DE1812937C3 - 4- (Ammoäthansulfonylamino) -antipyrine and Aminoäthansulfonyl-p-phenetidine and process for their preparation - Google Patents

Description

4- (AcyJaminoäthansu] fonylamino) -antipyrine hydrolyte-DiftErfindung concerns 4- (Aminoäthansulfonylamino) -3 »sierl are:
antipyrine and aminoethanesulfonyl-p-phenetidine of
general formula ^^ _ CNHSO ₂ CH ₂ CH ₂ NHAc

Z-NHSOj-CHj-CH ₂ -NHR (I) i

35 CH ₃ N CO >

in Z the 4-antipyryl group,

CH ₃ C = CI

I! 40

CH ₁ N CO - = CNHSO ₂ CH ₂ CH ₂ Nh ₂

\. ^y (Ia)

^N CO

I 45 /

C, H _S

where Ac stands for an acyl group.

or the p-ethoxyphenyl group, the acyl compound can in addition to the initially

and R is hydrogen, an acetyl group or a manner mentioned, also in a manner known per se Is nicotinoyl group. by the reaction of 4-aminoantipyrine with acyl

The invention also relates to a process for the production of aminoethanesulfonyl halide.
Production of these compounds, which are characterized as acyl groups in this combination

It is known that aliphatic acyls, preferably acetyl, as well as a halide of the general formula 55 aromatic acyls, preferably nicotinoyl, in Be

costume.

Z - NHSO, - CH ₂ - CH, X (11) For example, acids,

metallic sodium (sodium alcoholate) or alkali

in which X halogen means the halogen to be used with success.

Amino group, the acetylamino group or the nico group is particularly preferred to use tinoylamino group and the concentrated alkali metal hydroxide solution thus obtained, in particular the reaction product, optionally deacylated or special from NaOH and KOH solutions.
acylated. The compound of group Ib with R = H, 'that

The new compounds are used as remedies. Aminoethanesulfonyl-p-phenetidine, can be used in analogous ways reversible. For example, the compounds are, in 65 ways, by hydrolysis of acylaminoethanesulfonyldenes Z is 4-antipyryl (hereinafter referred to as I a), p-phenetidine can be prepared. As preferred acylals Analgesics can be used. These substances (Ia) also include acetyl and nicotinoyl have a structure that is called a combination of.

Also the acylaminoätbansulfonyl-p-pbenetidine autoclave with 10g acetamide implemented. The reaction can in a manner analogous to the antipyrine addition mixture was taken up in 150 ml of water and extracted in the manner mentioned at the outset by reacting with ethyl acetate. After peeling p-Phenetidine with acylaminoethanesulfonyl halide of the extractant was taken to the residue can be obtained. 5 distilled under reduced pressure. The 4- {AcetyIamino-

The 4- (Aminoäthansulfonylamtno) - äthansulfonylamino) antipyridine was obtained as a light yellow antipyrine forms obtained after recrystallization from oil.

Water colorless needles of melting point 185 ⁰ C, the boiling point of the product was 264-267 ° C.

(Decomposition). Elemental analysis for C ₁₅ H ₂₀ N ₁ O ₄ S gave the

The aminoethanesulphonyl-p-phencditin forms colorless needles with a melting point of 149 to 153.degree. C. after recrystallization from ethyl acetate. Calculated: C = 51.15%, H = 5.68%, N = 15.91%; The hydrochloric that is found from the ethanolic solution: C = 51.21%, H = 5.58%, N = 16.13%. Solutions of the free base when passing in hydrogen chloride separates in the form of colorless needles, 15 example melts at 175 to 179 ^° C. The free base can also

can easily be converted into other salts, for example 2.6 g of 4- (chloroethanesulfonylamino) antipyrine

in the succinate, melting point 117 to 119 ^° C. (decomposition), in the presence of 2.5 g Cu ₂ Cl _{2 for} 5 hours at 100 ^° C. the fumarate, melting point 196 to 198 ° C. (decomposition) or that in the autoclave implemented with 10 g of nicptinic acid. Flavanate, m.p. 208-211 C (decomposition). ao The reaction mixture was dissolved in 100 ml of water

For comparison, the common salts of 4- (Aminoäthansulfonylamino), also slightly increased and extracted with ethyl acetate, melt - after the ester had been stripped off, the residue was recrystallized from antipyrine at 162 to 166 ° C (fumarate) and 120 to much ethanol, with the colorless 122 ^J C (flavanate). 4- (Nicotinoylaminoethanesulfonylamino) needles

The salts can be obtained in an advantageous manner for the purification of antipyrine hydrochloride in 60% yield tion of the free bases can be used. became. The melting point of the needles was 238

The compounds of formula I where R = H can to 239 ⁰ C (Ze * ietzung). also by hydrazinolysis of the acyl compounds. . . .

will hold. The hydrazine hydrate used here e 1 s ρ ι e

is preferably used in equimolar amounts to the acyl 30 10 g chloroethanesulfonyl-p-phenetidine were used in connection. The reaction is best carried out in the presence of 1.0 g of Cu ₂ Cl _{2 for} 5 hours at 100 ° C. in alcohol, preferably in ethanol or ethanol, in an autoclave with 20 g of anhydrous ammonia, with heating. The reaction mixture became more concentrated

The halides of the form. «II, acidified in the X preferred hydrochloric acid, then with sodium carbonate wise chlorine, bromine or iodine, especially chlorine, is made weakly alkaline and then with are also new compounds and can be extracted in chloroform. After removing the Chlorosich In a known manner, by converting 4-amino forms, the residue was repeated from acetic antipyrine or p-phenetidine recrystallized with ethyl haloethylsulfonyl ester, the amino halide can be obtained. ethanesulfonyl-p-phenetidine from melting point 149 to

The exchange of the halogen of the halides of 40 153 ° C was obtained in 88% yield. Formula II against the amino group, the acetylamino When introducing hydrogen chloride into ethanol

group or the nicotinoylamino group takes place before solutions of the free base obtained in this way, the hydro preferably fell under pressure, using catalysts, preferably chloride, in the form of colorless needles with a melting point of NaI, Cu ₁ Cl, or NH ₄ I 175 to 179 ° C out. be able. The preferred reaction partner is 45 B bis ρ ie 1 5

Ammonia, acetamide or nicotinic acid amide are used. 67.5 g of chloroethanesulfonyl-p-phenetidine were in

The invention is described below with reference to training the presence of 5 g of Cu ₂ Cl EADERSHIP Examples ₂ 5 hours at 100 ⁰ C in f detail. Autoclave reacted with 10 g of acetamide. The reaction

50 mixture was taken up in 150 ml of water and Example 1 _{extracted with} chloroform. After removing the

10 g of 4- (chloroethanesulfonylamino) antipyrine were chloroform, the residue thus obtained was _{recrystallized from water in the presence of 1.0 g of Cu 2} Cl _{2 for} 5 hours at 100 ° C., the acetaminoethane being reacted in _{an autoclave with 20 g of anhydrous NH 3.} sulfonyl-p-phenetidine in the form of needle-like crystals. Hydrochloric acid acidified 55 from melting point 142 to 148 ° C in one yield and the precipitate obtained is filtered off. The filtrate obtained by 40% was made weakly alkaline with sodium carbonate _R. ■ \ f.

and extracted with ethyl acetate. Who spat for an egg

The residue obtained was stripped off with 25 g of chloroethanesulfonyl-p-phenetidine were in

combined with the filter residue. The combined residues of 2.5 g of Cu ₂ Cl, 5 hours at 100 ^° C. in the stand were recrystallized from water, the autoclave being reacted with 20 g of nicotinic acid amide. The 4- (Aminoäthansulfon-ylamino) -antipyrin (decomposition reaction mixture was obtained in 100 ml of water at 185 ° C) in general 91% yield. taken and extracted with chloroform. After the chloroform had been stripped off, the residue evaporated

B eis ρ ie 1 2 ⁶ 5 benzene recrystallized, whereby the nicotinoylamino-

Ethanesulfonyl-p-phenetidine in the form of colorless needles

10 g of 4- (Chlotäthansulfonylamino) -antipyrin were obtained with the melting point 69 to 74 ° C in a yield in the presence of 5 g Cu ₂ Cl ₈ 5 hours at 100 ⁰ C im of 51%.

5 6

Example 7 stands with powdered sodium hydrogen carbonate

neutralized before recrystallization from water. 4- (Amino & tbansulfoRylamino) -antipyrine was with

Glacial acetic acid, acetic anhydride or acetyl chloride around- Example 11 set and then renewed with sodium carbonate 5

The neutralized reaction mixture would be 3 g of 4- (Amino8thanesulfonylamino) antipyrine

extracted with ethyl acetate. After removal, dissolved in 8 ml of anhydrous pyridine and added with 2 g

the extractant was admixed with the reverse nicotinic acid chloride hydrochloride obtained in this way. The Mi

stood distilled at 18 torr. The 4- (acetylamino ethane is left to stand overnight and then

. sulfonylarnino) antipyrine, which is heated on a water bath for 1 hour at a bath temperature.

from 200 to 280 ⁰ C passed, was in the form of After cooling the reaction mixture, this is

obtained light yellow oil. adjusted to pH 9 with a sodium carbonate solution

. · Ι ₈ ^u ° d evaporated to dryness in vacuo. The return

Example 8 _stanc j _w j _{r £} j _m j _t activated carbon mixed and made of water

3 g of 4- (Aminoätha ".sulfonylamino) -antipyrin were 15 recrystallized, whereby the 4- (Nicotinoylaminoäthan-

dissolved in 8 ml of pyridine and treated with 2 g of nicotinic acid chloride sulfonylamino) antipyrine in a yield of 3.6 g

hydrochloride added. The mixture was in the form of fine needles mil: a melting point of

Left to stand overnight at room temperature. From which 198 to 201 ⁰ C (decomposition) is obtained. That way

The reaction mixture was then obtained under the product is easily dissolved in chloroform and ethanol

reduced! Pressure removed the pyridine. Soluble after Um- ao, but hardly, soluble in ethyl acetate

crystallize the yellow residue obtained in this way ester, benzene and ether,

from a lot of ethanol 3.5 g of 4- (Nicotir.oylamino-..

ethanesulfonylamino) -antipyrinhydroch.orids in the form of egg spat

colorless needles with a melting point of? 38 to 239 ^C C To produce the acetyl compounds, one sets (decomposes). Treatment of the hydro-aminoethanesulfonyl-p-phenetidine with glacial acetic acid, acetic chloride with sodium carbonate converted the free amine acid anhydride or acetyl chloride. Obtained after neutral with a melting point of 198 to 201 ^C C (decomposition of the reaction mixture with sodium carbonate decomposition). is cooled and the deposited residue

The hydrochloride is an ethyl acetate, recrystallized from water.

Benzene, acetone and chloroform only slightly soluble, 30 For example, 5 g of aminoethanesulfonyl

but easily soluble in water. p-phenetidine in 10 ml of warm acetic anhydride

When using nicotinic acid chloride to be dissolved and heated for about 10 minutes. After leaving

In place of the nicotinic acid chloride hydrochloride was used to cool the reaction mixture, 50 ml of water

Product obtained in the same yield. added and the resulting mixture cooled,

.... 35 whereupon colorless needles separated out

Example y water were recrystallized. That in one way

A mixture of 31 g of 4- (Aminoethanesulfonyl- acetylaminoamino) antipyrine (0.1 mol), 22.8 g of nicotinic anethanesulfonyl-p-phenetidine had a melting point hydride ^ 0.1 mol) and 65 ml of anhydrous pyridine was from 142 to 148 ⁰ C.
in a three-necked flask with stirring for 5 hours 40 bis ο ie 1 13
warmed on a boiling water bath. The pyridine was then stripped off under reduced pressure of 2.4 g of aminoethanesulfonyl-p-phenetidine (0.01 mol) and the residue from a large amount of ethanol was dissolved in 8 ml of pyridine and crystallized using 2.0 g of nicotine. The 4- (nicotinoylaminoethanesulfonyl acid chloride hydrochloride (0.01 mol) was added. The amino) antipyrine hydrochloride was heated in an amount of 45 minutes. The mixture was heated for 30 minutes and then 9.1 g in the form of colorless crystals with a melting point at room temperature overnight from 238 to 239 ^C C (decomposition). The pyridine was then removed under reduced pressure and the residue was repeatedly recrystallized from benzene. The yield of nicotinoyl

50 aminoethanesulfonyl-p-phenetidine was 1.5 g in the form

A: Mixture of 31.0 g of 4- (Aminoät! Iansulfonyl- of colorless needles with a melting point of

amino) antipyrine (0.1 mol), 12.3 g nicotine acid 69 to 74 ° C.

(0.1 mol) and 380 ml of p-cymene was added with stirring to Example 14
in a three-necked flask for about 4 hours

2.4 g of aminoethanesulfonyl-p-phenetidine (0.01 mol) were heated in a moisture separator tube to 180 to 190 "C. The water formed was azeotropically distilled off in 30 ml of ethyl acetate containing 2.0 ml - Nicotinic acid chloride hydrochloride (0.01 mol) was added to cool, the p-cymene was stripped off under reduced pressure and refluxed for 1 hour on the water bath and the residue was boiled from water. After removal of the ethyl acetate crystallized. (Nicotinoylaminoethanesulfonyl-60 remained a white-yellow solid residue, which was dissolved in amino) -antipyrine (melting point 198 to 201 ° C under as little water as possible and then decomposed) was obtained in a yield of 8.5 g by adding a saturated solution of sodium, hydrogen carbonate it was made alkaline

With the additional use of 0.5 g concentrated, a yellow oil is produced which solidifies on cooling

Sulfuric acid could be used as a catalyst for the condensation. The residue was

reaction, the same yields were obtained. In filtered and recrystallized several times from benzene, where-

in this case the p-cymene became after the reaction with the nicotinoylaminoethanesulfonyl-p-phenetidine

stripped off under reduced pressure and the return in a yield of 2.0 g in the form of colorless needles

with a melting point of 69 to 74 ⁰ C was obtained.

Example 15

24.4 g of aminoethanesulfonyl-p-phenetidine (0.1 mol), 22.8 g of nicotinic anhydride (0.1 mol) and 70 ml of anhydrous pyridine were placed in a three-necked flask and heated on a boiling water bath with stirring for 5 hours. After removing the The residue was made pyridine under reduced pressure by adding saturated sodium hydrogen carbonate solution made alkaline, with a yellow Ö! goodbye, that solidified by cooling could be brought. After filtering off the residue and repeated recrystallization Benzene became the nicotinoylaminoethanesulfonylp-phenetidine obtained in the form of colorless needles with a melting point of 69 to 74 ° C. The yield was 7.7 g.

Example 16

24.4 g of aminoethanesulfonyl-p-phenetidine (0.1 mol) and 12.3 g of nicotinic acid (0.1 mol) were stirred in 380 ml of p-cymene in a three-necked flask with a moisture trap at 180 to 190 ^° C. for 4 hours heated, the water of condensation being removed azeotropically. After completion of the reaction

ίο and cooling was the p-cymene under reduced Distilled off pressure and the residue dissolved in as little water as possible. The solution obtained was made alkaline by adding a saturated sodium hydrogen carbonate solution, whereby a

»5 yellow oil parting. By cooling the oil solidified and after repeated recrystallization from benzene gave 8.1 g colorless « Nicotinoylaminoethanesulfonyl-p-phene needles tidins with a melting point of 69 to 74 ° C.

Claims (2)

1 2 4-Aminoaptipyrin, which is a useful analgesic acid with low toxicity, with tawrin, an aminosulfonic acid with surface activity. Hey 1. 4- (Aminoäthansulfonylaroipo) -antipyrine and human application show the advantageous intrinsic Aminoäthansulfonyl-p-phenetidines of the general 5 shafts of the compounds according to the invention formula are that acetylation and other detoxification mechanisms in the living organism the therapeutic ^z - NHSO, - CHg - CH, - NHR, do not reduce the effectiveness of the compounds. The compounds are readily soluble in water in the Z the 4-antipyryl- or the p-ethoxyphenyl- io and at the same time moisture-resistant. The watery one group and R is hydrogen, an acetyl group or solution is so extremely stable that if you is a nicotinoyl group. leave a 10% solution to stand for 18 months 2. Process for the preparation of the compounds 99.8% of the activity remain unchanged ^
according to claim 1, characterized in that the compounds in which Z is p-ethoxyphenyl in a manner known per se in a halide 15 (hereinafter Ib) can be used as analguticum-antipyresic general formula ticum. Due to their construction from phen acetin, which can be used independently Z - NHSOj - CH ₂ - CH ₁ X, Analgeticum-antipyreticum, combined with taurine, The compounds * b develop an excellent one in which X denotes halogen, the halogen against the ao activity. Salts of I b, e.g. B. the hydrochloride are Amino group, the acetylamino group or the well water-soluble and thus allow a wide Nicotinoylamino group exchanges and the so scope, in addition, are also behaved Reaction product, optionally deacy bonds Ib, extremely moisture-proof and tempered or acylated. temperature resistant. Your aqueous solutions are too »5 stable during long periods of storage. Your toxicity is low.
For the production of Ia with R = H, namely