SU799670A3 - Method of preparing derivatives of fusidic acid or its salts - Google Patents

Abstract

A new series of fusidic acid derivatives, salts and easily hydrolyzable esters thereof, and processes for the preparation of these compounds are provided herein. The new compounds have the general formula in which the C24-25 bond is a single or a double bond, and in which Q1 and Q2 stand for or oxygen; A stands for oxygen, sulphur or a sulfinyl radical; R1 stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms, or such straight or branched alkyl radical having from 1 to 8 carbon atoms when substituted by halogen atoms of hydroxy, alkyloxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, arylamino, ??anoylamino or aroylamino groups; an alkenyl or alkynyl radical having from 7 to 6 carbon atoms, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, an aryl, aralkyl or heterocyclylalkyl radical, or such alkenyl or alkynyl radical having from 2 to 6 carbon atoms, such cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, such aryl, such aralkyl or such heterocyclylalkyl radical when substituted by halogen, nitro, lower alkyl, hydroxy or alkoxy radicals: or a heterocyclic radical having 5 or 6 ring atoms, containing oxygen, sulphur or nitrogen atoms, and selected from 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-furfuryl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4or 5-pyrimidinyl, 2- or 3-pyrazolyl, imidazolyl, 1-methyl-2-immdazolyl, triazolyl, 5-methyl-1,2,4-triazol-3-y1, tetrazoyl, 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl: and pharmaceutically acceptable salts and easily hydrolyzable esters thereof. These compounds show interesting antimicrobial and pharmotokinetic properties. These compounds can be used in the treatment of bacterial infections in humans and animals.

Description

its salts consist in the fact that a compound of the general formula and where (in has the above value Q means Q or a group. where RT, is a lower alkanoyl radical, U is chlorine, bromine, iodine, R is a lower alkanoyloxymethyl or aroyloxymethyl radical, an alkyl radical with 1-6 carbon atoms, a benzyl radical unsubstituted or substituted by a nitro group or a lower alkyl radical. A lower alkoxymethyl radical, a phenacyl radical unsubstituted or substituted in an aromatic nucleus by a lower alkoxy group, or a cyanomethyl radical is subjected to with the compound of the general formula | 1,, where R and A have the above meaning, and the resulting compound of the general formula T. in which Q, Q, j., R / RC and A have the above meaning, if desired, is subjected to hydrolysis and the resulting acid if desired, it can be converted to c followed by isolation of the desired product. The compound of the general formula is reacted with a compound of the general formula W, where L is oxygen when used as a solvent in the presence of a silver or mercury salt, for example, three fluoroacetate or silver carbonate or ac Mercury etheta, or bases, for example, potassium carbonate, sodium bicarbonate or sodium alkoxide. The reaction of a compound of the general formula T with a compound of the general formula w, g L is sulfur, is carried out in an inert organic solvent, preferably in ethanol or dimethylformamide, the presence of a base, e.g., caustic potash or sodium hydride. The hydrolysis of the resulting fusidic acid esters is carried out in aqueous methanol or ethanol in the presence of a base such as caustic potash or potassium or sodium carbonate. Example (1. 3-O-acetyl-1b-deacetoxy-1-bo-i-bromfosidic acid phenacyl ester. 1. 3-0-acetyl-1b-epideacetylfusidic acid phenacyl ester. 5.38 g (10 mmol) of the sodium salt 3- O-acetyl-1b-epidercetylfusidic acid and 2.2 g (11 mmol) of phenacyl bromide are dissolved in dimethylformamide (40 ml). After 16 hours, the solution is diluted with 150 ml of ether, washed with water (4 with 50 ml), dried and evaporated in vacuo to give 6.2 g of 3-0-acetyl-16-epidacetylfusidic acid phenacyl ester in the form of a colorless foam. 2. Z-O-adethyl-16-deacetoxy-16o-bromo-fusidic acid phenacyl ester. The suspension of 1.1 ml of C.40 mmol) of dimethylformamide and 5.05 ml (40 mmol) of phenyl chloroformate in 80 ml of petroleum ether (G, 50 ° C) is vigorously stirred at room temperature. After an hour, carbophenoxy-N, N- dimethyl formimidate as colorless crystals, which, with further stirring for 16 hours, turns into crystalline phenyl N, N-dimethyl form imidate chloride and then into N, N-dimethylformamide diphenylacetal by adding a solution of 3.76 g (40 mmol) of phenol and 5.56 m ( 40 mmol) of triethylamine in ether (10 ml). After an hour of triethyla1 "1monium chloride reflux Drain and wash with 50 mi petroleum ether, then add 2.0 ml (27 mmol) of acetyl bromide to the filter to obtain phenyl N, N-dimethyl formimidate bromide in the form of colorless crystals, which are collected and washed with 20 ml of petroleum ether until the phenylacetate is removed. The ammonium bromide obtained (6 g, 26 MOMOL) is very hygroscopic and it is immediately added to a solution of 6.2 g (9.8 mmol) of the 3-O-acetyl-16-epidacetylfusidic acid phenacyl ester in 40 ml of dimethylformamide. After 48 hours at room temperature, this solution was diluted with ether (100 ml), washed with 0.1 N sodium hydroxide (100 ml) and water (3 X 50 m), dried and evaporated. in a vacuum. Addition of 50 ml of methanol causes crystallization of the precipitate, the crystals are filtered off, washed with methanol, dried and yielded 5.2 g of 3-0-acetyl-16-deacetoxy-16a phenacyl ester of bromo-fusidic acid, 141-142 ° C. Example 2. Esters of 3-0-acetyl-16-deacetoxy-166-bromfusidic acid. 1. Under conditions approx. 1 (1) with the replacement of phenacyl bromide by other esterifying agents, the esters of Z-O-acetyl-16-epideacetyl-fusidic acid are given in table. 1. 2. Under conditions approx. 1 (2), 3-O-acetyl-16-deacetoxy-16 esters are prepared (3-bromo-fusidic acid, listed in Table 1. Example 3. 3-0-acetyl-1b-deace oxy-3-h-nitrobenzyl ester 1-b-6-bromo-fusidic acid, g (40 mmol) of 3-0-adethyl-16-epidai sodium salt, ethyl fusidic acid and 9.5 (44 mmol) p-nitrobenyl zilbromide was dissolved in dimethyl form amide (200 ml). This solution was left at room temperature for 16 hours, then add 36 g of M, H-dimethylformamidate bromide (see the preparation of this reagent in Example 1 (2)) and the resulting reddish-brown solution is kept at temperature for 48 hours. Methanol (700 ml) and water (280 ml) are added with stirring to precipitate a crystalline product, the crystals are filtered, washed with methanol-water (3: 1), dried, to obtain 26.1 g of complex 3-O-p-nitrobenzyl ester H-O-acetyl-16-de-acetoxy-16o bromfusidic acid. Tf, 151-1750 C. Example 4. 3-0-acetyl-16-deacetoxy-16a, -bromo-fumeic acid esters. In Example 3, using esterifying agents, the esters of 3-0-C1-acetyl-16-de-acetic-16-o (-bromo-fusidic acid) are listed. 2. Example 5. Z-O-acetyl-16-deacetoxy-16c6-bromo-fusidic acid sets benzyl ester. . 1, -Benzyl ester of 3-0 acetyl-Hb-diacetylfusidic acid To 84.7 g (0.17 mmol) of sodium salt of 16-deacetylfuzidic acid in 200 ml of dimethylformamide add 25 ml of benzyl bromide (0.21 mmol after stirring for 5 at room temperature, the resulting solution is cooled before and 200 ml (2.5 mmol) of pyridine and 170 ml (1.8 mmol) of acetic anhydride are added. After 16 hours at room temperature, the mixture is cooled again and 50 ml of water are added at stirring at a temperature below 15 ° C for 1 h. Then 800 ml of methanol and 400 ml of water are added. after stirring for 1 hour while filtering, wash with a mixture of ice and cold methanol (3 ml), dry and obtain 68 g of benzyl ester Z-O-acetyl-16-deacetylfusidic acid as colorless crystals,, 154- 158 ° C. 2. Benzyl ester of 3-0-acetyl-16-deacetoxy-16o-bromo-fusidic acid 68 g (112 mmol) of the above benzyl ester, 46.2 g (448 mmol) of sodium bromide, 22 ml (276 mmol) of pyridine and 400 ml of dimethylformamide are stirred for 30 minutes at room temperature and then cooled until 56.5 ml (448 ml mmol) of phenyl chloroformate for 45 minutes and the resulting mixture is stirred at room temperature for 18 hours, then the reaction product is precipitated by adding 400 ml of methanol and 300 ml of water as colorless crystals, which are filtered, washed with methanol-water (2x 60 ml) 2: 1) and petroleum ether (3 x 30 ml), dried, to obtain 62.9 g of benzyl ester Z-O-guschetil-16-deacetoxy-16o-bromo-fusidic acid, Tr, d, 124-126 ° C. Example 6. Esters of 3-0-acetyl-16-deacetoxy-16o-bromfusidic acid. under the conditions of example 5 (1), using phenacyl bromide or p-nitrobenzyl bromide, 3-0-acetyl-16-deacetylfusidic acid esters are obtained, which under the conditions of example 5 (2) turn into 3-0-acetyl- esters The 16-deacetoxy-16o-boomfusidic acid listed in Table 3. Example 7. Pivaloyloxymethyl ester of Z-O-acetyl-16-de-acetic-16c-bromo-fusidic acid. 1. Pivaloyloxymethyl ester of 3-0-acetyl-16-deacetoxy-16O1-bromo-fusidic acid. 17.4 g (28 mmol) of pivaloyloxymethyl 3-0-acetyl-16-epidacetylfusidic acid ester is dissolved in 200 ml of dry ether and 16 g (60 mmol) of triphenylphosphine and 20 g (60 mmol) of tetrabromethane are added. After stirring for 3 hours at room temperature, the recovery mixture is filtered to remove the triphenylphosphine acid. The filtrate is evaporated in vacuo and the residue is purified by rotography on a column of silica-, spruce (cyclohexane: ethyl acetate-8: 2) to obtain 10.6 g of the complex pivaloxyxyl methyl ester H-O-acetyl-16 deacetoxy-16 ° C-bromo fusidic acid as colorless crystals of HN . 120-122 ° C (ether-petroleum ether). 2. Complex pivaloyloxymethyl firm 3-0-acetyl-16-deacetoxy-16c3. Bromfusidic acid. 5 g of complex pivasioyloxymethyl-. The 3-O-acetyl-16-deacetoxy-16ob-bromo-fusidic acid ester obtained above was epimerized to 1bo11-compound by reacting with 5 g of tetrabutylammonium bromide in 60 ml of acetonitrile for three days at room temperature. The reaction mixture is evaporated in vacuo and ether is added to the residue. The crystals were filtered off, washed with water (2 W. 50 ml), dried, evaporated in vacuo to give 4.87 g of 3-acetyl-16-deacetoxy-16-bromo-fusidic acid complex pivaloyloxymethyl ester as a colorless gum. Example 8. Acetoxymethyl ester of Z-O-acetyl-16-deacetoxy-16o: -bromo-fusidic acid. 1. Complex acetoxymethyl ester-3-0-acetyl-16-deacetoxy-p) -bromofusic acid. According to the method described in Example 7 (1), using acetoxymethyl ester 3-0-acetyl-16-epidacetylfuzilic acid, acetoxymethyl ester 3-0-acetyl-16-deacetoxy-16E-bromofusidic acid is obtained, Tfj 119-120 2 Complex acetoxymethyl ester of 3-0-acetyl-16-deacetoxy-16c-bromo-fusidic acid. According to the method described in Example 7 (2), using acetoxy methyl ester Z-O-ace. Tetl-16-deacetoxy-16 L-bromo-fusidic acid, 3-0-acetyl-16-deacetoxy-16o-bromo-fusidic ester is obtained. acids, Tr, (. 102-105 Example 9. 3-O-acetyl-16-deacetoxy-16o bromo-24, 25-dihydrofusidic acid, phenacyl ester. 1. 16-deacetyl-24, phenacyl ester, 25-dihydrofusidic acid. To a solution of 4.99 g (10 mmol) of the sodium salt of 16-deacetyl-24,25-dihydrofusidic acid B and 25 ml of dimethyl formamide, 1.99 g (10 mmol of phenacyl bromide and the mixture is stirred at room temperature for 4 hours. After dilution of the esters (100 ml), the mixture is washed with water (4 1 25 ml), the organic phase is separated, dried and concentrated to approximately 20 ml, left in the refrigerator for 2 hours, the crystals filtered off, washed with ether, dried, 4.52 g of the desired product is obtained, Tp 92-94 ° C (decomposition). 2. 3-0-acetyl-16-deacetyl-24, 25-dihydrofusidic acid phenacyl ester. To a stirred solution of 2.38 (4 mmol) of phenacyl ester of 16-deacetyl-24,25-dihydrofusidic acid in 8 ml of pyridine was added 4 ml of acetic anhydride and the mixture was left at room temperature for 16 h, diluted the reaction mixture 60 ml of diisopropyl ether, the crystals are collected, washed with diisopropyl ether, dried, to obtain 1.92 g of the target product, 133-1350C. 3. 3-0-acetyl phenacyl ester; 1-16-deacetoxy-16o-bromo-24, 25-dihydrofusidic acid. 1.26 ml (10 mmol) of phenyl chloroformate was added dropwise with a stirred solution of 1.59 g (2.5 mmol) of 3-0-acetyl-16-deacetyl-24,25-dihydrofusidic acid, 1, phenacyl ester, 03 g (10 mmol) of sodium bromide and 0.52 ml (6.5 mmol) of pyridine in dimethylformamide (15 ml). After completion of the addition (15 minutes), the reaction mixture was stirred for 2 hours at OC and then for 16 hours at room temperature. While adding dropwise 15 ml of a mixture of methanolum (1: 1) to the mixture being stirred. precipitation of a crystalline substance takes place, which is filtered off, washed with methanol, dried, to obtain 1.22 g of the desired product, Trp. 127-129 ° C-. Recrystallization of the methylene chloride mixture from the mixture yields an analytically pure substance. Tr ,. 130-1320С. Example 10. Esters of 3-0-acetyl-16-deacetoxy-16a; bromo-24, 25-dihydrofusidic acid. 1. Using benzyl bromide or p-nitrobenzyl bromide under the conditions of Example 9 (1), 16-deacetyl-24,25-dihydrofusidic acid esters are listed in Table 1. 4. 2. Under the conditions of Example 9 (2), derivatives of the 3-0-acetyl ester are obtained using 1b-deacetyl-24, 25-dihydrofusidic acid esters. 3. Under the conditions of Example 9 (3), using 3-0-acetyl-16-deacetyl-24, 25-dihydrofusidic acid esters, 3-0-acetyl-16-deacetoxy-16c1C-bromo-24, 25 esters are obtained. - dihydrofusidic acid are given in table. 4. Example 11. Benzoyloxymethyl ester, Z-O-formyl-16-deacetoxy-16o (; -bromofusidic acid. 1. 1. 16 ml of epidacetylfusidic acid, benzoyl-oxymethyl ester, 16.5 g (75 mmol) of 16-epidacetylfusidic acid, dissolve 150 ml of methanol and converted into sodium salt by titration with 5N sodium hydroxide using phenolphthalein as indicator. After evaporation to dryness in vacuo, the resulting amorphous sodium salt is dissolved in 150 ml of dimethylformamide, 14.8 g (82.5 mmol) of chloromethyl benzoate are added and the mixture is stirred at room temperature for 16 It is then added 200 ml and the mixture is extracted with 400 ml of ether, the organic phase is separated, washed with water (4x100 ml), dried and evaporated in vacuo to give 44.6 g of 16-epideacetylfusidic acid ester as an amorphous product. Benzyloxymethyl ester 3-0-formyl-16-deacetoxy-16cX-bromofusidic acid. Benzoyloxymethyl ester 16-epidacetylfusidic acid, obtained above, is dissolved in 300 ml of dimethylformamide, 67 g (about 290 mmol) of phenyl is added to the mixture -N, N-Dimethylforming datbromide reddish-brown solution was allowed to stand at 6-7 days. 150 ml of methol are added to the mixture and then with vigorous stirring water from a separatory funnel. The crystals are filtered, washed with methanol-water (1: 1), dried, to obtain 27.1 g of benzoyloxymethyl ester 3-0-form mil-16- deacetoxy-16o-bromf species acid, 131-135 ° C, after two recrystallizations from ether / methanol mixture Tn. 140-1420C. Example 12. Esters of 3-0-formyl-16-deacetoxy-16c-bromo-fusidic acid. Using benzyl bromide, chloromethyl pivalate or chloromethyl acetate under conditions of example 11 (1, 16 esters of fusidic acid 16 esters are obtained, from which C-O-phenyl-16-deacetoxy sio-16o-16 esters are prepared under conditions of example 11 (2) of bromfusidic acid listed in Table 5. Example 13. Benzyl ester of H-O-frrmyl-16-deacetoxy-16o-bromo-fusidic acid 1. Benzyl ester of 16-deacetylfusidic acid To a solution of 4.97 t (10 mmol) 1.5 ml (12.5 mmol) of benzene are added to sodium salt of 16-deaiethylfusidic acid in 25 G4P dimethylformamide After adding 100 M water, the mixture is extracted with ether (2 x 50 ml) and the combined organic extracts are washed with water (4 x 20 ml), dried and evaporated in vacuo. The resulting residue is dissolved in 50 ml of ether, 50 ml of petroleum ether are added with stirring, the crystals are filtered, washed with ether-petroleum ether (1: 2), dried, and 4.92 g of the desired product, Tfl, 117-119 ° C. 2. Benzyl ester of 3-0-formyl-16-deazethylfusidic acid 4 ml of acetic anhydride is added dropwise while stirring a solution of 4.52 g (8 mmol) of benzyl ester of 16-deacetylfusidic acid in 8 MP of pyridine, and the mixture incubated at low temperature for 15 minutes Upon dilution of the stirred reaction mixture with 40 ml of diisopropyl ether, a crystalline product precipitates. After being kept in the refrigerator for 2 hours, the crystals are collected, washed with diisopropyl ether, dried, and 4.05 g of the expected product are obtained, T 143-145 ° C. Recrystallization from ether-diisopropyl ether gives an analytically pure sample with mp. 145-147 s. 3. Benzyl ester of 3-0-formyl-16-deacetoxy-16a: -bromo-fusidic acid. the conditions of example 5 (2) using benzyl ester Z-O-formid-16-deacetylfusidic acid; give the benzyl ester 3-0-formid-16-deacetoxy-16a; -bromo fusidic acid as colorless crystals with Tpl. 125-127 ° C. Example 14. Complex pivaloyloxymethyl ester Z-O-for-16-deacetoxy-16o-bromo-fusidic acid. 1. Pivaloyloxymethyl ester of 16-deacetylfusidic acid. To a solution of 5.8 g (10 mmol) of an amorphous silver salt of 16-deacetylfusidic acid in 50 ml of dimethylformamide was added 1.4 E ml (10 mmol) of chloromethyl pivalate and the mixture was stirred at room temperature for 48 hours. The reaction mixture was filtered, the precipitate was washed with ether (2 V 25 ml). The combined filtrate and washes were diluted with ether (100 ml), the mixture was washed with water (4 50 ml) and the organic phase was dried and evaporated in vacuo to give the ester as a yellowish foam, purified by silica gel column chromatography (developing solvent cyclohexane ethyl acetate (3: 7) gives the ester as an amorphous product, which crystallizes. NMR spectrum (CDCl ,,, f fire 0.90 (d, ZN), 0.93 (C, 3N), 0.98 (C, 3N), 1.22 (C, 9H), 1.38 ( C, ZN), 1.62 and 1.68 (2 br. C, 6H), 2.99 (M, 1H), 3.77 (M, 1H), 4.33 (M, 1I),, 00 (M, 1H), 5.12 (M, 1H), 5.15 and, 42 (D, I 7.2 Hz). 2. Composite pivaloyloxymethyl firm 3-0-formyl-1b-deacetylfusidic acid. of example 13 (2) using the pivaloyloxymethyl ester of 16-deacetylfusidic acid, the pivoyloxymethyl ester of 3-O-formyl-16-deacetylfusidic acid is obtained.

3. Pivaloyloxymethyl ester of 3-0-formyl-1b-deacetoxy-1bo-bromo-fusidic acid.

When using pivaloyloxymethyl ester of 3-0-formyl-16-deacetylfusidic acid under the conditions of example 5 (2), pivoyloxyloxymethyl ester of 3-0-formyl-16-deacetoxy-1B01 is obtained; -bromo fusic acid as a colorless foam

Nuclear Magnetic Resonance Spectrum (CDCl1, cG relative. TMS): 0.78 (C, 38), 0.87 (D, I 7.3 Hz), 1.00 (C, 3N), 1.23 (C, 9H) , lj47 (С, ЗН), 1.61, and 1.68 (br. С, 6Н), 3.45 (М, 1Н), 4.35 (М, 1Н), 5.08 (М, 1Н), 5.12 (M, 1H), 5.62 (M, 1H), 5.82 and 5.92 (D, I 6.2 Hz) and 8.15 (br C, 1H).

Example 15. Acetoxymethyl ester of Z-O-formyl-16-deacetoxy-1bO-bromo-24, 25-dihydrofusidic acid.

1. Acetoxymethyl ester of 16-epideacetyl-24,25-dihydrofusidic acid.

To a solution of 20.6 g (40 mmol) of the potassium salt of 16-epidecetyl-24,25-dihydrofusidic acid in 160 ml of dimethyl phosphate, 4 gl (44 mmol of chloromethyl acetate and the mixture is stirred at room temperature for 18 hours). After dilution with 500 ml of ether the mixture is washed with water (2. 150, 4. 75 ml) and the organic layer is dried and evaporated in vacuo to give the desired product as a colorless foam.

2. Acetoxymethyl ester of 3-0-formyl-16-deacetoxy-16o-bromo-24, 25-dihydrofusidic acid.

To a stirred solution (40 mmol) of the obtained ester and 20.6 g (0.2 mmol) of sodium bromide in 200 ml of dimethylformamide is added dropwise at 25.2 ml (0.2 mmol) of phenyl chloroformate, then the mixture is stirred at for 3-4 hours and at room temperature for 10-12 hours. The precipitate of sodium chloride is filtered off and washed with dimethylformamide ((2) C25 ml). To the combined filtrate and wash water is added

300 ml of methanol-water (1: 1) with stirring. The crystals are filtered off, washed with a mixture of methanolhyd (1: 1), dried, recrystallized from ether-diisopropyl ether, to obtain 15.35 g of the desired product, Tr. 126-127 ° C.

Example 16. 16-deacetoxy-16O4-bromo-fusidic acid esters. When using benzyl, phenacyl, pivaloyloxymethyl, acetoxymethyl or benzoyloxymethyl esters of 16-epidasecetylfuz.idovoy acid in

The conditions of Example 7 are the esters of 16-deacetoxy-16a-bromo-fusidic acid listed in Table 6.

Example 17. 3-0-acetyl-p-keto-16-deacetoxy-16-o5-bromofusidic acid phenacyl ester.

To a solution of 6.98 g (10 mmol) of 3-0-acetyl-16-deacetoxy-16O1-bromofuidic acid phenacyl ester in 70 ml of acetone is added 3 ml of Jones reagent and the mixture is stirred for 30 minutes at room temperature. After adding 100 ml of ether and 70 ml of water, the mixture is stirred for another 10 minutes. The organic layer is separated and the aqueous layer is again extracted with 100 ml of ether. The combined organic extracts are washed with water until neutral, dried and concentrated to about 50 ml, left in the refrigerator for 1 hour, the crystals are filtered, washed with ice-cold ether, dried, to give 5.37 g of 3-0-acetyl-phenyl ester -keto-16-deacetoxy-16og-bromofusidic acid, T pl, 120121 ° C. By concentrating the uterine fluid, another 0.95 g of the expected product is obtained, TPC. 114-115 ° C. Recrystallization from a mixture of methylene chloride-diisopropyl ether gives analytically pure substance, T, 120-121s.

With p 18. Benzyl ester of Z-O-acetyl-p-keto-16-deacetoxy-160-bromo-fusidic acid.

Under the conditions of example 17, using benzyl ester 3-0-acetyl-16-deacetoxy-16o-bromobusidic acid, benzyl ester 3-0-acetyl-p-keto-16-deacetoxy-16c-bromo-fusidic acid is obtained as a colorless foam. .

NMR spectrum (SOSTS, (f rel. TMS): 1.00 (C, 3N), 1.65 (C, 3N), 1.02 (D, 3N), 1.27 (C, 3N), 1, 62 and 1.68 (M, 6H), 2.06 (C, 3N), 3.30 (M, 1H), (M, 1H), 0.05 (M, 1H), 5.22 (SG, 2H), 5.60 (M, 1H), 7.35 (C, 5H).

Example 19. Acetoxymethyl ester of 3-0-formyl-p-keto-16-deacetoxy-16Y-bromo-24, 25-dihydrophusidic acid.

Using acetoxymethyl ester 3-0-formyl-16 deacetoxy-16C1.-Bromo-24,25-dihydrofusidic acid under conditions of example 17, we obtain the complex acetoxymethyl ester Z-O-formyl-p-keto-16-deacetoxy-16 ° C bromo-24, 25-dihydrofusidic acid as a colorless foam.

NMR spectrum (CDClj.c rel. TMS): 0.87 (D, 3 5.5 Hz), 1.02 (C, 3N), 1.04 (C, 3N), 1.25 (C, 3N) , 2.12 (C, ZN), 3.35 (M, 1H), 5.10 (M, 1H), 5.68 (M, 1H), 5, 81, and 5.90 (D, I 5i5 , 2 Hz) and 8.15 (M, 1H). Example 20. Acetoxymethyl ester of 3-keto-16-de-acetoc Si-16o-bromo-fusidic acid. 1. Complicated acetoxymethyl ester Z-keto-16-epidasetylfuzidovoy acid. To a solution of 3.06 g (6 mmol) of potassium salt Z-keto-16-epidacetylfusidic acid and 30 ml of dimethyl form amide was added 0.6 mp (6.6 mmol) of chloromethyl acetate and the mixture was stirred at room temperature for 18 hours then diluted with 100 ml of ether and washed with water (4 x 30 ml). The organic phase is separated, dried and evaporated in vacuo to give 3.2 g of the desired product as a colorless foam. 2. Acetoxymethyl ester of 3-keto-16-deacetoxy-16o bryumfuvidic acid. Under the conditions of Example Jr5, using acetoxymethyl ester 16-epideacetyl-24,25-dihydrofusidic acid, we obtain acetoxymethyl ester Z-keto-16-de acetoxy-16-bromo-fusidic acid, TPA. 144-145 C. Example 21. Methoxy complex methyl ester Z-O-acetyl-16-deacet hydroxy-16-chlorofusidic acid. 1.4 g (2.5 mmol) of the complex labels of s-methyl-3-acetyl-16-epidercetylfusidic acid simethyl ester, 2.6 g (10 mmol) of triphenylphosphine and 1.3 g (10 mmol) of N-chlorosuccinimide are dissolved in 50 The MP of dry ether is stirred for 1 h, the triphenylphosphine oxide is filtered off and the filtrate is evaporated in vacuo. The residue is purified by silica gel column chromatography (cyclohexane: ethyl acetate - 7: 3) under anhydrous conditions; 1.14 g of methoxymethyl ester 3-0-acetyl-16-des1-acetoxy-16 are obtained | -chlorfusidic acid, which is crystallized from petroleum ether and then from cyclohexane, Tl = 1451510s. Example 22. Benzyl ester of 3-0-acetyl-16-deacetoxy-16 | b. -Chlorfusidic acid. Carbophenoxy-N, N-dimethylformam, dat-chloride is obtained by adding 0.3 g (2.4 mmol) of phenyl chloroformate and 15 ml of dimethylformamide. To the resulting solution, 50 mg (0.82 mmol) of 3-O-acetyl-16-epidacetylfusidic benzyl ester was added, after 16-4 the reaction mixture was diluted with 100 ml of ether, washed with 2.5 ml of 2N. caustic soda and water (3% 25 ml), dried and evaporated in vacuo to obtain 480 mg of 3-0-acetyl-16-deacetoxy-16 benzyl ester | ) -chlorfusidic acid, which is crystallized from a mixture of ether ether and ethyl ester, T 163165 ° C. Recrystallization from ethyl acetate-petroleum ether gives an analytically pure compound, Tp-d. 165-16 bOs Example 23. Benzyl ester of Z-O-acetyl-16-deacetoxy-16 | - chlorofusidic acid. To an ice-cooled solution of 1.36 g of benzyl ester Z-O-schistil-16-deacetylfusidic acid, 10 ml of dimethylformamide and 0.44 ml of pyridine were added 1.13 ml of phenyl chloroformate for 30 minutes, stirred at room temperature for 16 hours, the resulting solution was diluted with 100 ml of ether, washed with 25 mp 2 n. caustic soda and water (3 x 50 ml) dried and evaporated in vacuo. The residue is dissolved in 10 ml of ether and precipitated with petroleum ether to give the benzyl ester of 3-0-acetyl-16-deacetoxy-1-1-chlorofusidic acid, Tr, d. 115-117 ° C. Recrystallization from ethyl acetate-ethyl ester mixture increases do 120-122s. Example 24. 16-Deacetoxy-16 | - isopropylthiophus acid. 1. p-nitrobenzyl ester of 3-0-acetyl-16-deacetoxy-G6p | -isopropylthiofusidic acid. 28.6 g (40 mmol) of 3-acetyl-16-deacetoxy-16c p-nitrobenzyl ester of 1-bromofusidic acid was added to a solution of potassium hydroxide (10 g, 85% pure, 150 mmol) and 30 ml (320 mmol a) isopropylmercaptan in 100 ml of ethanol and the suspension is stirred for four days. Then 500 ml of water are added, the crystals are filtered off, washed with water-ethanol (1: 2) and dried, to give 21.5 3-O-acetyl-16-deacetoxy-1b1b-isopropylthiofusidic acid p-nitrobenzyl ester, Trd. 157-16lOc. 2. 16-Deacetoxy-16 | L-isopropylthiofusidic acid. A suspension of the above p-nitro-benzyl ether in a mixture of 800 ml of thanol and 200 mp 2 n. aqueous sodium hydroxide is heated for 3 hours. The resulting dark solution is acidified with 125 ml of 4N. hydrochloric acid and process for 5 min 5 g of activated carbon, a mixture of hot. After filtration, 500 ml of water are added and then after cooling to room temperature, the romantic product is filtered off, washed with water and dried, and 14.1 g of 16-deacetoxy-16p) isopropylthiofusidic acid, y, are obtained. 223-229 seconds, recrystallization. C 2-butanone gives analytically Tpd 229-231 ° C. raw connection Example 25. Simple 1b L-thiofir-16-deacetoxyfusidic acid.

1. Simple 1b | 4-thioesters of 3-0-acetyl-16-deacetoxyfusidic acid-nitrobenzyl ester.

According to the procedure described in reference 24 (1), using the mercapanes listed in .tab.7, 16 |) simple thioesters of the 3-0-acetyl16-deacetoxyfusidic nitro-nitrobenzyl ester are obtained, as shown in Table 2. 72 .1b (} - 16-deacetoxyfusidic acid simple thioesters.

According to the procedure described in s 24 (2), ISp-THO esters of 1b-deacetoxyfusidic acid are obtained. eight.

Example 26. 16-Deacetoxy-16} L-isopropylthio-24, 25-dihydrofusidic acid.

1. Complex p-nitrobenzyl ester of 3-0-acetyl-16-deacetoxy-16 |) -isopropylthio-24, 25-dihydrofusidic acid.

According to the procedure described in Example 24 (1), the 3-O-acetyl-16-deacetoxy-1b0 bromo-24, 25-dihydrofusidic acid p-nitrobenzyl ester is obtained by the 3-O-acetyl-16-deacetoxy p-nitrobenzyl ester -1b) -isopropyl o-24-25-dihydrofusidic acid in the form of colorless crystals, TPA. IZ-Ib S.

2.16-Deacetoxy-16} 1-isopropylthio-24, 25-dihydrofusidic acid.

According to the method described in example 24, from the complex p-nitrobenzyl ester Z-O-acetyl-16-deacetoxy-16 | -isopropylthio-24, 25-dihydrofusidic acid, get 16-deacetoxy-16 L-and 3 opylo-24,2 5-dihydrofusidic acid, Tf. 232-234 0.

Example 27. 16-Deacetoxy- 16 |) -cyclohexylthiofuzidic acid.

 g (2 mmol) of 3-O-acetyl-16-deacetoxy-16a p-nitrobenzyl ester; -bromfusidic acid is added to a solution of potassium hydroxide (400 mg, 85% purity, 6.1 mmol) and 2 ml (16 mmol ) cyclohexyl mercaptan in ethanol (100 ml) and the resulting solution is left at room temperature for 5 days. The reaction mixture is then diluted with 150 ml of ether, washed with water (3X 75 ml), dried

and evaporated in vacuo, the remaining oil, containing crude 3-acetyl-16-deacetoxy-16 b-cyclohexylthiofusidic acid p-nitrobenzyl ester, dissolved in 80 ml of ethanol and 20 ml of 2N is added. sodium hydroxide solution. After stirring for 3 hours, 100 ml of water are added and the resulting dark solution is acidified with 15 ml of 4N. hydrochloric acid and extracted twice with ether. The combined organic phases are washed with water (50 ml capacity), dried and evaporated.

The oily residue is purified by column chromatography on silica gel (ether-petroleum ether-acetic acid-70: 30: 0.5) under anhydrous conditions, to obtain 16-deacetoxy-16-cyclohexylthioufidic acid, .. 215-220 0 (ether - petroleum ether). Recrystallization from ethyl acetate-petroleum ether gives analytically pure compound, Tn, 216-220 0.

According to the procedure described in Example 27, the 16 | L-thioethers of 16-deacetoxyfusidic acid, shown in Table 2, are obtained. 9.

Example 28. 16 Deacetoxy-16 | -ethylthiofusidic acid.

To a solution of 2.5 ml (34 mmol) of ethyl mercaptan in 10 ml of dimethylformamide sodium hydride (650 mg, 55% suspension in oil, 15 mmol) is added. When the complete evolution of hydrogen is completed, 3-0-acetyl-16-deacetoxy-160-bromophosphate acid pivaloyloxymethyl ester (750 mg, 1.1 mmol) is added. After 1 h, the reaction mixture was diluted with ethyl acetate (50 ml) and extracted

1n. hydrochloric acid (25 ml) and water (2 X 25 ml). The organic phase is dried, filtered and evaporated.

in a vacuum. The resulting product is purified by silica gel column chromatography (ether — petroleum ether-acetic acid — 40: 60: 0.5) under anhydrous conditions, and 3-0-acetyl-deacetoxy-16-ethylthiofusidic acid is obtained in the form of a colorless gum, which is dissolved in a mixture of ethanol (20 ml) and 2 n. sodium hydroxide (5 ml) and left at 75 ° C for

2h The reaction mixture is then acidified with 1N. hydrochloric acid (15 ml) and extracted with ethyl acetate {50 ml).

The organic phase is washed twice with water (20 ml), dried, evaporated in vacuo, an oil is obtained which is crystallized from petroleum ether, Tsch 195-198 ° C.

According to the procedure described in Example 28, 16 || L-thioethers of 16-deacetoxyfusidic acid are obtained, as indicated in Table. ten.

Example 29. 16-Deacetoxy-16p - d-methyltetrazol-5-ylthio) -fusidic acid.

Following the procedure described in Example 27, using 5-mercapto-1-methyl tetrazole, 16-deacetoxn-16 | L-d-methyl tetrazol-5-ylthio) -fusidic acid is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl1, CNS TMS: 1.00 (C, 3N), 1.06 (C, 3N), 1.40 0 (C, 3N), 1.62 and 1.68 (M, 6H;, 6.17 (M, 1H), 3.75 (M, 1HB 3.87 (s, 3N), 4.37 (m, 1H) and 5.42 (m, 1 n).

PRI and MER 30. 16-Deacetoxy-16 - (2,5-dichlorophenylthio) -fusido acid. Following the procedure described in Example 27, using 2,5-di-chloro-phenylmercaptan, 1b-deadeto sibi1b-p | - (2,5dichlorophenylthio) -fusidic acid is obtained, Trd, 161-164 C. pp. 31. 1b (5-Tioethers-1b-deacetoxyfusidic acid. According to the procedure described in Example 27, the compounds indicated in Table 11 are prepared. Example 32. 11-Ket0-16-deacetoxy-16 5-isopropylthiof Species Acid. Under the conditions described in Example 27, 3-bromo-fusidic acid, 6-bromo-fusidic acid, and isopropylcaptan, p-keto-1b-deacetoxy-1b-isopropane, is prepared from phenacyl ester of 3-0-acetyl-p-keto-16-deacetoxy-1c-6-bromo fusidic acid Ilthiofusidic acid with Tshch. 167-169C. Example 33. p-Keto-16-deace OXY-16P1-IZOPROPYLTIO-24, 25-dihydrofusidic acid. Following the procedure described in Example 27, from acetoxymethyl ester 3-0-formyl-11-keto-16-deacetoxy-16-bromo-24, 25-dihydrofusidic acid and isopropylmercaptan get 11-keto-16-deacetoxy-16 | 1-isopropylthio-24, 25-dihydrofu zidic acid with Trl. 189-1910s PRI me R 34. 3-Keto-16-deace hydroxy-16 L-isopropylthiofusidic acid. Following the procedure described in Example 27, from 3-keto-16-deadetoxy-16o bromofusidic acid adhetoxymethyl ester and isopropylmercaptan, we obtain 3-keto-16-deacetoxy-16p) isopropylthiofusidic acid, Tj 200-2030c. Rimet 35. 16-Deacetoxy-16p-ethoxyfusidic acid. 16.55 g (60 mmol) of silver carbonate are added to a suspension of 20.94 g (30 mmol) of 3-0-acetyl-16-deacetoxy-1.6ai-bromo-fusidic acid phenacyl ester in 300 m ethanol, the mixture is stirred in the dark at room temperature for 18 hours. The insoluble material is filtered off and washed with ethanol (2 X 30 ml). To the combined filter, wash and wash water is added 5N. aqueous sodium hydroxide (120 ml and the mixture is heated under reflux for 2 hours. After cooling to room temperature, most of the ethanol is removed in vacuo, ethyl acetate (150 ml and water (100 ml) is added to the residue. The mixture is acidified 4 hydrochloric acid, the organic phase is separated and the aqueous phase is re-extracted with ethyl acetate (5Q ml). The combined organic extracts are washed with water, dried and evaporated in vacuo to give an oily residue, which is crystallized from diisopropyl ether, colorless crystals are collected washed with diisopropyl ether and dried to give 5.42 g of 16-deacetoxy-16-ethoxy-fusidic acid, TPD. 169-171 ° C. After processing the mother liquor, 2.2 g of the desired product is additionally obtained. 168-170 C. Two recrystallizations from the methanol-diisopropyl ether mixture, an analytically pure compound is obtained, 177-178 C. Example 36. 16-Deacetoxy-16) -alkyloxy-fusidic acids. When replacing ethanol with the alcohols listed in Table 12, according to the procedure described in Example 27, 16 -deacetoxy-16r1-alkyl-hydroxyfusidic acids listed in table. 12. Example 37. 16-Deacetoxy-16 | ) - (2-fluoroethoxy) -fusidic acid. To a solution of benzoyloxy-1-ethyl ester Z-O-formyl-16-deacetoxy-160-bromo-fusidic acid (8.75 g, 12.5 mmol) in 25 mp of 2-fluoroethanol was added 6.89 g (25 mmol) of silver carbonate and the mixture is stirred at room temperature in the absence of light for 16 hours. The precipitate is filtered off, washed twice with ether and the combined filtrate and the washings are evaporated to dryness in vacuo. The remaining oil containing crude benzoyloxymethyl ester Z-O-formyl-16-deacetoxy-1b | - (2-fluoroethoxy) -fusidic acid, dissolved in 85 ml of methanol, 3.46 g (25 mmol of potassium carbonate are added and the mixture is stirred at room temperature for 30 minutes. Most of the solvent is removed by evaporation in vacuo and to the residue 100 ml of water and 100 ml of ether are added.After acidifying the stirred mixture with 1N hydrochloric acid, the organic layer is separated, the aqueous layer is extracted twice with ether (50 ml) and the combined organic phases are washed with water until neutral. The ether solution is extracted with 0.5 N. sodium hydroxide (3 X 50 ml) and washed with water (3 x 25 mp). To the combined aqueous phases and the wash waters, ether (100 ml) is added and the stirred mixture is acidified with 4N hydrochloric acid. After separating the organic layer, the aqueous layer is extracted with ether (50 ml) and the combined organic the extracts are washed with water until neutral, dried and evaporated in vacuo.The resulting morph residue is dissolved in 30 ml of isopropyl ether and a crystal is precipitated by rubbing with a stick on the walls of the vessel. After keeping in the fridge overnight, the crystals are filtered, washed with diisopropyl fiber and dried to give 2.32 g

1b-deacetoxy-1b - (2 fluoroethoxy) -fusidic acid, Trd. 153-1BO C. In addition, 0.48 g of the desired product C is obtained from the mother liquor; M.p. 155-159 C. Double recrystallization from methanol-diisopropyl ether gives analytically pure product, T 162-1620c.

Example 38. 16-Deacetoxy - 16ft-alkyloxyfusidic acids.

According to the procedure described in Example 37, 1b-deacetoxy-16 {-alkyloxyfusidic acids are obtained, indicated in Table. 13.

Example 39. 16 {3-Ethers of 16-deacetoxyfusidic acid. According to the procedure described in Example 37, 1b-ethers of 16-deacetoxyfusidic acid, shown in Table 1, are prepared. 14.

Example 40. 16-Deacetoxy-1b) ethoxy-24,25-dihydrofusidic acid.

Under the conditions described in example 35, from phenacyl ester 3-0-acyl-16-deacetoxy-1b | L-bromo-24, 25-dihydrofusidic acid, 1b-deacetoxy-16 | 5-ethoxy-24,25-dihydrofusidic acid is obtained. acid, Tp / 192-193

Example 41. 16-Deacetoxy-16p) -alkyloxy-24,25-dihydrofusidic acid.

Following the procedure described in Example 35, from phenacyl ester 3-0-acetyl-16-deacetoxy-16o-bromo-24, 25-dihydrofusidic acid, 16-deacetoxy-16 L-alkyloxy-24,25-dihydrofusidic acids are obtained, indicated in tab. 15.

Example 42. 11-Keto-16-deacetoxy-1b | a) ethoxyfusidic acid To a suspension of 5.57 g (8 mmol) of 3-0-acetyl-11-keto-16-deacetoxy-16o (, -bromo-fusidic acid) phenacyl ester (60 ml of ethanol) was added to 4.41 g (16 mmol silver carbonate and, while protecting the mixture from light, stirred for 18 hours at room temperature, the insoluble matter is filtered off and washed with ethanol (2 × 20 ml). The combined filtrate and washings containing 3-0-acetyl-crude phenacyl ester Meto-16-deacetoxy-163-ethoxyfueidic acid is diluted with ethanol (80 ml), a 5N aqueous solution is added. sodium hydroxide (32 ml) and the mixture is stirred for 20 hours at room temperature. The solvent is removed in vacuo, 100 ml of water and 100 ml of ether are added to the remaining oil and the stirred mixture is acidified by the addition of 4N hydrochloric acid. the phase is separated, the aqueous phase is re-extracted with 100 ml of ether and the combined organic extracts are washed with water until neutral, dried and evaporated in vacuo. The resulting oily residue was purified by silica gel column chromatography (ether-petroleum ether-acetic acid mixture under anhydrous conditions of 50: 50: 0.5) and the resulting 5 yellow amorphous product was crystallized from diisopropyl ether, to obtain 2.12 g 11 keto-16-deacetoxy-16 /} - ethoxyfusidic acid,. 166.-167 C. Recrystallization of Q from an ether-diisopropyl ether mixture gives an analytical sample, T, 167168C.

Example 43. 11-Keto-16-deacetoxy-16 | 5- (2-fluoroethoxy) -fusidic acid.

According to the method described in Example 42, 11-keto-16-deacetoxy-16 | 5- (2-fluoroethoxy) -fusidic acid is obtained in the form of colorless amorphous

powder. The compound can be converted to a crystalline sodium salt (see Example 45).

Example 44. Z-Keto-16-deacetoxy-16-ethoxyfusidic acid.

Following the method described in Example 37, from 3-keto-16-deacetoxy-16a-bromo-fusidic acid acetoxymethyl ester and ethanol, 3-keto-16-deacetoxy-16 /? -Ethoxyfusidic acid, TP / 1 is obtained. 177-179c.

Example 45. Sodium salts of 16/1 ethers, 16/2 tIoesters of 16-deacetoxyfusidic acid and its 3- and 11-keto derivatives.

A solution (10 mmol) of the corresponding fusidic acid in 25 ml of methanol is titrated with 2N. methanol sodium hydroxide using phenolphthalein as an indicator. After evaporation to dryness in vacuo, an oily or amorphous residue is obtained, which is treated with acetone (approximately 100 ml), the resulting solution is concentrated to about half the volume, and when rubbed with a stick against the walls of the glass, the desired sodium salt begins to crystallize. The mixture is left for 2 hours at room temperature, then the crystals are collected, washed with acetone and dried, and a pure sodium salt is obtained.

Sodium salt obtained by this method are given in table. sixteen.

Example 46. Calibva salt 16-deacetoxy-16}) - (2-hydroxyethoxy) -fusidic acid.

A solution of 2.64 g (5 mmol) per hemihydrate of 16-deacetoxy-16. (2-hydroxyethoxy) -fusidic acid in 10 ml of methanol is titrated with phenolphthalein 2N. methanol potassium hydroxide. After evaporation to dryness in vacuo, the resulting amorphous residue was dissolved in 2.5 MP of methanol, 60 ml of acetone was added and the mixture was concentrated to approximately 15 ml under reduced pressure. Dropped by rubbing the stick against the walls of the glass

the colorless crystal is filtered off, washed with acetone and dried, to obtain 2.32 g of the desired product.

.Table 1

Chloromethyl methyl ether

p-Benzylphenacyl bromide

p-methoxyphenacyl bromide

Bromoacetone with -Br JOOYa, ci -Gr CHjCOO

Also

.H

table 2

CH.

127

CHg COCjjH OCHj- 114-116

80-81

CHpi COCHj

Table 3 141-142 CHrji 157-159

CH CO-ct-BgCHg C Hg104-105

COOR,

CHjCO-rt-BrCH CftH NOa.147-149,

Table4

Table 5

TOP

Rj in conjunction

PL of general formula I

SNO, OSOS (SNZ) 1, Amorphous

123-125

SND OSOSNT, 125-127 CHjCfeHg

Their

"ABOUT

Table 6

V °

R in a compound of formula

CHaGj, H5

Amorphous CHaCOCfoHg To

105-106 Amorphous

25

dad

79967026

Ta.b faces /

(0)

 SR

167-168

CHgCHj 192-194 S.N.CH5, OH

188-191 CHji 167-170

CH, CH CH

SNG SNSSN ,,)

.104-112 CH. (CH-5), 150-157

100-109

Cyclopentyl 125-129 CHjji COOCH,

146-148

Furfuril

Table 8

In the compound, the General formula

Cyclopentyl

CH4COOH

FURFURIL

NMR spectrum (COC8, Zeotn. TMS): 0.97 (C, bN), 1.32 (C, ZN) and 1.68 (M, 6H), 3.00 (M, 1H), 3.73 ( M, 18), 3.78 (M, 2H), 4.22 (D, 1H), 4.30 (M, 1H), 5.10 (M, 1H), 5.1-6.4 (M , 2H) and 7.32 (M, 1H). 2-Phenylethylmer-CH2., Nd captan P-Butylmercaptan CH CHj CHijj CH, Methyl mercaptan

NMR spectrum (, b rel. TMS): 0.89 (D, D 6.3 Hz), 1.00 (C, ZN), 1.03 (C, ZN), 1.38 (C, ZN), 1.62 (M, 6H), 2.13 (C, 3N), 3.03 (M, 1H), 3.67 (M, 1H), 4.03 (D, C 9.1 Hz), 4 , 26 (M, 1H) and 5.10 (M, 1H).

BUT

tert-ButylmercaptanS (SNZ) s

PhenylmercaptanS, Nd

BenzylmercaptanSN C (, H

 NMR spectrum

(CDiOD.cT rel. TMS): 0.90 (D, ZN), 0.99 (C, 6H), 1, 37 (C, ZN), 1.62 and 1.66 (M, 6H), 2.58 (M, 2H), 3.00 (M, 1H), 3.67 (M, 1H), 4.11 (D, 1H), 4.24 (M, 1H), 5, 12 (M , 1H).

 NMR spectrum

(CDClj.tf rel. TMS): 0.95 (C,), 1.10 (C, 3N), 1, 35 (C. 3N), 1, (BO and 1.65 (M, 6H), 3 , 10 (M, 1H), 3.74 (M, 1H), 4.30 (M, 1H), 4.77 (D, 1H), 5.11 (M, 1H) and 7.0-7 , 4 (M, 5H).

 NMR spectrum

(CDCl ,,, cf rel. TMS): 0.97 (C, 6H), 1.36 (C, 3N), 1, 62 and 1.66 (M, 6H), 3.06 (M, 1H) , 3.66 (M, 1H), 3.74 (M, 2H), 4.08 (D, 1H), 4.24 (M, 1H), 5.14 (M, 1H) and 7.3 ( M, 5H).

Continued tabl, 8

II; O

 g

217-223 199-202 Amorphous

Table 9

T a b l and c a 10

200-203

h

Amorphous

Amorphous. 208-214 105-118 (decomposition) Amorphous

BUT

mercaptan

mercaptan captan Xity

Table 11

2-Azidoethylmer173-179

captainNjCHijCHij

2-methoxyethylCH, CH, jOCHj

Amorphous mercaptan

2-Isopropylthioux

ethyl mercaptan (CHj) a Same

149-152

CH, CH2SCH, jCH j CHj CHjiSCCCHj), 134-135

2-Cyclohexyl thioethyl mercaptan

And jurf

2-phenylthioethyl- "" (

Also

2-methylthioethyl tx

2-fluoroethylmer 157-159

CHjjCHgf NMR spectrum (CD30D, d rel. TMS): 1.00 (C, bH), 1.36 (C, 3N), 1.62 (M, 6H), 2.77 (M, 2H), 3, 51 (2H), 3.68 (C, 1H), 4.10 (D, 1H), 4.21 (M, 1H) and 5.11 (M, 1H). NMR spectrum (SOS.SYA rel. TMS); 0.96 (M, 6H), 1.22 (D, bN), 1.33 (C, ZN), 1.58 And 1.67 (M, bN), 2.73 (M, 4H), 2 , 91 M, 1H), 3.01 (M, 1H), 3.71 (M, 1H), 4.21 (M, 1H), 4.28 (M, 1H) and 5.08 (M, 1H ). Spectrum H1 # (COCIj, (I Rel. TMS): 0.99 (C, bN), 1.37 (C, ZN), 1.61 and 1.67 (M, 6H), 2.78 (M, 4H), 3.07 (M, 1H), 3.76 (M, 1H), 4.26 (D, 1H), 4.35 (M, 1H) and 5.12 (M, 1H). NMR spectrum (SOS1, f rel. TMS): 0.98 (M, bN), 1.35 {C, MN), 1.61 and 1.67 (M, 6H), 3.78 (M, 1H), 4 , 25 (M, 1H), 4.34 (M, 1P), 5.11 (M, 1H) and 7.1-7.5 (M, 5H). Nuclear Magnetic Resonance Spectrum (CDjOD, cf rel. TMS): 0.98 (C, 6H) n 1.36 (C, 3N), 1.62 (M, .6H), 2.10 (C, 3N), 2, 77 (M, 4H), 3.00 (M, 1H), 3.66 (M, 1H), 4.11 (D, 1H), 4.23 (M, 1H) and 5.13 (M, 1H ).

BUT

X

BUT:

BUT

BUT

1, 3-diacetoxypropanol

Table 12

CH (CH (OCOCHj) j Amorphous

33

Alyl alcohol 2-Butenl (i)

2-PROPINOL (1)

Cyclopentanol

799670 -34

Continued table. 14

154-156

128-135 (decomposition)

134-136 188-189

Cf) ONa

Ar-r

Table 16

sssn,

S o

H, ot-he

LON

Same same i ii

The same CHijCFj -f -

- -CHj CHijiF

at

and and

- -CHjCHj p

about

- -CHj CH j F

 II P

Also

I am II

CH, CH3 H.rf -ON

about

Claims (1)

Claim A method of obtaining derivatives of fu eidic acid of General formula j Τ ’ II jt 5 Η R ^ rooya h 1 10 I · ⁷ ι Η fifteen in which the Cr ^ j-C25 bond is single or double, and q ₂ is either oxygen, A is oxygen or sulfur, R is hydrogen, a lower alkanoyloxy-40 simethyl radical, an aryloxymethyl radical, R ^ is a straight or branched alkyl radical with 1 -8 carbon atoms, unsubstituted or substituted by amino, hydroxy, lower alkoxy, lower alkylthio, azado- ,. carboxyl groups, phenyl radical, one or more 'halogen atoms, cycloalkyl radical with 3-7 carbon atoms, alkenyl or alkynyl radicals with 2-6 carbon atoms, phenyl unsubstituted or substituted by one or more halogen atoms, five-membered heterocyclic radical with oxygen atoms or nitrogen, unsubstituted or substituted by a lower alkyl radical, or its salts, characterized in that, in order to expand the range of biologically active steroids, the compound of General formula C where has the above significance, means Qr, or 0B group. ⁿ _o1g , where R _a is a lower alkanoyl radical, Y is chlorine, bromine or iodine, R * is a lower alkanoyloxymethyl or aryloxymethyl radical, an alkyl radical with 1-6 carbon atoms, a benzyl radical unsubstituted or substituted by a nitro group or lower 35 by an alkyl radical, a lower alkoxymethyl radical, a phenacyl radical unsubstituted or substituted in the aromatic nucleus with a lower alkoxy group, or a cyanomethyl radical 4Q is reacted with a compound of the general formula I, R / H wherein R _t and A are as defined above, and the resulting compound of the general formula ΠΙ where Q) ,, Q _v A, R> | and R is the desired value, if desired, subjected to hydrolysis and the resulting acid • if desired, converted into a salt, followed by isolation of the target product. · Priorities by signs: 06.25.75 - and Q ₂ - groupι A'- oxygen or sulfur? 11/07/75 - and oxygen.