US3316253A - Oxido-steroids and process for their manufacture - Google Patents

Oxido-steroids and process for their manufacture Download PDF

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US3316253A
US3316253A US92162A US9216261A US3316253A US 3316253 A US3316253 A US 3316253A US 92162 A US92162 A US 92162A US 9216261 A US9216261 A US 9216261A US 3316253 A US3316253 A US 3316253A
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hydroxy
acid
oxido
oxo
ethylenedioxy
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Wettstein Albert
Anner Georg
Kalvoda Jaroslav
Jeger Oskar
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BASF Corp
Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • the process of the present invention consists in treating an lla-hydroxy-steroid, which contains no free hydroxyl group in position 20, with acyloxy radicals having an oxidising action and, if desired, in the resulting lzllot-oxidosteroid the oxido group is opened up by treatment with an acid or, after formation of an 0x0 group in position 3, also by treatment with a base.
  • the conversion according to the present process of the lle-hydroxy-steroids into lzlla-oxido-steroids can be carried out with acyloxy radicals having oxidising action more especially, by splitting metal acylates.
  • metal acylates may be mentioned more especially those of tetravalent lead in which the acyl radical is preferably derived from a lower aliphatic or aromatic acid, for example lead tetraacetate, lead tetrapropionate, lead tetrabutyrate, lead tetrabenzoate and the like.
  • suitable are the complexes of mercury acylates and silver acylates such as mercury acetate, silver acetate or silver benzoate with iodine.
  • the reaction is performed in a suitable solvent which is inert to the oxidising agent, such as hydrocarbons for example benzene.
  • hydrocarbons such as The process is advantageously performed at a temperature ranging from 50 to 150 C., but it can also be carried out at a temperature above or below this range.
  • the alcoholic radical is preferably one derived from a lower aliphatic'alcohol, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl alcohol or of an araliphatic alcohol, such as a monocyclic lower araliphatic alcohol e.g.
  • the starting materials may contain double bonds, for example, starting from carbon atom 5. Examples of specific starting materials are 3 B-acyloxy-l la-hydroxy-cholestane,
  • a -3,B l7B-diacyloxy-l la-hydroxy-androstene
  • the oxidation of the lla-hydroxy-steroids according to the present process leads as a rule to mixtures of the larlla-epoxides and lfizlla-epoxides in, which mixture depending on whether the rings A and B are cis-linked or trans-linked one or the other kind of isomer preponderates.
  • the present process enables the lz2-double bond to be introduced in a completely novel manner.
  • the 1a:l1m-oxido-steroids obtained by the present process can be opened up hydrolytically or acylolytically under the action of acids to form lZlla-dlOlS, monoacylates or diacylates thereof or halohydrins.
  • the steroid used for splitting the oxide contains an oxo group in position 3 or when such a group is formed during the splitting, for example from a B-ketal, the corresponding l-dehydro-llahydroxy compounds are obtained directly.
  • the lzlla-oxides of the compounds having no free or protected oxo group in position 3 are opened up for example by means of aliphatic carboxylic acids, such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifiuoroacetic acid, or in the case of a weak acid if of a strong acid, such as sulfuric or para toluenesulfonic acid. These agents yield above all monoacylates of the lzll-diols.
  • aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifiuoroacetic acid, or in the case of a weak acid if of a strong acid, such as sulfuric or para toluenesulfonic acid.
  • l-halogeno-l la-acyloxy-steroids are formed.
  • the main products formed are derivatives of A -l-hydroxy-steroids; for example, boron trifluoride etherate or para-toluenesulfonic acid in acetanhydride or propionic anhydride yields the M -1- acetates and A -l-propionates respectively.
  • the opening of the oxide is extremely easy and occurs, for example, even by simple heating with glacial acetic acid in the presence or absence of sodium acetate or potassium acetate. In this manner the A -3-oxo-1lot-hydroxysteroids are formed.
  • the scission of the ether ring also takes place under basic conditions, for example already by treating with alkali metal salts of aliphatic carboxylic acids, such as sodium acetate, potassium acetate, potassium propionate and the like.
  • alkali metal alcoholates, bicarbonates, carbonates and hydroxides for example sodium methylate, potassium isopropylate, potassium tertiary butylate, sodium bicarbonate, potassium carbonate, sodium hydroxide and the like; but also alkaline earth metal hydroxides, such as barium hydroxide, calcium hydroxide.
  • alkaline earth metal hydroxides such as barium hydroxide, calcium hydroxide.
  • aluminum alcoholates for example aluminum isopropylate or tertiary butylate, or tertiary aliphatic or cycloaliphatic amines, such as triethylamine, N-methylpiperidine, N-methyl-morphdine and the like. Scission can also be performed by chromatography on aluminum oxide.
  • the above-mentioned bases are used in suitable solvents in which the oxido compound and also the base is soluble, for example lower aliphatic alcohols, cyclic ethers or aromatic hydrocarbons or mixtures of these compounds.
  • the protected group in the 3-position of a resulting A -lzllaoxido-3-ketal can be split by mild acid treatment, for example with para-toluene sulfonic acid in acetone, or by a short warming with dilute acetic acid whereby surprisingly, not the A -3-ketones are formed-as in the case with compounds not containing a 1:l1ot-oxido groupbut the A -l:1la-oxido-3-ketones.
  • the 1p lle-oxidosteroids
  • the 1p under the influence of acids, yield, particularly in the presence of a ketal or carbonyl function at carbon atom 3, apart from 1-dehydro-3-oxo-1la-hydroxysteroids, mainly A -2z3-seco-llu-hydroxy-steroids, the ring A being split up during the formation of the latter compound.
  • lflzlla-oxido-3z20-bis ethyIenediOXy-Sapregnane yields on treatment with sulfuric acid in methanol the methyl ester of A -2:3-seco-11a-hydroxy-20-oxo- 5a-pregnane-3-acid.
  • the 2:3-seco compounds on treatment with concen trated sulfuric acid, in part yield 1-dehydro-3-oxo-steroid compounds, re-cyclization occurring.
  • 1:11a-0xido steroids of the pregnane series obtainable by the process of this invention, those merit special mention which are oxygenated in 3- and 18-position, in particular those which have an lit-positioned carboxylic acid group lactonized with a ZO-hydroxyl group.
  • 3-oxygenated 18:20-lactones of 1:11ot-oxido-20-hydroxypreganane-18-acids as e.g.
  • the 18:20-lactones of A -3- oxo- 1 a2 11a-oxido-ZOB-hydroxy-pregnene-18-acids or their 3-ketals can be converted, after opening up the 1:11aepoxide ring by the process of this invention, or by way of the 2:3-seco compounds mentioned, into the corresponding 1-dehydro-18z20-lactones of 20-hydroxy-pregnene-18-acids.
  • Compounds of this kind are suitable as intermediate products for the manufacture of physiologically active l-dehydrocorticoids having an oxygen function in 18-position.
  • the conversion of the aforementioned l-dehydro-lStZO-lactones of 20-hydroxy-pregnene- 18-acids can be illustrated as follows:
  • the 18:20-lactone of 3-oxo-1laz2Ofi-dihydroxyed pregnadiene 18 acid obtainable by the process of this invention is converted into the :18-lactone of 3-oxo-115:20 3-dihydroxy-A pregnadiene-18-acid by treatment of its tosylate with a base, e.g.
  • the carbonyl groups at carbon atoms 3 and 18 are treated with the quantity of lithium aluminum hydride calculated for the conversion of the lactone group in 18:11-position into an 18:1l-cyclosemiacetal group and for the reduction of the 3-oxo-group, after which the 3- hydroxy group is selectively re-oxidized under the conditions of the Oppenauer reaction, and the ZO-ketal group of the resulting product is hydrolyzed under acid conditions. In this manner the l-deyhdro-aldosterone is obtained.
  • the 18:20-lactones of A -3-oxo- 11a:ZO-dihydroxy-steroid-18-acids obtainable by the process of this invention can be converted by selective reduction of the 1:2- double bond, followed by isomerization, into the 18:20- lactones of A -3-oxo-11:20-dihydroxy-pregnane-l8-acids which in turn can be converted into the l1B:18-lactones of A -3,20-dioxo-1lfi-hydroxy-pregnene-l8-acids by the method described above.
  • These latter products are known intermediates for the manufacture of aldosterone or derivatives thereof.
  • Example 1 1.480 grams of A -3:20-bisethylenedioxy-1let-hydroxypregnene (melting at 215-217C.; obtained by ketalising 1lot-hydroxy-progesterone) are added to a stirred suspension previously boiled for 15 minutes of 1.5 grams of calcium carbonate and 4.5 grams of lead tetraacetate in cc. of methyl-cyclohexane, and the reaction mixture is refluxed for 18 hours, filtered, the filter residue is washed with ethyl acetate and ether, the filtrate is shaken once with 40 cc. of potassium iodide solution of 5% strength, once with 40 cc. of sodium sulfite solution of 10% strength and three times with water, dried and evaporated.
  • Example 2 300 mg of A -3 :20-bisethylenedioxy-1a:lla-oxido-pregnene in 12 cc. of acetone are treated with 50 mg. paratoluenesulfonic acid and the whole is stirred at room tem perature until all has passed into solution and the solution is kept for 14 hours, diluted with water, cooled to C., and the precipitated A -3:20-dioxo-1a:Ila-oxidopregnene is filtered off and washed with water.
  • One recrystallization from a mixture of methylene chloride and petroleum ether yields 95 mg. of the product which crystallizes in lustrous flakes and melts at 194-198 C. (uncorrected).
  • the infra-red spectrum of the product displays an absorption band at 588p.
  • the concentrated filtrate is saturated with sodium chloride and subjected to a conventional extraction with ether-l-methylene chloride (3:1), 132 mg. of a partially crystalline oil are obtained which yields on crystallization from ether 67 mg. of A -3z20-dioxo-lla-hydroxy-pregnadiene.
  • the melting point, mixed melting point and infra-red spectrum of this product are identical with those of the product described in Example 3.
  • the mother liquor contains a mixture of the aforementioned A -lzlla-ether and lla-hydroxy-diene.
  • Example 3 50 mg. of A -3:20 bisethylenedioxy pregnene are dissolved with heating in 5 cc. of acetic acid 80% strength, 30 mg. of sodium acetate are added, and the whole is heated for 2 hours at 100 C. The mixture is kept for 15 hours at room temperature, diluted with cc. of water, saturated with sodium worked up with ether-l-methylene chloride (3:1). When the isolated oil (32 mg.) is sprinkled with ether, it crystallizes. Two crystallizations from a mixture of methylene chloride, ether and petroleum ether yields A -3:20- dlOXO-lloc-hYdIOXY pregnadiene in fine needles melting at 220-2205 C.
  • the crude product is a mixture of A 3 ethylenedioxy-1a:11aoxido 20 oxo pregnene and A -3I20-dlOXO-10t211w oxido pregnene (strong absorption band in the infrared spectrum at 5.87-5.89p).
  • Subsequent chromatography on alumina yields the former compound in pure form melting at 135-139" C.
  • a 3:20 dioxo 1a:11aoxido-pregnene is converted into the isomeric A -3:20- dioxo-l1u-hydroxy-pregnadiene melting at 172175 C.
  • a :228 ma, E 11,600.
  • Example 5 3.0 g. of dried calcium carbonate and 10.0 g. of predried lead-IV-acetate in 300 ml. of cyclohexane are heated for 15 minutes at C. with stirring. After that, 3.0 g. of 3:ZO-bisethylenedioxy-l1a-hydroxy-5 3-pregnane are added and the mixture stirred for 17 hours while being resulting 0a,,8-UI1S3tLlI3t6d ketone The cooled reaction solution is potassium iodide solution, ml. of 10% sodium sulfite solution, and
  • 3:20-bisethylenedioxy-1lot-hydroxy-Zl-acetoxy-Sfi-pregnane obtainable by ketalization from 3:20 dioxo 11a-hydroxy 2l-acetoxy-Sfi-pregnane may also be converted into 3:20 bisethylenedioxy-laz 1 1a-oxido-2 l -acetoxy-5fi-pregnane.
  • Example 6 3.8 g. of 3:ZO-bisethylenedioxy-llot-hydroxy Six-pregnane are added to a suspension which has been heated at 100 C. for 15 minutes-0f 3.8 g. of calcium carbonate and 12.7 g. of lead-IV-acetate in 380 ml. of methylcycl-ohexane, and the whole stirred for 14 hours while being refluxed. Another 5.0 g. of lead-IV-acetate then added and boiling continued for 3 more hours. in the same manner as from a mixture of methylene chloride and petroleum ether yields 1.51 g. of 3:20 bisethylenedioxy-ltglla-oxido-5a-pregnane of melting point 203-206 C.
  • the 11ot-hydroxy-3:ZO-diketals of 5a and SB-pregnane, respectively, used as starting materials in Examples 5 and 6 are obtained from the corresponding 3a and 36:11adiacetoxy-ZO-oxo compounds by partial hydrolysis of the 3-acetates, oxidation by means of N-bromacetamide to the 3:20-diketone, ketalization, and subsequent alkaline hydrolysis of the Ila-acetate.
  • Example 7 200 ml. of cyclohexane, 2.0 g. of calcium carbonate, and 7.0 g. of lead-IV-acetate are heated to 80 C. for a short while, then treated with 1.50 g. of A -3-ethylenedioxy-l1whydroxy-17/3-acetoxy-17a-methyl androstene (prepared by partial hydrolysis of A -3-ethylenedioxy- 7 11o,17fl-diacetoxy-17u-methyl-androstene obtained from A -3-oxo-11a:17B-dihydroxy-17u-methyl "androstene by acetylation and ketalization). The mixture is refluxed with stirring for 16 hours. Working up in the usual manner (see Example yields 1.85 g.
  • Example 8 9.0 g. of 18:20-lactone of A -3-ethylenedioxy-1lo:20;8- dihy-droxy-pregnene-18-acid are stirred into a suspension, heated to 100 C., of 9.0 g. of calcium carbonate and 30.0 g. of lead-IV-acetate in 900 ml. of methylcyclohexane and the mixture boiled under reflux. After 1 hour another 10.0 g. of lead-IV-acetate and 5.0 g. of calcium carbonate are added, and after 13 hours another 10.0 g. of lead-IV-acetate. After a total of hours, the reaction is stopped and the product worked up. There are obtained about 12 g. of an oily product which is resolved into four components by chromatography over alumina (activity II).
  • Example 9 In a manner analogous to that described in the preceding example, there are obtained from 3fi-acetoxy-1lahydroxy-5u-spirostane and 3;8-acetoxy-1lu-hydroxy-cholestane with lead-IV-acetate 3p-acetoxy-1g:llot-oxido-iaspirostane and 3B-acetoxy-1g:lla-oxidO-Soc-cholestane respectively.
  • Example 10 210 mg. of 3:20-bisethylenedioxy-1o:11a-oxido-5flpregnane are dissolved in 20 ml. of glacial acetic acid,
  • Example 12 150 mg. of 3:20-bisethylenedioxy-1fi:lla-oxido-5apregnane are dissolved in 10 ml. of acetone and, after the addition of 25 mg. of para-toluene-sulfonic acid monohydrate, allowed to stand at room temperature for 18 hours. The solution is neutralized with a few drops of saturated sodium bicarbonate solution, concentrated under reduced pressure at 40 C., diluted with ether, and washed three times with water. On evaporation of the solvent there are obtained 138 mg. of crystalline glycol ester of 2.3 seco A 11o hydroxy 20 oxo 5; pregnene- 3-acid of melting point 103104 C.
  • Example 13 400 mg. of 3:20-bisethylenedioxy-1B:11oc-oxido-5apregnane are suspended in 8 ml. of methanol and, after the addition of 0.02 ml. of concentrated sulfuric acid, allowed to stand at 20 C. for 15 minutes. The mixture is shaken from time to time. The solution is then neutralized with saturated sodium bicarbonate solution, extracted with ether, the ethereal layer washed nuetral with water, dried and evaporated. For complete cleavage of the C-20 ketal, the resulting crude product is dissolved in 2 ml. of glacial acetic acid, treated with 0.5 ml. of water, and heated to 60 C. for 10 minutes. The subsequent working up yields 245 mg.
  • the same compound is obtainable also from the glycol ester described in Example 12 by hydrolysis to form 2:3- sec0-A 1loc-hydr0Xy-2O-oX0-5ot-pregnene-3acid and subsequent esterification by means of diazomethane.
  • Example 14 200 mg. of A 3 ethylenedioxy-1E:11-u-oxido-17fiacetoxy-17a-methyl-androstene, dissolved in 30 ml. of absolute tetrahydrofuran, are added dropwise with stirring and cooling to a suspension of 120 mg. of lithium aluminum hydride in 25 ml. of tetrahydrofuran. The reaction mixture is then refluxed for 2 hours with stirring, and worked up as usual. There is obtained the crude A -3- ethylenedioxy-lg:lla-oxido-l7fi-hydroxy 17a methylandrostene.
  • Example 150 ml. of absolute benzene, 1.50 grams of dried calcium carbonate and 5.0 grams of lead-IV-acetate freed from excess acetic acid in vacuo are boiled for a short time; 100 gram of A -3-ethylenedioxy-lla-hydroxy-17/3- acetoxy-l7a-methyl-l9-nor androstene (prepared from 110: hydroxy-l9-nor-methyltestosterone) is then added and the whole boiled under reflux for 18hours with stirring. The reaction solution which still contains excess lead-IV-acetate is filtered off from the inorganic portion and worked up as described in the preceding examples. 1.25 grams of crude cyclisation mixture are obtained which contains in addition the oily reaction product of the solvent.
  • Example 16 200 mg. of A --3 ethylenedioxy-luzllwoxido-lfliacetoxy-l7a-methyl-l9-nor-androstene dissolved in m1. of absolute tetrahydrofuran are added dropwise with cooling to a stirred suspension of 200 mg. of lithium aluminw num hydride in 95 ml. of tetrahydrofuran. When the addition is complete, cooling is replaced by. an oil bath and the reaction mixture boiled under reflux for'l hour with stirring. Working up in the customary manner yields 157 mg. of A -3-ethylenedioxy-la:lla-oxido-UB- hydroxy-17a-methyl-l9 nor androstene which may be subjected to hydrolysis either after recrystallization or directly.
  • R is a member selected from the group consisting of 0x0, lower alkylenedioxy, hydrogen and hydroxy and hydrogen and acyloxy
  • R is a member selected from the group consisting of an Ot-POSltlOIled hydrogen and a fl-positioned hydrogen
  • R is a member selected from the group of 0x0, lower alkylenedioxy, hydrogen and fl-hydroxy
  • hydrogen and B-acyloxy methyl and Er-hydroxy and methyl and fi-acyloxy
  • R is a member selected from the group consisting of hydrogen and methyl
  • said acyloxy radicals being derived from acids selected from the group consisting of lower aliphatic, monocyclic cycloaliphatic, monocyclic carbocyclic aryl-lower aliphatic, monocyclic carbocyclic aromatic, monocyclic heterocyclic aromatic monoand dicarboxylic

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