SU686623A3 - Method of producing pregnanic acid derivatives - Google Patents

Description

(54) METHOD FOR PREPARING DERIVATIVE ACID DERIVATIVES

the free acid is esterified or the ether is treated with an alcohol in the presence of a basic catalyst, followed by isolation of the desired product. Hydrocarbons, chlorinated hydrocarbons, ethers, ketones or alcohols are used as a solvent in the oxidation process. The reaction is carried out at O-l-SO C.

Saponification of the ester is carried out in water or an aqueous alcohol in the presence of acidic catalysts, for example hydrochloric, sulfuric acid or p-toluenesulfonic acid, or bases such as alkali, hydroxide of potassium carbonate or.

The etherification of the obtained acids is carried out with diazomethane or diazoethane or alcohols in the presence of carbonyldiimidazole, dicyclohexylcarbodnimide or trifluoroacetic anhydride. Acids are also converted to their silver salts and then treated. Alkyl halides of esters.

Free acids are also converted into esters with the appropriate dimethylformamide alkyl acetals. In addition, acids in the presence of strong acids as catalysts, for example hydrochloric, sulfuric, perchloric acids, trifluoroMethanesulfonic acids or p-toluenesulfonic acids, are esterified with alcohols or esters of lower carboxylic acids. Acids can also be converted into chloroanhydrides or anhydrides and then treated with alcohol in the presence of a basic catalyst.

Carboxylic acid salts are obtained by saponification of esters in the presence of basic catalysts or by neutralizing acids with alkali metal carbonates or bicarbonates. Example 1

a) A solution of 11.3 g of boC-fluoro-11 / 3-21-dioxy-16og-methyl-1, 4-pregnadivn-3, 20-dione in 500 ml of absolute methyl alcohol is mixed with Z.g of copper (II) acetate in 500 ml of absolute methyl alcohol. Solution

stirred for 170 hours at room temperature, then filtered; i concentrated in vacuo. The residue is mixed with a 10% solution

ammonium hydroxide and extracted with methylene chloride. The organic phase is washed several times with water, dried over sodium sulfate, and concentrated in vacuo. The residue is chromatographed on 1.3 kg of silica gel with 6–7% acetone-methylene chloride; after recrystallization from a mixture of acetone-hexane, 1.4 g of Bao-fluoro-11 L-20 ° methyl ester are obtained (gdioxy-3-oxo-1). 16c (1.-methyl-1,4-pregnadienoic-21-acid with mp. 1 × 1 192 ° C.

.0 (chloroform). 15700 (methanol).

Using an 8% -10% acetone methylene chloride mixture, after double recrystallization from an acetone-hexane mixture, 2.9 g of 6cC-fluoro-11p-20pp-dioxy-3-oxo-16cC-methyl-1, 4-pregnadienoic-21- methyl ester are obtained. acids with so pl. 128-130 s,

оС + (chloroform). UV: s4f 15200 (methanol)

b) 2.1 g of a mixture of methyl ester 6o (, - fluoro-11 | L-20c1p-dioxy-3-oxo-16o1-methyl-1, 4-pregnadienenoic-21-acid and methyl ester 6o6-fluoro-Ir 20p -dioxy-3-oxo-16cC-methyl-i, 4-pregnadienoic-21-acid is dissolved in 20 ml of methylene chloride, the plant solution is mixed with 20 g of active manganese oxide (IV) and boiled for 6 hours. After this manganese oxide (IY)

The mixture is filtered, the filtrate is evaporated and the residue is recrystallized from

mixtures of acetone-hexane, I get methyl ester 6c-fluoro-11 | B-hydroxy-3 |, 20-dioxo-1 bob-methyl-1,4-pregnadienoVOE-21-ACID in the amount of 45O mg and so pl. 182-184 / C.

ot + 144 (chloroform) UV 24f (methanol),

c) a solution of 250 mg of methyl ester 6oC-fluoro-11p) -20-dioxy-3-oxo-.

-16 DEG-methyl-1,4-pregnadienoic-21-acid in 3 ml of methylene chloride with 2.5 g of active manganese oxide (IV) is stirred for 45 minutes at

room temperature. Manganese oxide (IV) is removed by filtration, the filtrate is evaporated to dryness and the residue is recrystallized from acetone-hexane, to obtain 145 mg

6oC-fluoro-I-hydroxy-3, 20-dioxo-16cC-methyl-1,4-pregnadienoic-21-acid methyl ester with t, pl. 188 ° C.

 + 147 ° (chloroform). .UV: € f4r 16900 (methanol).

g) 4.3 G of methyl ester 6L-fluoro-11 | 1-20p-dioxy-3-oxo-1bo6-methyl-1, 4-prvnadadienoic-21-acid and 50 g of active manganese oxide (IV) in 50 ml of isopropyl alcohol

stirred for 25 hours at room temperature, the manganese oxide (IV) was separated. After evaporation of the solvent, the residue was recrystallized twice from hexane-acetone. The yield of 1.3 g of methyl ester 6oC-fluoro-11-hydroxy-3,20-dioxo-1 bob-methyl-1,4-pregnadienoic-21-acid with m.p., 189-191 C.

 + 145 (chloroform), UV f 241 17000 (methanol),

P r and m in p 2,

A solution of 5 g b s-fluoro-ir, 21-dioxy-16 1-methyl-1, 4-pregnadien-3,. 20-dione in 250 ml of absolute methyl alcohol mixed with 5 g of copper acetate

(Ii) 750 ml of absolute methyl

alcohol and stirred for 60 h at room temperature. The solvent is evaporated, the residue is mixed with 200 ml of methylene chloride and 250 g of active manganese oxide (IV) and the mixture is shaken for 24 hours at room temperature, filtered, concentrated and the residue is chromatographed on 250 g of silica gel. Using a 6-8% acetone-methylene chloride mixture, after recrystallization from an acetone-hexane mixture, 1.47 g of methyl ester 6o & fluoro-11p) -oxy-3,20-dioxo-16oC-methyl-1,4- Pregnadinovy-21-acid with so pl. 190-191 ° C.

, ® + 145 ° C (chloroform), UV; 242 16600 (methanol)

PRI me R 3.

A solution of 950 mg of methyl fluoride fluor-Irg-hydroxy-3.20 dioxo-16 ° C methyl-1, 4-pregnadienoic-21j-acid in 10 ml of methyl alcohol is mixed with 2 ml of 2 and caustic soda solution and left for 1 h at room temperature in an argon atmosphere. The solution is diluted with 100 ml of water and extracted with methylene chloride. The pH of the aqueous phase using 1 n. The hydrochloric acid solution is adjusted to 3-4 and extracted once more with methylene chloride. The extract is dried with sodium sulfate and concentrated in vacuo at. The crude product is dissolved in a small amount of ethyl acetate and crystallized at -30 ° C. The yield is 238 mg of 6s6-fluoro-11p-hydroxy-3, 20-dioxo-16c {.- methyl-1,4-pregnadienoic-21-acid with mp 228-230 ° C (melting with decomposition).

 + 195 ° (pyridine). UV: 245g 16400 (methanol).

Example 4

a) 6 g of bob-fluoro-lip) -21-dioxy-16c6-methyl-1, 4-pregnadien-3, 20-dione in 180 ml of n-butyl alcohol is mixed with 1.6 g of copper (II) acetate, leaving yut for 8 days. The separation is carried out analogously to example 1a. The crude product is chromatographed on 350 g of silica gel. Using a 9-11% mixture of acetone-methylene chloride, after recrystallization from a mixture of acetone-hexane, 960 mg of butyl ester 6oC-fluoro-11L-20o - dioxy-3-oxo-1-bo6gmethyl-1, 4-pregnadienoic-21 are obtained. -acids with m.p. 144-145 ° C.

g W 1 25

o6 + 3.4 ° (chloroform). UV: OL-JK

-241 J-D / OO (methanol).

l 1570

Using an 11–13% mixture of acetone methylene chloride, 1.9 g of a mixture from 6cC butyl ester of fluorine-11p-20oO-dioxy-3-oxo-16o (, -methyl-1,4-pregnadienoic-21-acid and butyl ester) is eluted 6c6-fluoro-11p-20 (b-dioxy-3-oxo-16s6-methyl-1, 4-pregnadienoic-21-acid. Using a 13-15% mixture, after recrystallization from acetone-hexane, butyl is obtained 6o-fluoro-11 (-20) p-dioxy-3-oxo-16c-methyl-1, 4-pregnadienoic-21-acid ester with mp 176-177 ° C.

  + 12 (chloroform) .UV: 15800.

c) 3 g of a mixture of 6cC-fluoro-11 butyl ether | | -20 ° C-dioxy-3-oxo-16c (.-Methyl-1, 4-pregnadienoyl-1-21-acid and boC-fluoro-ip-2 butyl ester.-Dioxy-3-oxo-1 boC-methyl- The 1,4-pregnadienoic-21-acid is reacted with manganese oxide (IV) under the conditions indicated in Example 1.The crude product is chromatographed on 125 g of silica gel. Using an acetone-hexane mixture of 8-10%,

5 after recrystallization from a mixture of acetone-hexane, 1.02 g of butyl ester 6O1 is obtained. -Fluoro-11p-hydroxy-3, 20-dioxo-16sCg-methyl-1,4-pregna (diene-21-acid with m.p. 1870 188 ° C.

CALC +141 ° (chloroform). UV: 242 17100 (methanol).

PRI me R 5.

five

a) A mixture of 8.2 g 6s; -fluoro-9o (-chloro-11 p-21-dioxy-16o: - methyl-1, 4-pregnadien-3, 20-dione, 200 ml of isobutyl alcohol and 4, 1 g of copper (II) acetate is heated for 53 h on steam

0 bath and, as described in example 1a, is subjected to separation. The crude product is chromatographed on 400 g of silica gel. l Using a 6-7% acetone-methylene chloride mixture, after recrystallization from an acetone-hexane mixture, 1 g of boC-fluoro-9c isobutyl ester, chloro-11 5-20 ° (. -Dioxy-3-oxo-.1 bo6- methyl-1, 4-pregnadienoic-21-acid with m.p., 189 ° C.

 + 48 ° (dioxane). UV:

0 23sr 15000 (methanol).

Using 8 10% methylene chloride-acetone mixture, after recrystallization from acetone-hexane mixture, 2.1 g of boC5-fluoro-9c-chloro-11 L-20pr-dioxy-3-oxo-16cc-methyl-3-isobutyl ester are obtained. 1 ,, 4-pregnadienova-21-. -acids with m.p. 215-216 p.

+ 39 (dioxane). UV:

23b 14800 (methanol).

0

b) 4.25 g of a mixture of 6cC-fluoro-9OO-chloro-11 2 | -20cX isobutyl ester of dioxy-3-oxo-16c. methyl-1,4-pregnadienoic-21-acid and 6c6-fluoro isobutyl ester 9o C.-chloro-4-20 pp-dioxy-35. -oxo-16a1-methyl-1,4-pregnavienoic-21-acid is dissolved in 40 ml of methylene chloride and mixed with 100 g of active manganese oxide (IV). After stirring for six hours, the manganese oxide (IV) is filtered off. After

0 Evaporation of the solvent and recrystallization twice from acetone-hexane gives 2.14 g of 6 ° C-fluoro-9L-chloro-11 L-oxo-3,20-dioxo-1 bs-methyl isobutyl ether

-1,4-pregnadienoic-21-acid with m.p. 206-208С.

ctl | f + 149 (dioxane). UV s (Methanol). Example 6

a) 16 g of 6c, 9c-difluoro-11 (5-21-dioxy-16c6-methyl-1, 4-pregnadien-3,20-dione, 8 g of copper (II) acetate and 1000 ml of methyl alcohol as described in Example 5a, reacted, separated and chromatographed. Using a 6-8% mixture of acetone-methylene chloride, after recrystallization from a mixture of hexane-acetone, 1.1 g of methyl ester 6ot, 9e.-difluoro-11p | -20o are obtained. (dioxy-3-oxo-1b "(.-methyl-1, 4-pregnadienoic-21-acid with mp. 174С.

 + 21 ° (dioxane). UV: 2Z8 16400 (methanol ;.

Using a 9-% and acetonmethylene chloride mixture, after recrystallization from an acetone-hexane mixture, 5.3 g of methyl ester 6ct, 9c6-diphtop-ll | i-20 3-dioxy-3-oco-16ct methyl-l, 4-pregnadienoic-21-acid with so pl. 236C.

fctJif + 17 (dioxane) .. UV: S36 16900 (methanol).

b) 12.1 g of a mixture from methyl ester 6ct, 9 o (j-difluoro-11p-2 OsC-dioxy-3-oxo-Gbsb-methyl-, 4-pregnadienoic-21-acid and methyl ester 6od, 9es6-difluoro -11 b, 20 pp-dixi-3-oxo-16cC methyl-1, 4-pregnadienoic-21-acid is mixed with 200 ml of acetone, 200 ml of methylene chloride. And 350 g of active manganese onis (IV), after three hours of stirring, is filtered from the active manganese oxide (IV), the solvent is evaporated and the crude product is recrystallized twice from acetone-hexane, to obtain 5.1 g of methyl ester 6ot, 9c-difluoro-11 | L-hydroxy-3, 20-dioxo-16oC-methyl-1, 4-pregnadieno howl-21-acids with mp. 207-208С.

  128 ° (dioxane). UV:

 17100 (methanol). Example7,

a) 16 g 6 1-fluoro-2-chloro-11p, 21-dioxy 16o1-methyl-1, 4-pregnadien-2, 20-dione and 8 g of copper (II) acetate in 800 ml of methyl alcohol are boiled in for 50 hours. The reaction mixture is separated as described in Example 1a. The crude product is chromatographed on 1.2 "kg of silica gel. Using an 8% -9% mixture of acetone-methylene chloride, after converting from an acetone-deacid mixture, 550 mg of 6cC-fluoro-2-chloro-11p-20c dioxy-3-oxo-1, 4-pregnadienoic-21-acid methyl ester are obtained. from m.p. 230-232 ° C.

cL -1,4 ° C (chloroform). UV: 14800 (methanol)

The acetonmethylene chloride is eluted with a 10-13% mixture. 10.5 g of the mixture

from methyl ester 6c-fluoro-2-chloro-11p | -20 dioxy 3-oxo-1, 4-pregnadienoic-21-acid and methyl ester 6o1-fluoro-2-chloro-11p -20pr-dioxy-3-oxo- 1, 4-pregnadienoic-21-acid as a viscous colorless oil. Using a 13-14% acetonmethylene chloride mixture, after recrystallization from an acetone-hexane mixture, 1.12 g of methyl ester 6c (gfluoro-2-chloro-11p-20pp-dioxy-3-oxo-1, 4-pregnadienoic-21- acids with mp 211-212 ° C.

oL -13 ° (chloroform). UV: EZSO 14800 (methanol).

b) 10.5 g of methyl 6oB-fluoro-2-chloro-11p, 20cX-dioxy-3-oco-16et-methyl-, 4-pro-diene-2-acid acid methyl ester and methyl 6o-fluoro-2-chloro methyl ether -1 If), 20 pp-diox |: and-3-oxo-.16.-methyl-1,4-pregnadienoic-21-acid is dissolved in 60 ml of methylene chloride and 150 g of active manganese oxide (IV) is oxidized at room temperature. temperature After filtration of manganese oxide (IV) and evaporation of the solvent, the crude product is recrystallized twice from acetohexane mixture to obtain 1.08 g of methyl 6cc fluorine-2-chloro-11p-oxy-3,20-dioxo-16 ° C methyl-1, 4-pregnadienene ester -21-acids with so pl. 208 ° C.

loi + 108 ° (dioxane). UV: 2so 15300 (methanol). Example 8

a) 5 g of BS-fluoro-11 (5-21-dioxy-16ez -methyl-1, 4-pregnadien-3,20-dione is mixed with 250 m of isopropyl spita and 2.5 g of copper (II) acetate. Mixed bales t under reflux for 6 hours and separated as described in Example 1a.The crude product is chromatographed over 250 g of silica gel using 7–9% acetone methylene chloride after recrystallization from acetone – hexane to give 309 mg. boC-fluoro-11 -20 L-dioxy-3-oxo-16a-methyl-1, 4 -pregnadienoic-21-acid isopropyl ester with mp 183-184С.

s. |, 5 + 8.5 ° (chloroform). UV: 42 15400 (methanol).

Using a 10-12% mixture of acetone methylene chloride after recrystallization from a mixture of hexane-acetone, 459 g of boC-fluoro-ir-20 isopropyl ether are obtained | -dioxy-3-oxo-16c6-methyl-1, 4-pregnadienoic-21-acid with so pl. 182-183 p.

o1 +19 ° (chloroform). UV 243 15500 (methanol).

b) A mixture of isopropyl ester of ba.-fluoro-11p) -20 1-dioxy-3-oxo-16o1g-methyl-1, 4-pregnadienoic-21-acid and isopropyl ether BL-fluoro-IR, 201-dioxy-3 -oxo-16cc-methyl-1, 4-pregnadienoic-21-acid is oxidized at the temperature indicated in example 16. catch it After hexacrystallization from a mixture of hexane-adhetop, 1.78 g of bob-fluoro-11 p -oxy-3, 20-dioxo-1bc1 isopropyl ester are obtained; Magil-1,4-pregnadienoic-21-acid with m.p. 219-220 ° C. , f 140 (chloroform). Example 9. a) In the reaction conditions described in Example 1a, however, using isoamyl alcohol as a solvent from 6cC-fluoro 11p-21-di-hydroxy-16 -mbtil-1,4-pregnadien-3,20-dione get a mixture of isoamyl ester 6c1C-fluoro-11) -20o-dioxy 3-oxo-1be -methyl-1, 4-pregnadienoic-21-acid and isoamyl ester boftor-11R-20oC | G-DIO SI-3-OXO- 1,4-pregnadioic-21-acid. b) 9.9 g of the mixture obtained were transferred under the conditions indicated in example 16 in 4 g of isoamyl ether 6-fluoro-11 ji-hydroxy-3, 20-lioxo-1bc methi -1.4-pregnadienoic-21 - acids with so pl. 189-190 ° C. o /, | f + 134 JJ - -g d. (chloroform) 4 Example 10. a) With the reaction conditions described in Example 1a, however, using tert-butyl alcohol as a solvent, 20 g of bs6-fluorine 11 | L-21-DIOXI-1 bob-methyl-, 4-pregnadien - 3, 20-dione receive a mixture of tert-butyl ester bs (.-Fluoro-11p -20c-dioxy-3-oxo-1bcC-methyl -1, 4-prvG nadienoic-21-acid and treg-butyl ester bob-fluoro-llp 20pp-diox 3-okso-166o6-methyl-1, 4-pregandiene-21-acid in the amount of 9.8 g b ) The mixture was prepared as described in Example 16, converted to the β6-fluoro-11p-hydroxy-3,20-dioxo-1bc6-methyl-1, 4-pregnadieno tert-butyl ester howl-21-acid. Yield 3.16 g (from cm x hexane-acetone), mp-. 175-ITG C. cC h - -127 (chloroform). Example 11. a) Under the reaction conditions described in Example 1a using ethyl alcohol as a solvent from 8.6 g of 1.9 DEG (.-Difter-ll iv21-Dioxy-1bc6-methyl-, 4-pregnadiadien-3, 20 -dione get 6.1 g of a mixture of ethyl BS1,9.-difluoro-Ir-20og ether-dioxy-3-oxo-16c {gmethyl-1, 4-pregnacienoic-21-acid and ethyl ester 6oi, EL-difluoro-11 jb ,, 20 jir-dioxy-3-oxo-16c (.-methyl-1,4-pregnadienoic-21-acid. b) 4.3 g of the mixture obtained are converted, as described in Example 16, to the 6ci ethyl ester -, 9ct-dipter-llp-okey-3,20 X yokoko-lbcC-methyl-l, 4-prognosis 21-kisloty, crude product twice perebrista Licking from I-ec San-Acetone yields 1.02 g of pure product with a melting point of 205-20 ° C. ci. + 126 ° (dioxane). Example 12. a) With the reaction conditions from 6c1 indicated in Example 4a. , 9o (-difluoro-11E, 21 dioxy-16oC-methyl-1,4-pregnadien-3, 20-dione receive a mixture of butyl ether 6d., 9ot-diphtho-lp-20ot-dioxy-3-oco-lbot-methyl -l, 4-pregnadienoic-21-acid and butyl ester 6at, 9Y - difluoro-1 ip f 20p | -dioxy-3-oxo-16aL-methyl-1, 4-pregnadkenoic-21-acid. b) The resulting mixture is converted as described in Example 4b into butyl ether, C, 9ci.-diphoter-ll) i-oxy-3,20-dioxy-lbat-methyl-, 4-predicted 21-acid, Example 13. a ) Under the reaction conditions described in Example 1a, 16 g of bl-fluoro-9o1-chlorolip, 21-dioxy-1, bcc-methyl-1,4-pregnadien-3, 20-dione are obtained. 15.4 g of a mixture of methyl esC-fluoro-9c {gchlor-11 5, 20L dioxy-3-oxo-1bobgmethyl-1, 4-pregnadienoic-21g acid and boC-fluoro-9c6-chloro-11 jb, 20 b-dioxy-3 oxo-1 bo1-methyl-1, 4-pregnadienoic-21-acid. b) 12.9 g of the mixture obtained was converted, as described in Example 16, into 5.4 g of bc-fluoro-Ess-chloro-11r) -oxy-3,20-dioxo-1bo methyl ester (, -methyl -1, 4-pregnadienoic-21-acid with a melting point of 22b-228C, + 154 (dioxane). EXAMPLE 14 a) With the reaction conditions described in Example 4a of 8 g of bo (. -fluoro-9-chloro-llfb, 21-dioxy-16dL-methyl-, 4-prognanedien-3, 20-dione receive the bcc-fluoro-9-chloro-Er bromide ester, 20 ° C-dioxy-3- oxo-16 1.-methyl-1, 4-pregnadienoic-21-acid and boOgfluoro-9-chloro-11 b butyl ester, 20p p-dioxy-3-oxo-1bo (t-methyl-1, 4-pregnadienoic) 21-acids. B) 5.3 g of the mixture obtained is translated as isano in example 4b to 1.11 g of butyl ester 6o6-fluoro-9.-chloro-Ir-hydroxy-3, 20-dioxo-16c3. methyl-1, 4-prvnadadienoic-21-acid with mp 181 -182 ° C. CL 149 (chloroform). Example 15. a) Under the reaction conditions described in example 1a, using iclohexanol as a solvent | from llp, 21-AHOKCH-6ct, 16sL-dimatyl-1, 4-pregnadien-3, 20-dione will receive a mixture of lip cyclohexyl ester, 20sCp-dioxy-3-oxo-bsz1, Gb-dimethyl-1, 4-presagnenoyl 21-acids and tsikkoke power ether 11 p, 2 About jbj. -dkok Si-3-oxo-b, 1bo (, - dimethyl-1,4-pregnaenoic-21-acid. b) The resulting mixture, as described by tsimer 1, is converted to the cyclohexyl ester of 11p-hydroxy-3,20-dioxo -bahn,16 dimethyl-1, 4-prvgnadienoicova-21-acid yn R and R 16 e. a) Using the procedure described in Example 1a for catching the reaction of 19.8 g of 6e1-fluoro-9a I / L-dichloro-21 -oxy-16cc-methyl-1,4-pregneschien-3, 20-dione after recrystallization from a mixture of acetone-hex, 12.3 g of methyl ester 6c6-fluoro-9 ° C are obtained, 11 | | -dichloro-20 pF-oxy-3-hydroxy-16cc-mvtil-1, 4-pregnadienoic-21-acid with m.p. 217-219 C. b) The resulting mixture is translated as described in Example 16 in 6.4 g of methyl ester of boS-fluoro-Esz, llE-di-chloro-3, 20-dioxo-6oi. -Methyl-1, 4-progranadione-21-acid with m.p. 218-220 C. ct.2.5 + 165 ° (dioxane). Example 17. a) Under the conditions described in example 1a for the reaction of tB, g Get, l i-diphop-9oi, -hlor-21-oxy-l6cC-methyl-l, 4-pregnadiene-3,20-dione after recrystallization from a mixture of hexane. acetone get 12.1 g of methyl ester of boC, 11p-difluoro-9c-chloro-20p) p-hydroxy-3-oxo-16 ° C methyl-1,4-pregnadienoic-21-acid with m.p. . 246-247. 6) The resulting product, as described in Example 1, is converted to 4.5 g of methyl 6ci ester, ll | - zlift-9c6-chlorop-3, 20-dioxo-16c {.- methyl-1,4-Prvnadadienoic-21-acid with m.p. 238-239 ° C. about 1.5 4- 136 (chloroform). . EXAMPLE 18, 50 mg of bcc-fluoro-lljb-hydroxy-3, 20-dioxo-16oC-methyl-1, 4-pregnadienoic-21-acid is dissolved in 3 MP of methylene chloride and mixed with 3 ml of ether diazotane solution. After 10 minutes, acetic acid was added dropwise until the yellow color disappeared, and the solvent was evaporated in vacuo. The starch is recrystallized from acetone-hexane. The yield of 38 mg of methyl ester 6oC fluorine-11 (L-hydroxy-3,20-dioxo-16c6-methyl-1, 4-pregnadieno 21-acid with mp 189-190 ° C. EXAMPLE 19 500 mg of BCC-fluoro-11) L-hydroxy-3,20-dioxo-16cC-methyl-1,4-pregnadienoic-21-acid is dissolved in 100 ml of absolute ether, mixed with 7 ml of butyl alcohol and 1.5 ml of dicyclohexylcarbodiimide. After eighteen hours stirring, dicyclohexyl urea is separated at room temperature. The filtrate is concentrated and the residue is chromatographed on silica gel. Using a 9-11% acetone-hexane mixture after the first installation from an acetone-hexane mixture, 256 mg of 6cC-fluoro-Ir-oxy-3,20-dioxo-1bs-methyl-1,4-pregnadienene-21 butyl ester are obtained. -acids with m.p. 185-187 ° C. Example 20, 5 g of butyl ether 6, with cpfluoro-11p-oxy-3, 20-dioxo-166-methyl-14-pregnadienoic-21-acid is dissolved in 300 ml of absolute ethanol and mixed with 250 mg of tert-butylate potassium. The mixture is boiled under argon for 1 h. The reaction product is precipitated with 1% acetic acid and the sediment is filtered off with suction. The crystalline crude product is dissolved in 100 ml of ethylene chloride, washed with a saturated solution of hydrogen carbonate and water. The solution is dried with sulfate sodium and release in vacuo from solvent. By recrystallization of the crude From the acetone-hexane mixture, 2.6 g of bob-fluoro-llpi-hydroxy-3,20-diox6-16o-methyl-1, 4-pregnadienoic-21-acid with m.p. + 143 ° (chloroform). Example 21 5 g of butic 6c-fluoro-11 L-hydroxy-3, 20-cyoxo-16ci.-Methyl-1, 4-pregnadienoro-21-acid ester are dissolved in 180 ml of anhydrous isopropyl alcohol and 150 mg of tert-butylate calcium are added. The solution is boiled for 19 hours under argon atmosphere. The reaction product is precipitated with 3 liters of ice water containing 2 ml of acetic acid. The precipitate is filtered off, dissolved in 100 ml of methylene chloride and the organic phase is washed with a saturated solution of sodium bicarbonate and water. The solution is dried with sodium sulfate, the crude product after evaporation of the solvent is chromatographed on 500 g of silica gel using acetone-hexane, and after recrystallization from hexane-acetone, 1.72 g of bo-C-fluoro-I-OXI-3- isopropyl ester is obtained. dioxo-16c6-methyl-1,4-pregnadienoic-21-acid with m.p. 223 C. v. If + 140 ° (chloroform Example 22. 1g of methyl ester 6o, ll | i-diphoter-9-chlorop-3,20-dioxo-16oL-methyl-i, 4-pregna dienoWoH-21-ACIDS dissolve in 50 ml of butyl alcohol and under argon atmosphere are mixed with 60 mg of potassium t-butylate, stirred for 1 hour at, diluted with 100 ml of methylene chloride and washed with 50 ml of 1% acetic acid and the organic phase is washed with water and dried with sodium sulfate. Crude the product is chromatographed on 300 g of silica gel using hexane-acetone; after recrystallization from acetone hexane, 615 mg of butyl ether is obtained. a 6d, Ir-difluoro-9-chloro-3, 20-dioxo-16cC-methyl-1, 4-pregnadienoevoi-21-ACID with mp 152 C. + 135 ° C (chloroform). Example 23i5r butyl ether 6cc-fluoro-11r-hydroxy-3,20-wild :: o-16 1-methyl-1, 4-pregnadienoic-21-acid, as described in example 20,

reacted with n; propyl alcohol and separated. after recrystallization from a mixture of acetone hexane, 2.07 g of 6O6-fluoro-11) oxy-3, 20-dioxo-1bc6-methyl-1, 4-pregnadienoic-21-acid propyl ester are obtained with m.p. ,

ci 140 (chloroform).

Example24. To a solution of 4.6 g of bcc-fluoro-11 |% -oxy-3, 20-dioxo-1br-methyl-1,4 pregnadienoic-21-acid butyl ester in 300 ml of sec-butyl alcohol is added 400 ml of tert- potassium butylate, heated to 80 ° C for 18 hours under an argon atmosphere, diluted with 300 ml of methylene chloride, and the solution was washed successively with 1% acetic acid and water. After drying with sodium sulfate and evaporation of the solvent, the crude product was twice recrystallized from acetone-hexane to obtain 1.35 g of bob-fluoro-ir-oxy-3, 2 O-dioxo-1 bob-methyl-1,4-pregnadienene ester -21-acids with so pl. .

(odlj, + 138 ° (chloroform).

Example 25, 5g of isobutyl ester b (X-fluoro-11 (-oxy-3,20-dioxo-16 ot-methyl-1,4-pregnadienoic-21-acid) is dissolved in 250 ml of isopentyl alcohol and mixed with 250 mg of tert. potassium butyl potassium chloride. The solution is heated for 1 hour under argon atmosphere, diluted with an equal volume of methylene chloride, washed with 1% acetic acid and water, the organic solution is dried with sodium sulfate and the solvent is distilled off in a vacuum. The crude product is chromatographed on 500 g of silica gel using a mixture of hexane-acetone and recrystallized from a mixture of acetone-hexane get 1, 92 g of isopentyl ester of bob-fluoro-11p-hydroxy-3,20-dioxo-1bc6-methyl-1, 4-pregnadienoic-21-acid with mp 192 ° C.

oi + 135 ° (chloroform).

Example 26. 9.9 g of bob-fluoro-Ir-hydroxy-3,20-dioxo-161-methyl-1, 4-pregnadienoic-21-acid methyl ester is dissolved in 250 ml of alopentyl alcohol and mixed with 200 mg of aluminum isopropoxide. The mixture is heated under argon for 8 hours to a temperature of 100 ° C, diluted with 250 ml of methylene chloride, washed with 1% acetic acid and water. The solution is dried with sodium sulfate and the solvent is distilled off in vacuo. After repeated recrystallization of the crude product from a mixture of / acetone-hexane, 4 g of isopentyl ester 6o6-fluoro-11 L-hydroxy-3,20-diox co-1 bo (g is methyl-1,4-pregnadienoic-21-acid with t .

cf, + 134 ° (chloroform),

Example 27 To a solution of 1 g of bos-fluoro-1p-oxy-3, 20-dioxo-16o1-methyl-1,4-pregnadienoic-21-butyl butyl ester in 100 ml of absolute methyl alcohol is added 100 mg of tert.-butylate potassium and the mixture is boiled under argon for 1 h, precipitated with ten times the amount of ice water, the precipitate is filtered off with suction, dissolved in methylene chloride, and the solution is washed with 1% acetic acid, saturated sodium bicarbonate solution and water. After drying with sodium sulfate, the solvent is distilled off in vacuo and the crude product is recrystallized from acetone hexane; 570 g of methyl bs3 ester (gfluoro-11p-hydroxy-3 f 20-dioxo-1bsb-methyl-1, 4-pregnadienoic-21-acid with mp 190 ° C.

lai + 145 (chloroform). Example 28. 4.8 g of butyl ester 6o (-fluoro-11p) hydroxy-3, 20-dioxo-1bo (, -methyl-1,4-pregnadnenoic 21-acid) is dissolved in 150 ml of isobutyl alcohol and mixed with 250 mg Potassium tert-butylate is heated to 90 HP in an argon atmosphere for 18 hours and the reaction mixture is separated as described in Example 25. The crude product is recrystallized from acetone-hexane to give 1.6 g of isobutyl ether 6cC-fluoro-11 ji- hydroxy-3, 20-dioxo-1-C-methyl-1, 4-pregnadienoic-21-acid with mp 200 ° C,

a + 139 (chloroform).

Example 29. 1.8 g of methyl Be6-fluoro-9c6, Ir-dichloro-3, 20-dioxo-1bcl-ieyl-1, 4-pregnadienoic-21-acid methyl ester is dissolved in 100 mp of n-butyl alcohol and mixed with 200 mg of potassium t-butylate, heated to argon atmosphere for 1 hour and the reaction mixture was separated as described in Example 25. The crude product was chromatographed over 250 g of silica gel using acetone hexane; 1.54 g of butyl ether was obtained. (.-fluoro-9 ° C, llf-di-chloro-3,20-dioxo-lb. -methyl-l, 4-pregnadienoic-21-acid, which melts at acetone-hexane at refining from a mixture of e 147 ° C.

 + 165 ° (chloroform).

Example 30. To a solution of 100 m.s. sodium in 100 ml of n-decanol was added 5 g of methyl ester of bob-fluoro-Ir-hydroxy-3, 20-dioxo-1bo (, methnl-1,4-pregnadienoic-21-acid It is heated for 28 hours at 100 ° C, mixed with 300 ml of methylene chloride, washed with 1% acetic acid, a saturated solution of bicarbonate and water. After drying with sodium sulfate, the methylene chloride is distilled off in vacuo, then decanol in high vacuum. the product is chromatographed on

500 ml of silica gel using acetone-hexane mixture to obtain 3.9 g of bob-Fluoro-11 | L-hydroxy-3, 20-dioxo-16C1-methyl-1,4-pregnadienoic-21-acid decyl ester, which after recrystallization from a mixture of acetone-hexane melts at 93.5 ° C.

 + 117 (chloroform).

Example 31. 700 mg of methyl; 6c6-fluoro-9s1-chloro-11p-hydroxy-3, 20-dioxo-1b (-methyl-1,4-pregnadienoic-21-acid) ester is dissolved by heating in 60 ml of ngbutyl alcohol and After cooling, the mixture is mixed with 20 mg of potassium t-butoxide. The solution is stirred for 2 hours under argon at room temperature, diluted with methylene chloride, and then, as described in Example 25, separated by chromatography on 250 g of silica gel, the mixture is obtained: acetone-hexane 610 mg of butyl ester 6o (.- fluoro-9c6-chloro-11 |} -oxy-3,20-dioxo-16cC-methyl-1, 4-pregnadienoic-21- acids. After recrystallization from acetone-hexane, 456 mg of this product is obtained, which melts at 180.8 ° C (with decomposition).

d.- 150 ° (chloroform).

Example 32, 1.8 g of butyl 6c-fluoro-11p-hydroxy-3,20-dioxo-16cc6-methyl-1, 4-pregnanthioic 21-acid is mixed with 30 ml of 2-propene-1- ol, 10 mg of hydroquinone and 100 mg of tert.-potassium butylate and heated for 18 hours to. under argon, the reaction mixture was separated as described in example 31, chromatographed on 250 g of silica gel using acetone hexane; 1.2 g of 2a-propenyl ester 6a-fluoro-1 1 (L-hydroxy-3, 20-dioxo- 1bs6-methyl-1, 4-pregnadienoic-21-acid. After one recrystallization from a mixture of acetone hexane, 340 mg of product are obtained, which melt at 159 ° C.

  + 1.42 (chloroform).

PRI 33, 1.2 g of bob-fluoro-Ir-oxy-3 butyl ester, 20-dioxco-16o (.-Methyl-l, 4-pregnadienoic-21-acid, 50 ml of ethylene glycol monomethyl ether and 100 mg tert potassium β-butylate is heated to 100 ° C for 5 hours. The reaction mixture is separated as described in example 27. Chromatography on 250 g of silt agel using acetone-hexane gives 730 mg of 2-methoxyethyl ether 6 ° (. 11 hydroxy-3, O-dioxo-Gbsb-methyl-, 4-pregnadienoic-21-acid, after a single recrystallization from an acetonehexane mixture, 169 mg of product are obtained, which melt at,

 135 ° (chloroform). Example 34.5g of 6s1-fluoro-11 p-hydroxy-3,20-dioxo-6c1b-methyl-1.4 pregmadieno-21-acid methyl ester is mixed with 30 ml of octanol and 250 mg of potassium t-butylate and heated for 48 hours before, the reaction product was separated as described in Example 29, and 3.9 g of 6c octyl ester (.-Fluoro-11p-hydroxy-3,20-dio, cco-16o methyl-1,4-pregrediolbenoyl) was obtained. -21-ACIDS in the form of a viscous oil. + 124 (chloroform).

Example 35. 1 g of 6-o-fluoro-11-butyl ester of L-hydroxy-3,20-dioxo-16 ° C methyl-1, 4-pregnadienoic-21-acid is mixed with 20 ml of 2-propyn-1-ol and 100 mg potassium tert-butoxide and stirred for 24 hours at room temperature. The reaction mixture was separated as described in Example 21, and 280 mg of 6c-fluoro-11p-hydroxy-3 2-propyl ester, 20-dioxo-16cC-methyl-1,4-pregnadienoic-21-acid with t were obtained. .pl. 179182 ° C.

25

  + 152 ° (chloroform).

5 Example 36. 4 g of 6cC-fluoro-11p butyl ether) -oxy-3,20-dioxo-1bo (.-Methyl-1,4-pregnadienoic-21-kislot) are mixed with 70 ml of benzyl alcohol and 100 mg of tert.- butylate

0 potassium and heated to 100 ° C for 28 h in an argon atmosphere. Separation of the reaction mixture was carried out as described in Example 25, and 810 mg of benzyl. BoC-fluoro 5 -11E-hydroxy-3,20-dioxo-1br6-methyl-1, 4-pregnadienoic-21-acid with t .pl. 213 ° C.

cL + 127 ° (chloroform). Example 37. 1g butyl

Q ester 6o-fluoro-1 lfi-hydroxy-3, 20-dioxo-1bs -methyl-1, 4-pregnadienoic-21-acid is mixed with 15 ml of (-) - 2-methyl-1-butanol and 25 mg tert potassium butyl acetate and heated to 100 ° C for

25 h. Separation of the reaction mixture

 carried out as described in Example 25, and 240 mg of 6-6-fluoro-11 p-hydroxy-3, 20-dioxo-16c-methyl-1, 4-pregnadienoic-21-acid with m.p. square 177 ° C.

 oL + 132 ° (chloroform).

Example 38: 1g of 6o6-fluoro-11 | b-hydroxy-3,20-dioxo-16o6-methyl--1, 4-pregnadienoic-21-butyl butyl ester is mixed with 25 ml of anhydrous 1,3-propanediol and 100 mg tert potassium β-butylate and heated to 100 ° C for 3 hours. The reaction mixture was separated as described in Example 21, and 510 mg of 3-hydroxypropyl was obtained.

0 ester of bob-fluoro-11 pr-oxy-3, -20-dioxco-16ot. -Methyl-1, 4-prognoxy-2-acid in the form of a viscous oil. cL + 120 ° (chloroform). Example 40. 3 g methyl

5 esters of 6cC-fluoro-Ir1-hydroxy-3,20-diox-, co-1b x-methyl-1,4-pregnadiene-21-acids under the conditions described in example 20 are treated with ngpentanol. The crude product is chromatographed on silica gel with acetone hexane and recrystallized from acetone-hexane. Yield 2.06 g of pentyl ester 6o6-fluoro-.11 L-hydroxy-3,20-dioxo-16oC-methyl-1, 4-pregnadien-21-acid with m.p. 152-153 ° C. S + 132 (chloroform). Spectrum: 42 16900 (methanol). Example 41. 1.5 g of methyl ester 6c-fluoro-11 () - hydroxy-3,20-dioxo-1 bob-methyl-1,4-pregnadiene-21-acid under the conditions indicated in Example 20 are treated with neopentyl alcohol. The crude product is chromatographed and recrystallized from acetone-hexane. Output 608 g of neopentyl ester of bob-fluoro-11 p-hydroxy-3, 20-dioxo-16c-methyl-1,4-pregnadien-21-acid with so pl. 187-189 p. (cC) + 128 ° (chloroform). UV spectrum: 42 16900 (methanol). Example 42 2g of methyl ester 6o |, -fluoro-11p-hydroxy-3, 20-dioxo-1-bob-methyl-1, 4-pregnadien-21-acid under the conditions specified in Example 20 are treated with cyclopropylmethanol. The crude product is chromatographed and recrystallized from acetone-hexane. Yield of 1.54 g of 6cC-fluoro-11p-hydroxy-3,20-dioxo-16oL-methyl-l, 4-prognadien-21-cyclocyclopropyl ether 6cC-fluoro-11p-oxy-c. 192-193 ° C. dL + 139 ° (chloroform). Example 43 1g methyl ester 6e (, - fluoro-11p-hydroxy-3,20-dioxo-1 b) 1.-methyl-1,4-pregnadien-21-acids under the conditions indicated in example 37, are treated ( ±) -2-Methyl-butan-1-ol. Y The yield is 488 mg of (+) - 2-methyl-but-1-yl ester 6a1-fluoro-11b-hydroxy-3, 20-dioxo-16c {, - methyl-1,4-pregnadien-21-acid with so pl. 177 ° C. lcL + 136 ° (chloroform). Example44. a) 107 g 9e (gfluoro-1113,17ot, 21-trioxy-16 (-methyl-1,4-pregnadien-3, 20-it is dissolved in 2 liters of glacial acetic acid and mixed with 10 g of water containing crystallization Zinc acetate, boil the reaction mixture for 4 hours, then precipitate with 10 liters of ice water. The precipitate is filtered and dissolved in methylene chloride, which is washed with water until neutral. The solution is dried with anhydrous sodium sulfate and evaporated in 112 g of a mixture of 9 ° C-fluoro-11 | 3.20 dioxy-3-oxo-16c6-methyl-1, 4.17 (20) -pregnatriene-21-al and 9o-fluoro-11E-oxy-20- acetoxy-3-ox -16E1: -methyl-1,4, 17 (20) - pregkatrian 21-al in the form of a viscous oil. B) 108 g of the above mixture is dissolved in 3 liters of methanol and mixed with a solution of 15 g of potassium hydroxide in 30 ml of water, boil under argon for 1.5 h, then distilled from methanol in vacuo.The residue is dissolved in 2) 1 of water and 2 liters of methylene chloride and the mixture is re-extracted with methylene chloride for further cleaning. The aqueous solution is acidified with 4 liters of sulfuric acid. extracted again several times with methylene chloride, which is then dried with sodium sulfate. After evaporation of the solvent in vacuo, 52 g of a mixture of 9c-fluoro-11 (, 20o6-dioxy-3-oco-16c. -Methyl-1, 4-pregnadiene 21-acids and 9c: C-fluoro-11, 20 5- dnoxy-3-oxo-16oC methyl-1, 4-pregnadien-21-acid B in the form of a solid crystalline precipitate. c) 36 g of the mixture of acids described above are mixed with 200 ml of methanol and cooled to 0 ° C. A solution of diazomethane is added in portions in 1 liter of ether, which is obtained from 30 g of nitroemethyl urea by decomposition with 40% potassium hydroxide solution. The mixture is left for 1 hour at room temperature. The solvent is filtered off with suction under reduced pressure. After that, the excess diazomethane is carefully decomposed with 5 ml of glacial acetic acid. The residue is dissolved in methylene chloride and the solution is washed repeatedly with water. It is dried over anhydrous sodium sulphate and the crude product is chromatographed on 750 g of silica gel. A 6-9% mixture of methylene chloride-acetone is eluted with 2.1 g of methyl ester 9c-fluoro-11p, 20c p-dioxy-3-oxo-16c1-methyl-1, 4-pregnadiene-21-acid. Recrystallization from acetone gives 1.22 g of substance with m.p. 199.3 ° C. cC + 2.8C (chloroform). A 1012% mixture of methylene chloride-acetone elutes 23.8 g of a mixture of 20aL and 20p compounds. A 13-14% mixture of methylene chloride-acetone elutes 1.19 g of methyl 9-fluoro-11 (B, 20 pp-dioxy-3-oxo-16 ° C methyl-1, 4-pregnadiene-21-acid. The crude product is recrystallized from an acetone-hexane mixture, 794 mg are obtained with a melting point of 206.5 ° C. s + 23 ° (chloroform). d) 18.3 g of a mixture of 20 ° (- and 20p-compounds under the conditions described in Example 16, is oxidized with active manganese oxide (IV). The crude product is chromatographed on silica gel with acetone-hexane and recrystallized from acetone hexane; 8.52 g of methyl ester 9c-fluoro-11p-hydroxy-16o are obtained (, methyl 3,20-dioxo -1, 4-pregnadien-21-acids with mp 21b-217С.

оС) fj 4-144 ° (chloroform). UV Spectrum; 16300.

Example44. 1.87g of methyl ester .9 1-fluoro-11p-hydroxy-16c, -methyl-3, 20-DIOXO-1,4-pregnadiene-21-acids under the conditions described in example 22 are converted to butyl ester 9o -fluoro-11p-hydroxy-16s1-methyl-3, 20-DIOXO-1,4 pregnadien-21-acids. Exit 430 mg of substance with so pl. 162-164C.

) + 139 (chloroform). UV spectrum: 219.

Example 45. Under the conditions described in Example 43a-g, 25 g of 11.17 of 21-trioxy-1,4-pregnadien-3,20-dione are converted to the methyl ester of 11p-hydroxy-3, 20-dioxy 1, 4-pregnadien-21-acid. Exit 5.7g.

Example 46 5.7 g of methyl 11p-hydroxy-3,20-dioxy-1,4-pregnadien-21-pregnanoic acid methyl ester under the conditions of example 20 are transesterified with ethanol to give 2.09 g of ethyl ester 11-oxy-3, 20-dioxo-1,4-pregnadien-21-pregnanoic acid with m.p. 188-189

1cc + 175 ° (chloroform). UV spectrum: 43 15700 (methanol).

Example 47

 a) Under the conditions indicated in example 4a, 20 g of 6c are converted (gfluoro-11p 21-diox 1-16c6-methyl-4-pregnen-3, 20-dione and 15.3 g of a mixture is obtained from butyl ether 6o (gfluoro-11 | 5, 20df-dioxy-3-oxo-1-bo-6-methyl-4-pregnan-21-acids and butyl ester 6c (, - fluoro-11 p1.20p-dioxy-3-oxo-16a (, - methyl 4-pregnan-21-acids and 300 mg of butyl ester 6cC fluoro-11p, 20 | 5p-dioxy-3-ox6-1boc-methyl-4-pregnen-21-acid with mp (4 ° С ( from the mixture methylene chloride - diisopropyl ether).

(c6 + 54 (chloroform). UV spectrum: g 15000 (methanol), as well as 2.8 g of boC-fluorine -lljb butyl ester, 20p | -dioxy-3-oxo-1bo6-methyl-4-pregne / -21- 101slots with mp. 139 ° C (from acetone-hexane mixture).

d.l + 65 (chloroform). UV spectrum: 2E7. 14,900 (methanol).

b) 15.3 g of the mixture obtained, under the conditions specified in Example 18, is reacted with manganese oxide (IV). The crude product is chromatographed with 9-10% acetone-hexane; this is obtained after recrystallization from acetone-hexane 4.0 and 6-6 fluoro-4-oxy-3 butyl ester, 20-dioxo-16c (. 4-pregnen-21-acids with mp 188;

-Q + iT6 (chloroform). UV spectrum: 2-6 16100 (methanol). PRIER 48.

a) under the conditions indicated in Example 4a, from 5.7 g, 21-dioxy-16 ° C methyl-1, 4-pregnadien-3.20-one is 5.8 g of a mixture of butyl ester I 20a -d6-xi-3- oxo-166-methyl-1,4-pregnadien-21-acid and butyl ether, 20 pp-dihydroxy-3-oxo-16e6-methyl-1, 4-pregnadien-21-acid, and also pure compounds: 230 mg of butyl ester 11 / i, 20 ° (dioxy-3-oxo-16cC-methyl 1, 4-pregnadien-21-acid with mp 166.3 ° C (from methylene chloride-diisopropyl ether mixture)

cL} + 2.7 ° (chloroform), UV spectrum: 544 14800 (methanol) and 880 mg of butyl ether 20fip-dioxy-3 oxo-16o (.-methyl-1,4-pregnadien-21-acid with m.p. 177.7 ° C (from acetone-hexane mixture).

p.2g + 12.7 "(chloroform). UV spectrum: ej44 14900 (methanol).

.6) 5.8 g of the mixture obtained, under the conditions indicated in Example 18, is reacted with manganese oxide (IV). A crude chromatographic product with 9-10% acetone-hexane is obtained after recrystallization from acetone-hexane mixture 2.88 g of 11/5-hydroxy-3,2-dioxo-16cC-methyl-1, 4- butyl ester pregnadien-21-acids with so pl. 149.8 ° C.

o6 + 151 ° (-chloroform). UV spectrum: .43 15900 (methanol).

Example 49. Under the conditions outlined in Example 3, 1 g of n-butyl-fluoro-ir-hydroxy-3, 20-dioxo-16o1-methyl-4-pregnon-21-acid butyl ester was washed. The crude product is dissolved in a small amount of ethyl acetate and. crystallized at -30 ° C.

Yield 458 mg 6o (, - fluorine-11 {L-hydroxy-3,2-dioxo-16 ct-methyl-4-pregnen-21-acids with mp 206-209 ° С.

oi + 184 ° (pyridine). UV spectrum 2-6- 14000 (methanol).

Example 50. 390 mg of bo-fluoro-11p | -oxy-16c1-methyl 3, 20-dioxo-1,4-prvnadadien-21-acid is dissolved in 50 ml of methanol and mixed with 10 ivin methanolic solution of potassium hydroxide. The solvent is evaporated in vacuo and the residue is mixed with 100 ml of ether. The precipitated 6o6-fluoro-11-oxy-16c sodium salt (-methyl-3,20-DIOXO-1,4-pregnadiene-21-acid) is filtered off with suction and dried under vacuum. The yield is 374 mg.

Example 51. 1 g of methyl 6oi, 11p-difluoro-9a6-chloro-16OOO-methyl-3, 20-DIOXO-1,4-pregnadien-21-acid was washed under the conditions of Example 3. The crude product is recrystallized from ovaty- from ethyl acetate npifi at room temperature, 380 mg of bcC, 11 5-difluoro-9c6-chloro-16: C-methyl-3, 20-dioxo-1,4-pregnadiene 21-acids are obtained c. 269.5 ° C (with decomposition).

{d.} + 154 ° (pyridine). UV spectrum: 236 15800,

Example 52. 750 g of methyl ester 6c {.- fluoro-2-chloro-11 | -oxy-3, 20-dioxo-16o.-methyl-1,4-pregnadi vn-21-acids under the conditions indicated in example 20 are treated with 30 ml of straight panol and 50 mg of tert-potassium butylate. After recrystallization from a mixture of mtylene chloride - diisopropyl ether, 351 mg of α-fluoro 2-chloro-11p-hydroxy-3,20-dioxo-166-6 methyl-1, 4-pregnadien-21-acid propyl ester are obtained with m.p., 167, 1 ° C d, 107 (chloroform). UV spectrum: (7,940, 249 1560 (methanol). Example 53. 1 g of butyl ester of ba, -fluoro-11-hydroxy-3,20-dioxo-16c1. Methyl-1,4-pregnadien-21-acid under conditions x, indicated in Example 39, is treated with + -mentol. The crude product is chromatographed on silica gel. Using a 12-14% mixture of acetohexane, after recrystallization from a mixture of methylene chloride-diisopr sawed ether, 293 mg (+) - menthyl ether 6ccC- Fluorine-11p-oxy-3,20-dioxo-166-methyl-1, 4-pregnadien-21-acids with mp 127-140 ° C. t 116 (chloroform). UV-Spectrum: 624 16200 (methanol). Example 54. 1g butyl ester 6O-fluoro-11p) -oxy-3,20-dioxo-16 Under methyl-1,4-pregnadien-21-acid under the conditions indicated in Example 39, treatment with (-) (IR) -menthol. The crude product is chromatographed. G using a 13-16% mixture of acetone-hexane is obtained after recrystallization and a mixture of methylene chloride-diisopropyl ether, 522 mg of (1E) -mento 6O-fluoro-11 (i-hydroxy-3,20-dioxo-16ot-methyl -1, 4-pregnadien-21-acids with a melting point of 136.8 ° C. s, + 77 ° (chloroform). UV spectrum: 24 15500 (methanol). Example 55. 1 g of butyl 6e6-fluoro-11 ester | -oxy-3,20-dioxo-166-methyl-1, 4-pregnadien-21-acids are dissolved in 20 ml of toluene, mixed with 10 g of (-) (IS) -borneol and 100 mg of potassium tert-butylate and heating for 20 hours at 110 ° C. Then concentrated in vacuo, the residue is concentrated in methylene chloride, washing with sat. The crude product is chromatographed on silica gel with acetone-hexane and recrystallized from methylene chloride-diisopropyl ether to give 464 mg of (13) -bornyl ester 6b -fluoro-11; 1-hydroxy- 3,20-dioxo-16s6-MB of thyl-1,4-pregnadiel-21-acids with a melting point of 227.9 ° C (with decomposition) 109 (chloroform). UV spectrum: 542 16900 (methanol). Example 56: 1g of 6O-fluoro-11p butyl ester) -oxy-3, 20-dioxo-16 (-methyl 1,4-pregnadien-21-acid) under the conditions of example 55 is treated with (+) - isoborneol. The crude product is chromatographed with acetone-hexane. After recrystallization from acetone-hexane mixture, 98 mg of (±) -isobornyl 6cir-fluoro-11 |) -oxy-3,20-dioxo-16s1-methyl-1, 4-pregnane- 21-acids with m.p. 218, (at decomposition). oL.- - + 64 (chloroform). UV spectrum: 24-2 16600 (methanol). Example 57. 1 g of 6c6-fluoro-11p-hydroxy-3, 20-dioxo-16c-methyl-1,4-pregnadien-21-acid is dissolved in 40 ml of tetrahydrofuran, mixed with 1 MP dimethylformamide dinopentyl acetal and 1 ml ( ±) (3) -2-butanol IG is left for 16 days at room temperature. It is then diluted with methylene chloride, washed with dilute hydrochloric acid, saturated sodium bicarbonate and water, and concentrated in vacuo. The residue is chromatographed on silica gel with acetone-hexane and recrystallized from methylene chloride di-isopropyl ether to give 115 mg of (R) -2-butyl 6o-ft6p-11p-hydroxy-3, 20-dioxo-16c-methyl-1,4- pregnadien-21-acids with so pl. 214.4 ° C. {s + 130 ° (chloroform). UV spectrum: 241 16100 (methanol). Example 58. Dissolve 1 g of 6-6-fluoro-11p-hydroxy-3,20-dioxo-16BC-methyl-1, 4-pregnadiene-21-acid in 15 ml of dimethylformamide dimethylpentyl acetal and 1 ml (-) (R) -2-butanol, as described in Example 57. The crude product is recrystallized from methylene chloride-diisopropyl ether, to give 51 mg of boC-fluoro-11p-hydroxy-3, 20-dioxo-16sb-methyl butyl ester 1, 4-pregnadien-21-acid with so pl. 215.8 ° C. + 118 (chloroform). UV spectrum: 24 14500. Example 59. 1g of 6 ° C-fluoro-11p-hydroxy-3,20-dioxo-16cC-methyl l-1,4-pregnadiene-21-acid butyl ester is dissolved in 10 ml (+) (S) -2-octanol is mixed with 100 mg of potassium tert.-butoxide and heated for 10 minutes at 90 ° C. The octanol is distilled off in vacuo, the residue is dissolved in methylene chloride, washed with sodium bicarbonate solution and water and concentrated in vacuo. The crude product is chromatographed on silica gel with acetone-hexane and recrystallized from methylene chloride-diisopropyl ether to give 305 mg (S) - 2-octyl ester 6c (, - fluoro-Ir-hydroxy-3,20-dioxo-16oC-methyl-1, 4-pregnadiene-21-acid with mp 132 ,.

f

t:

23

Claims (1)

686623 loi + 121 ° (chloroform). UV spectrum: € у4 - 16800 (methanol). Example 60, 1g of 6O1-fluoro-11 hydroxy-ester hydroxy-3,20-dioxo-16c (.-Methyl-1,4 pregnadien-21-kilo is treated with 10 ml of (-) (R) -2-octanol and 100 mg tert-butylate cata is as described in Example 59. The crude product is chromatographed on acetone-hexane on silica gel. After recrystallization from methylene chloride-diisopropyl ether, I get 326 mg (k) -2-octyl ester C-ft-11p- hydroxy-3,20-dioxo-1bcC-methyl-1,4-pregnadiene-21-acids with m.p., ctj + 120 (chloroform). UV spectrum: .4 16 & 00 (methanol). Invention Formula common prenanoic acid derivatives uly I vodorodf chloro or methyl; hydrogen, fluoro or chloro; 24 Z is hydroxy, fluoro or chloro; R is hydrogen or methyl; K 2 - hydrogen, an alkali metal atom, an alkyl radical with 1-12 carbon atoms, lower alkenyl, lower alkynyl, higher oxyalkyl, alkoxyalkyl nivsh, alkyl, enyl, menthyl, bornyl, cyclohexyl or cyclopropyl radikech; the dotted line indicates a possible double bond, characterized in that the compound of general formula II Z. where X, Y, 2, R, and R2 are as defined above, oxidized with manganese dioxide or lead dioxide or tetraacetate of lead in an inert solvent, optionally dehydrated at position 1, 2, or washed and the free acid esterilized or treated with alcohol in the presence of basic catalyst, followed by separation of the target product. Sources of information taken into account in the examination 1. Fizer L., Fizer M., Reagents for organic synthesis, M., Mir, 1970, Vol. 2, p. 221-222.