DE1048580B - Process for the preparation of 2-lower-alkyl-gu-fluoro-II ^, 17a, 21-trioxy-4,6pregnadiene- ^ O-diones and their 11-keto analogs - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

kl. 12 ο 25/05

INTERNAT. KL. C 07 C

PATENT OFFICE

C O 7 J j.- ·

EDITORIAL 1048

U 4400 IVb / 12 ο

BOOKING DATE: MARCH 1, 1957

NOTICE THE REGISTRATION AND ISSUE OF THE DISTRIBUTION CHRIFT: 15 J A N U A R 19 5

The invention relates to a method of manufacture of 2-lower-alkyl-9a-fluoro-II / S, 17a, 21-trioxy-4,6-pregnadiene-3,20-dione and their 11-keto analogs. The method according to the invention can be carried out by the following Formula scheme are shown: 5

CH ₂ OR

HO.

CH,

O'

O O

R ₁ OCC

R ₁ .

HO.
CH,

CH

CHJ

CH ₂ OR

II

CH ₂ OR

III

CH ₈ OH

CH

CH ₃ H

IV

35

Procedure.

for the production of 2-lower-alkylct-fluoro-11 / 3.17 a, 21-trioxy-4,6-pregnadiene-3,20-dione and their 11-keto analogs

Applicant:

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

Representative:

Dr. W. Beil and A. Hoeppener, lawyers, Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority: V. St. v. America March 29, 1956

J. Allan Campbell, John Claude Babcock and John Alexander Hogg, Kalamazoo, Mich.

(V. St. A.),
have been named as inventors

CH ₂ OR

CH

HO.

CH ₃

CH ₂ OR

C = O k OH

! Vi

0 '

CH ₂ OR

viii

CHOOR

OH

CH ₂ OH

C = O

CH,

In this formula scheme, R denotes the acyl group of an organic carboxylic acid with preferably 1 to 8 carbon atoms, R ₁ denotes a lower alkyl group with 1 to 8 carbon atoms, R ₂ denotes a hydroxyl group or keto oxygen, M denotes an alkali metal with an atomic weight of 6 to 41 and X. a halogen of 33 to 130 atomic weight.

The process according to the invention can be carried out in such a way that a 21-ester of the

ίο II / 3,21-Dioxy-4,6,17 (2q) - [cis] -pregnatrien-3-ones (I) in known Way with a lower oxalic acid dialkyl ester in the presence of an Alkaübasc in a 2-lower-alkoxyoxalyl-11 / S-oxy-21-acyloxy-4,6,17 (20) - [cis] -pregnatrien-3-one (II) transferred. This is on it with

¹ S a lower alkyl chloride, bromide or iodide with 1 to 8 carbon atoms in a known manner in a 2-lower-alkoxyoxalyl - 2 - lower - alkyl -lly? - oxy- 21 -acyloxy-4,6, 17- (20) - [cis] -pregnatrien-3-one (III) transferred, which in turn with an alkali base, z. B. an alkali metal alcoholate is hydrolyzed in a known manner. The 2-lower-alkyl-II / S, 21dioxy-4,6,17 (20) - [cis] -pregnatrien-3-one (IV) obtained then becomes the 2-lower-alkyl-Ily3-oxy in a known manner -21-acyloxy-4,6,17 (20) - [cis] -pregnatrien- 3-one (V) esterified, which then by the method of patent 957 661 with osmium tetroxide in the presence of a peroxide, such as hydrogen peroxide, or an amine oxide , such as N-methylmorpholine oxide, is converted into a 2-lower alkyl-11 / 3,17a-dioxy-21-acyloxy-4,6-pregnadiene-3,20-dione (VI). Treatment with an N-haloamide or N-haloimide and then with anhydrous sulfur dioxide according to the process of patent 1 029 375 gives the 2-lower-alkyl-17α-oxy-21-acyloxy-4 from compound (VI), 6,9 (11) -pregnatriene-3,20-dione (VII). If this is reacted with a hypohalous acid, 2-lower-alkyl-9a-halogen-II / ?, 17a-dioxy-21-acyloxy-4,6-pregnatriene-3,20-dione (VIII), the by reaction with a base such as anhydrous potassium acetate, 2-medrig-alkyl-9β, II / 3-oxido-17a-oxy-21-acyloxy-4,6-pregnadiene-3,20-dione (IX) is obtained in a known manner . If this is treated in a known manner in the presence of a strong acid with hydrogen fluoride or a compound donating hydrogen fluoride, 2-lower-alkyl-9cc-nuor-

The hydrolysis of this compound leads to the 2-lower-alkyl-11 ß, 17 a, 21 -trioxy ^ .o-pregnadiene-S ^ O-dione.

Optionally, the 2-lower-alkyl-9a-fluoro

the hydrolysis can be converted into the corresponding 11-keto compound by customary processes.

The compounds obtainable according to the invention represent valuable substances with adrenal cortical hormone activity and can also be converted into other therapeutically active compounds. So results the selective hydrogenation of 2-lower-alkyl-9a-haloII / 3,17a-dioxy-21-acyloxy-4,6-pregnadiene-3,20-dione in methanol solution using a palladium-carbon catalyst and potassium hydroxide by the method of U.S. Patent No. 2697106 et seq Hydrolysis of aldosterone-like 2-alkyl-9ct-halogenhydrocortisone with a strong anti-inflammatory effect. Of these, 2-methyl-9u-fluoro-hydrocortisone is one of the most important compounds. Receives in the same way by selective hydrogenation of the corresponding 11-keto analogs, e.g. B. of 2-methyl-9a-fluoro-17a-oxy-21-acy] oxy-4,6-pregnadiene-3, ll, 20-trione, the corresponding 2-methyl-9ot-fluorocortisone-21 esters. All of these connections have pronounced adrenal hormone-like Effect z. B. cause deposits in the liver with minor side effects. Though

5 6

the chlorine, bromine and iodine derivatives of the cortisone and hydrocortisone methylene chloride, ethylene dichloride, chloroform, tetrabonds alkylated in preferably in an organic solvent, such as the 2-position, have a remarkable effect; the largest chlorocarbon, a pentane or hexane, dissolved. However, the effectiveness of the 9a-fluorine compounds is observed for several hours, about 8 to 72 hours. The 2-methyl-9α-fluoΓ-ll / 3,17α, 21-trioxy- 5 den, at about room temperature (20 to 3O ⁰ C) in front of 4,6-pregnadiene-3,20-dione and its ester have a walk. Higher temperatures cause a considerably greater adrenal cortical hornion activity, particularly a reduction in the reaction time. It is useful to have the special glucocorticoid effectiveness, as the hydro-alkyl halide is the reaction product of the condensation cortisone. Add the 11-keto analogs, such as the 2-methylation stage, preferably after about 9a-fluoro-17a, 21-dioxy-4,6-pregnadiene-3, ll, 20-trione and any excess alkali catalyst present have destroyed its ester also has adrenal cortex hormone. Satisfactory yields are obtained even when effective. In addition, they show mineral corticoids as well as use of the free methylene compound of the metal anti-inflammatory effect. enolats. Alkali catalysts, such as sodium or potassium

When carrying out the carbonate according to the invention, accelerate this reaction,
A ll /? - Oxy-21-acyloxy-4,6,17 (20) - [cis] - »5 The removal of the alkoxyoxal group from the 2-stelpregnatrien-3-one in the presence of an alkali catalyst with formation of a 2 -lower-alkyl-II / I, 21-dioxy with a preferably lower oxalic acid dialkyl ester 4,6,17 (20) - [cis] -pregnatrien-3-one or its 21-ester condensed in an organic solvent. Appropriately takes place in the presence of an alkali catalyst, such as Nanetc solvents are aromatic hydrocarbons, trium or potassium carbonate, in the presence of water alcohols, ethers and aliphatic hydrocarbons, such as ao or a lower alcohol. It is favored by the non-hexane hydrocarbons, known by the commercial nature of hydroxide or alcoholate, in particular called “Skellysolve B”, and mixtures of methylate or ethylate ions. After the named solvent. Benzene with or without the addition of reaction, mixing it in a large amount of water, small amounts of an alcohol is preferred. The congealed and the product by customary methods, z. B. densation is usually carried out at temperatures between 25 by extraction, filtration, etc., isolated. The 2-alkyl-0 ⁰ C and the boiling point of the reaction mixture. At 11 / ?, 21-dioxy-4,6,17 (20) - [cis] -pregnatrien-3-one or its temperatures between 20 and about 70 ° C the 21-ester can proceed by recrystallization, further Ex-reaction satisfactorily quickly. The time required to complete the soaking, chromatographing etc. reaction as required is to be determined by the reaction temperature. If the acyl group is in temperature, the solvent, the chosen oxalic acid ester 30-21 position, it is a simple acid such as acetic or alkali catalyst. It can be between propionic acid, so it will be minutes and a few days at the same time as the alkoxyoxal-S. If you use group removed. The acyl group is derived from a methyl or Äthyloxalat and tertiary butyl alcohol at about sterically hindered acid such as Dineopentylessigsäure, 50 ⁰ C, as is usually done in a few minutes Trimethylessigsäurc u. The like., The acylate group is left more than 50 ° / _c ige implementation. The condensation 35 in the 21 position. In many other cases a mixture of ester and free alcohol is obtained which is advantageous in the absence of appreciable amounts. The ester can be made up of water. In order to ensure a practically complete exclusion of water by reacting the 21-oxy group with the anhydride, the acid halide or acid halide of an organic carboxylic acid, the solvent is carefully mixed with a drying agent, preferably 1 to 8 carbon atoms, in the usual way such as anhydrous sodium sulfate, calcium sulfate , Calcium 40 ways to be restored.

Chloride, phosphorus pentoxide, sodium or the like, dried The 2-lower-alkyl-II /? - oxy-21-acyloxy-

or, if aromatic hydrocarbons are used 4,6,17 (20) - [cis] -pregnatrien-3-one is then used to

before use some of these hydrocarbons-speaking 2-lower ^ g-alkyl-II / S, 17α-dioxy-21-acyloxy-

distilled off. 4,6-pregnadieti-3,20-dione oxidatively hydroxylated.

Suitable alkali catalysts are alkali metals, alkali metal alkoxides, the alkali metal alcoholates of which the alkali metal preferably has an osmium tetroxide and an oxygen from 6Atome, and an oxygen from 6Atom, are suitable their alkyl radical-giving oxidizing agent, such as hydrogen peroxide, contains 1 to 8 carbon atoms in the alcoholate. Alkyl peroxides, peracids, chloric acid, periodic acid, these are the alkali metal alcoholates, in particular 5 ° acetyl peroxide, benzoyl peroxide, tert-arainoxydper-sodium ethylate and sodium methylate, because of their oxides, organic iodoxides, lead tetraacetate, manioxide convenience and the good gandioxide obtainable with them Mercury diacetate (see U.S. patent results preferred. Theoretically required publications 2,662,584 "and 2,668,816 as well as patent 957,661" amount of catalyst is 1 mole per mole of steroid. In U.S. Patent No. 960,009).
Rule use something more than the theoretical amount. 55 According to the invention, hydrogen peroxide, amine

The alkali metal enolate thus formed can be oxidized by adding oxydperoxides and aryl iodoxides a large volume of an organic solvent, preferred for oxidative hydroxylation. Both in which the enolate is insoluble, such as ether, pentane or amine oxide peroxides, it is not benzene. Another method using aromatic amine oxide peroxides, especially around tridem the alkali metal enolate is preserved in somewhat purer form, ethylamine oxide peroxide and N-methylmorpholine oxide peroxide is that you have a cold aqueous oxide.

Solution of the alkali metal enolate precipitated as above.

acidifies, so that the free enol is excreted, and niche iodine compounds with at least one of the

then a solution of the free enol in ether or benzene represents an iodine atom bound, titratable oxygen atom,

treated with the equivalent amount of sodium methylate, 65 d. H. Iodoso, iodyl and iodoxy compounds as well

whereupon the sodium enolate is neither precipitated. their salts. The iodoso compounds have one that

The alkali metal enolate of the 2-lower iodooxy compounds thus prepared is bonded to the iodine atom

Alkoxy-oxalyl-II /? - oxy-21-acyloxy-4,6,17 (20) - [cis] -preg- oxygen atoms.

natrien-3-one is obtained by adding a lower alkyl- When carrying out the oxidative hydroxylation

halide alkylated. The steroid to be alkylated is that the starting steroid is expediently in an inert one

7 8

organic solvent, such as tert-butyl alcohol, di- temperature is between -40 and + 7O ⁰ C, the lower ethyl ether, tetrahydrofuran od. like. dissolved and the limit by the solubility of the reagents and Lo. Hydroxylating agent, preferably osmium tetroxide, solvent, the upper mixed by the amount of secondary and oxidizing agent. Advantageously, reactions are determined. Usually, preference is given to using the same room temperature (20 to 30 ^° C.) for all reaction participants and adding the hydroxylating agent according to reasons and because of the high degree of oxidizing agent that can be achieved with it. prey. A response time. between S minutes and

The osmium tetroxide can be used in amounts of, for. B. about 3 hours is usually sufficient. Temperatures 0.2 molar equivalents to about 0,001 molar equivalents added 3O ⁰ C, the reaction time greatly shorten so that the are. It is preferred not to use more than the reaction is complete after a short time. 0.05 molar equivalents. The obtained 2-lower-alkyl-II / ?, 17a-dioxy-21-acyl-

Theoretically, the formation of 17-oxy-20-keto-oxy-4,6-pregnadiene-3,20-dione-llj3-hypohalite is 21-acyloxysteroids 2 equivalents of oxidizing agent per then with anhydrous sulfur dioxide in the presence of moles of osmiate ester formed. It was treated with an organic base. The SO ₂ may, however, be found to be in the form of a liquid, or be formed in situ, e.g. B. Implementation usually more than the theoretical amount from an alkali metal hyposuhit. The reaction star oxidant must be used. To achieve the temperature is also between -40 and +70 ⁰ C, so for optimal results the oxidation should preferably be done at room temperature. Use the agent obtained in excess of the theoretically required 2-lower-alkyl-17a-oxy-21-acyloxy-4,6,9 (II) -pregnatriene-i amount. The best results will usually be obtained, so 3.20-dione is applied according to standard methods, e.g. B. after borrowed with about 2.2 to 2.75 equivalents of amine oxide peroxide, the reaction mixture was poured into excess water or aryl hydroxide, calculated on the starting steroid, is achieved with organic, not mixing with water. The course of the reaction can be isolated by titration of the solvent available. The extracts are easily followed, washed, dried and then preserved. Small amounts of water impair the evaporation. The crude 2-lower-alkyl-17a-oxy yield obtained, as a rule, does not. But if you want to use 21-acyloxy-4,6,9 (U) -pregnatrien-3,20-diones can in the usual way of hydrogen peroxide or an amine oxide, z. B. by recrystallization or if optimal results are obtained, one should be purified under prak- Cbromatographieren. The 2-lower-alkyl-17a agent can be used by adding anhydrous conditions, ie in a dry hypohalous acid, such as hypochlorous or nem tert-butyl alcohol or a similar solution of hypobromous acid. oxy-2l-acyloxy-4,6,9 (II) -pregnatriene-3,20-dione in one

The hydroxylation temperature is normally 2-lower-alkyl-9 (x-halogen-l 1 / 3.17a-dioxy-21-acyloxy-4,6-at about 15 to 30 ⁰ C; higher or lower temperature pregnadiene-3, 20-dione convert. The temperatures hypohalous, B. The hydro z. between about -10 and about +70 ⁰ C, the acid is usually used in situ, namely by but can be also applied. 35 reacting a N-N or Halogensäureamids -Halogenysis of the obtained 2-medrig-alkyl-II / ?, 17ct-dioxy-21-acyl acid imide with an acid.The reaction is preferably oxy-4,6-pregnadiene-3,20-dione with alkali, preferably at room temperature in the presence of an organic nitrogen, gives the free triol, which is carried out with halonic solvents; however, genides and anhydrides of carboxylic acids with 1 to slightly higher or lower temperatures can be re-esterified the hypohalous acid

Oxidation of the 21-acylate with chromic acid gives the agent which is advantageously used in molar form the corresponding 2-lower-alkyl-l 7 a-oxy-21-acyloxy ratio or an excess of z. B. 25% based 4,6 * pregnadien-3, lt, 20-trione. on the steroid. A large excess of sub-halogen

To the corresponding 9a-halogen compounds to acid donating compound is not desirable because obtained, the 2-lower-alkyl-II / ?, 17a-dioxy-21-acyl-45 the excess hypohalous acid with others oxy-4,6-pregnadiene-3,20-dione can initially react according to known positions on the molecule. The response time. Methods for 2-lower-alkyl-17a-oxy-21-acyloxy- can take between 4 and 5 minutes and 1 hour to be-4,6,9 (11) -pregnatriene-3,20-dione dehydrated. They carry. After the reaction has ended, the water is split off via water can be mixed with phosphorus oxychloride, hydrochloric acid by adding λόπ acid or sulfuric acid in acetic acid or by pyro- 50 sodium sulfite or other sulfites or hydrosulfites lysis can be achieved (see US Patents 2640838 destroyed. The product obtained, 2-lower-alkyl-9a-ha- and 2,640,839). According to a preferred embodiment, log-llß. ^ Ct-dioxy ^ l-acyloxy ^ .o-pregnadiene-S ^ -dione, In the form of the invention, the water is split off by means of which the halogen is chlorine, bromine or iodine Implementation of the 11/3 oxy compound with an N-Halo- from the reaction mixture by adding plenty of water genamid or N-haloimide, the halogen of which is one atomic 55 and extraction or filtration of the precipitated weight from 34 to 130 possesses, and treatment of the inter-bond gained. The crude product can by Ummcdiär The resulting 11-hypohalite was purified with dry crystallization from acetone and ^ Skellysolve B <r Sulfur dioxide. Usually one used to be related.

on the 11ß-oxysteroid, more than 1 molar equivalent. The 21-acylate obtained can be used in an alcoholic medium

N-haloamide or N-haloimide. The implementation hydrolyzed 60 and converted to other esters is carried out in the presence of lower fatty acid amides or ter · graze.

tiarer amines, the amine nitrogen of which is a member of an aroma- The oxidation carried out in the usual way

table ring forms. The base is preferably used in 21-Acylates which gives the pharmacologically active (aldog-large molar excess over the 11 / J-oxysteroid, steroid-like and anti-inflammatory) 2-lower alkyl- e.g. of 10 molar equivalents, and represents- 65 9α- halogen-17α-21-acyloxy-4,6-pregnadiene-3 ₍ ll, 20-trione _ι preferably, is the only solvent 9a-halogen-17a, 2l-clioxy-4,6-pregnadiene-3, ll, 20-trione, it can be kept in the presence of preferably not more than 0.1 mol.

equivalent water per mole of steroid. Great water to be used to produce the 9a-fluorine compounds

some of them lower the Axis spoil. The reaction temperature is first of all the 9 / ?, 11 / J-oxido compounds, i.e. the

9 10

2-lower-alkyl-9 / Ul / ^ oxiclo-17a-oxy-21-acyloxy-4,6-pre- and gives a with ferric chloride in aqueous methanol

grace-3,20-dione. The reaction takes place in a dark brown color. The ultraviolet spectrum revealed

in solution with a mild base with warming, the following values:

preferably in the absence of water to hydrolysis _U1 alcohol

to avoid the ester groups. 5 _e287 = 12225; _ε , ₇₀ = 7025;

Suitable bases are anhydrous potassium acetate in 0.01 / n-alcoholic H “SO.

Sodium bicarbonate, sodium acetate, etc., of which _£ __ 9375th _ε ^ · 8Ϊ75

Potassium acetate is preferred. The reaction time _in 0 01 / n-alcoholic KOH

γ, up to 24 hours, usually 3 to 12 hours. The _ 1407c. ₌ 7000

obtained 2-nicdrig-alkyl-9/5, ll /? - oxido-17a-oxy-21-acyl-10 ⁶²ⁱ " ^v ' ^a82

Oxy-4,6-pregnadiene-3,2Ö-dione is obtained by pouring into _{potassium enolate of} 2-methox> oxaly] -11 / 9-ox _3. -21-acctoxy-

plenty of water and extracting with methylene chloride or 4,6,17 (20) - [ci.s> pregnatrien-3-ons
other water-immiscible solvents

isolated. A solution of 1 g of Hp'-Oxy ^ l-acetoxy-

obtained 2-lower-alkyl-9/3, n /? - oxido-17a-oxy-21-acyl-15 4,6,17 (20) - [cis] -pregnatrien-3-one in 25 ecm benzene.

Oxy-4,6-pregnadiene-3,20-dione is in solution in counter-it is heated to about 80 ° C (back nut temperature)

waiting a strong acid with 48 ° / _o sodium hydrogen fluoride, and outputs a suspension of 0.8 cc and Mcthyloxalat

acid treated. Methylene 0.25 g of potassium hydride in 5 ecm of benzene are used as the solvent. The mixture

Chloride, ethylene dichloride, chloroform, carbon tetrachloride - is refluxed under Rübren for 2 hours,

fabric, etc., of which methylene chloride is preferred. 20 cooled, filtered and the precipitate collected. Of the

A suitable strong acid with a catalytic effect is per- precipitate is washed three times with 25 ecm of benzene each time

chloric acid, toluenesulfonic acid, sulfuric acid and the like. Die and dried. It consists of the potassium enolate des

The reaction takes place at room temperature, preferably 2-methoxyoxalyl-II /? - oxy-21-acetoxy-4,6,17 (20) - [cis] -

with stirring, and requires 1 to 24 hours. In the pregnatrien-3-ons.

Usually 1 to 12 hours are sufficient. After the end of the 25th.
Reaction, the mixture is poured into water and with ^b) _2-y l Athox _y oxal-2-meth _y Hl / _{3,21-dioxy-4,6)} 17 (20) - -this [as] dilute base such as sodium - or potassium bi-pregnatnen-3-one
carbonate, neutralized. It is also possible to use an excess of 3 g of the strong base Naan obtained according to a). Then with a trium enolate in 120 ecm acetone, 6 g of anhydrous water-insoluble solvent such as methylene chloride, 30 lium carbonate and 18 ecm methyl iodide is extracted at room, the organic layer is stirred from the aqueous temperature for 5 days, then mixed with water phase separated, washed with water , dried and and the mixture evaporated three times with 50 ecm of methylene chloride each time. Crude 2-lower-alkyl-9a-fluoro-extracted. The combined extracts are with SaIzll / J ^ ot-dioxy ^ l-acyloxy ^ .o-pregnadiene-S ^ -dione. The solution is washed, dried and the raw compound, which has been kept dry, is then evaporated through as required. The yellow residue obtained is purified from acetone - recrystallization or chromatography. .vSkellysolve B «recrystallized.

The introduction of fluorine in the 9a position can also be "" .. ,, ", _{11 <o} ". . , . ,,, ^

take place on the free triol by adding the 2-lower-alkyl-2-methoxyoxalyl-2-methyl-II / 5-oxy-21-acetoxy-4,6,17 (20) -

9 / 3,11 / f-oxido- ^ a-oxy-iO-pregnadien ^ O-dione first [cis] -pregnatnen-3-one

under nitrogen with aqueous-alcoholic potassium hydroxide.

hydrolyzed oxide solution and then with hydrogen fluoride II / S-oxy-21-acetoxy-4,6,17 (20) - [cis] -pregnatrien-3-one in

implements. Acetone is made in a similar manner as above with methyl iodide

The 21-ester of 2-lower-alkyl-9a-fluoro41 / ?, 17a, and potassium carbonate reacted. After stirring for days

21-trioxy-4,6-pregnadiene-3,20-dione can be hydrolyzed at room temperature is filtered, the residue four-

and washed with acid halides or acid anhydrides in 45 times with hot acetone and the combined

Pyridine solution evaporated to dryness at room temperature in other 21-ester acetone solutions. The residue

be transferred. is recrystallized from acetone - "Skellysolve B".

The oxidation of the 2-lower-alkyl-9a-fluoro-II / ?, 17a-di-

oxy-21-acyloxy-4,6-pregnadiene-3,20-dione with chromium- ^ 2-methyl-II /? - oxy-21-acetoxy-4,6,17 (20- [cis] -pregna-

acid leads to the corresponding 11-keto compound, the 50 trien-3-one or 2-methyl-l 1 / 3.21-dioxy-4,6,17 (20) - [cis | -

also in the manner indicated above into the free pregnatrien-3-one
Triol can be transferred.

The following examples explain the invention. One dissolves 2.5 g of 2-ethoxyoxalyl-2-methyl-II / 5-oxy-

proper procedures. 21-acetoxy-4,6,17 (20) - [cis] -pregnatrien-3-one in 75 ecm

Examples. 55 methanol, 3 ecm 25 ° / ₀ igcs sodium methylate and

>, _T ^. ,,, r, v.,,, _, _. ,. . _{r is} stirred for 2 hours and 20 minutes under nitrogen. then

a) Natnumendat des 2-Athoxyoxalyl-l 1,?, 21 ^ οχν-4,6, ^^ _man ^ _{water and extraMert drdmal} ^ _each

17 (20) - [cis] -pregnatnen-3-ons _{50 cc methylene} moride. _The extracts are made with water

A solution of 1 g II / 3-Oxy-21-acetoxy-4,6,17 (20) - washed neutral against phenolphthalein, over water

[cis] -pregnatricn-3-one in 16 ecm of tert-butyl alcohol is dried 60 free sodium sulfate and evaporated to dryness.

heated to 63 ° C. This is done under nitrogen and steamed. The crude 2-methyl-llp \ 21-dioxy-4,6 obtained,

0.8 ecm of ethyl oxalate and 0.9 ecm of a 17 (20) - [cis] -prcgnatrien-3-one is in 10 ecm of pyridine and stirring

25% sodium methylate solution in methanol. Before 5 ecm acetic anhydride dissolved. After standing over

all sodium methylate is added, the night begins at room temperature (20 to 25 ° C)

Separate precipitation. The mixture is cooled to 30 ° C. and the solution is diluted dropwise with water and diluted with ether

uses 18 ecm of absolute ether. The mixture is extracted. The extracts are made with sodium bicarbonate

Stirred for 40 minutes, filtered and the precipitate washed with a thorough solution, dried over anhydrous sodium sulfate.

Lich washed with dry ether. The sodium obtained is dried and evaporated. The residue consists of

trium enolate des 2-ethoxyoxalyl-II / ?, 21-dioxy-4,6,17 (20) - a yellow, glass-like product. He will be over 50 g

[ice] -pregnatriene-3-one weighs 1.15 g (yield 100 ° / _o) 7o synthetic magnesium silicate known under the

Trade name »Florisil *, chromatographed, where to collect fractions of 150 ecm:

Table I.

fraction 5 solvent > Skellysolve B « 1: 1 1 10 " Skellysolve B " - methylene chloride .'Skellysolve B " 1. : 1 2 10 j'SkeUysolve B "-Methylene chloride -SkeUysolve B « 5: 95 3 to 20th Acetone- .'Skellysolve B » 8th: 92 6 to Acetone- 18: 82 11 to Acetone- 30: 70 18 to Acetone- 21 acetone 22nd acetone

Fractions 6 to 17 are combined, evaporated and again chroniatographed over 30 g of sFlorisil®, the fractions shown in Table II being obtained.

Table 11 volume
in ml Solvents 2:98 fraction 100 .? Skellysolve B " 4:96 1 to 4 100 Aceton-jiSkellysolve Be 6:94 5 and 6 100 Acetone -. "Skellysolve B" 8:92 7 to 9 100 Acetone - > Skellysolve B « 10:90 10 to 17 100 Acetone- ^ Skellysolve Bk 14:86 18 to 22 100 Acetone-.vSkcllysolvc B * 20:80 23 and 24 250 Acetone-sSkellysolve B " 25 and 26 250 Acetone-·. ¹ Skellysolve Br 27 and 28 250 acetone 29 to 31

35

Fractions 11 to 15 inclusive are combined and evaporated to give 2-methyl-t 1 /> - oxy-21-acetoxy-4,6,17 (20) - [cis] -pregnatrien-3-one. It cannot be crystallized. The ultraviolet absorption spectrum showed μ cine at 283 m. Absorbance of ε = 22925; [a] _D = + 150 ° (in chloroform).

0.55 g of the 2-methyl-II _j 6 ^> -oxy-21-acctoxy-4,6,17 (20) - [cis] -pregnatrien-3-one obtained and 15 ecm of 5% potassium carbonate in 80% Methanol is refluxed under nitrogen for 2 and 1/2 hours. It is then diluted with water and extracted with methylene chloride. The extracts are washed with water and dried. After removal of the solvent, the residue is recrystallized from ethyl acetate and 0.3 g of 2-methyl-H / 3,21-dioxy-4,6,17- (20) - [cis] -pregnatrien-3-one having a melting point of 147 to 155 ° C and A ^Ä tr '= 283

3-on from m.p.
ε = 24450.

147 to 155 ° C and A ^Ä

Analysis for C ₂ H ₃₀ O ₃ + 1/2 ethyl acetate:
Calculated ... C 74.57%, H 8.86%;
found .... C 74.52%, H 8.78%, 8.90%

₅₀

ηιμ;

55

d) 2-methyl-II / 3,17a-dioxy-21-acetoxy-4,6-pregnadiene-3,20-dione

A solution is prepared which contains 230 mg of 2-methylll / 5-oxy-21-acetoxy-4,6,17- (20) - | cis] -pregnatrien-3-one, 13 ecm of tert-butyl alcohol, 0, 15 ecm pyridine, 1 ecm N-methylmorpholine oxide hydroxide (4.4 N, based on thiosulfate solution) and 0.45 mg osmiuratetroxydinO.1 ecm tert-butyl alcohol and left to stand for 24 hours at room temperature. It is then diluted with water and extracted with methylene chloride. The combined extracts are washed with dilute hydrochloric acid, dilute sodium bicarbonate and water, dried and evaporated to dryness. The residue is over

a column of 15 g.? Vlorisil «chromatographed, whereby the fractions given in Table III are obtained:

Table III

fraction volume
in ecm Solvent 2:98 Ibis 3 100 "Skellysolve B" 4:96 ¹⁰ 4 to 6 100 Acetone-> Skellysolve Bs 6:94 7 to 9 100 Acetone "Skellysolve B" 10:90 10 and 11 100 Acetone-? Skellysolve B " 12:88 12 to 14 100 Acetone "Skellysolve B" 14:86 15 to 20 100 Acetone-sSkellysolve B " 20:80 ¹⁵ 21 and 22 100 Acetone -'- Skcllysolve B " 50:50 23 to 25 150 Acetone " Skellysolve B" 26 and 27 150 Aceton-vSkcllysolve B « 28 and 29 acetone

Fractions 15 to 18 are combined, evaporated and the residue is recrystallized from ethyl acetate-ether. The 2-methyl-II / ?, 17a-dioxy-21-acetoxy-4,6-pregnadiene-3,20-dione obtained melts at 211 to 216 ° C. The UV absorption spectrum showed a cine extinction of e at 284 μm. = 23425. The infrared spectrum shows that (3 the product is solvated. Otherwise the spectrum agrees with the assumed structure.

Analysis for C "., H ₃₃ O ₀ + 1 / 2MoI ethyl acetate:
Calculated ... C 68.10%, H 7.47%:
found .... C 68.21%, H 8.25%.

After 18 hours of heating at 100 ° C. over phosphorus pentoxide, the solvate yields pure 2-methyl-U _/ 3,17adioxy-21-acetoxy-4,6-pregnadiene-3,20-dione, which can be mixed with N-bromoacetamide in the presence of water 2-methyl- ^ a-oxy ^ l-acctoxy ^ ö-pregnadien-S.ll ^ O-trione oxidized and then with potassium carbonate under nitrogen to 2-methyl-l7u, 21-dioxy-4,6-pregnadiene-3, l 1,20-trione can be hydrolyzed.

e) 2-methyl-l7a-oxy-21-acetoxy-4,6,9- (11 ) -pregnatriene-3,20-dione

A mixture of 1 g of 2-methyl-11ß, 17ct-dioxy-21-acetoxy-4,6-pregnaclien-3,20-dione, 60 mg of N-bromoacetaniide and 6 ecm of pyridine is stirred in the dark for 5 minutes. The mixture is then cooled in an ice water bath and SO _{2 is passed} under the surface of the stirred solution until the potassium iodide-starch reaction is negative. Then 50 ecm of water are added and the mixture is kept at about 5 ° C. for 30 minutes. The white color formed. Precipitate is filtered off, washed with water and dried in vacuo. After recrystallization from acetone, pure 2-methyl-17a-oxy-21-acetoxy-4,6,9- (II) -pregnatriene-3,20-dione is obtained. If the propionate, butyrate, benzoate or the like is used instead of the 21-acetate, the corresponding 21-propionate, butyrate, benzoate etc. are obtained.

When hydrolysed with potassium carbonate in methanol or ethanol under nitrogen, the corresponding free Obtain diol.

f) 2-Methyl-9ix-bromo-II / ?, 17ct-dioxy-21-acetoxy-pregnadiene-S ^ O-dione

A solution of 1 g of 2-methyl-17α-oxy-21-acetox.y-4,6,9- (II) -pregnatriene-3,20-dione in 40 ecm of methylene chloride is mixed with 2 ecm of 71% perchloric acid in 20 ecm Water and 400 mg of N-bromoacetamide in 100 ecm of tert-butyl alcohol are added. It is left at room temperature for 30 minutes stand and mixed with a solution of 0.5 g of sodium sulfite in 24 ecm of water. The mix will

concentrated under reduced pressure, whereupon the solution becomes cloudy. By adding a mixture of 200 ecm ice and water will precipitate the product. The white crystalline precipitate from 2-methyl-9a-bromo-11j8,17adioxy-21-acetoxy-4,6-pregnadiene-3,20-dione is filtered off, washed with water and at room temperature dried in vacuum. Recrystallization from a mixture of acetone and Skellysolve B «gives pure 2-methyl-9 a-bromo-11 / 3,17 a-dioxy-21 -acetoxy- ^ o-pregnadiene-3,20-dione, this in a manner known per se with chromic acid to 2-methyl-9α-bromo-17α-oxy-21-acetoxy-4,6-prcgnadiene-3,11,20-trione can be oxidized.

g) 2-methyl-9β, ll /? - oxido-17a-oxy-21-acetoxy-4,6-pregnadiene-3,20-dione

A mixture of 0.5 g of 2-methyl-9a-bromo-ll ß, 17a- dioxy-21-acetoxy-4,6-pregnadiene-3,20-dione, 0.5 g of anhydrous potassium acetate and 20 ecm of acetone is Heated under reflux for 5 hours. The mixture is cooled to room temperature, poured into water and then extracted with methylene chloride. The methylene chloride extracts are dried over anhydrous sodium sulfate and evaporated. The residue is recrystallized three times from acetone and “Skellysolve B”. 5 2-methyl- 9β, 11 / J-oxido-17α-oxy-21-acetoxy-4,6-pregnadiene-3,20-dione is obtained.

h) 2-methyl-9a-fluoro-II (3, i7a-dioxy-21-acetoxy-4,6-pregnadiene-3,20-dione

1 g of 2-methyl-9 / ?, Upi-oxido-17a-oxy-21-acetoxy-pregnadiene-3,20-dione in 5 ecm methylene chloride is treated with 5 ecm 48 ⁰ Z ₀ IgCr hydrofluoric acid and 0.5 ecm 71 ° / treated _o perchloric acid at room temperature. One stirred for 6 hours vigorously and then poured into excess cold aqueous 5 ^N / ₀ igc sodium bicarbonate solution. The methylene chloride layer is separated, dried with anhydrous sodium sulfate and then evaporated. The residue is purified by recrystallization from Skellysolve Bv and acetone. The 2-methyl-9a-fluoro-U ^, 17a-dioxy-21-acetoxy-4,6-pregnadiene-3,20-dione obtained gives a infrared spectrum in chloroform which confirms the assumed constitution.

i) 2-methyl-9a-fluoro-II / 3,17a, 21-trioxy-4,6-pregnadiene-3,20-dione

1 g of 2-methyl-9a-fluoro-ll ^, 17a-dioxy-21-acetoxy-4,6-preggnadiene-3,20-dione is dissolved in 15 ecm of methanol. Nitrogen is passed through this solution for 10 minutes. Then 10 ecm of methanol containing 1 g of potassium carbonate and 2 ecm of water are added. The added solution was also previously freed from air by passing nitrogen through it. The mixture is refluxed under nitrogen for 40 minutes, cooled and poured onto 200 cc of crushed ice. The solution obtained is extracted twice with 50 ecm of methylene chloride each time. The methylene chloride extracts are dried, evaporated and the residue is recrystallized from ν Skellysolve B <; - acetone, pure 2-methyl] -9a-fluoro-II / S, 17a, 21-trioxy-4,6-pregnadiene-3.20 -dion receives.

A mixture is prepared which contains 0.5 g of 2-methyl-9a-fluorine -11 ß, 17a-dioxy-21-acyloxy ^ .o-pregnadiene-3,20-dione, 0.2 g of chromic anhydride, 10 ecm of glacial acetic acid

Contains 45 and 0.5 ecm of water. The mixture is stirred and then kept at room temperature for 8 hours. It is then poured into 50 ecm of ice water and neutralized with dilute sodium hydroxide solution. The resulting precipitate is collected on a filter and recrystallized three times from ethyl alcohol and "Skellysolve B" , 2-methyl-9a-fluoro-17a-oxy-21-acetoxy-4,6-preggnadiene-3, l 1,20-trione receives.

Claims (1)

Claim: Process for the preparation of 2-lower-alkyl-9a-fluoro-II / ?, 17a, 21-trioxy-4,6-pregnadiene-3,20-diones and their 11-keto analogs, characterized in that (1) II / 3-Oxy-21-acyloxy-4,6,17- (20) -pregnatrien-3-one, the acyl radical of which is derived from an organic carboxylic acid with 1 to 8 carbon atoms, in a known manner with a lower oxalic acid alkyl ester, the. Alkylgmppe contains 1 to 8 carbon atoms, in the presence of an alkali metal base, the alkali metal of which has an atomic weight between 6 and 40, condensed, the resulting alkali metal enolate of 2 - lower - alkoxy - oxalyl -11 /? - oxy - 21 - acyloxy-4,6 , 17- (20) -pregnatrien-3-one with a lower alkyl halide which contains 1 to 8 carbon atoms and whose halogen atom has an atomic weight between 34 and 130, converts in a known manner, the resulting 2 - low - alkoxyoxalyl - 2 - lower - alkyl-11 /? - oxy-21-acyloxy-4,6,17- (20) -pregnatrien-3-one with an alkali metal alcoholate, the alkali metal and alkyl radical of which correspond to the definition given above, hydrolyzed in a known manner, the obtained 2-nicdrig-AkyJ-ll ^, 21-dioxy-4,6,17- (20) -pregnatriene with an anhydride or halide of an organic carboxylic acid having 1 to 8 carbon atoms esterified in a known manner, the resulting 2-lower-alkylll / 3-oxy-21-acyloxy-4,6,17- (20) -pregnatriene according to the method of the godfather nts 957 661 hydroxylated with osmium tetroxide in the presence of N-methyl-morpaolinoxide-peroxide and pyridine, the resulting 2-nicdrig-alkyl -11 / ?, 17a-dioxy-21-acyloxy-4,6-pregnadiene-3,20-dione treated by the process of patent 1029375 with an N-haloamide or N-haloimide and then with anhydrous sulfur dioxide, to the resulting 2-lower-alkyl-l 7 a-oxy-21-acyloxy-4,6,9- (ll) -pregnatriene-3,20-dione, a sub-halogenous acid, the halogen atom of which has an atomic weight between 34 and 130, is added, the resulting 2-lower-alkyl-9o-halogen-II / 3,17a-dioxy-21-acyloxy-4,6 -pregnaclien-3,20-dione with anhydrous alkali acetate, the alkali metal component of which corresponds to the definition given above, treated in an essentially anhydrous solvent in a known manner, the resulting 2-lower-alkyl-9 / 3,11 /? - oxido-17a -oxy-21-acyloxy-4,6-pregnadiene-3,20-dione cleaves in a known manner with hydrogen fluoride in the presence of a strong acid, if necessary the received old 2-lower-alkyl-9a-fluoro-il / 3,17a-dioxy-2l-acyloxy-4,6-pregnadicn-3,20-dione is oxidized in a known manner and the resulting 2-lower-alkyl-9a- ( luor-17a-oxy-21-acyloxy-4,6-pregnadiene-3, l 1,20-trione resp. the corresponding 11 / Ϊ-oxy compound in llf?, 17a-dioxy-4,6-pregnadiene-3, ll, 20-trione resp. 2-lower-alkyl-9 "- fluoro-11 ß, 17a - dioxy - 4,6 - pregnadiene - 3,20 - dione hydrolyzed. «09 729/283 1.