BE594849A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 
 EMI1.1
 



  "Process for the preparation of steroldest products obtenug."
The present invention relates to the preparation of steroid compounds and more particularly to 6-lower alkyl esters of 17'alpha-hydroxyprogesterone
 EMI1.2
 and in particular to 6-methyl-17.alpha-hydroxyprogesterone esters and to the intermediates necessary for their production, in particular to a process for the preparation of 6-alkoul (inf.) -
 EMI1.3
 17.alpha-hydroy progesterone.

 <Desc / Clms Page number 2>

 



   . The preparation of said compounds can be shown - following the appended table. In the formulas of this table, R is an alkylene radical containing no more than 8 carbon atoms inclusive, and the bonds attaching oxygen to the carbon are separated by a chain of at least two and no more of three carbon atoms, R 'is a lower alkyl radical containing 1 to 4 carbon atoms and Ac is an acyl radical of an organic carboxylic acid and preferably a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms included.



   The method according to the invention comprises the treatment
 EMI2.1
 of a 17.alpha-hydroxnrogenterone-3.20-bis- (alkylene-o6tal) (I) by means of im paracid such as performic, peracetic and perbenzolque acids so as to obtain 5salphar6. alpha-ox3.do-1.alpha-hydroxpregnane-3.20-dione-320-bis- (alkylene-ketal) (II), the treatment of 5.alpha.6.alpha-oxydo-17. alpha-hydnoxgpnegan-3.20-dione-3.2c-bis (alkyl-ketal) (II) by means of a lower alkyl-metal compound, preferably an alkyl-metal halide as a methyl reagent
 EMI2.2
 de Grignard so as to obtain the 5.alpha.l7.alpha-dih, ydro- 6.béta-alcoyl-presnane-3.20-àione-3.20-bis- (alcoylne-kétal) (III), hydrolysis by means of 'an aqueous acid in an appropriate solvent for the diketal' obtained (III) with obtaining 5.

   
 EMI2.3
 alpha.l'7.alpha-dib, ydroxy-6.bta-alcoylpregnane-3.20-dione (IV) and dehydration of 5.alpha.l? .alpha-àihydnoxy-6-al-coylpregnane-3.20-dione ( IV) thus obtained by means of a base or an acid to obtain 1a.6-alkyl-1? .Apha-hydroxy-4 pre-genene-320-dione (6-alkyl-17.alpha-lydroxpaoesterone) ( V).



  Stronger 460ncentnations of base or acid give the 6.alpha epimer of V, while milder conditions produce the 6.beta isomer. 6.beta-alkyl-17.alpha-hydroxyprogesterone can also be converted to 6.alpha-
 EMI2.4
 alkyl-17.alpha-hydroxyprogesterone by enolizing agents

 <Desc / Clms Page number 3>

 such as acids or mineral bases such as sulfuric, perchloric, hydrochloric, nitric, (extended), sodium or potassium hydroxide or carbonate.



   The esterification of the 'tertiary alcohol group
 EMI3.1
 17.alpha of 6-alkyl-17.alpha-hydroxyprogesterone (V) to obtain the acylute of 6-alkyl-17.alpha-hydroxyprogesterone (VI) is carried out by heating the raw material (V) with an anhydride of an acid selected or by reaction between 0 and 35 C with an acid anhydride in the presence of an acid catalyst, for example toluenesulphonic acid, sulfuric acid, etc.



   The present invention proposes to provide esters of 6-alkyl-17.alpha-hydroxyprogesterone and their
 EMI3.2
 intermediates, such as 6-alkyl-l7.alpha-hydroiyprogesterone, 5.alpha.l7.alpha-dibydroay-6: bta-alcoylprâgnane-3.20-dione, and its alkylene-ketals, having 1 to 8 carbon atoms in the alkylene chain. It intends to provide a
 EMI3.3
 production process of 6-alkyl-17.alpha-hydroxprogesterone esters (6.alpha and 6.beta epimers) and 6-alkyl-17.alpha-hydroxyprogesterone, 5.alpha.l? -pha-dihy- intermediates. droxy-6.b3ta-methylpregnane-3.20-dione and their 3.20-bis- (alkylene-ketal). It particularly proposes to provide a
 EMI3.4
 process for the manufacture of the 17-esters of 6.alpha-methYl-1'7 * alpha-hydroxyprogesterone, in particular acetate.

   Other objects will become apparent in the course of the present description.



   New products obtained by the
 EMI3.5
 the invention, namely the esters of 6-alkyl-17.alpha-iydroxyprogesterone, are useful as agents, r # ¯¯ir¯. progestational, oral or parenteral. Due to their effect analogous to those of progesterone, the esters according to the invention are applicable in "cyclic" therapy in which the estrogenic and progestational hormones are administered together or successively to promote the re-establishment of normal endometrial-ovary-pituitary relationships.

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 previous in cases of menstrual disorders.



   Tablets for oral use (50,000) are prepared using the following types and amounts of materials.
 EMI4.1
 



  17.alpha-acetate of 6.alpha-methyl-'7.alpha-hydro progesterone 155.5 gr Lactose from Codex 1362 gr
An aqueous oral suspension is prepared containing
 EMI4.2
 for each dose of 5 cc 5 mg of 6.alpha-methyl-17.alpha-hydroxyprogesterone bgta-cyclopentylpropionate using the following types and amounts of materials:

   
 EMI4.3
 6 # alpha-methyl-alpha-X1 progesterone b8ta-cyc1opent-propionate, micronized 1 gr
 EMI4.4
 
<tb> Citric <SEP> <SEP> from <SEP> Codex <SEP> 2 <SEP> gr
<tb>
<tb> Benzoic acid <SEP> <SEP> from <SEP> Codex <SEP> 1 <SEP> gr
<tb>
<tb> Methylparaben <SEP> of <SEP> Codex <SEP> 2 <SEP> gr
<tb>
<tb> Propylparaben <SEP> of <SEP> Codex <SEP> 0.5 <SEP> gr
<tb>
<tb> Glycerin <SEP> from <SEP> Codex <SEP> 150 <SEP> cc
<tb>
 
 EMI4.5
 Agragante powder from Codex?, 5 6a
 EMI4.6
 
<tb> Concentrate <SEP> of essence <SEP> scented <SEP> 0.2 <SEP> cc
<tb>
<tb> Sucrose <SEP> of <SEP> Codex <SEP> 400 <SEP> gr
<tb>
<tb> Deionized <SEP> water <SEP> Q.S.P. <SEP> 1000 <SEP> cc
<tb>
 
The citric acid is dissolved in 500 c of water.

   Benzoic acid and parabens are added to glycerin, in
 EMI4.7
 a separate container, followed by 6 alpha-metbyl-J-alpha-hydroxyprogesteron beta-cyclopentylpionate and tragacanth and partfms, in the order listed. Mix until a uniform suspension is obtained and then add to the aqueous solution with rapid stirring. Finally, the sugar is added and the whole is mixed thoroughly and then passed through a colloid mill. Enough water is used to rinse the mill and the rinse water is used to bring the final volume to 1000 cc.



  The power of the suspension is evaluated and used in the clinic.

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   For parenteral administration, an aqueous suspension of 17 alpha-hy- esters can be used. droxy-6-methyl-progesterone.



   Instead of the 17-ester of 6.alpha-methyl-17.alpha-hydroxyprogesterone, equivalent amounts of the iso-
 EMI5.1
 beta mothers or other esters 6.alpha- or 6.bgta-alkyl (inf.) - 17.alpha-hydroxyprogesterone in which the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.

   Other esters of 6-alkyl-17.alpha-hydro-xyprogesterone used are propionate, butyrate, isobuty-
 EMI5.2
 spleen, valerate, isovalerate, hexanoate, heptanoate.octanoate, beta-cyclopentylpropionate, benzoate, toluate, phenylacetate, phenylpropionate, hemisuccinate, beta-dimethyl-glutarate, cyclohexyl-formate, decanote, undecanoate, laurate, undecanoate, laurate, undecanoate, laurate, undecanoate acrylate, crotonate, formate, phenoxyacetate, etc.

   The unesterified compound, 6.alpha-methyl-17.alpha-hydroxy-progesterone, is not only an im-
 EMI5.3
 carrying in the production of the active steroid esters mentioned above, but it also mediates in the production of the active sterols of the adrenal cortex.
 EMI5.4
 For example, the fermentation of 6. alpha-methyl-17. alpha-bydroprogesterone with Cunninghamella blakesleeana gives the anti-inflammatory hormone with strong adrenocortical activity, the
 EMI5.5
 6. alpha-methyl-ll.bta. the 7. alpha-di3, 4-ydro-preguene-3,20-dione.

   Additional fermentation in stages doia 6.alpha- nethl-ll.bta.l7.alpha-dihydro-4-pregnene-3.2G-çlione by means of Ophiobulus herpotrichus Centraalbureau voor Schimmelcultur, Baarn, Holland, then of Septomyxa affinis, ATCC 6737 , produces the anti-inflammatory and anti-rum compound
 EMI5.6
 very active tismal, 1-deslydro-6.alpha-methylhydrocortisone.



   The starting compounds according to the invention are the 3.20-diketal of 17.alpha-hydroxyprogesterone, produced

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 as shown in preparations 1 and 2.



   To carry out the process according to the invention, the 3.20-bis- (alkylene-ketal) of 17-alpha-hydroxy-progesterone is dissolved in an inert organic solvent such as chloroform, methylene chloride, ethylene dichloride, carbon tetrachloride, benzene, toluene, etc., and it is treated with a peracid such as an organic peracid such as performic, peracetic, perpropionic, perbenzoic, monoperphthalic, etc. . The reaction is generally carried out at low temperatures, for example between -10 and +10 C. However higher or lower temperatures such as -30 up to 440 C are suitable.



   In the preferred embodiment of the invention, temperatures between zero and 5 ° C., a chlorinated hydrocarbon such as chloroform or methylene dichloride and peracetic or perbenzoic acid are used. The peracid is generally used in the amount of 10 to 20% in addition to the amount theoretically required, up to 500% thereof.



   When the reaction is complete, the mixture is neutralized, preferably with sodium or potassium carbonate or bicarbonate, washed with water and the 3.20-bis- (alkylene-ketal) of 5.alpha is recovered. 6.alpha-oxydo-17.alpha-hydroxy-prégnane-3.20-dione by evaporation of solvents. Recrystallization from organic solvents such as methanol, ethanol, Skellysalve B (hexanes), heptanes, benzene, toluene, etc., provides 3.20-bis- (alkylene-ketal). pure 5.alpha-6.alpha-oxydo-17.alpha-hydroxypregnan.



   This compound thus obtained, dissolved in a suitable inert organic solvent such as tetrahydrofuran, benzene, toluene, diethyl ether, dipropyl ether, etc., the higher boiling point solvents being preferable such as tetrahydrofuran and benzene is reacted

 <Desc / Clms Page number 7>

 with an alkyl metal compound, in particular a metal methyl halide such as chloride, bromide or io-
 EMI7.1
 hard methyl-magnesium, methyl-lithium, dimethyl-cadmium, etc.

   Other organometallic agents which can be used are ethyl-, propyl- and butyl-magnesium bromide or
 EMI7.2
 corresponding alkol-sodium or alkyl-potassium compounds, alkyl-cadmium halides and dialkyl-cadmium compounds in which the alkyl group has 1 to 4 carbon atoms.
 EMI7.3
 carbon, etc., 1-magnesium brine and methyl-magnesium iodide being preferable. In the preferred mode of carrying out the invention, this reaction starts at room temperature or below, temperatures between 0 and 30 ° C being preferable.

   After addition of the methyl halide
 EMI7.4
 magnesium or other met.-xethyl-metal halide, the temperature is raised and the reaction mixture is heated to about reflux temperature for one to forty-eight hours.



   In general, a large excess of Grignard's reagent (10 to 500 molar equivalents) is used. The temperature applied to the Grignard addition reaction is generally between 25 and 100 C, the preferred range being 60 C up to the reflux temperature of the mixture.



   When the reaction is complete, the reaction product is decomposed under neutral conditions. According to the preferred embodiment of the invention, the reaction product is decomposed by mixing the reaction mixture with a saturated aqueous solution of ammonium chloride, cooled, then stirred for a period ranging from a few minutes to a hour. The aqueous layer is then separated from the organic layer.



   The organic phase is washed, dried and evaporated to obtain a residue of 3.20-bis- (alkylene ketal) of
 EMI7.5
 5.alpha.l'7.alpha-dib, ydrox9-6.bta-methyl prégnane-3.20-d.ione.



  This latter compound can be purified by the usual methods such as recrystallization and / or chromatography using organic solvents, as deemed necessary.

 <Desc / Clms Page number 8>

 



  5. alpha 3.20-bis- (alkylene ketal). 1'7. alpha-
 EMI8.1
 dibydroxy-6.bgta-methylpregnane-3.20-dione thus obtained is then hydrolyzed in a water-miscible solvent, preferably
 EMI8.2
 presence in a hydro-alkanolic or acid acetonic medium. The preferred solvent alkanols are methanol and ethanol, but other water-miscible solvents such as tertiary butanol, propyl alcohols, propyl alcohols, dioxane, acetone, etc. can be used. etc. To the solution of the stereoid is then added an orbanic or mineral acid, preferably a mineral acid such as sulfuric acid or hydrochloric acid, but it is also possible to use organic acids such as formic, acetic, propionic or toluene acids. - sulfonic.

   The mixture thus obtained is preferably heated to reflux to accelerate the hydrolysis, then neutralized by means of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or other alkaline solutions and then concentrated so as to obtain a raw product formed from
 EMI8.3
 5.alpha.l.al..pha-dihydroxy-6.beta methyl prégnane-3.20-dione. The crude product can be purified using known techniques, e.g. recrystallization from organic solvents such as acetone, ethyl acetate, "Skellysolve B" (hexanes), methanol, tertiary butyl alcohol, ether, etc., or mixtures of these solvents so as to obtain 5.alpha.
 EMI8.4
 pure 7.alpha-dihydroxy-6.bta-methyl-pregnan-3.20-dione.



  The 5.alpha.17.alpha-dihydroxy-6.bOta-methyl-pregnan-3.20-dione thus obtained is then dehydrated. Dehydration can be carried out in an alkaline solution or in an acidic solution. According to the preferred mode of implementation of the invention, the acid dehydration is applied. The steroid is dissolved or suspended in solvents inert to the acid used, such as methylene chloride, chloroform, dioxane and carbane tetrachloride, and the selected acid is added to the solution or suspension. Acids of particular interest for this reaction are strong acids such as

 <Desc / Clms Page number 9>

 gaseous hydrochloric or hydrobromic acid, sulfuric acid, etc., with gaseous hydrochloric acid being preferred.

   For dehydration by means of a base, the steroid is dissolved in methanol, ethanol, dioxane or other usual solvents inert with respect to the base used, the solution is purged of its oxygen by nitrogen blowing and the mixture is left to regulate with an oxygen-free alkaline base solution. The preferred bases are sodium or potassium hydroxide; however, alkali metal alkoxides, barium hydroxide, calcium hydroxide, etc. are suitable.



   Depending on the amount of acid or base used, the 6 alpha or 6 beta isomers are obtained. Dehydration first produces the 6 beta isomer which, being less stable in strong acids or bases; undergoes rearrangement to the 6. alpha isomer. If, at the start of the dehydration reaction, the medium is strongly acidic or basic, only 6 is obtained.
 EMI9.1
 alpha-alkyl-17.alpha-hydroxyprogesterone, while a weak acidic or basic medium gives 6.bta-alkyl-17.alpha-hydro-xyprogesterone. The 6.beta isomer can then be converted to the 6. alpha isomer by treatment with a strong acid or a strong base.
 EMI9.2
 



  The 6-alkyl-17.alpha-hydroxyprogesterones are isolated from the reaction mixture and purified by the usual methods, for example by dilution with water and depletion of the mixture with a solvent immiscible with water. 'water, such as methylene chloride, chloroform, hexanes, benzene, ether, etc., evaporation of the solvent and recrystallization of the solids thus obtained from an organic solvent, such as
 EMI9.3
 methanol, ethanol, "kellysolve B" (hexares), ethyl acetate, benzene, etc. to give pure 6-alkyl-17.alpha-hydroxy-progesterone.

   
 EMI9.4
 The esterification of the Falcoyl-17.alpha-hydroxyprogesterone thus obtained is carried out by well known methods.

 <Desc / Clms Page number 10>

 esterification of tertiary hydroxyl groups, for example those of Huang-Minlon et al., J.Amer.Chem.Soc., 74, 5394 (1952). Huang-Minlon et al describe a "cold process" and a "hot process", both of which are equally useful.
 EMI10.1
 in the verification of 6.alpha-alkyl-17.alpha-bydroxyprogesterones. If, in the esterification of the 6.beta isomer, we. wants to obtain the beta-isomers, moderate conditions are necessary (cold process, low amount of acid catalyst), otherwise a conversion of isomer 6 would occur.

   beta to 6.alpha isomer. The following examples provide details of these various methods.



   The following preparations and examples illustrate the processes according to the invention but should not be considered as limiting.



  Preparation 1.- 3.20-bis- (ethylene-ketal) of 17-alpha-hydroxyprogesterone
A solution is prepared containing 50 g of 17 alpha-hydroxyprogesterone in 1 liter of benzene, 100 ml of ethylene glycol and 2.5-g of para-toluenesulphonic acid monohydrate.



   This mixture is heated under reflux for seventeen. hours with a carbide-tipped water collector to remove the water from the reaction. After this reflux period, 6.5 ml of pyridine are added to the solution and the mixture is cooled to room temperature. The lower glycol layer is separated and the. washes it with benzene. The benzene layer and the benzene wash liquors are mixed and the solution is divided into two equal parts, one of which is used.
 EMI10.2
 lized to isolate 3,20-bis- (etb, ylene-ketal) from 17.alpha-hydroxyprogesterone as follows. The benzene solution is washed with a 5% solution of sodium carbonate, water and a saturated solution of sodium chloride.

   After drying on

 <Desc / Clms Page number 11>

 anhydrous magnesium sulfate, the solution is concentrated to dryness under reduced pressure. The residue is recrystallized by taking up with hot methylene chloride, added. so much acetone and boiling to drive off the chloride
 EMI11.1
 methylene until a fluid volume of about 200 ml is obtained. The solution is then subjected to refrigeration for about sixteen hours and 17.8 g of crystals are collected by filtration. We obtain a second harvest which gives 3.7 gr
 EMI11.2
 of cotopose. The total yield of 3.20-bis- (ethylene-acetal) from 17.alpha-hydroxyprogesterone is 20.3 g (64.3% of the theoretical yield).

   Recrystallization of 3.20-bis- (ethylene-
 EMI11.3
 ne-ketal) of crude 1ααα-hydroxyprogesterone in methanol gives pure diketal melting at 209-211 C and a rotational power of (Ó) D = -49 (in chloroform).
 EMI11.4
 



  Analysis. Calculated for 0 2.5H.3ê.5 C = 71.74; H - 9.15 Found 0 - 71.65; H - 9.38 Preparation 2. - 3.20-bis- (propylene-ketal) of 17.alpha-hydroxyprogesterone
In the same manner as that given in Preparation 1, the 17-alpha-hydroxyprogesterone is dissolved in benzene and propylene glycol, heated under reflux in the presence of para-toluene sulfonic acid for a period of. eighteen hours so as to obtain the 3.20-bis- (propylene-
 EMI11.5
 ketal) of 17 alpha-lydroxyprogesterone.



   In the same manner as in preparations 1 and 2, other 3.20-bis- (alkylene ketals) of 17 are prepared.
 EMI11.6
 alpha-hydroxyprogesterone by reaction at reflux temperature of solutions of 17 alpha-hydroxyprogesterone in benzene, toluene, 1 ',' hexane, heptane, or other inert organic solvents, with 1 . 2-alkanediols or 1.3-alkanediols, such as butane 1.2-diol, butane-1.3-diol, penta-

 <Desc / Clms Page number 12>

 ne 1. 2- and 1.3-diols, hexanols. 2- and 1.3-diols, heptane- 1.2- and 1.3-diols, octane-1.2- and 1.3-diols or other alkanediols of the formula:

   
 EMI12.1
 Jans which is not an integer having a value of 1 or 2, and R1 and R2 are hydrogen or lower alkyl radicals containing up to 6 carbon atoms and in which the total number of atoms of carbon present in the alkanediol is up to 8, in the presence of a strong acid such as toluenesulphonic acid, ortho-chlorobenzenesulphonic acid, sulfuric acid, etc., of so as to obtain the 3.20-bis- (alkylene-ketal) of the corresponding 17.alpha-hydroxy-progesterone. Representative examples are 3.20-bis- (1.3-propylene-ketal) of 17.alpha-hydroxyprogesterone, 1. 2- and 1.3-butylene-ketals, 1. 2- and 3,4-pentylene-dice. - stalls, etc.



    EXAMPLE 1 - 5.6-Oxydeo-17.alpha-hydroxyprenane-3 3.20-bis- (ethylene-ketal). 20-dione.



   A solution is prepared by heating 19.96 g (0.0477 mol) of 3.20-bis- (ethylene-ketal) of 17.alpha-hydro-progesterone and 500 ml of benzene. After dissolution, the flask is cooled to 5 ° C. and a mixture of 3.68 g (0.0449 mol) of sodium acetate and 174 ml of 40% peracetic acid is introduced with stirring. The reaction mixture is stirred in an ice bath for three hours. The lower peracidic layer is separated and extended with water / exhausted twice with benzene. The top layer is neutralized by adding a cold 10% sodium hydroxide solution, with stirring, and in an ice bath.

   The speed of addition

 <Desc / Clms Page number 13>

 sodium hydroxide is adjusted so as to maintain the temperature below 10 C. The benzene extracts of the peracidic layer are added, the layer is separated and the benzene layer is washed with a cold solution 10% sodium hydroxide and saturated sodium chloride solution. All the aqueous layers are washed again with the same portion of benzene. The mixture of benzene layers is dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue is recrystallized from acetone using methylene chloride to facilitate solution.

   The crystallized material was collected by filtration and recrystallized from methylene chloride and acetone to give a total of 8 g of 5.6-oxido-17 3.20-bis- (ethylene-ketal). alpa-hydroxyprégnane, melting at 211-215 C. For the analysis, a new recrystallization is carried out from methylene chloride and acetone which gives the pure product, melting at 216-218.5 C and a rotary power. (Ó) D - -70 in chloroform.



  Analysis. Calculated for C25H38O6: C - 69.09; H - 8.81%
Found: 0 - 69.05; H - 9.04%
In the same way, we obtain the 3.20-bis- (ethylene-ketal) of 5.alpha.6.alpha-oxide-17.alpha-prégnane by substitution of performic acid, perbenzoic acid or l monoperphthalic acid to peracetic acid in the previous example.



  EXAMPLE 2 - 3.20-bis- (propylene-ketal) of 5.alpha.6.alpha-oxydo-17, alpha-hydroxypregnan-3,20-dione.



   As shown in Example 1, the reaction of 3.2-bis (propylene-ketal), 17-alpha-hy- peracetic acid and droxyprogesterone with anhydrous sodium acetate in solution

 <Desc / Clms Page number 14>

 chloroform gives the 3.20-bis- (propylene-ketal) of 5.alpha .6.alpha-oxid.-17.alpha-hydroxypregnan.- 3,20-dione.



   In the same manner as in Examples 1 and 2, other 3.20-bis- (ketals) of 5. alpha are prepared. 6.alpha-oxido-
 EMI14.1
 17'alpha-hydropregnane by reaction of the corresponding 1? .Alpha-hydrozy progesteronebis # setal with a peracid such as performic, peracetic, perpropionic, perbenzoic monoperphthalic acids, at low temperatures usually between -10 and +10 C .

   Examples of representative compounds so prepared are 3.20-bis- (1.3-propylene-ketal)
 EMI14.2
 5.alpha.6.alpha-ozydo-l7.alpha-hydroregnane-3.20-dione, 3â20 bis- (1.2.tylene-ketal) of 5'alpha.6.alpha-osydo- 17. alpha-hydroxyprégnane- 3.20-dione, the 2.3- and 1.3-hutylene ketals of 5. alpha. 6.oxido-17.alpha-hydroxy-pregnane-3.20- dione, 1.2-, 2,3-, 2.4- and 1.3 pentylene-ketal and 1.2-, 1.3-hexylene, 1.2-, 1.3-heptylene, xxt 1.2 -, 1.3-octylene-ketals of 5. alpha. 6. alpha-oxido-17. alpha-hydroxyprregna-3.20-dione, etc.



  EXAMPLE 3- 3.20-bis- (ethylene ketal) of 5. alpha. 1'7. alpha-
 EMI14.3
 , dihyàro-6.béta-meth, plpregnan, e-3.2a-dione To a solution of 91.6 gr of 3.20-bis (-ethylene-ketal) of 5. alpha. 6. alpha-oxido-17. alpha-hydroxypregnan-3.20-dione in 3,500 ml of freshly distilled tetrahydrofuran 1170 ml of a commercial 3 M methyl-magnesium bromide solution are added. The reaction mixture is boiled to remove 1800 ml of solvent by distillation, then one add 1 liter of freshly distilled tetrahydrofuran. The boiling is continued at reflux for a period of 16 hours.

   The solution is then concentrated to about half of its original volume by distillation and poured slowly with vigorous stirring into a large volume of ice-cold water.

 <Desc / Clms Page number 15>

 holding 340 gr of ammonium chloride. The aqueous solution is saturated with sodium chloride and exhausted with benzene. The benzene extract was washed with saturated brine and the two aqueous layers washed again with the same portions of benzene. The mixture of the benzene layers is dried over anhydrous sodium carbonate and the solvent is removed under reduced pressure, to give 90.5 g.
 EMI15.1
 3.20-bis- (ethylene-ketal) 5.alpha.l7.alpha-di? droxy-6. Crude crystallized beta-methyl-pregnan-3.20-dione.

   Half of the residue, i.e. 45.2 g, is recrystallized in acetone and a little methylene chloride and 34.4 g of 3.20-bis- (ethylene-ketal) of 5 are obtained. .alpha-dihydroxy-6.beta-methylpregnane-3.20-dione. A sample recrystallized from acetone and methylene chloride for analysis melts at 160-163 C and has a optical rotation (Ó) D = -38 in chloroform.
 EMI15.2
 



  Analysis. Calculated for C26H4206 s C a 69e30; H = 9i4O
Found: C - 68.90; N = 9.78 EXAMPLE 4 -
 EMI15.3
 3.20-bis- (propylene-ketal) of 5. alpha.l'7. alpha-dilydro- 6.bAta-methylpregnane-3.20-dione from 3.20-bis- (Propylene-ketal) of 5.alpha.6.alpha-odo-l'7.alpha-hydroxypregnane- 3.20-dione .



   In the same manner as in Example 3, the treatment of a 3.20-bis- (propylene-ketal) solution of 5.
 EMI15.4
 alpha.6.alpha-oxydo-1? .alpha-hydroxypregnane3.20-dione in benzene by means of methyl-magwnesium iodide in ether gives 3.20-bis- (propylene-ketal) of 5.alpha . 17. alpha-
 EMI15.5
 dilydro-6.bta-metb, plpregnane-3.20-diou.
As shown in Examples 3 and 4, other bis-ketals, reacted with
 EMI15.6
 methyl-magnesium bromide or mC-tbyl iodide - magnesium in

 <Desc / Clms Page number 16>

 
 EMI16.1
 solution as in tetrahydrofuran, benzene, ether or mixtures thereof, etc., give the 3.20-bis-ketals of 5.alpha. L7.alpha-d.üpdro-6.bta-methglpregnane-3.20-dione correspon-. dants.



   As shown in Examples 3 and 4, the reaction of 3.20-bis (alkylene ketals)
 EMI16.2
 of 5. alpha-6. alpha-oxido-17. alpha-hydroxypregnane-3.20-dione with alkyl-magnesium halides, such as ethyl-, propyl-, isopropyl-, butyl- or isobutyl-magnesium bromides or iodides gives 3.20-bis- (alkylene ketals) of the 5.alpha-
 EMI16.3
 6-hydroxy-6-alkyl-17. Corresponding alta-lpdropregnane-3.20-dione, wherein the alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.



  EXAMPLE 5-
 EMI16.4
 5.aipha.i? .Aiphâ-dihydnow-6.héta-wéthyipneégnane-3.2o-dione A solution is prepared containing 38.9 gr of 3.20-. 5.alpha.17.alpha-dihydroxy-6.bgta-methylpregnane-3.20-dione bis- (ethylene-ketal) in 389 ml of boiling acetone. Then 39 ml of normal sulfuric acid are added in portions while rotating and seeding with the product. Boiling is continued for a further two minutes and the mixture is allowed to stand at room temperature. The mixture is then spread with 1500 ml of water, cooled and filtered.



  The precipitate is washed with water, with extended ammonium hydroxide and water and dried under vacuum in an oven for about 16 hours. The yield is 31.2 gr which is made re-
 EMI16.5
 crystallize by dissolving in 1200 ml of dimethylformamide, heating at 150 C, cooling slightly, then adding 12 ml
 EMI16.6
 hot water. The recrystallized 5.alpha.17.alpha-dihydnoxy-6.béta-wéthylpiégnane-3.20-dione thus obtained weighs 28.75 g and its melting point is 270-275 C. After further re-crystallization

 <Desc / Clms Page number 17>

 crystallization from aqueous dimethylformemide, the melting point changes to 274-279 C.



    EXAMPLE 6
 EMI17.1
 6. alpha-met3y1-17. .l.pha-hydrogyprogestérQne A suspension is made by introducing 2 g of 5.alpha.l? .alpha 'droly-6.béta-methyl-pnégnane-3.2O-àione. in 200 ml of chloroform. The suspension was cooled in an ice bath with stirring followed by blowing hydrochloric gas into the reaction mixture for 80 minutes with continuous cooling and stirring. After blowing with nitrogen for a period of 15 minutes, the solution is washed with water, with 1N sodium bicarbonate solution, and then again with water. The aqueous layers are washed again with a thread portion! chloroform and the washings and the remainder of the chloroform solution are combined.

   After drying over anhydrous magnesium sulphate, the chloroform solution is concentrated to dryness; then the residue is taken up in a small volume of methylene chloride, treated with the aid of anhydrous magnesium silicate ("Magnesol") and filtered. Acetone is added to the solution and the solution is boiled to remove methylene chloride. After concentrating the solution to a volume of about 15 ml, it is cooled and the crystals collected by filtration. 1.37 g of crystals are obtained which are recrystallized from acetone, which gives 6.alpha-methyl-17.alpha-hydroxyprogesterone melting at 220-223.5 C and rotatory power. of (Ó) D = +75 in chloroform.
 EMI17.2
 



  Analysis. Calculated for C22H2: C is 76.70; H = 9.36full
Found: C, 76.24; H = 9.30 EXAMPLE 7 -
 EMI17.3
 6.bta-metbyl-l7.alpha-hydroxyprogesterone Oxygen is removed from a 400 ml solution

 <Desc / Clms Page number 18>

 of pyridine, 100 ml of ethanol, 25 ml of water and containing. 3 ml of normal sodium hydroxide solution by blowing with nitrogen for a few minutes. 5 g of 5.alpha are added.
 EMI18.1
 17.alpha-dihydroxy-6.b3ta-methylpregnane-3.20-dione.

   The mixture is stirred vigorously and the steroid is completely dissolved after 25 minutes. After a total reaction time of three and a quarter hours the reaction is stopped by the addition of one ml of acetic acid. and the mixture is concentrated to dryness under reduced pressure.



   The dry residue is taken up with about 500 ml of a hot mixture of acetone and ethylene chloride.



  The solution was filtered to remove material insoluble in organic solvents and the filtrate was concentrated to about 110 ml, cooled, and the crystals thus obtained were collected by filtration. A yield of 3.70 g of
 EMI18.2
 6.bta-metb, yl-17.alpha-hydroxyprpgestone crude which, after recrystallization from acetone, melts at 232-240 C and possesses. a rotary power Ó) D = + 34.



  EXAMPLE 8 - alpha
 EMI18.3
 6. alpha-metiyl-17., Jydroprogesterone from 6.beta-met7, yl-17. alpha-idroxyprcgerone A mixture of 2 g of 6-beta-methyl-17-alpha-3-hydroxyprogesterone, 0 ml of methanol and 10 ml of 2N sulfuric acid is heated under reflux for one hour. neutralize with sodium bicarbonate solution and most of the methanol is removed under reduced pressure. The addition of a further quantity of water to the residual slurry dissolves the precipitated sodium sulfate and leaves a crystallized precipitate of raw product which is filtered, washed with water and dried.

   The crude product thus obtained is recrystallized in a mixture.

 <Desc / Clms Page number 19>

 s ge of methylene chloride and "Skellysolve B" (hexane)
 EMI19.1
 and the 6.al) Ea-wetEyl-1? .alpha-hydroxyprogesterone is obtained.



  6-methyl-17-alpha hydroprogesterone is a hypnotic and sedative agent and can be used orally, together with sodium hexobarbital (Evipal
 EMI19.2
 sodium) * 6-methyl-17-alpha-hydroxyprogesterone also inhibits estrogenic and androgenic activity when used in injectable form.



   In the same way as indicated in the example
 EMI19.3
 ple 6, by triting at the reflux temperature the 5.alpha-l? eal-pha-dihydroxy-6.b8ta-alcoylprégnano-3.20-dione with mken, with an acid such as c-hydrochloric acid. 9 'gas and gaseous brogydric acid, the corresponding 6.alpha-alkyl-17.alpha-hydroxy-, progesterone is obtained, for example 6.alpha-ethyl-17.
 EMI19.4
 alpha-hydroxyprogesterone, 6.alpha-propy-l7.alpha-bydrory-progesterone, 6: alpha-isopropyl-l7.alphàydroxprogesterone, 6.alpha-butyl-17.alpha-hydroxyprogesterone, 6.alpha-isobutyl-l7 .alpha-hydroprogesterone, etc.



   Likewise, by treating the 5.alpha.17.al- ss with an acid or a base at a very low concentration.
 EMI19.5
 pha-dihydroxy-6.beta-alcoylpregnane-3.20-dione, bn obtains the. - Corresponding 6.beta-alkyl-17.alpha-hydroprogesterone such as 6.beta-ethyl-17-alpha-hydroxyprogesterone, 6.btai. propyl-17.alpha-hydroxprogesterone, 6.bgta-isopropyl-17; alpha-hydroxyproges terone, 6.beta-butyl-17. alpha-hydrox-progesterone, 6.beta-isobutyl-7. alpha-hydroprogesterone, etc.



  EXAMPLE 9-
 EMI19.6
 6.alpha-methyl-17.alpha-hydroir7-progesterone 17-acetate 1 g of 6.alpha-methyl-17.alpha-hydro-xyprogesterone is dissolved in a mixture of 10 ml of acetic acid and

 <Desc / Clms Page number 20>

 2 ml of acetic anhydride, while heating. After dissolving, the mixture is cooled to 15 ° C. and 0.3 g of para-toluenesulfonic acid is added. The mixture is allowed to stand for two and a half hours at room temperature, the pink solution is poured into ice-water so as to obtain an amorphous solid which is collected by filtration. The precipitate is washed carefully with water and then dissolved in 10 ml of methanol and 1.5 ml of methylene chloride.

   The solution is concentrated to 10 ml, spread with 0.5 ml of 10% sodium hydroxide, boil for one minute and cool. The product is recrystallized so as to obtain lamel-
 EMI20.1
 6.alpha-methyl-1.alpha-hydroprogesterone 17-acetate having a melting point of 205-209 C and a optical rotation (Ó) D = + 56 in chloroform.



  EXAMPLE 10 - methyl
 EMI20.2
 6.a1Pha? AlPha-hydroxyprogesterone 17-propionate 1 g of 6.alpua-methyl-17-alpha-hydro-xyprogesterone is heated in a water bath with 25 ml of propionic anhydride. After six hours of heating to about 100 ° C., the mixture is poured into 200 ml of ice water and the solids are collected by filtration. 6.alpha-methyl- 17-propionate
 EMI20.3
 Crude alpha-hydroxyprogesterone thus obtained is washed with water and then redissolved in methanol and methylene chloride.



  To the methylene chloride-methanol solution thus obtained, a small amount of 10% aqueous sodium hydroxide is added and the mixture is heated at a moderate boil for two minutes. The mixture is then neutralized by the addition of acetic acid and the organic layer is separated from the aqueous layer. The organic layer is washed several times with water until all traces of inorganic salts have disappeared, dried and evaporated. We recrystallize

 <Desc / Clms Page number 21>

 the residue twice in methanol and acetone
 EMI21.1
 and pure 6.alpha-metbyl-17.alpha-hy-droxyprogesterone 17-propionate is obtained.



    : EXAMPLE 11- 17-benzoate of 6.alpha-methyl-17.alpha-hydroxy-progesterone
The mixture is refluxed in 50 ml of benzene for
 EMI21.2
 a period of six hours 1 g of 6.alpha aethyl-17.alpha-haydro-xy-progesterione and 1 g of isopropenyl benzoate in 50 ml of benzene. The mixture is poured into ice water and the solids collected on filter paper. The solids are redissolved in 15 ml of methane containing 0.5 ml of water and about 50 mg of sodium hydroxide. The mixture is heated in a water bath for ten minutes, then allowed to evaporate. The solids thus obtained are redissolved in methanol and acetone and recrystallized twice from methanol and acetone so as to obtain pure 6.alpha-methyl-17.alpha-dihydroxyprogesterone 17 benzoate.



    EXAMPLE 12 -
 EMI21.3
 6.beta-metbyl-1? .Alpha-hydroxypnogesterone acetate In the same way as described in Example 9, 1 g of 6.beta-methyl-17.alpha-; ydrozyprogesterone is treated by means of. acetic anhydride in the presence of 0.1 g of para-toluenesulfonic acid. After one hour, the mixture is poured into ice water and the solids collected by filtration. Recrystallization of the solids from methanol and methylene chloride gives 6.beta-methyl-17.alpha-hydrozyprogesterone 17-acetate.



  EXAMPLE 13 -
 EMI21.4
 17 - 6.bgta-methyl-17.al-pha-hydroxyprogesterone benzoate
In the same way as in Example 11, the 6.beta-methyl-17.alpha-hydroxyprogesterone is treated by means of isopropenyl benzoate so as to obtain 17-benzoate
 EMI21.5
 of 6.beta-met.yl-17.alpha-hyd.roByprogesterone.

 <Desc / Clms Page number 22>

 



    EXAMPLE 14 - 6.alpha-methyl-17.alpha-hydroxyprogesterone 17-butyrate
As shown in Example 9, the treatment
 EMI22.1
 ment of 6.alpha-1ethyl-1? .alpha-hydroxypnogesterone by means of hutyric anhydride in the presence of two drops of sulfuric acid gives the 17-butyrate of 6.alpha-methyl-17.alpha-
 EMI22.2
 iydrozprogestéronè.



    EXAMPLE 15 - xy
 EMI22.3
 6. alpha-methyl-17 17-valerate. alpha-hydroprogesterone As shown in Example 9, treatment of 6.alpha-methyl-7.alpha-hydroxyprogesterone with valeric anhydride gives 6.alpha-methyl-17 17-valerate. .alpha-hydroxyprogesterone.



    EXAMPLE 16 -
 EMI22.4
 6.alpha-methyl-17-hexanone, drozprogestarone As shown in Example 9, the treatment of 6.alpha-meth ,, vl-17.alpha-hydroxyprogesterone with Hexanoic anhydride in the presence of toluenesulfonic acid gives 6.alpha-methyl-17.alpha-hydroxyprogesterone 17-hexanoate.



  EXAMPLE 6.alpha-methyl-17.alpha-hydroxyprogesterone 17- 17-phenylacetate
As shown in Example 9, the treatment
 EMI22.5
 ing 6.alpha-methl-I7.alpha-hydroxyprogestone by means of phenylacetic anhydride gives 17-phenylactate ds 6.alpha-
 EMI22.6
 methyl-17.alpha-hydroprogesterone.



    EXAMPLE 18 - 6 alpha-methyl-17.alpha-hydroxyprogesterone 17-phenylpropionate As indicated in Example 9, the treatment
 EMI22.7
 Treatment of 6.alpha-methyl-17.a1pha-hydroxyprogestbrone with phenylpropionic anhydride gives 6.alpha-meth, yl-17.alpha-hydroxyprogesterone 17-phenylpropionate.

 <Desc / Clms Page number 23>

 



  EXAMPLE 19 -
 EMI23.1
 6 -propionate 6.bta-methyl-17-alpha-hydroxprogesterone As indicated in Example 12, the treatment of 6-beta-methyl-17-alpha-hydroxprogesterone with propionic anhydride in the presence of small amounts of acid catalyst (toluenesulfonic acid) at room temperature
 EMI23.2
 biante gives 6.b $ ta methyl-l.alpha-hydro-progesterone 17-propionate.



  EXAMPLE 20 -
 EMI23.3
 6.bgta-methyl-17.alpha; -bydroxyprogesterone 17-butyrate As shown in Example II, the treatment of 6, beta-methyl-1? .Alpha-hydnoxypnogestenone with butyrate. isopropenyl in the presence of toluenesulonic acid at room temperature (20 to 25 C) gives 17-
 EMI23.4
 6-beta-methyl-17 butyrate. alpha-hydroprogesterone.



  EXAMPLE 21 - 6.bta-methl-17-valerate DLO As shown in Example 11, the treatment of 6.bta-metb, yl-17.alpha-iydroxyprogesterone with - isopropenyl valerate in the presence of toluenesulphonic acid at room temperature gives 6 beta-17-valerate.
 EMI23.5
 methyl-17. alpha-hydroxyprogesterone.



  EXAMPLE 22 - 6.bta-methl-17-hexanoate, 7.alpha-hydroxyprogesterone As indicated in Example 11, the treatment of 6.bgta-methyl-17.alpha-hydroxyprosesterone with hexanoate of isopropenyl in the presence of toluenesulphonic acid at room temperature gives 6 beta-17-hexanoate.
 EMI23.6
 methyl-1? .alpha-hydnoxypnogestenone.



  EXAMPLE 23 - 1? - (bgta-cyclopentyl-propionate) 6.beta-methyl-17.alpha-hydroprogesterone

 <Desc / Clms Page number 24>

 As shown in Example 11, the treatment
 EMI24.1
 treatment of 6.beta-met # 1-1? .alpha-bydnoxypnogàEone by means of isopropenyl beta-cyclopentyl-propionate in the presence of toluenesulfonic acid at room temperature gives the
 EMI24.2
 6.bgta-methyl-17.alpha-hydroxyprogesterone 17- (beta-cyclopentyl-propionate).



  EXAMPLE 24-
 EMI24.3
 6.bOta-methyl-17-phenylacetate 17.alpha-hydroxnrogesterone As shown in Example 11, the treatment of 6.beta-methyl-17.alpha-Yyd, roxprogesterone with propenyl phenylacetate in the presence of toluenesulfonic acid at room temperature gives 17-phenylacette of
 EMI24.4
 6.beta-methyl-17.alpha-nydroxyprogesterone.



  As described in Examples 9 to 24, A'other exten # 6e the 6.alpha- and 6.beta-methyl-17.alpha-bydroxypro- Sesterone and others 6.alpha- and 6.bgta -alkyl (inf.) - 17.al-pha-hydroxyprogesterone can be prepared by reacting the isopropenyl anhydride or acylate of a selected acid with the steroid, followed, if desired, by hydrolysis by means of an extended alkali hydroxide with production of enolic acylates.

   In this way, the acetate, propionate, butyrate, iscbutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, benzoate, phenylacetate, phenylpropionate are prepared;
 EMI24.5
 beta-cyclopentylpnopionate, decanoate, undecanoate, laurate, zndéoylénate, crotonate, acrylate, etc, of 6.alpha- and 6.bta-methyl-17'alpha-hydropogestrone, 6.alpha- and 6.bgta-ethyl- 17'alpha -hydroxyprogesterone, 6.alpha- and 6.beta-pnopyl-1? .al- pha-hydroxyprogesterone, 6.alpha- and 6.beta-isopropyl-17.alpha-hydroxyprogesterone, 6.alpha- and 6.beta-btyl -17.alpha-hydroxy-progesterone, 6.alpha- and 6.bta-isobutl-17.alpha-b, ydxprogesterone, etc.

 <Desc / Clms Page number 25>

 



   The invention is of course not limited to the exact operational details, nor to the precise compounds described, and is susceptible of numerous variations without departing for all that from its scope and spirit.
Manufacturing process of 6-alkyl-17-aoylates
 EMI25.1
 17 a1pa-hyaroxyprog6sterone, which includes:

   the treatment of a 3.2a-bis-aaylene-ketal of 17.alphe-hydroxyprogenterone whose alkylene chain does not contain more than 8 carbon atoms inclusive and the oxygen-carbon bonds are separated by at least 2 and not more of 3 carbon atoms, by means of a
 EMI25.2
 peraolde, so as to obtain 6.20-bis-alkyllene-oetel of 5.alpha-6.a7.pha-ozydo-1? .alpha-hydro = yprenan-3.20-dione corresponded; the treatment of the bis-alkylene-ketal thus produced by means of a Grignard alkyl reagent, the alkyl group of which contains 1 to 4 carbon atoms, so as to obtain
 EMI25.3
 negate the 3.20-bis-alkylene-oetal of the corresponding 5.alpha.17.alpha-6.beta-alkylpregnane-3.20-dione;

   , Hydrolysis of the bis-alkylene-ketal thus obtained by means of an acid, so as to
 EMI25.4
 obtain 5.alphall.?.alpha-dihydrozy-6.béta-alcoylprégnaae- 3.20-dione; and the dehydration of 5., lpha, 17, elpha-dihyàro-XY-6-elcoylpi-agan-3.20-dione obtained by means of an acid or a base with the formation of 6-elcoyl-l? ealpha -hydroxyprogesterone.


    

Claims (1)

2. The method of claim 1, wherein EMI25.5 a.alpha-alcoyl-17.alpha-hydrozyprogesterone is acylated to obtain the 17, elpha-aeylate of 6-aleoyl-l'l.alpha-hydroayprogesterone. 3. The method of claim 1, wherein (the dehydration is carried out by means of a strong mineral acid fix®. 4. A method according to vendioation 2, in which <Desc / Clms Page number 26> the acylating agent is an acyl anhydride or an isopropenyl acylate in which the acyl radical originates from a carboxylic acid, from a hydrocarbon containing 1 to 12 carbon atoms inclusive. 5. A process according to claim 2 or 4, wherein the acylation is carried out by means of acetic anhydride in the presence of an acid catalyst, such as toluene-sulfonic acid. 6. A process for the production of 6-methyl- 17-acylate EMI26.1 17.alpha-hydroxyprogesterone according to any preceding claim which comprises dehydrating a 5.alpha, 17-alpha-dihydroxy-6.beta-methylpregnane-3,20-dione with a compound selected from among the following. strong acids and alkali metal hydroxides to obtain 6-methyl-17.alpha-hydroxyprogesterone, and esterification thereof with an acylating agent selected from acid anhydrides and isopropenyl acylates in which the acyl radical comes from a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, to obtain EMI26.2 denote the corresponding 6-methyl-17-alpha-hydroxyprogesterone 17-aoylate. 7. A process for the production of 6.alpha- 17-acetate EMI26.3 methyl-17ralpha-hydroxyprogesterone according to claim 6 which comprises dehydrating µ, alpha> 17. alpha-dihydroxy-6 -methylpregnane-3,20-diene with a strong anhydrous mineral acid to obtain 6.alpha -methyl-ll.alpha-hydroxy-rogesterone, and esterifying it with acetic anhydride in the presence of an acid catalyst to obtain 17-acetate EMI26.4 of ô.alpha-methyl-17.elpha-hydmzyprogesterone. 8. A process for the production of 6.alpha-methßt-17-alpha-hydroxyprogesterone 17-acetate according to claim 6 which comprises dehydrating 5.alpha, 17-alpha-dihydrozy-6. beta-methylpregnane-3,20-dione with dilute alkali to obtain <Desc / Clms Page number 27> EMI27.1 6fl -methyl-17.alpha-hydroxyprogesterone, isomerization thereof with a strong mineral acid to obtain 6.alpha-methyl-1? .elpha-hydroxypro5esterone, and ethylation thereof with. acetic anhydride in the presence of toluene-sulfonated acid to obtain 6-alpha-methyl-1-alpha-hydroxyprogesterone 1? -acetate. 9. A process for the production of 6-methyl- 17-acylate EMI27.2 17.alpha-hydroxyprogesterone, according to any one of claims 1 to 5, which comprises the treatment of 6-methyl-17. alpha-hydroxyprogesterone with an acylating agent chosen from acid anhydrides and isopropenyl acylates of oarboxylic acids of hydrocarbons, the acyl radicals of which contain 1 to 12 carbon atoms, to obtain 17-acylate of 6 -methyl- EMI27.3 17 * alpha-hydroxyprogesteronee 10. A process for the production of 6.alpha- 17-acetate EMI27.4 methyl-17-alpha-hydroxyprogesterone, which comprises esterifying 6.alpha-methyl-1? .alpha-hydroayprogesteroae with acetic anhydride in the presence of an acid catalyst to obtain 17-acetate. 6.alpha-methyl-17.alpha-hydroxyprogesterone. 11. The products and intermediates obtained by means of the processes according to any one of the preceding claims and as described, in particular: EMI27.5 a) 6-methyl-17.alpha-hydroxyprogesterone; b) 6.bgta-methyl-17.alpha-hydroxyprogesterone; o) Goalpha-methyl-17.alpha-hyclroxyprogesterone; d) 6-methyl-17.alpha-hydroxyprogesterone 17-acylate; e) lower fatty acid esters of 6-methyl-17.alpha-hydroxyprogesterone; f) 6.alpha-methyl-17.alpha-hydroxy-progesterone 17-acetate; EMI27.6 g) 6.bgta-methyl-17.alpha-hydroxy-progesterone 17-acetate. ,