BE570226A - - Google Patents

Description

       

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   The present invention relates to a novel advantageous process for the preparation of fluoro-pregnenes of formula:
 EMI1.1
 in which R1, R2 and R3 represent hydrogen or a free or esterified hydroxy group, R4 represent hydrogen or a methyl group, X represent hydrogen, a chlorine or fluorine atom, and Y two atoms of hydrogen, an oxo group or hydrogen, and a hydroxy group, free or esterified.



   This new process is characterized by the fact that compounds of the formula are treated with boron trifluoride: @
 EMI1.2
 in which R1, R2, R3, R4, X and Y have the meaning given above, and which have in position 3 and / or 20 hydrogen and a free or esterified hydroxyl group, or a free or ketalized oxo group , that a free or esterified hydroxy group or a ketalized oxo group located in position 3, is converted into a free oxo group, that the compounds 6ss-fluoro-5 [alpha] -hydro- are cleaved from water (dehydrated) xylated compounds obtained, that the # 4-3-oxo-6-fluorinated compounds is isomerized into # 4-3-oxo-6 [alpha] -fluorinated compounds, then that,

   hydrolysis at any reaction stage of the esterified hydroxy groups or when the free hydroxy groups are esterified,
Compared to the process described in the patent application filed on March 22, 1958 in the name of the company SYNTEX SA and having the title: “New pregnadienic compounds and process for their preparation”, the process of the present invention has the great advantage that no longer has to work with hydrofluoric acid.

   The reaction with boron trifluoride can be carried out in the usual vessels, for example made of glass or of steels. In addition, the fact that during the cleavage of 5,6-epoxides into 6ss-fluoro-5 [alpha] -hydroxy compounds , hydrofluoric acid can be replaced by boron trifluoride is very surprising, since it is known that the steroid-9,11-epoxides, when treated with boron trifluoride, are not transformed into fluorhydrins, but into 11-ketones.



   The reaction according to the invention, of the starting substances on boron trifluoride, for example on an etherate of boron trifluoride compound of addition of boron trifluoride with ether is advantageously carried out at room temperature, in a suitable solvent. such as ether, dioxane, benzene, toluene or mixtures of such solvents o 6ss-fluoro-5 [alpha] -hydroxyl compounds are then formed which, to be dehydrated into # 4-3-oxo-6ss- fluoro-pregnenes, are treated with alkali metal hydroxides, for example with sodium or potassium hydroxide, or with thionyl chloride or tri-

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 phosphorus bromide in a tertiary organic base such as pyridine,

   collidine or dimethylaniline. If the dehydration is carried out with acidic agents such as inorganic acids, in particular with hydrochloric acid in glacial acetic acid, then simultaneously a reversal occurs.
 EMI2.1
 in position 6, and the 4-3-oxo-6a-fluoro-pregnenes are obtained. Under these conditions, the ± 4-3-oxo-6fi-fluorinated compounds are isomerized to A4-3-oxo-6a-fluorinated compounds.
 EMI2.2
 The obtained 4-3-oxo-6a-fluoro: -pregnenes, which contain esterified hydroxy groups, for example in the 17 and / or 21 position, can be hydroxylated to free hydroxyl compounds according to known methods, for example using alkali metal alcoholates, hydroxides, or carbonates.

   In a way
 EMI2.3
 analogously, the 6p-fluoro-5a-hydroxyl compounds which optionally occur as by-products and which have hydroxyl groups esterified in the 3 and / or 20-position, can be converted into 3- and / or 20-hydroxyl compounds.



   The possibly necessary dehydrogenation of the 3- and / or 20-hydroxy groups to 3- and / or 20-oxo groups takes place in a known manner, for example by oxidation with chromium trioxide in glacial acetic acid or pyridine.



   For the esterification of hydroxy groups, for example at the 17 and / or 21 position, the reaction is carried out in the usual manner, with acid halides or anhydrides, advantageously in the presence of tertiary organic based, such as pyridine. , or in the presence of acid catalysts, for example p-toluenesulfonic acid.

   These esters are derived from carboxylic, aliphatic, alicyclic, aromatic, araliphatic or heterocyclic carboxylic, thiocarboxylic or sulphonic acids, for example formic, acetic, propionic acids, butyric acids, valerian acids such as n-valerianic acid or
 EMI2.4
 trimethylacetic acid, caproic acids, such as -trimethyl- propionic acid, cenanthic, caprylic, pelargonic, capric, undecylenic acids, for example undecylenic acid proper, lauric, myristic, palmitic or stearic and oleic acids, cyclopentyl-cyclohexyl - or phenyl-acetic or propionic acids, benzoic acid, phenoxy-alkane-oiques, such as phenoxy-acetic acid,

   p- acid
 EMI2.5
 chloro-phenoxy-acetic, 2, Q.-dichloro-pheno, y-acetic acid, 4-tert-butyl-phenoxy-acetic acid, 3-phenoy-propionic acid, 4-phenoxy-butyric acid, furan-2-carboxylic acid, 5-tertio-butyl-furan-2-carboxylic acid, 5-brom-furan-2-carboylic acid, nicotinic acid, as well as dicarboxylic acids, such as oxalic -, succinic, or glutaric acids, substituted carboxylic acids, such as p-oeto-carboxylic acids, for example aoetylacetic, propionylacetic, butyrylacetic or capri-nuclelacetic acids, amino acids, etc.



   The 5,6-epoxides used as starting substances and corresponding to the formula given at the beginning are known or can be obtained according to methods.
 EMI2.6
 methods known from the corresponding A 5-compounds
The products of the process are characterized by high biological activity in the liver glycogen test and in the particle size test. Unlike many non-fluorinated corticosteroids in the 6 [alpha] position, 6α-fluorocortico-steroids do not or only exhibit a small sodium retention side effect.



   The process described also embraces the embodiments in which only part of the operations of the process are carried out or in which one starts from an intermediate product obtained at any stage of the process and carries out the still missing phases of said process.



   The present invention also relates, as new industrial products, to products conforming to those defined above.

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   The invention is described in more detail in the non-limiting examples which follow, in which the temperatures are indicated in degrees centigrade.
Example 1
 EMI3.1
 In a solution of 3 g of 5 (i) 6cx-epoxy-pregnan-3i-, 17a, 20,21-tetrol-11-one in 150 cm3 of ether and 150 cm3 of benzene, is added dropwise. drop, with stirring, 3 cm3 of a borono trifluoride etherate The reaction mixture is stirred for 3 hours at room temperature, then washed with water, with sodium bicarbonate solution and again with water , dried over sodium sulfate and evaporated to dryness.

   We obtain as residue the
 EMI3.2
 Crude 3,17,20,21-tetracetate of 63-fluoro-pregnan-3,5cx, 17tx, 20,21-pentol-11-one which can be used without purification for the following stage
The above tetracetate is mixed with 50 cm3 of a 0.2notmal solution of perchloric acid in methanol, then boiled for two hours at reflux, cooled and diluted with water. The precipitate is separated by filtration, washed with water and evaporated in vacuo;

   we obtain the crude 17-acetate
 EMI3.3
 6-fluoro-prégnanem3,5cx, 17a, 20,21-pentol-11-oneo
This 17-acetate is dissolved in 20 cm3 of pyridine, cooled to 0, added 1.1 mol of acetic anhydride, left to stand for 18 hours at 0, then for 2 hours at approximately 25, The mixture is poured into water. water, extract the reaction product with ethyl acetate, wash the organic solution with water, dilute hydrochloric acid and again with water, dry over sodium sulfate and evaporate. dried up.

   The residue is the crude 17,21-diacetate of 6ss-
 EMI3.4
 fluoro-prégnane-3 (3-, 5a, 17a, 20,21-pentol-11-one4 3'g of crude 1721-diacetate of 6-fluoro-prégnane-3,5oc, 17ac, 20,21- are dissolved. pentol-11-one. in 150 cm3 of acetone, cooled to 0 and added dropwise, stirring, at 0, an oxidation solution of 1.6 g of chromium trioxide in 1.4 cm3 of sulfuric acid and 2 cm3 of water. This addition takes place in 2 minutes; the mixture is stirred for a further half an hour at 0 o After having diluted with water, the product is extracted with ether and the ethereal solution washed. with water, dried over sodium sulphate, filtered and evaporated to dryness.
 EMI3.5
 in this way the crude 17,21-diacetate of 6 (3-fluoro-pregnan-5-lTcx, 21-triol-3,11,20-trione.



   The above diacetate is dissolved in 100 cm3 of glacial acetic acid In the solution, a slow stream of hydrochloric gas is passed for 2 hours at 18, diluted with water, the product is extracted with water. ethyl acetate, wash the ethyl acetate solution with water, with 5% sodium carbonate solution and again with water, dry over sodium sulfate, filter it and evaporated to dryness. The residue is crude 6 [alpha] - fluoro-cortisone diacetate which can be purified by crystallization from a mixture of acetone and hexane.



   3 g of the crude dioxane of 6α-fluoro-cortisone are dissolved in 30 cm3 of a 1% methanolic solution of potassium hydroxide, then left to stand for 2 hours at 0, under a nitrogen atmosphere. The mixture is neutralized with glacial acetic acid, diluted with water and extracted with ethyl acetate; the extract is washed with 1 water, dried over sodium sulfate and evaporated to dryness.

   By crystallizing the residue from a mixture of acetone and hexane, one obtains
 EMI3.6
 60E-fiuoro-cortisonee
The starting material used can be prepared as follows:
To a solution of 5 g of cortisone 21-acetate in 250 cm3 of acetic anhydride, 3 g of p-toluene-sulfonic acid are added and the solution is left to stand for 70 hours, stirring occasionally. time. Then poured into water.

   The precipitate is separated by filtration, washed until neutral reaction, dried in air and crystallized from methanol; we get the. triacetate

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 EMI4.1
 A 35-pregnadien317cx, 21-triol-11,20-dionea
4 g (the triacetate is dissolved in 200 cm3 of methanol, cooled in an ice bath and carefully added, with constant stirring, at a temperature below 0, a solution of 2 g of boron hydride and sodium in 20 cm3 of water After stirring for 2 hours at 0, neutralized with acetic acid, concentrated in vacuo until approximately 30 cm3, then added.
 EMI4.2
 te 200 cm3 of water.

   The 15-Pregnene-317c, 20,21-tetrol 11-one 17-acetate which has precipitated is filtered off, dried, dissolved in 20 cm3 of pyridine. then treated with 4 cm3 of acetic anhydride. After maintaining the mixture overnight at room temperature, it is poured into water, filtered, crystallized from a mixture of acetone and hexane, and in this way the tetracetate is obtained.
 EMI4.3
 α 5-Pregnene-3P, 17ct, 20,21-terol-11-one.



  In 300 cm3 of chloroform, 3 g of the tetracetate of L5 pregnene-3-17 x20,21-tl-11-oae are dissolved, 1.5 mol of monoperphthalic acid dissolved in ether are added, then left to stand for 20 hours at room temperature. Water is then added, the organic layer is separated, washed with water, with sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated to dryness under vacuum.
 EMI4.4
 in this way the crude tetracetate of 5cx-6a epor-pregnan-3i-17tx, 20, 21-tetrol-11-one which is purified by crystallization from a mixture of acetone and hexane.



   Example 2
Cooled to 0, a solution of 1 g of crude 17,21-diacetate from
 EMI4.5
 6-fluoro-prégnane-5a, 'jot, 21-triol-3,11,20-trione described in Example 1, in 10 cm3 of pyridine, add dropwise, with stirring, 1 cm3 of thionyl chloride, keeping the temperature at 0. After stirring for 2 hours at C, poured into water, the product is extracted with ethyl acetate, the organic solution washed with dilute hydrochloric acid, with a 5% solution of- sodium carbonate and-with water, dry it over sodium sulfate
 EMI4.6
 and evaporates it to seo. The residue is the crude 17,21-diacetate of 6fi-fluoro-aortisone which is purified by crystallization from a mixture of acetone and hexane.



   The crude diacetate is dissolved in glacial acetic acid and treated with dry hydrochloric gas, as described in Example 1, it occurs
 EMI4.7
 an inversion in position 6, with formation of the α-fluoro-eartieone diacetate described in Example 1.



   Example 3
Treated according to the indications of Example 1, 1 g of 17,21-diae-
 EMI4.8
 crude tate (obtained according to this example) of 6-fluoro-pregnan-5a1'oG, 21-triol-3,11,20-trione per 30 cm3 of a 1% methanolic solution of hydroxide. potassium; there is dehydration at carbon 5 and hydrolysis
 EMI4.9
 acetylated hydroxy groups, and 6β-fluoro-aortisone is formed.



   Example 4
The treatment of 6p-fluorocortisone diacetate which is described in Example 2, according to the method described in the preceding example, leads to the
 EMI4.10
 6µ-fluorocor% isone which is identical to the final substance of Example 3, Example 5
 EMI4.11
 If in Example 1, we do not start with 21-cortisone acetate, but its 90E-ahlorinated derivative and its 9a-fluoréy derivative and uses the methods of Examples 1 to 4, its then obtains the products intermediates and the following final substances:

   

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 EMI5.1
 9cx-ehloxo-3'S-prégnad5.ene-3,17oc, 21-triol-lle2O-dione and 9ac-fluoro-3 5-prégnad.ene-3, 17cx 21-triol-11-20- triacetates dione the tetraoetates of 9a chloro-5-pregnene-3-17oc, 20,, 21-tetrol-ll-one and of 9a-fluoroA '= pregnene-3,17a, 20,21-tetrol-11-one, . tetracetates of 90E-ohloro-50e-60E-epox, γ-prenan-3 ,.

   17, 20,, 21-tetrol-11-one and 9cx-fluoro-5cx 6oc-epoxy-pregnan, 3-17a, 20,21-tetrol-II-one,, 3,17,20,21- tetracetates, 17-monoacetates, and 17,21-diaoetates of 63-fluoro-9a-chloro-prgnane-3,5,17,20,21-pentol-11one and of 6i, 9cx-difluoro-prégnane-3, 5a, 17,20,21-pento7.-li-one, the 17,21diacetates of 6fi-fiuono-90E-chiono-pregnan-50E, 17G, 21-trioi-3,11,20-tnione and 6 , 9cx-difluoro-prégnane-5cx 17x, 21-triol3,11., 20-r.one, the diacetates of 6p-fluoro-ga, -fluoro-cortisonee of 60E-fiuono-90E-ohiono-contisone, of 6, 9a difluoro-cortisone and 6a, 9cx-difluoro-cort.soneo The final substances are 6o-fluoro-9cx ehloro-cortisone, 6c α-difluoro-cortisone, 6-fluorogcc-chloro-cortisone and 6,9a-difluoro-cortisoneo
Example
A solution of 1 g of 6-fluoro-cortisone in 10 cm3 of pyridine is mixed with 0,

  5 g of acetic anhydride, then leave to stand for 4 hours at room temperature. The mixture is poured into water, heated for half an hour in a water bath and cooled. The precipitate is filtered off and crystallized from a mixture of acetone and hexane; 6-fluorocortisone 21-acetate is thus obtained
When replacing acetic anhydride by: 1 anhydride or the chloride of another carboxylic acid comprising, for example, from 3 to 12 carbon atoms
 EMI5.2
 carbon, we then obtain the corresponding 21-esters of 60-fluoro-cortisone.



  In an analogous manner, the 21-esters of 6a-and 6fluoro-9o-chloro-cortisone, 6a, and 6-9a difluoro-cortisonea are prepared. Example 7 A a solution of 3 g of 3 -acetate of 5cx, 6cx-epo pregnan 3 -ol- 20-one melting at 168-169 and exhibiting a specific optical rotation [[alpha]] D = + 9 (in chloroform), in 300 cm3 of a mixture with equal parts of ether and benzene, 3 cm3 of a boron trifluoride etherate are added, then left to stand for 3 hours at room temperature o The solution is then washed with water, dried over sodium sulfate , filter and evaporate to dryness. The residue is chromatographed on neutral aluminum oxide;

   we get 3-acetate
 EMI5.3
 6fi-fluoro-pnégnane-3fi-50E-aliol-2o-one which melts at 223-224 and has a specific optical rotation [[alpha]] D = + 42 (in chloroform)
A mixture of 3.5 g of the above 3-acetate and a 0.2-normal solution of perchloric diacid in methanol is boiled for 2 hours at reflux, then treated as indicated in Example 1; we get 6ss-fluoro-
 EMI5.4
 pnégnane-3fi, 5y-ioi-20-oneo
A solution of 3 g of the crude diol in 150 cm3 of acetone is cooled to 0 and an octanormal solution of chromium trioxide prepared from 1.6 g of chromium trioxide, concentrated sulfuric acid and 'water.

   After the
 EMI5.5
 treatment described in example 1, 6-fluoro-pregnan-5a ol-3,20-dione is obtained which melts at 274-278 and has a specific optical rotation [[alpha]] D = + 81 (in pyridine) . ,
 EMI5.6
 Dehydration of 6p-fluoro-prégnane-5a-01-3e2O-dione using a mixture of thionyl chloride and pyridine or using potassium hydroxide provides 6µ-fiuoro-pnogpsterone which melts at 156-158; absorption spectrum in the ultra-violet: s max = 234 mu, 1 109 e = 4). '! 2..If dehydration

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 is carried out using a mixture of a halogenated hydracid and glacial acetic acid, we obtain 6a-fluoro-progesterone having a rotatory power
 EMI6.1
 specific 1-ral D '+ i91; absorption spectrum in the ultraviolet:

   fi = 236 bzz, loge = 4.19 If in the example above, we start from 3,17-d.iacetate of 5a 6a .epoy-prêgnane-3-1'a d3.ol-20-one as final substances the 17-acetate of 6tx-fluoxo-17a hrd.ror-progesterones respectively the 6p-isomer is obtained.



  Analogously, 17-propionate and 17-caproate can be obtained from 6K-fluoro-17oro6-hydroxy-progesteroneo. The 5 <X? 6 <? -Epoxides used as starting substances can be prepared as indicated. of Example 1 starting from the corresponding # 5-pregnenes.



   Example 8
According to the indications given in Example 1 or in Example 7, treatment is carried out with a boron trifluoride etherate in solution in ether and
 EMI6.2
 benzene, 3 g of 1721-diacetate of 5oc, 6tx-epox, p-pregnan-3,17a, 21-trial-20-one which melts at 198-200. and exhibits specific optical rotation [[alpha]] D = - 54 (in chloroform); we obtain the 17,21-diacetate of 6p-fluoro-prégnane-
 EMI6.3
 3,5cx, 17a21-tetrol-20-one which melts at 176-178 and exhibits specific optical rotation / oc7 -n = - "57 (in chloroform).



  Oxidation of the above diacetate as described in Example 1 affords 17,21-d.aaetate of 6-fluoro-pregnan-5cx, 17a, 21-triol-3, 20-dione, melting at 225- 227 and exhibiting specific optical rotation [[alpha]] D = + 0, a compound which, on treatment with a mixture of hydrochloric gas and acid
 EMI6.4
 from glacial acetic to. 18, is dehydrated to 17,21-d.acetate of 6ex-fluoro-A4pnegenene-170E, 21-iol-3, .20-dione; absorption in the ultra-violet spectrum T 236 m #, log # = 4.22, $ [[alpha]] D + + 53 (in chloroform).



   The hydrolysis of this diacetate using a methanolic solution in
 EMI6.5
 1, of potassium hydroxide, at 0, leads to 6cx-fluoro-4-prêgnene-17cx, 21-dioZ-3,20-dione which melts at 203-205 and exhibits specific optical rotation [[alpha]] D = + 135 (in chloroform).
 EMI6.6
 



  The 17,21-diacetate of 5a-6tx-epogy-pregnan-3-17cx, 21-triol-20-one which is used as the starting material can be obtained by oxidizing with monoperphthalic acid on 17, 5-Pregnene-3-17oc 21-diacetate, 21-triol-20-one ...



   Example 9
In a manner analogous to those of the indications given in Example 8, starting from 3-formate-17,21-diacetate of 5 [alpha], 6 [alpha] -epoxy-
 EMI6.7
 prêgnan-3,17a21-triol-20-one which melts at 238-240 and has a specific optical rotation fOE j D = -570 (in chloroform), the 3-formate-17, 21-diacetate of 6-fluoro -Pregnan-3-5ac, 17a 21-létro-20-one melting at 199-200 and exhibiting specific optical rotation [[alpha]] D = - 46 (in chloroform).



   For partial hydrolysis, it is left to stand for 7 hours at. at room temperature., 5 g of the above compound, with 5 cm3 of concentrated hydrochloric acid, in 150 cm3 of dioxane and 30 cm3 of water. After isolating the product

 <Desc / Clms Page number 7>

 
 EMI7.1
 reaction, the 17,21-diacetate of 6 fluoro-pregnan-33, 5oc, 17cx, 21-tetrol-20-one described in Example 8 and which, by dehydration using a mixture of thionyl pyridine chloride, provides 17,21-diacetate
 EMI7.2
 6S fluoro-4-pregnene-170E, 21-diol-3,20-dione. By treatment with a 1% methanolic solution of potassium hydroxide, the latter diacetate can be hydrolyzed to 6-fluoro-, 4-pregnene-17oG, 21-diol-320-dion.



  According to the indications provided in Example 6, the 6a-fluoro- 4 prégnèn.e-17a, 21-diol-3,20-dione and the z-isomer can be converted into their esters, in particular into their 21-mono- esters, such as 21-mono-acetates. '
EXAMPLE 10.



   A 3 g solution of 5 [alpha] 6 [alpha] -epoxy- 17,21-diacetate is treated.
 EMI7.3
 pregnan-317c, 21-triol-11,20-dione in 300 cm3 of: a mixture of equal parts of ether and benzene, with per 3 cm3 of a boron trifluoride etherate, left to stand for 3 hours at room temperature, then process as in the example
 EMI7.4
 ple 1; the 17,21-diacetate of 6-fluoro-pregnane-33,5a, 17a-21-tetrol-11,20-dione is obtained.



  In 100 cm3 of acetone, 2 g of 17,21-ï.diacetate of 6) 3fluoro-pregnan-3,5a, 17a, 21-tetrol-11,20-dic.e are dissolved, cooled to 0 and, While stirring at a temperature below 0, an octanormal solution of chromium trioxide, prepared from 1.2 g of chromium trioxide, concentrated sulfuric acid and water is added dropwise. The mixture is stirred for 5 minutes at 0, water exhausted with ether is added and the ethereal solution is washed with water, dried over sodium sulfate, filtered and evaporated to dryness. By crystallizing the residue from a mixture of acetone and hexane, 17,21-diacetate is obtained.
 EMI7.5
 6S-fluoro-pregnan-5tx, 17a, 21-tricl-3,11,20-trione.



   1.8 g of the above 17,21-diacetate is dissolved in 80 cm3 of glacial acetic acid and a slow stream of hydrochloric gas is passed for 2 hours at 18. The solution is poured into water, the precipitate is separated by filtration, washed with water, dried and crystallized from a mixture of acetone and hexane; the 17,21-diacetate of 6α-fluoro-cortisone is thus obtained.



   1 g of this diacetate is suspended in 10 cm3 of absolute methanol, cooled to 0 and a methanolic solution of sodium methoxide (140 mg of sodium in 10 cm3 of methanol) is added. The addition takes place dropwise, at 0, with stirring, under a nitrogen atmosphere. After one hour, the mixture is poured into 100 cm3 of a saturated solution of sodium chloride cooled with ice and containing 0.5 cm3 of glacial acetic acid. The precipitate is separated by filtration, washed with water and recrystallized from acetone; 6α-fluoro-cortisone is thus obtained.



   The starting material can be obtained as follows:
 EMI7.6
 To a solution of 7.5 g of 16a, 17'X-epoxy-A-prengen-3,21-diol-11,20-dione diacetate in 150 cm3 of methylene dichloride is added dropwise, stirring, over 10 minutes, 5.1 cm3 of a 30% solution of dry hydrobromic gas in glacial acetic acid. After adding water, the organic layer is separated, washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo at a temperature below 35. We
 EMI7.7
 In this way the 21-acetate of 16α-bromo-5-pregnene-3j3,17cc, 21-triol-11,20-dione is obtained. The sample for analysis is obtained by crystallization from a mixture of acetone and hexane.
 EMI7.8
 



  7.5 g of the crude 21-acetate of 16p-bromo-A 5¯pregnene-3,17a, 21-triol-11,20-dione are added to a suspension of 15 g of Raney nickel in 300 cm3 of methanol, boil the mixture for 2 hours at reflux, with stirring, cool, filter under a nitrogen atmosphere and wash the residue with methanol.



  After having combined the filtrates, they are evaporated to dryness and the residue crystallizes from a mixture of acetone and hexane; obtains the 21-acetate from # 5-pregnene-

 <Desc / Clms Page number 8>

 
 EMI8.1
 -3.17cx21-triol-11.20-dione.



   While stirring, a suspension of 6 g of the above compound in 150 cm3 of 85% formic acid is heated for 2 hours at 70, then cooled.



  The crystalline precipitate of 3-formate-21-acetate is then separated by filtration.
 EMI8.2
 of h5-pregnene-3, .174, 21-triol-11, 20-dion.



   Stirred for 9 hours at room temperature, a mixture of 5 g of the above compound, 120 cm3 of acetic anhydride and 1.7 g of p-toluenesulfonic acid, then poured into frozen water. For the hydrolysis of the excess acetic anhydride, the mixture is stirred and the crystalline precipitate is then separated by filtration, washed with water, dried and recrystallized from a mixture of acetone and hexane; we obtain the 3-formate-17,21-diacetate of
 EMI8.3
 Q, -Pregnene-3,17,21-triol-11,20-aione.



   A solution of 5 g of the above triester in 150 cm3 of dioxane is mixed with 40 cm3 of water containing 5 cm3 of concentrated hydrochloric acid, then stirred for 8 hours at room temperature. The mixture is poured into water, left to stand overnight in a cooler, filtered, washed with water, dried and crystallized from a mixture of acetone and hexane; we get the 17,21-diacé-
 EMI8.4
 tate of 5-pregene-317a, 21-triol-11,20-dione.



  Treated with 1.8 mol of monoperphthalic acid in ether is a solution of 4 g of the 17,21-diacetates of j, 5-pregnene-3,17a, 21-triol-11,20-dione in 80 cm3 of chloroform, let the mixture stand for 20 hours at room temperature and pour into water. The organic layer is separated, washed with water, with a solution of sodium bicarbonate and again with water, dried over said sodium sulfate, filtered and evaporated to dryness in vacuo. By crystallizing the residue from a mixture of acetone and hexane, the product is obtained.
 EMI8.5
 5α, 6cx-epogy-pregnan-3,17c 17,21-diacetate, 21-triol-11,20-dione.



  Example II.



  Following the indications given in Example 1, a
 EMI8.6
 solution of 3 g of 3,20-bis-ethylene-toioxy-50E, 60E-epoxy-pregnan on a boron trifluoride etherate, then the reaction product is isolated, thus obtaining 6fl-fluoro-3,20-bis -ethylenedioxy-pregnan-] OE-ol.



   To a solution of this bis-ketal in 150 cm3 of acetone and 5 cm3 of water, 400 mg of p-toluenesulfonic acid are added and left to stand for 6 hours at room temperature, then poured into water, separated by filtration,
 EMI8.7
 then, after having dried the 6p-fluoro-prégnane-5OE-01-3,20-dione obtained, it is recrystallized from a mixture of acetone and hexane.



   1 g of the 6ss-fluorinated derivative is dissolved in 50 cm3 of glacial acetic acid, then a stream of dry hydrochloric gas is passed through the solution for 4 hours. By isolating the reaction product as indicated in
 EMI8.8
 the previous examples, 6tx-flzoro-progestéron.e is obtained which, after recrystallization from a mixture of acetone and hexane, melts at 146-148 and exhibits a
 EMI8.9
 specific rotational power, ra, 7, =. 191 (in chloroform).



  6ft-fluoro-11a-hydroxy-progesterone 17-acetate prepared in an analogous manner starting from 3-ethylene-dioxy-50e-60E-epoxy-pregnan-l7tx-ol-20-one 17-acetate melts, after recrystallization from a mixture of acetone and hexane, at 249-251 and exhibits a specific optical rotation [[alpha]] D = + 55 (in chloroform).



   Following the indications given in the previous examples, it is possible to
 EMI8.10
 converting the 50E, 60E-epoxy compounds indicated under I into 6a- and 6p-fluorinated derivatives mentioned under II; as intermediates, the corresponding 6ss-fluoro-5a-hydroxyl compounds are obtained:

 <Desc / Clms Page number 9>

 
 EMI9.1
 
<tb>
<tb> @
<tb> 17-caproate <SEP> from <SEP> <SEP> 3-ethylene- <SEP> 17-caproate <SEP> from <SEP> <SEP> 6 [alpha] - <SEP> and <SEP> of
<tb>
 
 EMI9.2
 dioy-5cx, 6-epoxy pregnane-6P-fluoro-17a-hydroxy-17cx-ol-20-one; progesterone; 21-acetate of 3-ethylene-21-acetate of substance S dior-5ot, 6cx ëpoyr-prëgnane- (Reichstein) 6cx- and 6-fluorinated;

   
 EMI9.3
 
<tb>
<tb> 21-ol-20-one;
<tb> 17-propionate <SEP> from <SEP> 3,20-bis- <SEP> 17-propionate <SEP> from <SEP> the <SEP> 60: - <SEP> and
<tb>
 
 EMI9.4
 ethylenedioBy-5a, 6cx-êpo of 63-fluoro- 6 -pregnen,
 EMI9.5
 
<tb>
<tb> Pregnan-21-ol; <SEP> 21-01-3,20-dione;
<tb> 17,21-diacetate <SEP> of <SEP> the <SEP> 3- <SEP> 17,21-diacetate <SEP> of <SEP> the <SEP> substance <SEP> S
<tb>
 
 EMI9.6
 ethylenedioxy-50e, 60e-epoxy- (Reichstein) 6a- and 60-fluorinated;
 EMI9.7
 
<tb>
<tb> Pregnan-21-ol-20-one; <SEP> @
<tb> 17,21-diacetate <SEP> of <SEP> the <SEP> 3- <SEP> 17,21-diacetate <SEP> of <SEP> the <SEP> 6a- <SEP> and <SEP> of <SEP> the
<tb>
 
 EMI9.8
 ethylenedioxy-5a, 6a-epoxy-6S-fluoro-cortisone;

   Pregnan-17a, 21-Diol-11, 20-
 EMI9.9
 
<tb>
<tb> dione;
<tb> 17,21-diacetate <SEP> of <SEP> the <SEP> 9 [alpha] - <SEP> 17,21-diacetate <SEP> of <SEP> the <SEP> 6 [alpha] - <SEP > and <SEP> of <SEP> the
<tb>
 
 EMI9.10
 chloro-3-ethylenedioxy-63-fluoro-9a-chlorocortisone; 5ac, 6oc-epor-prenan-17ac, 21-diol-11,20-dione; 9tx-17,21-diacetate, 6oc- and fluoro-3-ethylenediog -21-diacetate, p-6-fluoro-9a-fluoro-cortisone.



  5a, 6ce-epoxy-pregnan-17a, 21-diol-11,20-dione.



   Instead of the above 17,21-diacetates, it is possible to start from 17,21 diesters of acids of higher molecular weight, for example 17-acetate-¯ 21-propionate; the corresponding 17,21-diesters are then obtained as final substances.



   The hydrolysis of 17-mono- and 17,21-di-esters to free 17-hydroxyl and 17,21-dihydroxyl compounds is carried out according to the indications given in the preceding examples. In this way, starting from the esters described above, the free compounds below are obtained: 6 [alpha] - and 6ss
 EMI9.11
 fluoro-17o: -hydroxy-progesterone, substance S (Reichstein) 6a-and 6-fluorinated, 6ac- and 6S-fluorocortisone, 6cx- and 6-fluoro-9a-chloro-cortisone, 6c- and 6p-fluoro-9oc-fluoro-cortisone, 6oc- and 6-fluoro-4-pregnene-21-ol-3,20-dione.



   The free compounds obtained can be converted into their esters; in particular in 21-esters, by operating according to the indications given in the preceding examples o
Example 12.



   As described in Example 1, reacting with an etherate of
 EMI9.12
 boron trifluoride, 3 g of 3920-bis-ethylene-dio3cY% - 5ae 6cx-epvxy pregnan-17aol; 6fi-fluoro-3,20-bis-ethylenedioxy-prégnane-50E, 170E-diol is obtained which, treated according to Example 1 with a mixture of hydrochloric gas and glacial acetic acid, is converted into 6oc-fluoro- 17x-hyâro, y-progesterone.



  If the above bis-ketal diol is treated with p-toluenesulfonic acid in acetone, 6fl-fluoro-pregnan-50e, 170E-diol-3,20-dione is obtained which, using a mixture of thionyl chloride and pyridine, or using a 1% methanolic solution of potassium hydroxide, is dehydrated
 EMI9.13
 into 6-fluoro-17a-hydroyprogesterone. The 6-fluorinated derivative obtained can be isomerized using a mixture of chlor-

 <Desc / Clms Page number 10>

 
 EMI10.1
 hydric and glacial acetic acid to 6cr-fluoro-17a-hYdroxy.-Progesterone.



  Example 13.



  Stirred for 12 hours at room temperature, a mixture of
 EMI10.2
 2 g of 6a-fluoro-17hdro progesterone of 10 cm3 of acetic anhydride and 200 mg of p-toluene-sulfonic acid, then pour the whole into water; after having isolated the reaction product, the diacetate of 6-fluoro- A, 5 pregnadiene-317oc-di dil-20-0l is obtained which, hydrolyzed for one hour at 5-10 using a 1% methanolic solution of potassium hydroxide, provides the 17-acetate of 6a-fluoro-17a-hydroxy-progesterone.



  Similarly, 6oc- and 6p-fluoro-17a b.rdrog, p-progesterone can be converted to other esters, such as 17-formates, 17-propionates and 17-caproates.



   Example 14.



   Following the indications given in example 1, we treat by a
 EMI10.3
 boron trifluoride etherate, 3 g of 20-ethylenedio 5a, 6cx-epoxy-pregnan-31c-diol 3-acetate; after having isolated the reaction product, the 3-acetate of 6fluoro-20-ethylenediozy-prégnane-35cx17c triol is obtained.



   To a solution of 1 g of the above acetate in 50 cm3 of tetrahydrofuran is added 500 mg of lithium aluminum hydride, boiled for one hour at reflux, cooled and decomposed the excess hydride into adding ethyl acetate. When dried, the solution in ethyl acetate abandoned
 EMI10.4
 evaporated in vacuo 6-fluoro-20-ethylenedioxy-pregnâ, ne-3,5cx, 17 [alpha] -triol.



   To a solution of the above crude triol in 10 cm3 of pyridine is added to 0 a solution of 800 mg of chromium trioxide in a mixture of 3 cm3 of pyridine and an em3 of water, then the mixture is allowed to stand. overnight at room temperature. It is then diluted with 50 cm3 of ethyl acetate, filtered through celite, the filtrate washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated to dryness. By crystallizing the residue from a mixture of acetone and hexane, the product is obtained.
 EMI10.5
 6p-fluoro # 20ethylenedioxy-prégnane-5K, 17 <x-diol-3-one which, by treatment with a mixture of hydrochloric gas and glacial acetic acid, is transformed into 6ac-fluoro-17a hydro progesterone.



  The 6p-flucro-20-ethylenedioxy-pregnan-3p, 5a, 17 # -triol described above provides, upon cleavage of the ketal with a mixture of p-toluenesulfonic acid and acetone, the corresponding 20-ketone which, by oxidation with chromium trioxide in pyridine or glacial acetic acid, is oxidized
 EMI10.6
 into 6fl-fluoro-pregnan-50E, 170E-di.ol-3,20-aione. The transformation of this compound into 6a fluoro-17a hdragy-protone takes place according to the indications provided in the preceding examples.
Example 15.
 EMI10.7
 



  A solution of 3 g of the 16,17-diacetate of 3-ethylenedioxy-5oc, 6a-épor-prégnan, e-16a, 17oc-diol-20-one in a mixture of 150 cm3 of ether and 150 cm3 of benzene, per 3 cm3 of boron trifluoride etherate, let the mixture stand for 3 hours at room temperature and then dilute it with water, separate the organic solution, dry it over sodium sulfate and evaporates it. After chromatographing the residue on neutral aluminum oxide
 EMI10.8
 6-fluoro-3-ethylene-diogy-pregnan-cx? 16-17a-triol-20-one 16,17-diacetate is obtained.



   In a solution of 2 g of the above ketal in 150 cm3 of acetone and 3 cm3 of water, 400 mg of p-toluene-sulfonic acid are added and the mixture is left to stand for 6 hours at room temperature, diluted with water, separates the precipitate by draining, dries it and crystallizes it in acetone; we get-

 <Desc / Clms Page number 11>

 
 EMI11.1
 6-fluoro-pregnane-5a, 16a, 17oc-triol-3,20-dione 16,17-diacetate.



   A solution of 2 g of the above diacetate in 100 cm3 of glacial acetic acid is mixed with 2 cm3 of a concentrated aqueous solution of hydrochloric acid; this mixture is maintained for one hour at room temperature, diluted with water, filtered off, dried and crystallized from a mixture of acetone and
 EMI11.2
 hexane; 4-6-fluoropregnene-16a, 17a = diol-3,20-dione is obtained 16,17-diacetate.



   The diacetate obtained can be dehydrogenated in position 1 as follows:
A mixture of 2 g of the diacetate, 100 cm3 of absolute tertiary butanol, 0.8 g of selenium dioxide and 0.5 cm3 of pyridine is boiled for 72 hours in a nitrogen atmosphere, cooled, filtered through celite and evaporate the filtrate to dryness under vacuum. The residue is dissolved in acetone, decolorized with activated charcoal and evaporated. Chromatography of the residue on neutral aluminum oxide gives the 16,17-diacetate of 6 1,4-6ss-fluroro-
 EMI11.3
 Pregnadiene-16a, 17a-diol-3,20-dinone.



  The starting material can be prepared, for example, as follows: A mixed mixture is stirred for 24 hours at room temperature.
 EMI11.4
 holding 5 g of 4-pregnne-16a, 17a-diol-3,20-dione, 500 cm3 of benzene, 50 cm3 of acetic anhydride and 2 g of p-toluene-sulfonic acid, diluted with water, wash the organic solution with water, with 5% sodium carbonate solution and again with water, dry it over sodium sulfate and evaporate the solvent. Crystallization of the residue from acetone affords the 16,17-diacetate
 EMI11.5
 l, ° -Pregnenē-16a, 17a-diol-3,20-dion.



   A mixture containing 5 g of the above diacetate, 300 cm3 of benzene, 35 cm3 of ethylene glycol and 250 mg of p-toluenesulphonic acid is boiled for 12 hours, while continuously removing the water formed. Then added to the cooled mixture 50 cm3 of a 50% solution of sodium carbonate and 500 cm3 of water, the benzene layer washed with water, dried over sodium sulfate and evaporated. The residue consists of the crude 16,17-diacetate of # 5-3-
 EMI11.6
 .¯ethrqènediogy-pregnene-16a, 17tx-diol-20-one. It can be hardened by crystallization from a mixture of acetone and hexane.



   A cooled solution of 5 g of the above ketal in 100 cm3 of chloroform is mixed with a solution in ether containing 1.2 mol-equivalent of monoperphthalic acid; after leaving it for 16 hours at 0-5 in the dark, it is poured into water. The organic solvent is separated, washed with water, dried over sodium sulfate and evaporated. In process-. After purification by chromatography, the 16,17-diacetate of
 EMI11.7
 3-ethylenedioxy-50e, 60E-epoxy-pregnan-160e, 170e-diol-20-oneo Example 16.



  In a manner analogous to that described in Example 15, one obtains,
 EMI11.8
 starting from 3-ethylene toioxy-50E 16,17,21-triacetate, 60E-epoxy-prégnanel6oc, 17tx-2d; -triol-20-one, to 6-fluoro-pregnane 16,17,21-triacetate -5a16oc, 17a, 2cL-ttrol-320-dione which, on treatment with hydrochloric acid, is converted into the 16,17,21-triacetate of ° -6S-fluoro-pregnen-16a, 17a, 21-triol - 3,20-dione. By dehydrogenating this product with selenium dioxide, the 16,17,21-triacetate of 1-6 (3fluoro-pregnadiene 16c, 17cx 21-triol-3, 20-dione is obtained.



   The starting material can be prepared in a manner analogous to
 EMI11.9
 that described in Example 15, starting from 1 -pregnene-16a, 17as21-triol-3,20-dione.



   Example 17
In 75 cm3 of glacial acetic acid, 1.5 g of 16,17-diacean are dissolved.

 <Desc / Clms Page number 12>

 
 EMI12.1
 6fl-fiuono-preenane-50E, 160E, 170e-% rioi-3,20-dione obtained according to Example 15, then passed for 2 hours in a stream of dry hydrochloric gas.



  The reaction mass is then poured into water, filtered off, washed, dried and the product obtained crystallizes from a mixture of acetone and hexane; we obtain
 EMI12.2
 -6α-fluoro-pregnene-16,17-diacetate-16a, 17a-diol-3,20-dione. By dehydrogenating this compound with selenium dioxide, 1,4¯6a-fluoro-pregnadiene-16a, 17a-diol-3,20-dione 16,17diacetate is obtained.



  In a manner analogous to that indicated in the preceding examples, the 16,17,21-triaceate can be converted from 6-fluoro-pregnan-5a, 16a, 17a-21-tetrol-3,20-dione described in Example 16, in the 16,17,21-triacetates of 46a fluoro-pregnene-16as17a, 21-triol-3,20-dione and of ALE4- 6tx-fluoropregnadiene-16a17a, 21-triol-320- dione.



  Analogously, the 16,17-diacetate of 6-fluoro-3-ethylenediogy-pregnan-5a, 16a, 17a-triol-3,20-dione and 16,17,21triacetate of 6p can be converted. -fluo: ro-3-ethyleneâioxj-prégnane-50C, 16a, 17OE, 21-tetrol-3,20- dione, using dry hydrochloric gas, by splitting the ketal and elimination
 EMI12.3
 of water, into the corresponding '-6α-fluoro-3-ketones. Instead of the above diacetate and triacetate, it is also possible to start from higher diesters or triesters, for example esters derived from acids comprising from 3 to 12 carbon atoms.
Example 18.



   Has a solution of 6 g of 2a-methyl-3-ethylene- 17,21-diacetate
 EMI12.4
 diog, p-5a, 6a epoxy-prégnane17a, 2Z-diol-20-one in 600 cm3 of a mixture of equal parts of ether and benzene, 6 cm3 of a boron trifluoride etherate is added, then leave the mixture to stand for 3 hours at room temperature. After washing the organic solution, drying it over sodium sulfate and evaporating it, 6ss-fluoro-2 17,21-diacetate is obtained [ alpha] -methyl-
 EMI12.5
 3-ethylenedioxy-pregnan-50E, 170E, 21-triol-20-one which is purified by chromatography.



   By treating the above diacetate with hydrochloric gas according to the indications of the preceding examples, the 17,21-diacetate of the
 EMI12.6
 A4-6OE-fluoro-2a-methyl-pregnene-17OE, 21-dïol-3,20-dione which crystallizes in a mixture of acetone and hexane and which, hydrolyzed according to the indications of the preceding examples using 'a 1% methanolic solution of po-
 EMI12.7
 tassium, can be converted to, 4-6a fluoro-2a-methyl-peg.nene-17a, 21; -diol-3,20-dione.



   By dehydrogenating the above diacetate, using sodium dioxide
 EMI12.8
 lenium, 14-6a-fluoro-2a-methyl-pregnna- 17,21-diacetate is obtained; αiene-170E, 21-diol-3,20-dione which can be hydrolyzed to give free 17,21-diol.



   The 17,21-diols obtained can be converted into their 21-monoesters, such as acetates, cyclopentylpropionates and trimethylacetates, according to known methods.



   The starting material used above can be obtained according to the indications given in the previous examples, starting from # 4-2 [alpha] -
 EMI12.9
 methyl-pregnene-17a, 21-diol-3,20-dione, by acetylation at position 17,21, ketalization at 3 and epoxidation at position 5a, 6a.



   CLAIMS.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

A process for preparing fluoropregnenes, characterized in that compounds of the formula are treated with boron trifluoride: <Desc / Clms Page number 13> EMI13.1 in which R41, R2 and R3 represent hydrogen or a free or esterified hydroxy group, R is hydrogen or a methyl group, X is hydrogen, a chlorine or fluorine atom, and Y is two atoms of hydrogen, an oxo group, or hydrogen and a free or esterified hydroxy group, and which in position 3 and / or 20 have hydrogen or a free or esterified hydroxy group, or a free or ketalized oxo group, that a free or esterified hydroxy group or a ketalised oxo group in position 3 is converted into a free oxo group, that they are dehydrated EMI13.2 6p-fluono-50E-hydroxylated compounds obtained, the 64-3-oxo-6p-compounds are isomerized to -3mog-6a-fluorinated compounds, followed by any reaction stage which the esterified hydroxy groups are hydrolyzed, or the free hydroxy groups are esterified. The present process can be further characterized by the following points: EMI13.3 1) In the 6-fluoro-5a-hydrogyl compounds obtained which have in position 3 and / or 20 ketalized oxo groups, these are converted into free oxo groups. EMI13.4 2) In the obtained 6j3-fluoro-5o-hydroxyl compounds which have free or esterified hydroxy groups in the 3 and / or 20 position, these are converted into oxo groups. EMI13.5 3) The 6p-fluoro-5a-hydroxY-3-oxo-pregnans are dehydrated using sodium or potassium hydroxide, thionyl chloride or phosphorus tribromide, or using an acid . EMI13.6 4) The isomerization of 4-3-oxo-6-fluoro-pregnens to 4-3-oxo6a-fZuoro-pregnenes is carried out using inorganic acids, for example hydrochloric gas. 5) Only part of the process operations are carried out, or one starts from an intermediate product obtained at any stage of the process and carries out the still missing phases of said process. 6) 5a, 6a-epoxypregnane-3 is used as starting substance, EMI13.7 17OE, 20.2a-tetrol-11-one or one of its esters. 7) 9cx-chloro-5a, 6a-epoxypregnan-3i, 17a, 20,21-tetrol-11-one or one of its esters are used as starting material. 8) 9a fluroro-5a, 6a-epoxypregnan-3,17a, 20,21-tetrol-11-one or one of its esters are used as starting material. 9) 5a, 6a-epozy pregnan-3-17a, 21-triol-11,20-dione or one of its esters are used as starting material. 10) 5a, 6a-epoy-pregnan-3-ol-20-one or one of its esters are used as starting material. <Desc / Clms Page number 14> EMI14.1 11) 5cx, 6α-epogy-prenan-3,17ac, 21-triol-20-one or one of its esters are used as starting material. EMI14.2 12) As starting material 3,20-bis-ethylenedioxy- EMI14.3 5OE, 60E-epoxy-pregnan or one of its esters. EMI14.4 13) As starting material 3,20-bis-ethylenedioxy- EMI14.5 5OE, 60E-epoxy-pregnan-170E-ol or one of its esters. 14) As starting material, 3-ethylene-dioxy-50e, 60E-epoxy-pregnan-17,21-diol-11,20-dione or one of its esters is used. 15) As the starting material, 3-ethylenedioxy-50e, 60e-epoxy-pregnan-160E, 170e-diol-2o-one or one of its esters are used. 16) As starting material, 3-ethylenedioxy-50e, 60E-epogv-prenan-16atl7a, 21-triol-20-one or one of its esters is used. 17) As starting material 2tx-methyl-3-ethylenediog, y-5a, 6a-poay-pregnan-1oc, 21-diol-20-one or one of its esters is used. EMI14.6 18) As new industrial products: products conforming to those obtained according to the process defined above.