DE1115246B - Process for the preparation of therapeutically active steroid compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY GERMAN MmL · PATENT OFFICE

kl. 12 ο 25/05

INTERNAT.KL. C 07 C

EXPLAINING EDITORIAL 1115 246

U644irVb / 12o

REGISTRATION DATE: AUGUST 21, 1959

NOTIFICATION OF REGISTRATION AND ISSUE OF EDITORIAL: OCTOBER 19, 1961

The invention relates to a process for the production of therapeutically active steroid compounds with a halogen atom in the 2-position of the steroid nucleus. The obtainable according to the invention Compounds have the general formula:

CH ₉ OR "

Y
I. C = O OH - i
I.

in which X = fluorine, chlorine, bromine or iodine, Y = hydrogen, fluorine, chlorine, bromine or iodine, R '= H, / S-OH or keto oxygen and R ″ = hydrogen or the acyl radical of a carboxylic acid with 1 to 12 carbon atoms means. You will receive according to the following reaction scheme:

Ac-O-CH

CH ₂ -O-Ac

C = O
^CH «L ~~ OH

CH,

IV

Method of manufacture

of therapeutically effective

Steroid compounds

Applicant:

The Upjohn Company, Kalamazoo, Mich. (V. St. A.)

Representative: Dr. W. Beil and A. Hoeppener,

Lawyers, Frankfurt / M.-Höchst, Antoniterstr.

Claimed priority: V. St. v. America 8 September 1958 (No. 759 400)

Alan Hart Nathan, John Alexander Hogg and William Paul Schneider,

Kalamazoo, me. (V. St. A.),

have been named as inventors

CH ₂ -O -Ac

HO

109 709/425

CHp-0-Ac

OH

CH "—O —Ac

CH.

C = O ■ »L - OH

VIII

in which Y '= chlorine, bromine or iodine and Y "= fluorine, chlorine, bromine or iodine, X represents the ones given above Has meaning and Ac is the acyl radical of a carboxylic acid with 1 to 12 carbon atoms.

To produce the starting material used in accordance with the invention, 11-ketoprogesterone is added by the process of US Pat. No. 2,790,814 with about 2 molar equivalents of sodium methylate and about 2 to 10 mols of diethyl oxalate in tert. Reacted butyl alcohol, then treated with about 3 mol of chlorine and finally treated with a small excess of sodium methylate and methanol, whereupon the 2-chloro-3,11-diketo-4,17 (20) - [cis] -pregnadiene-21 - methyl carboxylate is obtained. If 11/3 oxyprogesterone is used, the corresponding 11 /? - oxy compound is formed. The 11-keto and 1 l / S-oxy compounds are converted into 2-chloro-1 / 3,21-dioxy-4,17 (20 ) - [cis] -pregnadiene converted that the 3-position keto group of the 2-chloro-3-keto-4,17 (20) - [cis] -pregnadiene-21-carboxylic acid alkyl ester, which contains an oxygen function in the 11-position, is protected, z. B. by conversion into an enol ether or a ketal group and then reduced with lithium aluminum hydride, sodium aluminum hydride, etc., the carboxylic acid ester group being converted into an oxymethyl group and the 11-position keto group, if present, into a Η, ΟΗ group. By hydrolysis of the enol ether or ketal group in the 3-position, the 2-chloro-1 ljS, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one is obtained. Acylating before this hydrolysis, the 21-position hydroxyl group, one obtains the in-3 position protected 2-chloro-ll _j 6-oxy-21-acyloxy-4,17 (20) - [cis] -Pregnadien-3-one , which can be selectively hydrolyzed and converted into 2-chloro-l /? - oxy-21-acyloxy-4,17 (20) - [cis] -pregnadien-3-one.

If one uses fluorine or fluorine in place of chlorine in the above-mentioned USA patent specification Iodine heptafluoride or bromine, the corresponding ones are obtained 2-fluoro or 2-bromine compounds. The 2-fluoro compounds can also be reacted obtained the 2-chloro steroids with a metal fluoride will. The 2-iodine compounds are made by reacting 2-chloro-1 l / ?, 21-dioxy-4,17 (20) -pregnadien-3-one or acetone obtained.

An alternative procedure for the preparation of 2-fluoro-II / ?, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one leads according to Hogg and coworkers in J. Am. Chem. Soc, 77, p. 4436 (1955), starting from 11 ^, 21-Dioxy-4,17 (20) - [cis] -pregnadien-3-one or its 21-esters, via the 2-alkoxyoxalyl-II / 3,21-dioxy-4,17 (20) - [cis] -pregnadien-3-one and the 2-fluoro-2-alkoxyoxalyl-1 l / ?, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one or their Ester.

To carry out the process according to the invention, the 2-halogen-II / S, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one is used in a manner known per se with osmium tetroxide and an oxidizing agent such as hydrogen peroxide, a peracid, an alkyl peroxide, an amine oxide peroxide, such as N-methylmorpholine oxide peroxide, an aryl jodoxy, such as phenyl iodosoacetate, z. According to one of the U.S. Patents 2,769,825 and 2,769,823 or in J. Am. Chem. Soc, 77, p. 4436 (1955), described process oxidatively to 2-halogen-II / ?, 17 ", 21-trioxy-4-pregnen-3,20-dione-21-acylathydroxyHert. If necessary, the acyloxy group in the 21-position can then be converted into a free hydroxyl group and the 11-position hydroxyl group with chromic acid or an N-halo amide or imide to the keto group oxidize.

5 6

For the subsequent introduction of dissolved hydrogen, if desired, and the 2-halogenognesiumsilicate is chromatographed over a column of 35 g of a fluorine atom in the 9 "position. The desired II / SjTa ^ l-trioxy- ^ pregnen-S ^ O-dione ^ l-acylate, by-product was eluted with a mixture of 15 and 20%, sometimes with sulfuric acid and preferably with acetone in hexanes. 0.351 g of 2-fluoro of a hypohalous acid was obtained, followed by anhydrous 5 ll ^ na ^ l-trioxy ^ -pregnen-S ^ O-dione ^ l-acetate, the sulfur dioxide to the corresponding 2-halo-17 «, after recrystallization from a Melted ethyl acetate 21-dioxy-4,9 (II) -pregnadiene-3,20-dione-21-acylate dehydrohexane mixture at 194 to 199 ° C; dratized. The addition of hypochlorous, under- [x \ _D = + 172 ° (CHCl ₃ ); X _max = 243 ηιμ; a _M 14875. Bromous or subiodous acid for this compound gives the corresponding 2,9oc-dihalogeno analysis for C ₂₃ H ₃₁ O ₆ F: llftna ^ l-trioxy ^ -pregnen-S ^ O-dione ^ l-acylate, the calculated ... C 65.38, H 7.40, F 4.50; by treatment with a base, e.g. B. Found anhydrous ... C 65.68, H 7.85, F 3.97. Potassium acetate, the corresponding epoxy compound
supplies. By hydrolysis with the exclusion of atmospheric oxygen

The reaction of the epoxide with hydrogen fluoride is obtained from it 2-fluorine-l / S, 17 ", 21-trioxy- or agents releasing hydrogen fluoride leads to 4-pregnen-3,20-dione with a melting point of 212 to 221 ° C. 2.9 «-Difluoro-II / 3.17a, 21-trioxy-4-pregnen-3,20-dione-21-acylate, its 11-position hydroxyl group is subsequently oxidized and its 21-position acyloxy group b) 2-fluoro-17 «, 21-dioxy-4-pregnen-3, ll, 20-trione hydrolysed can be. 20 21 acetate

The new steroid compounds containing a halogen atom in the 2-position according to the invention. A solution of 0.35 g of sodium dichromate disposes of excellent physiological effectiveness in hydrate and 0.8 cm ^{3 of} concentrated sulfuric acid in and differing in their effect on 5 cm ^{3 of} water Room temperature cooled the mineral and hydrogen change advantageously from 25 and then with a solution of 0.5 g2-fluorine-l Ιβ, Πα-, the naturally occurring adrenal cortex- 21-trioxy-4-pregnen-3,20-dione-21- acetate in 15 cm ³ mehormones such as hydrocortisone or cortisone. Mixed as a result of ethylene chloride. The mixture was stirred for 4 hours of its considerable anti-inflammatory effect and then extracted with methylene chloride, the fact that it was compared to that in the 2-position Cause water retention, they are finally washed with water, dried over sodium sulfate particularly suitable for treating inflammation, and the solvent evaporated. The crystalline residue in connection with chronic blood congestion was recrystallized from ethanol to remove heart defects and liver shrinkage. Fine white needles of 2-fluoro-kidney syndromes, eclampsia and pre-eclampsia were obtained. a melting point of 219 to 233 ° C. After still-

They can be recrystallized 4000 times in the form of polyethylene glycol.

or 6000, lactose and / or sucrose as a carrier tablets containing 229 to 244 ° C. can be administered orally. To the

topical application they are suitable as ointments, 40 analysis for C ₂₃ H ₂₈ FO ₆ :

Solutions, jellies, creams, suppositories, bougies, aqueous Calculated ... C 65.70, H 6.95, F 4.52;

Suspensions and the like are also found parenterally ... C 66.05, H 6.93, F 3.43. reversible. If necessary, the various

Application forms the effect of the invention It can be used in the following for the HjS-Oxyverbin-

are hydrolyzed according to the compounds available, in a reinforcing manner or in the manner indicated, additional substances are added, e.g. B. Antibiotics

or sulfonamides. _c ) 2-fluoro-17 «, 21-dioxy-4.9 (1 l) -pregnadiene-

Example 1 3,20-dione-21-acetate

a) 2-fluoro-1 / 3.17 ", 21-trioxy-4-pregnen- 5o To a solution of 530 mg 2-fluoro-1 l / 5.17", 21-tri

3,20-dione-21-acetate oxy-4-pregnen-3,20-dione-21-acetate in 5 cm 'pyridine

225 mg of N-bromoacetamide were obtained under nitrogen

A solution of 0.503 g of 2-fluoro-1, 21-dioxy- was added. Was left for 30 minutes at room temperature 4.17i20) - [cis] -pregnadien-3-one-21-acetatin6.5 cm ³ tert. While standing under nitrogen, the reaction mixture cooled butyl alcohol, 0.65 cm ³ pyridine and 2 cm ³ 55 to 10 to 15 ° C and passed sulfur-methylene chloride by the process of dioxide gas over the surface until the solution was at the USA patent 2,769,823 with 1.58 mg of Os- acidified iodine starch paper no longer stained.While mium tetroxide and 600 mg N-methylmorpholine oxide the sulfur dioxide feed line, the reperoxide warmed up in tert. Butyl alcohol mixed and then action mix. The temperature was stirred by cooling at room temperature for 17 hours. 0.1 g of FiI- 60 from the outside and kept below 30 ° C. by varying the sulfur dioxide removal aid and 2 cm ^{3 of} 1% strength aqueous sodium hydro supply. The sulfite solution was then added, the solution was then left to stand for 15 minutes at room temperature. The mixture was filtered, diluted with water and ^{extracted with ether and the reaction mixture was poured into 30 cm 3 of} ice water. The ether solution was extracted with water and the gummy precipitate which separated out was ^{extracted with dilute hydrochloric acid and an aqueous sodium 65 with 50 cm 3 of} ether. The ether extract was washed chloride solution, Ge over sodium sulfate washed ^e / r oig hydrochloric acid solution and water, dried and the solvent evaporated at 5 °. The dried over anhydrous sodium sulfate and the remaining oil (0.48 g) was evaporated in hexane carbon solvent, whereupon 2-fluoro

17 ", 21-dioxy-4,9 (1 l) -pregnadiene-3,20-dione-21-acetate obtained from melting point 242 to 243.5 ° C.

d) 2-fluoro-9 "-bromo-1 l / ?, 17a, 21-trioxy-4-pregnen-

3,20-dione-21-acetate

To a solution of 332 mg of 2-fluoro-17 «, 21-dioxy-4,9 (II) -pregnadiene-3,20-dione-21-acetate in 5 cm ^{3 of} methylene chloride and 9.9 cm ^{3 of} tert. Butyl alcohol was a solution of 0.83 cm ^{3 of} 72% perchloric acid in 5.8 cm ^{3 of} water and then a solution of 142 mg of N-bromoacetamide in 2.5 cm ^{3 of} tert. Given butyl alcohol. After stirring for 15 minutes, a solution of 142 mg of sodium sulfite in 7 cm ^{3 of} water was added. The mixture was concentrated under reduced pressure at about 60 ° C to a volume of about 25 cm ³ . It was then cooled in an ice bath and 35 cm ^{3 of} water were added with stirring. After stirring for 20 minutes, the deposited solid was filtered off. The obtained crystals were washed with water and air-dried. 2-Fluoro-9 "-bromo-l / ?, 17a, 21-trioxy-4-pregnen-3,20-dione-21-acetate with a melting point of 142 ° C. (decomposition) was obtained.

e) 2-fluoro-9 / S, llß-oxido-17 «, 21-dioxy-4-pregnen-

3,20-dione-21-acetate * ⁵

406 mg of potassium acetate were added to a solution of 406 mg of 2-fluoro-9 "-bromo-1 3, 17", 21-trioxy-4-pregnen-3,20-dione-21 acetate in 15 cm ^{3 of acetone, and} the resulting suspension was refluxed for 18 hours. It was then concentrated on the steam bath to a volume of 5 cm ³ , after which 10 cm ^{3 of} water were added. The precipitated product was filtered off and recrystallized from acetone. 2-Fluoro-9β, 11β-oxido-17 «, 21-dioxy-4-pregnen-3,20-dione-21-acetate with a melting point of 208 to 211 ° C. was obtained.

f) 2,9-Difluor-II / 5,17 «, 21-trioxy-4-pregnen-

3,20-dione-21-acetate

1.2 cm ^{3 of} 48 were added to a solution of 230 mg of 2-fluoro-9/3, 11JS-oxido-17 «, 21-dioxy-4-pregnen-3,20-dione-21-acetate in 5 cm ^{3 of methylene chloride} % aqueous hydrogen fluoride solution given. The 2-phase system was stirred for 20 minutes, then ^{diluted with 15 cm 3 of} methylene chloride and carefully ^{poured into 40 cm 3 of} water containing 4 g of sodium bicarbonate. It was shaken well in order to neutralize the excess hydrogen fluoride, then the methylene chloride was separated off and the aqueous phase was extracted with fresh methylene chloride. The combined methylene chloride solutions were dried over anhydrous sodium sulfate, ^{diluted with 25 cm 3 of} ether and chromatographed over 20 g of magnesium silicate. The chromatographic column was eluted with hexane mixtures containing increasing proportions of acetone. Practically pure 2.9 "- difluoro -1 \ β, \ Ίκ, 2 \ - trioxy-4-pregnen-3,20-dione-21 acetate was obtained. M.p. = 214 to 217 ° C; λ ££ = 239 πιμ; ε = 15550.

By oxidation of chromic acid in acetic acid, it can be converted into 2,9 "-difluoro-17", 21-dioxy-4-pregnen-3, l 1,20-trione acetate and / or by hydrolysis with potassium carbonate in the absence of oxygen in methanol in 2.9 a-difluoro-17 ", 21-dioxy-4-pregnen-3, ll, 20-trione or 2.9 "- Difluor-11jS, 17", 21-trioxy-4-pregnen-3,20-dione converted will. The free 21-alcohols yield with suitable acylating agents other desired 21-esters of lower aliphatic cycloaliphatic or aromatic acids, which can optionally be substituted.

Example 2

a) 2-chloro-11,17, 21-trioxy-4-pregnen-3,20-dione-21-acetate

To a solution of 267 mg of 2-chloro-11jS, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one-21-acetateatin 13 cm ³ tert. Butyl alcohol were 0.127 cm ^{3 of} pyridine and then a solution of 245 mg of N-methylmorpholine ^{oxide peroxide in 1 cm 3 of} tert. Butyl alcohol and 2.4 mg OsO ₄ in 0.5 cm ³ tert. Given butyl alcohol. The N-methylmorpholine oxide peroxide was obtained by reacting N-methylmorpholine with 2 molar equivalents of anhydrous hydrogen peroxide in tert. Butyl alcohol made. The mixture was kept at a temperature of about 25 ° C for 18 hours and then mixed with 0.5 cm ^{3 of} an aqueous 0.5 N Na ₂ S ₂ O ₄ solution and some filter aid. The solution was filtered and most of the tert. Butyl alcohol distilled off under reduced pressure at room temperature. The residue was ^{diluted with 10 cm 3 of} water, which was added in small portions. The steroid precipitate was filtered off and dried. It gave 2-chloro-11JS, 17 ", 21-trioxy-4-pregnen-3,20-dione-21-acetate with a melting point of 175 to 178 ° C. The process described above can also be carried out on other esters of 2-chloro ll / ?, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-ons and on the free 21-alcohols. The 1-position hydroxyl group can then be oxidized and the 21-position acyloxy group can be hydrolyzed in the manner indicated below.

b) 2-chloro-11jS, 17a, 21-trioxy-4-pregnen-3,20-dione

A solution of 438 mg of 2-chlorohydrocortisone acetate in 4 cm ^{3 of} methanol was freed of oxygen by passing in nitrogen, as was a solution of 404 mg of potassium bicarbonate in 4 cm ^{3 of} water. The two solutions were mixed at a temperature of 18 to 20 ° C. under nitrogen and stirred for 5 hours at room temperature in the absence of oxygen. The solution was then neutralized with glacial acetic acid. The neutral solution was concentrated under reduced pressure at room temperature and then kept in a refrigerator at a low temperature for 16 hours. The precipitated 2-chlorohydrocortisone was filtered off and dried.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of therapeutically active steroid compounds of the general formula CH ₂ OR " in which X = fluorine, chlorine, bromine or iodine, Y = hydrogen, fluorine, chlorine, bromine or iodine, R '= H, / S-OH or keto oxygen and R " 10 = Hydrogen or the acyl radical of a carboxylic acid, with osmium tetroxide and an oxidation with 1 to 12 carbon atoms means, thereby characterized oxidatively hydroxylated, optionally that draws that a 2-halogen-11jS, 17a, 21-trioxy-4-pregnen- Compound of the general formula 3,20-dione-21-acylatin9 (II) position dehydrated ₅ the obtained 4,9 (11) -Pregnadiene derivative with a Ac - O - CH _2x ^ / H treated hypohalous acid, from which he hold 9 "-halogen-II / S-oxy compound hydrogen halide splits off the 9 / 3.11 / S-oxido compound obtained treated with hydrogen fluoride or a compound releasing hydrogen fluoride, optionally the 11 / J hydroxyl group oxidized and optionally the 21-position acyloxy group hydrolyzed. 2. The method according to claim 1, characterized in that the starting material is 2-fluoro-II / S, 21-dioxy-4,17 (20) - [cis] -pregnadien-3-one-21-acetate in which X has the meaning given and Ac is the and, as an oxidizing agent, an amine oxide peroxide Acyl radical of a carboxylic acid with 1 to 12 carbon atoms or an aryl jodoxy used. © 109 709/425 10.61