SU512706A3 - Method for producing pleuromutilins - Google Patents

Description

And the residue of the acid is a reactive ester. The resulting pleuromutilins of the formula are converted into acid salts or quaternary salts if necessary. The interaction of compounds of formula II with compounds of formula III is carried out in an organic solvent medium (low alcohols, ketones) in the presence of a base, in the range of Peratur from room temperature to the boiling point of the reaction mixture. The starting / 1st compounds of the form / ml are taken into account by the interaction of alkyl- or aryl sulphonates 1Y O-CO-CHj-O-SOj-R, SC, OH where 1 have the abovementioned "Ry-: alkyl or aryl radical" phenol or thiophenolates where V and Z are as defined above. Me - io alkali metal. In turn, compounds of the formula LV, where 4 is ethylradiksg, are obtained by sulphorylation of a compound of the scientific research institute of the formula V. 0-CO-CHt-OH alkyl- or aryl sulfonates in A-SDj-Ry, gd (in Ai I, have the aforementioned by reducing the sulfonate in y, where R is the vinyl vinyl dial. Example II; 14-Dvzokk-14-C (2-dimethylacno-etoxy) -phenylmercap ToJ-acetoximuthylin, G; 100 mg solution of 9 9 10 ml of ethyl methyl ketone, added 30 mg of dimethylaminoethyl chloride hydrochloride, 150 mg of dry potassium carbonate, 30 mg of potassium iodide and a mixture of ki 11 h. Then the solvent is distilled off, the residue is dissolved in ethyl acetate, washed three times with water, dried with sodium sulfate and concentrated. The product is isolated by preparative thin-layer chromatography on silica gel in a 1: 2 chloroform-methanol system. Example 2. 14-Deoxy-14-4- (3-dimethylaminopropoxy) -phenylmercapto-acetoximutilin. To 100 mg. 14-deoxy-14- (4-hydroxyphenylmercapto) -acetoxyl (55 ml of sodium methoxide in 2 ml of methyl ethyl ketone are successively added to ml. Netanol and 35 mg of 3-dimethyl51-aminopropyl chloride hydrochloride. The mixture was stirred for 3 hours under nitrogen at room temperature and then boiled for 14 hours. After evaporation, the residue was dissolved in ethyl acetate, washed three times with water, dried over sodium sulfate, and concentrated. The product is purified by TLC chromatography on silica gel in a chloroform-methanol system. Example 3. 14-deoxy-14-.4 g (2-diethylaminoeth-6-x) -phenylmercapto acetymimutiline. 960 mg of 14-deoxy-14- (4-oxphenylmercapto) -acetoximuthiline are dissolved in 20 ml of absolute methanol, 120 mg of sodium methoxide are added and the mixture is evaporated to dryness in vacuo. The residue was dissolved in a mixture of 4 ml of 8ODY and 20 ml of xylene, 360 mg of diztilaminoethyl chloride hydrochloride, 420 mg of potassium carbonate were added and the reaction mixture was heated & hours at a bath temperature. The xylol fuy is pumped 5 times with water. The combined aqueous extracts of Aki are reacted with rae one-time with ethyl acetate, and the combined Organic are evaporated in vacuo. The rest of the solution is 10 ml of 10 ml of methylene chloride and transferred to HYDROCHLORIDE at pH 1 ml of 5.8 n essential acid of basic acid. The hydrochloride is dissolved with 3 to 6 ml of methanol (after removing the p "| boilers), diluted with 30 ml of distilled water and extracted once using only 80 ML of ether. The aqueous hydrochloride solution thus purified is evaporated in vacuo at a bath temperature of approximately. In thin-layer chromatography on silica gel Q, the substance in the chloroform-methanol system 1: 2 is homogeneous. The foamy product is suYat in vacuum over potassium hydroxide. PRI me R 4. 14-Deoxy (2-diethylaminoethoxn) -phenylmercapto acetoxydihydromutilin, 14-Deoxy-14-tooyloxyacetoxy1-hydromutilin. . A. K 8.66 g of dihydroplevromutilin in 30 ml of dry pyridine with and

6.10 g of p-toluene phosphoric acid were added in a strong first mixture; stirred for 2 hours at -15 ° C and another 1 hour at 0 ° C. The reaction solution was poured into ice water, the product was dissolved in methylene chloride, and the organic phase was washed with ice water and with a saturated sodium bicarbonate solution. After drying over sodium sulfate and evaporation, a product with a softening point of 78-8 O c is obtained.

B. 0.53 G 14-Deoxy-14-tooyloxy acetoximutiline is hydrogenated in 10 ml of ethyl acetate at atmospheric pressure and at room temperature with 0.10 g of 10% palladium and coal. The calculated amount of hydrogen is absorbed in approximately 1 hour. By filtration, the solution is freed from the catalyst and evaporated in vacuo; thraam 78-80 0.,

l4-J4e3OKCM-l4- (4 hydroxyphenylmercapto) -acetoxydihydromutilin. 6.00 g, 14-deoxy-14-tosyloxy-acetoxydihydromutilin was dissolved in 15 ml of methyl ethyl ketone, 1.60 g of thiohydroquinone was added under a nitrogen atmosphere. A solution of 0.35 g of sodium in 25 ml of abs was added dropwise with stirring and stirring. ethanol, and then stirred for another 5 h. The reaction mixture is acidified with 10% acetic acid (pH 4/5) and evaporated in vacuo. The residue is dissolved in ethyl acetate | 3 and diluted with water and extracted with 4 aze-1-tylacetate. The combined organic phases are dried once with water, dried over sodium sulfate and evaporated in vacuo. The substance crystallizes out and the form of hexane; m.p. 191-194 S.

11-4-Deoxyidi714- {2-diethylamino-, ethoxy) -phenylmercapto-acetoxane dihydrmutilin. 147Dezoksi-14- (4-gidroksifenilmerkapto) -atsetoksidigidromutilin reacted with hydrochloride diegilaminoz1tilhlorida similar to the previous tsriieray to form 14-dezrksi-14-14- (2-diethylaminoethoxy-) g -fenilmerkapto acetoxy-to digidromutilina.

PRI me R 5.; 1; 4-deoxy-14 - (dimethylaminoethyl mercapto) -phenyl mercapt acetoxymutyl. 0.57 g of dithiorezorecine add nitrogen atmosphere to a solution of 46 mg of sodium in 5 mp abs. ethanol. With vigorous stirring, solution of 1.59 i 14-deoxy-14-tosyloxy-acetoximutylin in 10 ml of methyl methyl ketone is added dropwise. After stirring for two hours at room temperature, the reaction mixture is evaporated to dryness in vacuo / the residue is dissolved in 5 ethyl acetate, taken up in water, dried over magnesium sulphate and evaporated. The raw product is added to a solution of 74 mg of sodium in 15 ml of abs. After the addition of 0.94 g of dimide hydrochloride dimethylaminoethyl chloride, it is heated for 5 hours. The dimethylaminoethylchloride solvent is heated for 5 hours. The solvent is removed in vacuo, and the residue is chromatographed on a silica gel column with a mixture of chloroform and methanol (1.

Example 6. Analogously to Example 3 and when starting with a suitable starting product. the following compounds are obtained, i

14 Dexxy-14 - (- 3- (K-Piperidino) -propoxy-phenyl-mercapto-acetoximuthil. ..1,

5.33 g of 14-deoxy-14-tsiloxyacetoxbimutilium are reacted with t If57 g 2-mer1 | aptophenol and 0.25 g of sodium in 10 ml of abs. this yga as described in example 4, and processed in a similar way. 14-Deoxing 14- (2-hydroxyfennylmercapto) -acetoximuthylin crystallizes from chloroform; m.p. 150-1 2. It forms 14-deoxy-1-g-C- (2-dimethylamino-ethoxy) -phenyl merc A-tbl-acetoxnmutilin when combined with diethylaminoethyl chloride hydrochloride.

, l4-Deoxy-14- - (diethyl No.ShHOem Phenylmercapto-acetoximutyl.

Claims (1)

1. The method of obtaining | 11 levomutyls of the formula I .z - ((S, v-x OCOCHfT. Oh sn. where k denotes an ethyl or wynyl radical; ; P is an integer from 2 to 5; yinij or the same means an atom, OR ra: 9 or 10 means an oxygen atom or set)  an alkyl radical or T b together with nitrogen. They form a hydroxy group, which may contain sulfur, an acid or a group NR as another heteroatom, where F is lower; Dlxl-or the most hydroxyalkyl radical, or their salts with acids, or quaternary salts, which distinguish the IS by the fact that the compound of the formula And where |, .Y and I have the above values, is subjected to interaction with the compound of the formula W A - (snOp- (mt where, 1lj and Rj and rt are as indicated, A is the ACID residue of the reaction of the optional ester, followed by isolation of the desired product in the free state, in the form of its salt with acids or quaternary, salts of known primitives. means an ethyl or vinyl radical; It J, and R g is an alkyl radical, or PjHRjBMecTe with a nitrogen atom will please heterocyclic7 which may contain sulfur, oxygen or NH group as another heteroatom, where lower alkyl, Y represents sulfur atom, Z represents oxygen atom, Z-CCHj residue n-NRjj-Tj is in position 4 of the phenyl ring, n is an integer from 2 up to 5; 25.05.72; -Y and Z - the same "means an atom of a ber, or a different type. means an oxygen or sulfur atom; a lower oxysyl radical.