DE1296631B - Process for the preparation of 16-fluoromethylene steroids - Google Patents

Description

or an O-acyl group and St an optionally reversible, which result in physiologically acceptable esters.

unsaturated and / or substituted steroid residue of Pregnan series means with hydrogen bromide in the presence of an inert solvent under not treated under aqueous conditions and given

For example, the following acids or their derivatives suitable for esterification can be used be: carboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, trimester

if in the obtained 16-fluoromethylene steroid of 20 ethyl acetic acid, caproic acid, oenanthic acid, caprylic acid

general formula II

HC

R,

OC

-OH

CHF

sXi

acid, palmitic acid, undecylenic acid, benzoic acid, hexahydrobenzoic acid, cyclopentyl, cyclohexyl or arylacetic and propionic acids, such as phenylacetic or phenylpropionic acid, and halocarboxylic acids, such as chloroacetic acid,, etheric acids or heterocyclic acids, such as furancarboxylic acid (2) or II nicotinic acid. If necessary, you can also go to

Production of water-soluble derivatives with dicarboxylic acids, amino or alkylaminocarboxylic acids or esterify with phosphoric or sulfuric acid. In this way, z. B. produce: oxalates, succinates, Maleates or the acid addition salts of aminocarboxylic acid esters, e.g. B. of aspartic acid or diethylaminoacetic acid esters. For esterification

wherein R ₁ , R ₂ and St have the meaning given, the hydroxyl groups in 17 a- and / or

In addition to the free acids, derivatives which can be used according to methods known per se are 21-position

estert. for example their halides, anhydrides, thiol

It has now been found that the process is derivatives and ketenes. For transesterification methods of the main patent, surprisingly, lower alkyl esters are also suitable for Ver, Use of hydrogen chloride instead of bromine For the process of the invention can be used as hydrogen chloride can be carried out if one basically uses all 16a, 17a-Oxide larger ones with 40 starting material Amounts of acid and / or with longer react steroids of the Pregnan series are used, which in tion times works. With the same reaction time, the amount of acid per mole of steroid must be used when working with Hydrogen chloride about 10 times as large as when using hydrogen bromide. More advantageous 45 it is to lengthen the reaction times or to use an analogous, higher-boiling solvent.

The invention relates to a process for the production of 16-fluoromethylene steroids of the

16 / J position have a fluoromethyl group and those in 17 /? position by a

/ R ₁

- COHC group

^X R ₂

are substituted (R ₁ and R ₂ have the meaning given). The starting material is preferred

CH ₇ F

General formula II given below, which adds steroids of the following general formula in 50 consists in the fact that a steroid of the initially question: mentioned general formula I with hydrogen chloride treated in the presence of an inert solvent under non-aqueous conditions, wherein one with larger amounts of acid and / or with longer reaction times and / or at higher reaction temperatures works, and that optionally in the 16-fluoromethylene steroid formed General formula II referred to above, the hydroxyl groups in 17 a- and / or 21-position after 60 Esterified methods known per se.

As inert solvents, for. B. benzene, toluene, tetrahydrofuran, acetone, chloroform, carbon tetrachloride, ether, dioxane, ethyl acetate or glacial acetic acid can be used. Particularly high yields are achieved if the reaction is carried out in a mixture of ether and dioxane. The R ₁ and R ₂ have the meaning given, R ₃ reaction temperatures can be between about -10 ° CH ₁ H; H ₁ OH; Η, Ο-acyl or = O, R ₄ H, halogen

or alkyl, R ₅ Η, ΟΗ; Η, Ο-acyl or = O, R ₆ H or halogen.

The serpentine lines are intended to express that the respective substituents can have α or ^ -configuration. In addition to or instead of the substituents R ₃ to R ₆ , in the 1 (2), 4 (5), 5 (6), 6 (7), 9 (11) or II (12) -position, a or several double bonds may be present.

The following compounds may be mentioned as starting materials: 160-fluoromethyl-16a, 17a-oxido-allopregnan-30-ol-2O-one and its 3-acylate; 16 /? -Fluoromethyl -16a, 17a-oxido -4- pregnen-3,20-dione; 160-fluoromethyl - 16a, 17a-oxido-4 - pregnen - 21 - oil - 3.20 - dione; 16/7 - fluoromethyl-16 a, 17 a - oxido - 4 - pregnen -11 0.21 - diol - 3.20 - dione; 16 /? - Fluoromethyl- 16 «, 17a-oxido-4-pregnen-3,11, 20 - trion - 21 - oil; 6u - methyl - 160 - fluoromethyl-16a, 17a - oxido - 4 - pregnen - 3.20 - dione; 6a - methyl 160 fl uormethyl-16 ", 17a-oxido-4-pregnen-11 0.21-diol-3,20-dione; 9a-fluoro-160-fluoromethyl-16a, 17a-oxido-4-pregnen-l 10,21-diol-3,2O-dione; 9a-fluoro-160-fluoromethyl-16a, 17a-oxido-4-pregnen-II / i-ol-3,20-dione; 6a-methyl-9a-fluoro-160-fluoromethyl-16a, 17a-oxido-4 - pregnen - 110.21 - diol - 3.20 - dione; 6a - methyl-9a-fluoro-16 / f-fluoromethyl-16a, 17a-oxido-4-pregnen-110-ol-3,2O-dione and their 1-dehydro derivatives and, if the compounds have a 21-hydroxyl group have their 21-acylates.

The steroids of the general formula I mentioned at the beginning can be used as starting material from the corresponding 160-chlorine, 160-bromine or 160-iodomethyl-16a, 17a-oxido-steroids obtained by treatment with silver or mercury fluoride will. The 160-chloro-, 160-bromo- or 160-iodomethyl-16a, 17a-oxido steroids required for this reaction can be obtained by treating 16-methylene-17a-hydroxy steroids with elemental chlorine or bromine or with N-chlorine, N-bromine or N-iodosuccinimide.

According to the invention, compounds of the following general types are obtained as preferred end products Formula:

, R ₁

belonging to series, increased glucocohicpide and anti-inflammatory Effect.

The products of the process are intended to be medicinal products are used and can be processed into apes for pharmaceutical purposes usual preparation forms. For example, tablets, coated tablets, solutions, suspensions, syrups, sprays, Prepare ointments, powders and injection solutions.

At pie 1 1

The solution of 3.6 g of 160-fluoromethyl-16a, 17a-oxido-progesterone in a mixture of 110 ml of dioxane and 110 ml of ether, which contains 10 g of hydrogen chloride, is refluxed for 24 hours. The deep black solution is evaporated and the residue is recrystallized from acetone. This gives 16-fluoromethylene-17a-hydroxy-progesterone with a ^{temperature of 249 to 251 °} C .; [α] + 13.4 ° (chloroform). X _max : 239.5 ηΐμ, ε = 17,200.

Example 2

3.6 g of 160-fluoromethyl-16a, 17a-oxido-progesterone are refluxed for 24 hours in 100 ml of ethyl acetate containing 10 g of hydrogen chloride. To the work-up carried out as in Example 1 gives lo-fluoromethylene-na-hydroxy-progesterone from F. 248 to 25 Γ C.

Example 3

In the solution of 0.9 g of 160 fluoromethylddd

wherein R ₁ to R _{6 have} the meaning given.

The wavy lines are intended to express that the respective substituents can have the α or 0 configuration. In addition to or instead of the substituents R ₃ to R ₆ , in the 1 (2), 4 (5), 5 (6), 6 (7), 9 (11) or II (12) -position, a or several double bonds may be present.

The steroids obtained by the process according to the invention, if they belong to the progesterone series, have increased gestagenic activity, especially in the form of their 17a-acylates, if the corticoid-21-acetate is introduced into 100 ml of anhydrous dioxane until dry hydrogen chloride is saturated. After standing for 4 days at room temperature, the reaction mixture is evaporated under reduced pressure. The residue is taken up in acetone, treated with charcoal for 1 hour and filtered through a column of silica gel. The eluates are evaporated and the oil obtained is rubbed with methanol. The 16-fluoromethylene-1,4-pregnadiene-110,17a, 21-triol-3,20-dione-21 acetate crystallizes. M.p. 224 to 226 ° C; [α] f + 36 ° (dioxane).

Example 4

In the boiling solution of 1.2 g of 160-fluoromethyl-16a, l 7a-oxido-4-pregnen-21-ol-3,20-dione-21-acetate in 5 ml of dioxane and 50 ml of toluene is hydrogen chloride for 5 hours initiated. The solution is then freed from hydrogen chloride by blowing in nitrogen, heated with charcoal for 30 minutes, filtered and evaporated. After taking up the residue in acetone, crystallized pure 16-fluoro methylene-4-pregnene-17a, 21-diol-3,20-dione 21-acetate, mp 200-203 ⁰ C; X ^ _1x 240 ηΐμ, ε = 17600; [α]? + 60 ° (chloroform).

Claims (2)

Patent claims: 1. Process for the preparation of 16-fluoromethylene steroids of the formula / R, HC CHF where R _{1 is} hydrogen or a lower alkyl group, R _{2 is} H, OH or an O-acyl group and St is an optionally unsaturated and / or substituted steroid radical of the pregnane series, by treating a 16 /? - fluoromethyl-16a, 17a-oxido-steroid formula 10 CH ₂ F StV wherein R ₁ , R ₂ and St have the meaning given, with a hydrogen halide in the presence of an inert solvent under non-aqueous conditions and optionally subsequent esterification of hydroxyl groups present in the products obtained in the 17a and / or 21 position according to the main patent 1180 744 , characterized in that the hydrogen halide used here is hydrogen chloride in such a way that one works with larger amounts of acid and / or with longer reaction times and / or at higher reaction temperatures. 2. The method according to claim 1, characterized in that the solvent for the Reaction with hydrogen chloride a mixture of ether and dioxane is used.