Abstract of
GB784855
The invention comprises saturated and unsaturated 14-methylpregnane compounds containing free or functionally converted hydroxy or oxo groups in the 3- and 20-positions (with or without other substituents, viz., further free or functionally converted hydroxy or oxo groups, especially in the 21- and/or 11-position, or a free or esterified hydroxy group or a hydrocarbon radical in the 17-position); and the preparation thereof by treating a D 3(5)-3 : 14-dimethyl-A-norpregnene compound, containing a free or functionally converted hydroxy or oxo group in the 20-position, with an oxidizing agent suitable for splitting a C-to-C double bond, and condensing the 5-oxo group in the resulting 4 : 5-seco-3 : 5-dioxo-14-methylpregnane compound with the 4-methyl group by means of an alkaline condensing agent, followed, if desired, by interconversion of any free or functionally converted hydroxy or oxo group (especially conversion of a D 4-3-oxo compound into a D 5-3-hydroxy compound by formation of the 3-enol acetate and subsequent reduction), and/or by saturation of the 4 : 5- or 5 : 6-double bond with hydrogen. Suitable oxidizing agents are hexavalent chromium compounds, permanganate, ozone, or peroxide compounds (advantageously in the presence of osmium tetroxide), and, depending on the agent chosen, the 3 : 5-double bond is split up directly or with intermediate formation of ozonides, glycols or oxides, the ozonides being split hydrolytically or oxidatively, the oxides hydrolysed to glycols, and the glycols split by means of, for example, chromic acid, lead tetracetate or periodic acid. As alkaline condensing agents, which may be used in an anhydrous solvent or in aqueous solution, are specified alkali and alkaline-earth metal hydroxides and alcoholates, and strong organic bases such as secondary and tertiary amines and quaternary ammonium hydroxides. In examples: (1) D 3(5)-3 : 4-dimethyl-11-oxo-20 - acetoxy - A - norpregnene is treated with osmium tetroxide in pyridine, the product is refluxed with mannitol and potassium hydroxide in benzene and ethanol, the resulting glycol is oxidized with lead tetracetate in chloroform and glacial acetic acid, and the oxidation product is shaken with potassium hydroxide in dioxane to form D 4 - 3 : 11 - dioxo - 14 - methyl - 20 - hy - droxypregnene, which is oxidized with chromic acid in acetic acid to 14-methyl-11-oxoprogesterone (purified by chromatography); the D 4-3-oxo compound can be converted to the corresponding D 5-3-hydroxy compound via the D 3(4) : 5(6)-3-enol acetate; (2) 14-methyl-11-oxoprogesterone is shaken with palladiumbarium sulphate catalyst in ethyl acetate in a hydrogen atmosphere to produce 14-methyl3 : 11 : 20-trioxopregnane. Starting materials. D 3(5)-3 : 14 - Dimethyl-Anorpregnene compounds are obtainable by conversion of the 3-hydroxy-4 : 4-dimethyl grouping present in the tetracyclic triterpenes (e.g. lanosterol and its derivatives degraded in the side chain) according to the following reaction scheme: <FORM:0784855/IV (a)/1> The preparation of the starting material of Example (1) from 4 : 4 : 14-trimethyl-3-hydroxy11 : 20-dioxopregnane (obtainable from lanosterol by the process of Specification 779,941) is described in detail, the intermediate products being 3-isopropylidene-14-methyl-11 : 20-dioxo-A - norpregnane, 3 - isopropylidene - 14 - methyl - 11b - hydroxy - 20 - acetoxy - A - norpregnanes (by an intermediate partial reduction and esterification, not shown above), 14-methyl-3-oxo-11b - hydroxy - 20 - acetoxy - A - norpregnanes and 3 : 14 - dimethyl - 11 - oxo - 3 - hydroxy-20-acetoxy-A-norpregnane (after reoxidation of the 11b -hydroxy group).
1 A process for the manufacture of 14methyl pregnene compounds which in the 3and 20-positions contain free or functionally converted hydroxy or oxo groups, wherein a 70 AW:5-3:14-dimethyl A-nor-pregnene compound which contains in 20-position a free or functionally converted hydroxy or oxo group is treated with an oxidizing agent suitable for splitting up a C-C-double bond, the 5-keto 75 group in the resulting 4: 5-seco-3: 5-diketo-14methyl-pregnane compound is condensed with the 4-methyl group by means of an alkaline condensing agent and, if desired, any free or functionally converted hydroxy or oxo group 80 is converted into one another 4 2 A process as claimed in claim 1, wherein any 4-3-keto-14-methyl pregnene compound obtained is converted into a A'-3-hydroxy-14methyl pregnene compound by way of the 3 85 enol acetate and subsequent reduction in the 3-position.
3 A process as claimed in claim 1, wherein in any 3-keto or 3-hydroxy-14-methyl pregnene compound obtained a 4: 5 or 5: 6 90 positioned double bond is saturated with hydrogen.
4 A process as claimed in any one of claims 1-3, wherein A':5-3: 14-dimethyl-ll-keto-20acetoxy-A-nor-pregnene is used as starting 95 material.
A process for the manufacture of new saturated and unsaturated 14-methyl pregnane compounds conducted substantially as described in any one of the Examples herein 100 6 Saturated and unsaturated 14-methyl pregnane compounds which in the 3 and 20position contain free or functionally converted hydroxyl or oxo groups.
7 14-methyl 11-keto-progesterone 105 8 A 4-3: 11-diketo-14-methyl-20-hydroxypregnene.
9 3:11:20-triketo-14-methyl-pregnane.
ABEL & IMRAY, Agents for the Applicants, Quality House, Quality Court, Chancery Lane, London, W C 2.
boiled under reflux for 6 hours The reaction mixture is worked up in the usual manner by extraction with ether The crude glycol obtained is mixed with 20 cc of acetic acid, 10 cc of chloroform, 20 cc of water and 3 gm of lead tetra-acetate and allowed to stand for 15 hours at room temperature After reacetylation of the 17-hydroxyl group of the isolated oxidation product by treatment with 15 cc of acetic anhydride and 15 cc of pyridine there is obtained a mixture of 14methyl-3-keto 11/ hydroxy-20-acetoxy-Anor pregnanes, isomeric at the carbon atom The crude substance is suitable for the subsequent reactions without further purification.
The 3-ketone as obtained above is dissolved in 100 cc of dry benzene and the solution is added dropwise to a stirred Grignard solution prepared from 3 4 gin of magnesium and gin of methyl iodide in 200 cc of dry ether After distillation of 100 cc of the solvent and replacement by 100 lcc of dry benzene, the mixture is refluxed for 6 hours.
The product isolated in the usual manner is treated once more with methyl magnesium iodide as described above in order to transform any unreacted 3-ketone into the carbinol The reaction product is reacetylated by treatment with a mixture of 15 cc of acetic anhydride and 15 cc of pyridine In order to oxidize the hydroxyl group in position 11, the crude acetate is dissolved in 25 cc of methylene chloride and 75 cc of glacial acetic acid and allowed to stand for 3 5 hours with a solution of 1 gin of chromic acid in 90 % acetic acid The reaction mixture is worked up in the usual manner to give 3: 14-dimethylll-keto 3 hydroxy 20 acetoxy-A-norpregnane.
For the dehydration of the 3-carbinol group Ling the crude compound as obtained above is dissolved in 60 cc of dry xylene and refluxed for 5 hours with 5 gin of Fuller's earth (activated by heating at 320-330 ' C for 3 hours under 12 mm pressure) After filtration and removal of the solvent by evaporation, there are obtained 1 6 gin of a crude product which is chromatographed over 50 gin of aluminium oxide Elution with a mixture of petroleum ether and benzene ( 4:1) gives 600 rng of A 3 (' 3:14 dimethyl 11 keto 20acetoxy-A-nor-pregnene melting at 206-208 C after recrystallization from methanol, l'hlD= + 126 (c= 1 08).
EXAMPLE 2.
A solution of 20 mg of 14-methyl-1-ketoLeamington Spa: Printed for tier Majesty's Stationery Office, by the Courier Press -1957.
Published at The Patent Office, 25, Southampton Buildings, London, W O 2, from which copies may be obtained.
784,855
Description
PATENT SPECIFICATION
784,s 855 Date of Application and filing Complete Specification: Jan 28, 1954.
4 " No 2661/54.
l Sffi @) Application made in Switzerland on Jan 29, 1953.
Application made in Switzerland on Nov 30, 1953.
0 m /9 Complete Specification Published: Oct 16, 1957.
Index at acceptance:-Class 2 ( 3), C 3 A 7 (A 3: C: El: J 1), C 3 A 8, C 3 A 14 B( 2 E: 8 C), U 4 (A 1: A 2: B 1:
CI: C 4: C 5).
International Classification:-C 07 c.
COMPLETE SPECIFICATION
Manufacture of Methyl Steroids We, CIBA LIMITED, a body corporate organised according to the laws of Switzerland, of Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
This invention relates to the manufacture of saturated and unsaturated 14-methyl-pregnanecompounds which in the 3 and 20-positions have free or functionally converted hydroxyl or oxo groups These steroids may also be further substituted, especially in the 21 and/ or 11-position, by a free or functionally converted hydroxyl or oxo group and also in the 17-position by a free or esterified hydroxyl group or a hydrocarbon radical In the unsaturated compounds the double bond advantageously occupies the 4:5 or 5: 6position and/or the 9: 11-position Of particular importance are, for example, 14-methylprogesterone, 14-methyl ll-ketoprogesterone, 14-methyl-desoxy-corticosterone, 14-methylcortisone and 14-methyl-dihydrocortisone.
Some of the new methyl steroids prepared according to the invention are useful as intermediates for the above mentioned compounds.
The above mentioned substances however have themselves valuable pharmacological properties and can be used therapeutically The AW3: 11: 20-triketo-14 methyl-pregnene, for instance, has a gestagenic activity.
The new methyl steroids can be made by treating a A':s-3: 14-dimethyl-A-nor-pregnene compound, which contains in 20-position a free or functionally converted hydroxy or oxo group, with an oxidizing agent, suitable for splitting up a C-C-double bond, condensing the 5-keto group in the resulting 4: 5-seco3: 5 diketo-14-methyl pregnane compound with the 4-methyl group by means of an alkaline condensing agent and if desired, converting any free or functionally converted hydroxy or oxo group into each other.
The starting materials can be obtained in various ways Thus, the 3-hydroxy-4: 4dimethyl-grouping present in the tetracyclic triterpenes, e g, lanosterol and its derivatives degraded in the side chain, can be converted into the A:5 _ 3 _methyl A-nor-grouping according to the following diagram of partial formula:
G 3 _C C-C QX 0)<)\C \ O S ets}/3 C 0:
For the oxidation of the A':5-3:14dimethyl-A-nor-pregnene compounds there is used e g, a compound of hexavalent chromium such as chromic acid, or also permanganate, ozone, peroxides, such as perbenzdic acid, monoperphthalic acid or hydrogen peroxide, advantageously in the presence of osmium tetroxide Depending on the oxidizing agents used, the 3: 5-double bond is split up directly or there are first obtained ozonides, glycols or oxides The ozonides can be split up hydrolytically, or oxidatively, while the oxides can be converted into glycols by hydrolysis.
The splitting up of these glycols is performed, lPricg r"l 4 S 6 d e.g, by means of chromic acid, lead tetracetate or periodic acid.
For the cyclicization of the resulting 4: 5soco-3: 5-dikleto-14 mnthyl-pregnane compounds into the A-3-keto-14-methyl-pregnene compounds by condensation of the 5-keto group with the 4-methyl group, alkaline condensing agents, are used There may be used an alkali metal hydroxide or alcoholate or an alkaline earth metal hydroxide or alcoholate, for example a hydroxide or alcoholate of sodium, potassium, lithium or calcium, or a strong organic base, such as a secondary or tertiary amine, or a quaternary ammonium 2 784,855 hydroxide, e g triethylamine or piperidine in the presence of an acid, such as glacial acetic acid, or trimethyl benzyl ammonium hydroxide There may be used a solution in an anhydrous solvent, such as benzene, alcohol or ether, or an aqueous solution.
The \ 4-3-keto-14-mnethyl-pregnane compounds resulting from the cyclicization can be converted into A 5-3-hydroxy-14-methyl0 pregnane cempaunds e g by way of the 3enol acetates and subsequent reduction in the 3-position In the 3-keto and 3-hydroxycompounds so obtained, the double bond in 4: 5 or 5: 6-position can be saturated with hydrogen These reactions, as also the conversion of substituents in 20 and/or 11position, can be conducted in a conventional manner.
The following Examples illustrate the invention:
EXAMPLE 1.
A solution of 407 mg of A 3 '5-3:14dimethyl-11-keto-20 acetoxy-A-nor-pregnene in 20 cc of pyridine is admixed with 300 rag.
of osmium tetroxide and allowed to stand at room temperature for 5 days The solution is then evaporated to dryness, the residue mixed with a mixture of 10 cc of benzene, 20 cc of ethanol, 5 cc of water, 2 gmn of mannitol and 1 gin of potassium hydroxide and the whole is boiled under reflux for several hours After cooling, water is admixed, the whole extracted with ether and the ethereal extract washed with water, dried and evaporated The glycol obtained is oxidized in a mixture of 10 cc of chloroform and 10 cc of glacial acetic acid at room temperature with 1 3 gin of lead tetracetate The oxidation product isolated by extraction with ether is then dissolved in 35 cc of dioxane and vigorously shaken with a solution of 3 5 gin of potassium hydroxide in cc of water for 1 hour at room temperature The reaction product is isolated by the addition of water and extraction with ether.
100 mg of the A 4-3: 11-diketo-14-methyl-20hydroxy-pregnene obtained are then treated with 50 mg of chromic acid in 95 % acetic acid After the addition of aqueous sodium sulphite solution, the reaction mixture is extracted with ether and the ethereal solution washed, dried and evaporated The crude product thus obtained is purified by chromatography over I 0 gin of aluminium oxide Elution with a mixture of petroleum ether and benzene gives the 14-methyl-1-ketoprogesterone of the formula:
which, after recrystallization from methanol, melts at 233-235 C; l lD= + 302 ' (c= 1 30 in chloroform) 60 The 3-keto group can be converted into a hydroxyl group and thereby the 4:5 double bond shifted into the 5: 6-position by known methods via the A:::-3-enol acetate and reduction in the 3-position 65 The A'5 '-3: 14-dimethyl 11-keto-20acetoxy-A-nor-pregnene used as starting material can be obtained as follows:
The 4: 4: 14-trimethyl-3-hydroxy-11: 20dilketo-Frn Bane obtainabl from lanost-rol by 70 the process described in Specification No.
779,941 is converted into 3-isopropylidene-14methyl- 11: 20-diketo-A-nor-pregnane by treating a suspension of 8 4 gmn of the above named starting material in a mixture of 840 75 cc of benzene and 840 cc of petroleum ether with 7 1 gin of phosphorus pentachloride in an atmosphere of dry nitrogen The substance dissolves within 10 minutes with evolution of hydrogen chloride After 90 minutes the evolu 80 tion of gas ceases Water is added and the reaction mixture is stirred for one hour The organic phase is washed neutral, dried and chromatographed over 85 gm of aluminium oxide Elution with a mixture of petroleum 85 ether and benzene gives 5 5 gmin of 3-isopropylidene-14-methyl 11:20-diketo-A-norpregnane which, after recrystallisation from methanol, melts at 143-145 C llD = 102 (c= 0 71 chloroform) 90 For the reduction of the keto groups in positions 11 and 20 a solution of 3 gin of the above substance in 90 cc of benzene is treated with a slurry of 3 gin of lithium aluminium hydride in 60 cc of ether The reaction mix 95 ture is worked up in the usual manner and the crude product is acetylated by treatment with 30 cc of acetic anhydride in 30 cc of pyridine The mixture of 3-isopropylidene-14methyl-ll/3-hydroxy 20 acetoxy-A-nor 100 pregnanes, isomeric at the carbon atom 20, can be separated by fractional crystallisation from a mixture of methylene chloride and methanol.
The isomers melt at 241-244 C or 1821840 C respectively, l-lD = + 35 (c= 1 03 in 105 chloroform) or lD= + 40 ' (c= 1 12 in chloroform) It is, however, advantageous not to separate the isomers at this stage.
The replacement of the 3-isopropylidene group by an oxo group is carried out as 110 follows:
To a solution of 1 85 gin of the above mixture of isomers in 60 cc of dry pyridine are added 1 3 gin of osmium tetroxide and the mixture is allowed to stand at room 115 temperature for 4 days After evaporation of the solvent the residue is dissolved in 40 cc of benzene and 40 cc of ethanol, mixed with a solution of 8 gmn of mannitol and 8 gin of potassium hydroxide in 20 cc of 120 water and 40 cc of ethanol and the whole is 784,855 progesterone in 10 cc of ethyl acetate is shaken with 20 mg of palladium-barium sulphate catalyst for 3 hours in a hydrogen 60 atmosphere at room temperature After removal of the catalyst and evaporation of the solvent, the 14 -metrlhyl 3:11:20 triketopregnane is obtained which shows no absorption in the ultra violet spectrum at 240 m/u 65
