Patent GB-809465-A (GB)
Title: Improvements in or relating to 6-methyl steroid compounds
Inventor: COOLEY GEORGE
IPC: C07J1/00
Filed: 1956-03-26
Abstract: The invention comprises 11a -hydroxy-6a -methyl - progesterone, 5a ,11b ,17a ,21 - tetrahydroxy - 6b  - methyl - allopregnane - 3,20 - dione and 3,3 : 20,20 - bis - ethylenedioxy - 6b  - methyl - 5a  - pregnane - 5a ,11b ,17a ,21 - tetrol, and a process for the preparation of steroids having apart from the substituents at the 11-and 17-positions the general formula <FORM:0809465/IV (b)/1> by reacting 3,3-ethylenedioxy- D 5-steroid compounds having apart from the substituents at the 11- and 17-positions the general formula <FORM:0809465/IV (b)/2> with an organic per acid to form a 5a ,6a -epoxide compound having apart from the substituents at the 11 and 17-positions the general formula <FORM:0809465/IV (b)/3> treating the 5a ,6a -epoxides with a methyl organo-metallic reagent to form 3,3-substituted - 5a  - hydroxy - 6b  - methyl - steroids having apart from substituents in the 11- and 17-positions the general formula <FORM:0809465/IV (b)/4> regenerating the 3-oxo group to form a 5a -hydroxy - 6b  - methyl - 3 - oxo - steroid having apart from substituents in the 11- and 17-positions the general formula <FORM:0809465/IV (b)/5> and dehydrating the 5a -hydroxy-6b -methyl-3-oxo-steroids with a source of hydrogen ions.  The treatment with the organic per acid usually forms a mixture of the 5a ,6a - and 5b ,6b -epoxides from which the required a -epoxide may be isolated, for example, by fractional crystallization or chromatography on to alumina. Suitable organic per-acids are perphthalic and perbenzoic acids, and a suitable methyl organo-metallic reagent is a Grignard reagent such as methylmagnesium halide.  The 3,3-ethylenedioxy radical may be converted to the 3-oxo radical by careful treatment with dilute acid such as acetic acid.  The dehydration step may be carried out on the 5a -hydroxy compound itself, or a 5b -hydroxy compound in which the 3-oxo radical is condensed with a hydrazine to form a hydrazone is warmed with an organic solution containing acetic acid or very dilute hydrochloric acid in ethanol to form the hydrazone derivative of the 6-methyl-3-oxo-D 4-steroid from which the free 6-methyl-3-oxo-D 4-steroid may be regenerated.  Suitable dehydration reagents for use on the 5a -hydroxy compound itself are alkaline dehydrating agents such as aluminium alkoxides or very dilute aqueous alcoholic solutions of alkali metal hydroxides or carbonates, and acidic dehydrating agents such as thionyl chloride in pyridine, hydrogen chloride in an organic solvent such as chloroform, or very dilute solutions of hydrochloric acid in a lower aliphatic alcohol under reflux conditions.  The product of the dehydration step may be a 6b -methyl- or 6a -methyl-3-oxo- D 4-steroid or a mixture thereof.  In the case where a 6b -methyl-3-oxo- D 4-steroid is obtained, it may be isomerised to the corresponding 6a -methyl compound by the method described in Specification 802,005.  The process may be applied to 3-oxo- D 4-steroids of the androstane and pregnane series which may be additionally substituted by an ethinyl group, for example at C17, hydroxyl, for example at C11, C17 and C21, and oxo groups, for example at C17 and C20.  It is preferable to protect oxo groups prior to the reaction with the organometallic reagent, for example, by ketal formation, and subsequently regenerate the oxo groups.  If acyloxy substituents are present, conversion to free hydroxy groups takes place during the above process.  In the examples: (1) 17b  - hydroxy - 6a ,17a  - dimethylandrost - 4 - en-3-one is prepared by treating 17b -acetoxy-3,3 - ethylenedioxy - 5a ,6a  - epoxy - 17a  - methylandrostane with monoperphthalic acid to form 17b  - acetoxy - 3,3 - ethylenedioxy - 5a ,6a  - epoxy - 17a - methylandrostane, reacting this compound with methyl magnesium iodide, the product being purified from aqueous acetic acid thus regenerating the 3-oxo group to form 5a ,17b  - dihydroxy - 6b ,17a - dimethylandrostan-3-one, and dehydrating this compound to form the desired product by reacting with hydrogen chloride in ethanol or by converting the 5a ,17b  - dihydroxy - 6b ,17a  - dimethylandrostan-3-one to the 3-semicarbazone, treating with glacial acetic acid to yield the 3-semicarbazone of the desired product and regenerating the 3-oxo group; (2) by a series of steps as in (1) 3,3-ethylenedioxy-5a ,6a -epoxyandrostan-17b  - ol, 3,3 - ethylenedioxy - 6b  - methylandrostan - 5a ,17b  - diol, 3,3 - ethylenedioxy - 6b  - methylandrostan - 5a ,17b  - diol - 17 - acetate, 17b  - acetoxy - 5a  - hydroxy - 6b  - methylandrostan-3-one, and 6b -methyltestosterone acetate (the dehydration is effected with thionyl chloride) are prepared, and 6b -methyltestosterone is isomerized to 6a -methyltestosterone by heating with methanolic potassium hydroxide or aqueous alcoholic potassium carbonate; (3) 6b -methyl-progesterone is prepared by treating 3 : 3,20 : 20 - bisethylenedioxy - 5a ,6a  - epoxyallopregnane with monoperphthalic acid, treating this product with methyl magnesium iodide to form 3 : 3,20 : 20-bis-ethylenedioxy-5a -hydroxy-6b -methylallopregnane, treating this product with aqueous acetic acid to form 5a -hydroxy - 6b  - methylallopregnane - 3,20 - dione, and dehydrating this product with thionyl chloride in pyridine; 6a -methylprogesterone is prepared by treating 6b -methylprogesterone with methanolic potassium hydroxide or ethanolic hydrogen chloride; (4) 6a -methylcholest-4-en-3-one is prepared by forming 3 : 3-ethylenedioxy - 5a ,6a -epoxycholestane and 3,3-ethylenedioxy - 5a  - hydroxy - 6b  - methylcholestane by the method of (1), dissolving the latter compound in methanol and heating to dryness to form 5a  - hydroxy - 6b  - methylcholestan - 3 - one, and dehydrating this compound by heating in ethanolic hydrogen chloride; (5) 6a -methylethisterone is prepared by treating 17b -acetoxy-3,3 - ethylenedioxy - 17a  - ethinylandrost - 4 - en with monoperphthalic acid to form a mixture of the corresponding 5a ,6a - and 5b ,6b -epoxides which are separated by fractionation, reacting the 5a ,6a -epoxide with methyl magnesium iodide to form 3,3-ethylenedioxy-5a ,17b -dihydroxy - 17a  - ethinyl - 6b  - methylandrostane, treating this compound with aqueous acetic acid to form 5a ,17b  - dihydroxy - 17a  - ethinyl - 6b  - methylandrostan-3-one, and dehydrating this compound with ethanolic hydrogen chloride; (6) 11a -hydroxy-6a -methylprogesterone is prepared by forming 3 : 3,20 : 20-bis-ethylenedioxy-5a ,6a  - epoxypregnan - 11a  - ol by the method of Example (1), treating this compound with methyl magnesium iodide and subsequently with oxalic acid to form 5a ,11a -dihydroxy-6b -methyl-5a -pregnane-3,20-dione, and dehydrating this compound with methanolic hydrogen chloride to form 11a -hydroxy-6a -methylprogesterone; (7) 6a -methyl-hydrocortisone is prepared by forming 3 : 3,20 : 20-bis-ethylenedioxy-5a ,6a  - epoxypregnan - 11b ,17a ,21 - triol and 3 : 3,20 : 20 - bis - ethylenedioxy - 6b  - methyl - 5a  - pregnane - 5a ,11b ,17a ,21 - tetrol by the method of Example (1), treating the latter compound with methanolic dilute sulphuric acid to form 5a ,11b ,17a ,21 - tetrahydroxy - 6b  - methyl - allopregnane - 3,20 - dione, and dehydrating this compound with methanolic dilute sodium hydroxide solution or ethanolichydrogenchloride. 3,3-Ethylenedioxy- D 5-steroids are prepared by treating 3-oxo- D 4-steroids having apart from the substituents at the 11- and 17-positions the general formula <FORM:0809465/IV (b)/6> with a ketalizing agent, e.g. an aliphatic or alicyclic a b -glycol containing between 2 and 8 carbon atoms or an a ,g -glycol containing between 3 and 9 carbon atoms.  Thus the reaction may be carried out with ethylene glycol in the presence of an acidic catalyst such as toluene p-sulphonic acid.  In the examples, 17b -acetoxy-3 : 3 - ethylenedioxy - 17a  - methylandrost - 5 - ene, 3,3 - ethylenedioxy - 17b  - acetoxy - 17a  - ethinylandrost - 4 - ene, and 3 : 3,20 : 20 - bis - ethylenedioxy-pregn-5-ene-11a -ol are prepared.  Specifications 801,201, 802,003 and 802,004 also are referred to.