirred for a further 12 hours at 45 ° and then neutralized with a little 50% sulfuric acid until a drop of the neutralized mixture on moistened brilliant yellow paper is only slightly orange. Then at a pressure of about 10 to 12 mm of mercury and a distillation temperature of 85 to 95 ° 455 ecm of nitrobenzene are distilled off in vacuo. The brown distillation residue is ^{vigorously stirred with 940 g of 12.5 0} ZoIgCr sodium hydroxide solution for 3 hours at 85 to 90 °, the nitrobenzene still present is then separated off at 45 to 50 ° and the saponification liquor is stirred twice with 100 ecm of benzene each time at 45 to 50 ° . 1,8-Bis-dimethylaminooctane can be regenerated in good yield from the solvents separated off from the saponification liquor in this way.

The saponification liquor obtained after separation of the solvent is for 5 hours at 96 bis 98 ° further stirred. The excess alkali is then added at 20 ° with about 120 ecm of dilute hydrochloric acid (1: 1 v / v) neutralized, treated the solution with decolorizing charcoal and filtered. After neutralizing the Sodium salt solution with dilute hydrochloric acid (1: 1 v / v) the 6- (p-aminobenzenesulfonamido) -2, 4-dimethylpyrimidine is obtained in a yield of 78%, calculated on the 6-amino-2,4-dimethylpyrimidine used.

65 Example 6

115 ecm of nitrobenzene are introduced and, with vigorous stirring at 20 to 25 °, 15 g of 6-amino-2,4-dimethylpyrimidine and then 42.75 g of anhydrous ρ-acetylaminobenzenesulfonic acid chloride are added. The mixture is then kept at 65 ° for 1 hour with the exclusion of moisture and 21.6 g of 1,9-bisdimethylaminononane ( _{b.p. 02 mm} 74 °), dissolved in 25 ecm of nitrobenzene, are added dropwise at 45 ° over the course of 10 hours. The light brown reaction mixture is stirred for a further 12 hours at 45 ° and then neutralized with a little 50% strength sulfuric acid until a drop of the neutralized mixture on moistened brilliant yellow paper is only slightly orange. Then at a pressure of about 10 to 12 mm of mercury and a distillation temperature of 85 to 95 ° 115 ecm of nitrobenzene are distilled off in vacuo. The brown distillation residue is vigorously stirred with 235 g of 12.5% sodium hydroxide solution for 3 hours at 85 to 90 °, the nitrobenzene still present is then separated off at 45 to 50 ° and the saponification liquor is stirred twice with 50 ecm of benzene each time at 45 to 50 ° . From the solvents separated off in this way from the saponification liquor, 1,9-bis-dimethylaminononane can be obtained in good yield, for. B. regenerated by distillation under reduced pressure. As a result of its low solubility in water, it can optionally also be recovered by steam distillation.

The saponification liquor obtained after separation of the solvent is for 5 hours at 96 bis 98 ° further stirred. The solution is then treated with coloring charcoal at 20 ° and filtered. To Neutralization of the sodium salt solution with dilute hydrochloric acid (1: 1 v / v) gives 6- (p-aminobenzene sulf onamido) -2, 4-dimethylpyrimidine in a yield of 79%, calculated on the amount used 6-amino-2,4-methylpyrimidine.

Claims (6)

PATENT CLAIM! 1. A process for the preparation of sulfonamide derivatives by reacting aromatic sulfonic acid halides with amines in the presence of basic condensing agents, characterized in that the basic condensing agent used is ω, ω'-bis-dimethylamino alkanes whose alkylene chain has at least 6 carbon atoms. 2. The method according to claim 1, characterized in that one is used as the condensing agent ω, ω'-bis-dimethylamino-alkanes, their alkylene chain 6 to 9 carbon atoms is used. 3. The method according to claim 1 and 2, characterized in that one benzenesulfonic acid halides, which have a substituent which can be converted into an amino group in the p-position, reacts with heterocyclic amines, in the benzenesulfonamides obtained, the substituent in the p-position converted into a free amino group and, if substituted by a sulfonic acid radical Benzenesulfonamides are formed, this residue is split off. 4. The method according to claim 1 to 3, characterized in that one benzenesulfonic acid halides, which have a substituent which can be converted into an amino group in the p-position, with 6-amino-pyrimidines implemented. 5. The method according to claim 1 to 4, characterized in that one. Benzenesulfonic acid halides, which in the p-position one into an amino 7 * 8 have group transferable substituents, 7. The method according to claim 1 to 6, characterized in that Reacts with o-amino-2,4-dimethylpyrimidine. indicates that the aromatic sulfone 6. The method according to claim 1 to 5, characterized in that the acid halide is used in excess. indicates that the aromatic sulfone acid halide p-acetylaminobenzenesulfonic acid- 5 Publications considered: chloride used. German patent application N 6534 IVb / 12p. © 709 50OT02 5.57