CS219306B2 - Method of making the new pleuromutilines - Google Patents

Abstract

1410506 A substituted 14-dexosymutilin SANDOZ Ltd 2 Oct 1972 [5 Oct 1971 25 May 1971] 16338/75 Divided out of 1410505 Heading C2C The invention comprises 14-desoxy-14-[(2- diethylaminoethyl) mercaptoacetoxy] mutilin which may be prepared by reaction of 2-diethylamino ethanethiol hydrochloride with 14- desoxy-14-tosyloxyacetoxymutilin in ethylmethylketone in the presence of sodium ethoxide. The hydrochloride and diethylmethylammonium salts may be prepared by reacting the full compound with methanolic HCl or methyliodide respectively. Pharmaceutical compositions having antimicrobial activity and prophylactic activity comprise 14 - desoxy - 14 - [(2 - diethylaminoethyl)mercaptoacetoxy]mutilin with a pharmaceutically acceptable diluent or carrier.

Description

The invention relates to a process for the preparation of the novel pleuromutilins of the general formula I,

wherein Y represents a sulfur atom bound to a mutilin residue, and

R2 and R3 each represent an alkyl group having from 1 to 10 carbon atoms, or R2 and R3 together with the nitrogen atom form a 5- to 7-membered heterocyclic ring which may contain, as another heteroatom, sulfur, oxygen or -N = R4, where

R 4 is C 1 -C 5 alkyl or C 1 -C 4 hydroxyalkyl, as well as their acid addition salts and quaternary salts.

According to the invention, the novel pleuromutilins of the formula I and their acid addition salts as well as the quaternary salts are prepared by the preparation of a compound of the formula II wherein:

R 1 is an ethyl or vinyl group, n is an integer ·. 2 to 5,

X stands for - sulfur atom or - group —У

with-

219308 (lt) wherein R 1 is as defined above, and

R 5 is C 1 -C 5 alkyl or phenyl, optionally substituted with C 1 -C 5 alkyl, reacted with a compound of formula III,

R2 Z

HX 1 (GH ₂ ) _n -N, R 3 (III) wherein η, X, R 2 and R 5 are as defined above, and the resulting pleuromutilins of formula I are optionally converted to their acid addition salts or quaternary salts.

For example, the process of the invention can be carried out by dissolving an acid addition salt of a compound of formula III, for example a hydrohalide, or the free base, in a solution of sodium in an anhydrous lower alcohol such as ethanol. To this solution is then added a solution of the compound of formula II in an inert solvent, for example an aliphatic ketone such as methyl ethyl ketone or dimeithyl ketone. The reaction is preferably carried out at room temperature up to the boiling point of the reaction mixture, in particular at 25 to 55 ° C, and lasts for 2 to 12 hours. The compounds of formula I may be converted into their acid addition salts or vice versa.

The corresponding quaternary salts can be obtained from the compounds of the formula I by known methods.

The alkyl groups R 2 and R 3 preferably contain 1 to 8 carbon atoms. The alkyl group R 4 preferably has 1 to 3 carbon atoms, the hydroxyalkyl group (the same symbol preferably has 2 carbon atoms).

Compounds of formula I and their pharmacologically acceptable addition salts with. acids and quaternary salts have interesting biological and especially antimicrobial properties at low toxicity and can therefore be used as pharmaceuticals. These substances exert a inhibiting effect on bacterial growth, as evidenced by in vitro examination or by n-and agar plate assay or in vivo experiments in mice using different strains of bacteria. This braking effect was detected starting at a concentration of about 0.002 to 5 (zg / ml, in particular a braking effect against mycoplasmas, which appeared starting at a concentration of 0.08 to 2.5 µg / ml, was found. effective antibiotics.

The compounds of formula I and optionally their water-soluble, physiologically acceptable salts can be administered as medicaments in appropriate dosage forms together with inorganic or organic pharmacology. non-toxic excipients. For example, they are used as ingredients in capsules, injectable or drip formulations containing a plurality of active ingredients sufficient to achieve an optimum blood level of about 10 to 500 mg per capsule.

Mycoplasma inhibitory activity was tested in vitro on the following organisms:

1. M. hominis · II,

2. M. bbvigenitaliuím,

3. M. gallisepticum

4. M. sp. ISRí, ‘

5. M. laidlawii,

6. M. hominis I

7. M. hyorhinis.

The results obtained using compounds corresponding to formula I are shown in Table I below.

TABLE I

Substance Minimum Inhibitory Concentration in µg / ml organisms 7 1 2 3 4 5 6 14-Mutllyl-3-morpholino-propylamine-N, N-diacetate 14-desoxy-14- [• (3-morpholino- 15.0 3,125 0,078 12.5 250 7.81 15.0 propylamino · acetoxy] mutilin 62.5 5 1,25 31.25 500 12.5 25 14-desoxy-14- [2-diethylamino- ethylthio acetoxy] mutilin 0.312 0.625 0,039 3,125 15.6 0.195 0.78 14 * desoxy-14- [· (2-dimethylamino-) noethylthio) acetoxy] mutilin 14-desoxy-14- [2-diethylamino- 1.56 0.31 0.019 3,125 15,625 <0.97 12.5 ethylamino-acetoxy] mutilin 14-desoxy-14 - [(2-piperidino- 15,625 5 2.5 31.25 500 3,125 ethylthio) acetoxy] mutilin 14-desoxy-14 - [(2-morpholino- 1,25 0.39 0.156 6.25 15.6 1.9 ethylthio) acetoxy] mutilin - - 0.97 7.81 - 0.97 7.81

The following table II summarizes the results in these tables the results of the in vivo tests performed at DE95, expressed in µg / kg weight.

TABLE II

Substance

Strept infection. haem.

per os subcutaneously

Strept infection. Aronson per os subcutaneously

Staph infection. aureus DE95 in mg / kg per os subcutaneously

14-desoxy-14 - [(2-dlethylaminoethylthio Jacetoxy) mutilin iodide 14-desoxy-14 - [(2-trimethylammonioethylthio) acetoxy] butiline

52.2 37.0 113 - 8.1 - 78.5 87.1 101

134 92.9 23.8 - - - 229 112 42.4

The abbreviations of the micro-organisms in the heading of Table II have the following meanings:

Strept. haem. = Streptococcus haemolyticus, Strept. aronson = Streptococcus aronson, Staph. aureus = Staphylococcus aureus.

Acute toxicity

The acute toxicity of the compound of formula I was determined in mice. The results are shown in Table III and are given the DL50 for some compounds.

TABLE III

Substance DL50 in mg / kg per os subcutaneously 14-de ^l desoxy-14- [(2-diethylaminoe'thylthio) - acetoxy] mutilin 477.9 197.5 14-desoxy-14 - [(2-trimethylammonio- Ethylthio Jacetoxy] mutilin 727.6 10.62 14-desoxy-14 - [ ^; (2-diethylaminoethylthio) acetoxy] dihydro-mutilin 620.6 256.0

The pleuromutilin derivatives according to the invention are furthermore excellent additives for animal feed compositions. They can thus be added to the feed for prophylactic reasons at concentrations between 0.05 to 5 ppm.

Further, the compounds of the invention may be added to the drinking water.

Starting materials of formula IIIa,

wherein R 5 is as defined above are known.

Starting materials of formula IIb,

wherein R 5 is as defined above, may be obtained by:

a] a compound of formula IV

reacts with a compound of formula V,

A-SO 2 -R 5, (V) wherein R 5 is as defined above, and A is an acidic residue of a reactive ester, or

β), the compound of formula IIa is reduced.

The reaction according to process a) can be carried out in an inert solvent, for example in an aromatic hydrocarbon such as toluene, benzene and the like, but preferably in a solvent which at the same time acts as an acid scavenger such as pyridine. For example, p-toluenesulfochloride is used as the compound of formula (V). For example, the reaction may be carried out at temperatures between -15 to -10 ° C and lasts between 2 and 4 hours.

The hydrogenation according to (3) is conveniently carried out by treatment with hydrogen in the presence of a hydrogenation catalyst, for example a palladium or platinum catalyst on carbon in an inert solvent, for example ethyl acetate and at room temperature.

Compounds of formula IIIa,

Rz \ N- (CH _{2) n} -SH,

From R 5 (IIIa) wherein n, R 2 and R 3 are as defined above, one can be obtained by reacting a compound of formula VI,

R 2 of A - '(CH ₂ ) _n -NR 5 (VI) wherein n, R 2, R 3 and A have the meanings given above, with thiourea and subsequent alkaline hydrolysis of the resulting complexes.

Compounds of formula IIIb,

R 2 = N - CH 2 CH 2 - SH,

OF

R 5 (IH b) wherein R 2 and R 3 are as defined above, can be obtained by reacting a compound of formula VII,

Rz \

NH,

OF

R 3 (VII) wherein R 2 and R 5 are as defined above, with ethylene sulfide.

Compounds of formula IIIc, < ^{CH 2} > S. ^s - \ J%

(IIIe) wherein R 2, R 3, n and Y are as defined above, may be obtained by reacting a compound of Formula VI with a compound of Formula VIII,

where

Y is as defined above and

Me denotes an alkali metal atom.

If the preparation of the starting materials is not described, they are known or can be prepared by known methods, optionally according to the analogy of the methods described herein or according to the analogy of known methods.

Particularly preferred compounds of formula I are those wherein R1 is a vinyl group, n is 2, X is a sulfur atom, R2 and R3 are each a C1-C10 alkyl group, or R2 and R3 together with the nitrogen atom form a five- to 7-membered heterocycle containing, in addition to the nitrogen atom, a ring containing = N — R4, wherein R4 is C1 -C5 alkyl or C1 -C4 alkyl, in particular 14-desoxy-14- acid fumarate; [(2-diethylaminoethyl) mercaptoacetoxyjmutilin.

In the following examples, which illustrate the invention in more detail, but do not limit it in its entirety, all temperature data are given in degrees Celsius.

Example 11? 4-Desoxy-14 - [(2-dimethylaminoethyl) mercaptoacetoxy] mutilin

To a solution of 1.40 g of sodium in 50 ml of anhydrous ethanol, 2.70 g of phosphorus pentoxide-dimethylaminoethantiol hydrochloride was added portionwise under nitrogen.

Then 10.60 g of 14-desoxy-14-tosyloxyacetoxymutilin, dissolved in 30 ml of ethyl methyl ketone, are added dropwise with stirring. The reaction mixture was stirred at room temperature for 4 hours and at 50-55 ° C for 30 minutes. It is then concentrated to near dryness, the residue is dissolved in ethyl acetate and the product is taken up in aqueous phase by shaking with 3 parts of 2N hydrochloric acid. From this, the base can be re-extracted with ethyl acetate by adding sodium hydroxide. The acetate solution was washed twice with water, dried with magnesium sulfate and evaporated in vacuo.

The hydrochloride is obtained with methanolic hydrochloric acid in vacuo or taken up in methylene chloride, adding an equivalent amount of ethereal hydrochloric acid and evaporating in vacuo. After drying with potassium hydroxide the substance softens around 95 °.

For the preparation of trimethylammonium iodide, 870 mg of 14-desoxy-14 - [(2-dimethylaminoiminomethylmercaptoacetoxymutilin) was refluxed for 1 hour in 15 ml of methanol with 3 ml of methyl iodide. The precipitate formed by the further addition of ether is filtered off with suction, washed well with ether and dried with phosphorus pentoxide (softening point 150-160 °).

To prepare trimethylammonium chloride, the inverter column with 120 g of anion exchange resin, Cl &apos; -form, 0.15-0.3 mm grain size, was washed with distilled water until no chlorine was detectable in the eluate. It is sucked dry, suspended three times in methanol-methylene chloride (4: 1) and washed again. 35 g of trimethylammonium iodide are dissolved in 300 ml of the above solvent mixture and slowly dripped through the converter column. Trimethylammonium chloride (iodine content <0.2%) is obtained by steaming. Unlike trimethylammonium iodide, it is readily soluble in water. Mp 146-150 °.

Example 2

14-Desoxy-14 - [(2-piperidinoethyl) mercapto-acetoxy] mutilin

0.63 g of sodium is dissolved in 50 ml of anhydrous ethanol, 2.17 g of piperidinoethanethiol hydrochloride are added in portions to the ethyl acetate solution, and then 6.4 g of 14-desoxy-14-tosyloxyacetoxymutilin dissolved in 30 ml of ethyl methyl ketone is added dropwise. . Stir 4 hours at room temperature. The work-up was carried out as described in Example 1. The crude product was purified by chromatography on silica gel with methanol-chloroform (2: 1) and methanolic hydrochloric acid to be converted into the hydrochloride which, after trituration with ether and after drying softening point 88-92 °.

Example 3

14-Desoxy-14 - [(2-diethylaminoethyl) mercaptoacetoxy] dihydromutilin

a) 14-Desoxy-14-tosyloxyacetoxydihydromutilin (method a)

To a solution of 8.86 g of dihydropleuromutilin in 30 ml of dry pyridine at -15 DEG was added, at vigorous stirring, 6.10 g of p-toluenesulfochloride. Stir for 2 hours at -15 ° and then for an hour at 0 °. It is then poured onto ice water and the product is taken up in methylene chloride. The organic phase is washed successively with ice-water and then with saturated sodium bicarbonate solution under cooling. It is dried over sodium sulphate and evaporated to give a uniform product with a softening point of 78-80 ° according to thin layer chromatography.

(b) 14-Desoxy-14-tosyloxy-acetoxyhydromutilin (Procedure (3)

0.53 g of 14-desoxy-14-tosyloxyacetoxymutilin is hydrogenated in 10 ml of ethyl acetate in the presence of 0.10 g of 10% palladium.

on carbon as catalyst at -atmospheric pressure and at room temperature. The calculated amount of hydrogen is absorbed after about 1 hour. The solution was freed from the catalysts by filtration and evaporated in vacuo. Softening point 70 - 80 °.

c) 14-Desoxy-14 - [- (2-diethylaminoethyl) mercaptoacetoxy] dihydromutilin

5.35 g of 14-desoxy-14-tosyloxyacetoxydihydthe romutilin are dissolved in 15 ml of warm ethyl methyl ketone and 1.70 g of diethylaminoethanethiol hydrochloride in a previously prepared solution of sodium ethylate (from 650 mg of sodium in 25 ml) is added dropwise under nitrogen. absolute ethanol). After stirring for four hours at room temperature and heating for 30 minutes at 50-55 °, it is worked up as described in Example 1. The hydrochloride has a softening point at 45-48 °.

Analogously to Example 1, diethylmethylammonium iodide can be obtained. Softens at 115-118 °.

Example 4

14-D esoxy-14 - ['(2-diethylaminoethyl) mercaptoacetoxy] mutilin

1.30 g of sodium are dissolved in 50 ml of anhydrous ethanol. 3.40 g of phosphorus pentoxide-dried, finely-powdered diethylaminoethanthiol hydrochloride were added in portions under nitrogen to the obtained solution. Then a solution of 10.60 g of 14-desoxy-14-tosyloxyacetoxymutilin in 30 ml of ethyl methyl ketone is added dropwise with stirring. Stirring is continued for 4 hours at room temperature, then held at 50-55 ° C for 30 minutes and then concentrated to near dryness. The residue was taken up in ethyl acetate and the base was extracted with three portions of 2N hydrochloric acid. The bases are again taken from the aqueous phase made alkaline with sodium hydroxide (pH 11) into ethyl acetate. The ethyl acetate layer was then washed twice with water, dried over sodium sulfate and evaporated in vacuo.

By analogy to Example 1, hydrochloride can be obtained with a softening point at about 100 ° and diethylmethylammonium iodide with a softening point at 110-115 °.

Example 5

14-Desoxy-14 - [(2-morpholinoethyl) mercaptoacetoxy] mutilin

Sodium ethylate solution was prepared from 0.21 g of sodium and 20 ml of anhydrous ethanol, and then 0.80 g of morpholinoethanethiol hydrochloride was added portionwise under nitrogen. A solution of 2.12 g of 14-desoxy-14-tosyloxyacetoxymutilin in 10 ml of ethyl methyl ketone was added dropwise to this mixture with stirring, and it was stirred at room temperature for 12 hours. It was then concentrated to a large concentration in vacuo, ethyl acetate and 2N hydrochloric acid were added and, after separation of the layers, extracted twice more with 2N hydrochloric acid. The acid solution was then basified with sodium hydroxide and the precipitated free base was taken up in ethyl acetate and the solution dried over magnesium sulfate was evaporated in vacuo. Purification was performed by chromatography on silica gel with a 1: 1 mixture of chloroform and methanol. Softening point of hydrochloride: 70 °.

Example 6

14-Desoxy-14 - [(2-diethylaminoethyl) mercaptoacetoxy] mutilin

First, 10.0 g of sodium are dissolved in 350 ml of anhydrous ethanol and, after cooling the solution, 24.0 g of dry diethylaminoethanethiol hydrochloride are added in portions under nitrogen. A solution of 79.5 g of 14-desoxy-14-tosyloxyacetoxymutilin in 250 ml of ethyl methyl ketone is then added dropwise with stirring. After stirring at room temperature for four hours, it is concentrated to near dryness in vacuo, taken up in ethyl acetate and washed thoroughly with water. The solution was dried with magnesium sulfate and evaporated in vacuo. The residue of the crude base was dissolved in 80 ml of methylene chloride and 40 ml of a 5.8 N solution of hydrochloric acid in ether was added. After evaporation of the solvent, it is dissolved in 120 ml of methanol. It is poured into 700 ml of distilled water and extracted 5 times with a total of 700 ml of ether. Thin-layer chromatographically uniform aqueous hydrochloride solution is evaporated after vacuum filtration at a bath temperature of about 30 ° to give a foamy product which is dried under vacuum at 60 ° with potassium hydroxide.

g of crude 14-desoxy-14 - [(2-diethylaminoethyl) mercaptoacetoxy] mutilin is dissolved in 50 ml of ether. This solution is mixed all at once with a solution of 8.5 g of fumaric acid in 100 ml of methanol, heated to approximately 30-40 °, and then carefully concentrated in vacuo. Finally, it is diluted in portions with a 2: 1 mixture of ether and petroleum ether, rapidly crystallizing the salt. Crystallization is completed in 8-12 hours under refrigeration. After aspiration and washing with ether and petroleum ether, the product is dried on silica gel at 20 DEG C. in vacuo. Obtained as methanol. solvate. The product can be freed from solvent after spraying for drying under vacuum at 80 ° and then has a melting point of 110-115 °.

Example 7

14-Desoxy-14 - [(2-diisopropylaminoethyl) mercaptoacetoxy] mutilin

1.54 g of diisopropylaminoethanethiol are added under nitrogen to a solution of 0.35 g of sodium in 25 ml of anhydrous ethanol. A solution of 5.33 g of 14-chloro-144'0'8-chloro-5-acetonitrile in 15 ml of ethyl methyl ketone was added dropwise, stirred for a further 5 hours at room temperature and then evaporated to dryness in vacuo. The residue taken up in ethyl acetate is washed five times with water, dried over magnesium sulphate and evaporated again to dryness. It is then taken up in 30 ml of chloroform, 6 ml of a 5.8 N solution of hydrochloric acid in ether are added under ice-cooling, then the solvent is removed in vacuo and the foamy residue is carefully digested three times with anhydrous ether. The ether is removed. After purification, the hydrochloride is chromatographically uniform (silica gel G, chloroform / methanol 1: 2).

Example 8

14-Desoxy-14 - [(2-di-n-butylaminoethyl) mercaptoacetoxy] mutilin

1.80 g of di-n-butylaminoethanethiol are treated with 0.35 g of sodium in 25 ml of anhydrous ethanol and 5.33 g of 14-desoxy-14-tosyloxyacetoxymutilin in 15 ml of ethyl methyl ketone as described in Example 6, and converted into the hydrochloride . This is taken up in 15 ml of methanol, poured into 100 ml of water and then extracted five times with a total of 100 ml of ether. The aqueous solution was evaporated in vacuo at a bath temperature of about 30 °. The product is uniform in a thin layer chromatogram (silica gel G, ethyl benzoethane 2: 1 and chloroformornethainol 1: 2) and, after drying in vacuo, has a softening point of 85-90 °.

219396

Example 9

14-Desoxy-14 - [(2-hexahydro-1H-azepin-1-yl) ethylmercaptoacetoxy] mutilin

a) 2- (Hexahydro-1H-azepinyl) ethanethiol

Hex-ahydr-o-1H-azepine was heated to 100 ° with a solution of ethylene sulfide in benzene at a molar ratio of 6: 1 in an autoclave for 21 hours. After cooling the reaction mixture, it was separated from the polymeric material, washed with benzene, the solvent was evaporated and the product was distilled through a Vigreux column. Boiling point of the title compound 105 - 107 ° C / / 27 Pa.

b) 14-Desoxy-14- [2- (hexahydro-1H-azepin-1-yl) ethylmerk-apto-acetoxy] mutilin

1.60 g of (2- (hexahydro-1PI-azepinyl) -ethanethiol) were reacted with 0.35 g of sodium in 25 ml of anhydrous ethanol and 5.33 g of 14-desoxy-14-tosyl-3-oxyacetoxxmuttiin in 15 ml. Ethyl methyl ketone as described in Example 8 and converted into the hydrochloride The purification is carried out by taking up in 15 ml of methanol, diluting with 100 ml of water and shaking five times with 100 ml of ether each time. softens at 110 - 120 °.

Example 10

14-Desoxy-14 - {[2- (4-m-ethyl) plp-erazino] ethyl-mercapto-oacetoxy] mutilin

4.24 g of 14-desoxyoxy-14-tosyloxyacetoxymutilin, dissolved in 12 ml of ethyl methyl ketone, is added dropwise under nitrogen to a solution of 1.22 g of (4-methylpiperazino) ethanethiol - and 0.28 g of sodium in 20 ml of anhydrous ethanol and 4 ml. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the residue was taken up in ethyl acetate and shaken three times with water. The acetate solution is extracted 3 times with 20 ml of 2N hydrochloric acid each time, the aqueous phase is made alkaline by cooling with 6N sodium hydroxide solution and the liberated base is shaken with ethyl acetate. Evaporation of the solution dried over magnesium sulfate afforded the free base which was converted to the dihydrochloride as described in Example 9. The crystalline dihydrochloride had a melting point of 185-188 °. Its crystalline bis-hydrogen fumarate also has a melting point of 170-176 °.

Example 11

14-D-esoxy-14 - {[2- (4-hydroxyethyl) piperazino-ethyl-mercaptoa-ethoxy] mutilin

(a) 4-Hyddox: yethylpiperazinoethanthiol

According to an analogy of Example 9a-4-hydroxyethylpiperazine with ethylene sulfide was reacted in a 3: 1 molar ratio for 17 hours.

The boiling point of the title compound is 97.5 ° / 13 Pa.

b) 14-D-esoxy-14- [21- (4-hydroxyethyl) piperazine-o-ethylmercaptoacetoxyjmutilin

1.81 g of (.alpha.-hydroxy.-1-oxyethylpiperazino) ethanethiol, is added, under nitrogen, to a solution of 0.35 g of sodium in 25 ml of anhydrous ethanol, and then a solution of 5.35 g of 4-desoxy- is added dropwise. Of 1-tosyloxyacetoxymutilin in 15 ml of ethyl methyl ketone. After stirring at room temperature for 4 hours, the solvent is removed in vacuo, the residue is taken up in 50 ml of methylene chloride, washed 5 times with water and dried over magnesium sulfate. To the solution was added 5 mL of 5.8 N ethereal hydrochloric acid. Upon further addition of ether, crystalline hydrochloride precipitates, which softens at 192-197 °.

5.50 g of the crude base of the title compound are taken up in 80 ml of dichloromethane and a solution of 2.40 g of maleic acid in 15 ml of absolute methanol is added. By slowly adding anhydrous ether, crystalline bis (hydrogen maleate) precipitates, and is filtered off with suction and washed with ether. Melting point of bisphhydrogen maleate] 137-139 °.

Example 12

H-DesoKy-H- (2'-dimethylammoethyl] mercapto-acetoxy] dihydromutilin

The procedure is as described in Example 6, and 60 g of 14-desoxy-14-tosyloxyacetoxydihydromutilin, 7 g of sodium and 13.5 g of dimethylamino ethanethiol hydrochloride are reacted.

Trimethylammonium iodide was prepared from the base analogously to Example 1. Softening point 123-128 °.

Analogously to Example 1, trimethylammonium chloride is obtained from trimethylammonium iodide.

Example 13

-4-Desoxy-4- [3- (diethylaminoethylmethoxy) methylmeeraptoacetxy] mutilin

(a) 3- (Diaminophen hythecapto) thiophenol

1.42 g of dithioresorcin are mixed with a solution of 1.72 g of diethylaminoethyl chloride hydrochloride and 0.54 g of sodium methyl alcohol in 10 ml of methanol and 2.09 g of potassium carbonate in 10 ml of water. After addition of 10 ml of xylene, the mixture was refluxed for 8 hours. It is then diluted with water and extracted three times with ethyl acetate. The aqueous phase is then treated with 10% acetic acid until the oily precipitate is complete, shaken 3 times with ethyl acetate, and the solution in ethyl acetate is evaporated after drying over magnesium sulfate. After distillation at a bath temperature of 135 ° and a pressure of 67 Pa, a colorless oil is obtained which oxidizes rapidly in air.

b) 14-Desoxy-14- [3- (diethylaminoethylmercapto) phenylmercaptoacetoxy] mutilin

0.40 g of 3- (diethylaminoethylmercapto) thiophenol is dissolved under nitrogen in a solution of 37 mg of sodium in 10 ml of anhydrous ethanol, then 1.02 g of 14-desoxy-14-tosyloxyacetoxymutilin dissolved in 10 ml of ethyl methyl ketone is added dropwise. The mixture was stirred at room temperature for 3 hours and refluxed for 1 hour. Then the solvent is evaporated off under vacuum, the residue is taken up in ethyl acetate and shaken three times with water. The acetate solution, dried over magnesium sulfate, was evaporated, taken up in a small amount of chloroform, a small excess of ethereal hydrochloric acid was added and evaporated again. After being taken up in a small amount of ethanol, it is diluted with water and extracted four times with ether. The filtered aqueous solution was then evaporated in vacuo at 30 ° to give glassy hydrochloride.

Example 14

14-Desoxy-14- [· (2-pyrrolidinoethyl) mercaptoacetoxy] mutilin

(a) Pyrrolidinoethanthiol

A solution of 42.67 g of pyrrolidine, distilled over potassium hydroxide in 75 ml of anhydrous toluene, was heated to reflux while the feed was cooled with dry ice with acetone. 30.04 g of ethyl 2-mercaptoethyl carbonate are added dropwise with stirring over one hour. After boiling for a total of 8 hours, the solvent is then removed in vacuo and the residue is distilled through a Vigreux column. Boiling point 60-637933 Pa, nD ²⁰ = 1.5008.

(b) 14-Desoxy-14 - [(2-pyrrolidinoethyl) mercaptoacetoxy] mutilin

5.33 g of 14-desoxy-04-tocyloxyacetoxymutilin dissolved in 15 ml of ethyl methyl ketone are added dropwise under nitrogen to a solution of 1.26 g of pyrrolidinoethanethiol and 0.35 g of sodium in 25 ml of anhydrous ethanol. The reaction mixture was stirred at room temperature for 4 hours. The solvent was then removed in vacuo and worked up as described in Example 6. T. Softening of hydrochloride 97-100 °.

Example 15

14-De-soxy-14 - [(3-dimethylaminopropyl) mercaptoacetoxy] mutilin

2.14 g of β-dysoxy-14-tosyloxyacetoxymutilin are dissolved in 10 ml of ethyl methyl ketone and added dropwise under nitrogen to a previously prepared solution of 0.48 g of 3-dimethylaminopropyl mercaptan and 0.14 g of sodium in 10 ml of anhydrous ethanol. The mixture was stirred at room temperature overnight after removal of the solvent. The mixture was worked up as described in Example 6 and purified by shaking the aqueous hydrochloride solution with ether. A white powdered hydrochloride is obtained with a melting point of 120-125 °.

Example 16

By analogy to the foregoing examples and using an appropriate amount of suitable starting materials, the following compounds are obtained:

(a) 14-desoxy-14 - [(3di-n-butylaminopropyl) mercaptoacetoxy] mutilin whose hydrochloride has a softening point of 45-48 °;

b] 14-desoxy-14 - [(2-di-n-butylaminoethyl) mercaptoacetoxy] dihydromutilin, the hydrochloride of which has a softening point at about 90 °;

c) 14-desoxy-14 - {[2- (4-methylpiperazino) ethylmercapoacetyl] dihydromutilin whose crystalline dihydrochloride melts at 220-225 °;

d] H-desoxy-N-2- (1-hydroxyethylpiperazino) ethyl mercaptoocyloxydilhydromutilin whose dihydrochloride has a softening point of 135-140 °;

e] H-desexyl-H- [3- (dimethylaminoethyl) mercapto] phenyl mercapto] acetoxymutilin.

f) According to the analogy of Example 9a, N, N-bis- (2-ethylhexyl] amine-ethylsulphide was reacted in a 3: 1 molar ratio for 17 hours to give 2- [N, N-bis- (2-ethylhexyl) amine-thiethethiol, boiling point 105 · -107 ° C / 27 Pa, from which, by reaction with 14-desoxy-14-osloxyacetoxymutilin, 14-desoxy-14 - {- '- 2-hyl- (2-ethylhexyl) aminoethyl] mercaptoacetoxymutilin is obtained; the hydrochloride has a softening point of about 60 °.

g] By analogy to Example 9a, thiomorpholine is reacted with ethyl ether in a 4: 1 molar ratio for 22 hours. Ethanol is obtained by boiling 46-47 ° C / 667 Pa, from which, by reaction with 11-desoxy-14-4ooyloxyacetoxymutilin, 14-dosoxy-14 - [(2-thromorpholinoethyl) mercaptoacetoxy] mutilin is obtained, the hydrochloride of which is softening point 120-125 °.

Claims (5)

A process for the preparation of novel pleuromutilins of the general formula I having 1 to 5 carbon atoms, which is reacted with a compound of the general formula III, wherein: R 1 is an ethyl or vinyl group, n 'is an integer of 2 to 5, X represents a sulfur atom or a group R2 OF HX- (CH _{2) n} -N \ R 5 (III) wherein η, X, R 2 and R 5 have the meanings given above, and the obtained pleuromutilins of the general formula I are optionally converted into their acid addition salts or quaternary salts. 2. A process according to item 1 for the preparation of novel pleuromutilins of the general formula I, wherein R1 represents an ethyl or vinyl group, n is an integer having a value of 2 to 5, X represents a sulfur atom or a group -Os- wherein Y is a sulfur atom attached to the mutilin residue and R 2 and R 5 are each C 1 -C 10 alkyl; or R 2 and R 5 together with the nitrogen atom form a 5- to 7-membered heterooyl ring which may contain, as an additional heteroatom, oxygen or O-N-R. 4, wherein R4 is C1 -C5 alkyl or C1 -C4 hydroxyalkyl, as well as acid addition salts and quaternary salts thereof, wherein the compound of the formula R1 is as defined above and R 5 represents a C 1 -C 5 alkyl group or a phenyl group optionally substituted by an alkyl radical wherein Y is as defined in point 1, R 2 and R 5 each represent an alkyl group having 1 to 5 carbon atoms, or R 5 and R 5 together with the nitrogen atom form a 5- to 7-membered heterocycle which may contain, as an additional heteroatom, a sulfur or oxygen atom; denotes an alkyl group having from 1 to 5 carbon atoms, as well as their acid addition salts or quaternary salts, characterized in that - the compound of the formula (II) in which R 1 and R 5 are as in point 1 is reacted with the compound of formula (III), in which η, X, R2 and R5 are as defined above, and the pleuromutilins of formula (I) obtained are optionally converted to their acid addition salts or quaternary salts. 3. The method of item 1 for the preparation of the novel pluromutilins of formula I wherein R1 is ethyl or vinyl, n is an integer of 2 to 5, X is either a group wherein Y is as defined in 1 and R2 and R 5 is each an alkyl group having from 1 to 10 carbon atoms, or-R 2 together with R 3 together with the nitrogen atom forms a 5- to 7-membered heterocycle which may contain, as an additional heteroatom, a sulfur, oxygen or = N-R 4 group, R4 denotes an alkyl group having from 1 to 5 carbon atoms or hydro A C 1 -C 4 xylalkyl group, as well as their acid addition salts and quaternary salts, characterized in that the compound of formula (II) wherein R 1 and R 5 are as defined in point 1 are reacted with the compound of formula III wherein n, X, R 2 and R 3 are as defined above, and the pleuromutilins of formula I obtained are optionally converted into acid addition salts or quaternary salts. 4. A process according to claim 1 for the preparation of novel pleuromutilins of the general formula I, wherein R1 is an ethyl or vinyl group, n is an integer of 2 to 5, X is a sulfur atom or Y is as defined in point 1, R a and R 3 are in each case an alkyl group having 1 to 10 carbon atoms, with at least one of the alkyl groups having 6 to 10 carbon atoms, or R 2 and R 3 together with the nitrogen atom form a 5- to 7-membered heterocycle containing = N — R4, wherein R4 represents a C1 -C4 hydroxyalkyl group, as well as their acid addition salts and quaternary salts, characterized in that the compound of the formula II wherein R1 and R5 are as in step 1, reacts with a compound of formula III, where η, X, R2 and R5 are as defined above, and the resulting pleuromutilins of formula I 'are optionally converted into their acid addition salts or quaternary salts. 5. A process according to claim 2 for the preparation of 14-desoxy-14 - [(2-diethylamino) ethyl] mercaptoacetoxyjmutilin acid fumarate, characterized in that 14-desoxy-14-tosyloxyacetoxymutilin is reacted with diethylaminoethanthiol and the 14-desoxy-14 obtained. + (2-Diethylaminoethyl) mercaptoacetoxy] mutilin is reacted with fumaric acid.